ELSEVIER SAUNDERS 1600 John F. Kennedy Blvd., Ste 1800 Philadelphia, PA 19103-2899 TEXTBOOK OF ENDOCRINE SURGERY ISBN 0-7216-0139-1
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NOTICE Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the EditorslAuthors assumes any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book.
Textbook of endocrine surgery / [edited by] Orlo H. Clark, Quan-Yang Duh, Electron Kebebew. - 2nd ed. p. . crn. Includes bibliographical references and index. ISBN 0-7216-0139-1 I. Endocrine glands-Surgery. 2. Endocrine glands-Diseases. I. Clark, Orlo H. II. Duh, Quan-Yang. III. Kebebew, Electron. [DNLM: 1. Endocrine System Diseases-surgery. 2. Endocrine Glands-surgery. WK 140 T355 2006] RD599.T492006 2005042824 617.4' 4-dc22
Acquisitions Editor: Judith Fletcher Publishing Services Manager: Tina Rebane Project Manager: Norm Stellander Design Manager: Gene Harris
Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication We would like to dedicate this book to our wives, Carol, Ann, and Tida, and families, and to Ms. Kate Poole. Their wonderful support helped to make this book possible.
Claudette Abela-Forman EK, MD Assistant Professor, Department of Ophthalmology, Medical University of Vienna; Senior Resident, General Hospital of Vienna, Vienna, Austria Metabolic Complications of Primary Hyperparathyroidism Bo Ahren, MD, PhD Professor, Department of Medicine, Lund University, Lund, Sweden Pancreatic Endocrine Physiology Goran Akerstrom, MD, PhD Professor of Surgery, Uppsala University; Professor of Surgery and Chief of Endocrine Surgery, Department of Surgical Sciences, University Hospital, Uppsala, Sweden Natural History of Untreated Primary Hyperparathyroidism Maha AI-Fehaily, MD Associate Consultant, Breast and Endocrine Surgery, King Faisal Specialist Hospital and Research Centre, Department of Surgery, Riyadh, Saudi Arabia Sporadic Nontoxic Goiter Saif AI-Sobhi, MD, FRCS (Glas), ABIS Chairman, Department of Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Parathyroid Hyperplasia: Parathyroidectomy Ahmad Assalia, MD Deputy Director, Department of Surgery, Rambam Medical Center, Haifa, Israel Laparoscopic Adrenalectomy Jon Armstrong, MD Clinical Instructor, University of Perth, Royal Perth Hospital; Senior Surgeon, General and Endocrine Surgery, Royal Perth Hospital, Perth, Western Australia, Australia Adrenocortical Carcinoma: Nonfunctioning and Functioning Sylvia L. Asa, MD, PhD Professor, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto; Pathologist-in-Chief, University Health Network, and Medical Director, Toronto Medical Laboratories, Toronto, Ontario, Canada Anaplastic Carcinoma of the Thyroid Gland
Anders O. J. Bergenfelz, MD, PhD Associate Professor, Lund University; Consultant Surgeon, Department of Surgery, University Hospital, Lund, Sweden Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) Piero Berti, MD Professor of Surgery, University of Pisa; Assistant, S. Chiara Hospital, Pisa, Italy Minimally Invasive Parathyroid Surgery Michael Sean Boger, MD, PharmD House Officer, Department of Internal Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina Graves' and Plummer's Diseases: Medical and Surgical Management H. Jaap Bonjer, MD, PhD Professor of Surgery, Dalhousie University; Director of Minimally Invasive Surgery, Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada Technique of Parathyroidectomy Bert A. Bonsing, MD, PhD Staff Surgeon, Department of Surgery, Leiden University Medical Center, Leiden, Germany Occurrence and Prevention of Complications in Thyroid Surgery Michael Brauckhoff, MD Department of General, Visceral, and Vascular Surgery, University of Halle, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract James D. Brierley, MB BS, MRCP, FRCP, FRCP (C) Associate Professor, Department of Radiation Oncology, University of Toronto, Toronto; Staff Radiation Oncologist, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada Anaplastic Carcinoma of the Thyroid Gland Hajo A. Bruining, MD, PhD Emeritus Professor of Surgery, Erasmus University, Rotterdam, The Netherlands Technique of Parathyroidectomy
v
vi - - Contributors Laurent Brunaud, MD, PhD Professor of Surgery, University of Nancy; Staff Surgeon, Department of General and Endocrine Surgery, Chu Nancy-Brabois, Nancy, France Comparative Genomic Hybridization in Thyroid Neoplasms; Neuroendocrine Tumors Blake Cady, MD Professor of Surgery, Brown Medical School; Interim Director, Comprehensive Breast Center, Rhode Island Hospital, Providence, Rhode Island Predictors of Thyroid Tumor Aggressiveness Denise M. Carneiro-Pia, MD Fellow, Department of Endocrine Surgery, University of Miami/Jackson Memorial Center, Miami, Florida Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism Herbert Chen, MD, FACS Chief of Endocrine Surgery, and Assistant Professor of Surgery, University of Wisconsin, Madison, Wisconsin Hiirthle Cell Adenoma and Carcinoma Polly S-Y Cheung, MB BS (HK) Consultant Surgeon, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong Medical and Surgical Treatment of Endemic Goiter Orlo H. Clark, MD Professor of Surgery, Department of Surgery, University of California, San Francisco, School of Medicine, San Francisco, California Sporadic Nontoxic Goiter; Thyroiditis; Papillary Thyroid Carcinoma: Rationale for Total Thyroidectomy; Potentially New Therapies in Thyroid Cancer; Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy; Parathyroid Hyperplasia: Parathyroidectomy Roderick Clifton-Bligh, MBBS, PhD, FRACP Honorary Senior Lecturer in Medicine, University of Sydney; Staff Specialist in Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia Thyroid Physiology Alan P. B. Dackiw, MD, PhD Assistant Professor of Surgery, Johns Hopkins University, Baltimore, Maryland Transplantation of Endocrine Cells and Tissues Leigh Delbridge, MD, FRACS Professor of Surgery, University of Sydney; Head, Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia Thyroid Physiology
Michael J. Demeure, MD Chief, Section of General Surgery, Professor of Surgery, Arizona Health Sciences Center, Tucson, Arizona Mechanisms and Regulation of Invasion in Thyroid Cancer Gerard M. Doherty, MD M. W. Thompson Professor of Surgery, University of Michigan, Ann Arbor, Michigan Follicular Neoplasms of the Thyroid Henning Dralle MD Head, Department of General, Visceral, and Vascular Surgery, University of Halle, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract Quan-Yang Duh, MD Professor of Surgery, University of California, San Francisco, School of Medicine, San Francisco, California Potentially New Therapies in Thyroid Cancer; Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) Erol Duren, MD Professor Emeritus, Department of Surgery, University of Istanbul, Cerrahpasa Medical School; Medical Director and Chief of Surgery, Istanbul German Hospital, Istanbul, Turkey Recurrent Thyroid Cancer Mete Duren, MD Professor, Department of Surgery, University of Istanbul, Cerrahpasa Medical School, Istanbul, Turkey Recurrent Thyroid Cancer Kathryn L. Edmiston, MD Assistant Professor of Medicine, Associate Director, Breast Center, University of Massachusetts Medical Center, Boston, Massachusetts Chemotherapy for Unresectable Endcorine Neoplasms E. Christopher Ellison, MD Professor and Chair, Department of Surgery, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Multiple Endocrine Neoplasia Type 2B Gennaro Favia, MD Professor of Surgery and Head, Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Padova, Italy Cushing's Syndrome
Contributors - - vii
Volker Fendrich, MD Resident in Surgery, Philipps University; Resident in the Department of Visceral, Thoracic, and Vascular Surgery, Klinikum Der Philipps-Universitat, Marburg, Germany Localization of Endocrine Pancreatic Tumors
Oliver Gimm, MD Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle-Wittenberg, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract
Douglas L. Fraker, MD Jonathan Rhoads Associate Professor of Surgery; Vice Chairman, Clinical Affairs, and Director, General Surgery, University of Pennsylvania, Philadelphia, Pennsylvania Factors That Predispose to Thyroid Neoplasia
Victor Gorelev, MD Professor of Surgery, Heinrich Heine University, DUsseldorf, Germany Oncogenes in Thyroid Tumors
John R. Frandon, BSc, MD, FRCSt Formerly Professor of Surgery, University of Bristol, United Kingdom Surgical Embryology and Anatomy of the Adrenal Glands Yoshihide Fujimoto, MD, PhD Former Professor of Surgery, Department of Endocrine Surgery, Tokyo Women's Medical University, Tokyo; Adviser of the Hospital and Director, Division of Thyroid-Endocrine Surgery, Cancer Institute Hospital, Tokyo, Japan Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy Shuji Fukata, MD Chief of Internal Medicine, Kuma Hospital, Kobe, Japan Hypothyroidism Michel Gagner, MD, FRCS, FACS Professor of Surgery, Weill Medical College of Cornell University; Chief, Laparoscopy and Bariatric Surgery, Department of Surgery, New York-Presbyterian Hospital, New York, New York Laparoscopic Adrenalectomy Armando Gamboa-Dominguez, MD, PhD Associate Professor of Pathology, Facultad de Medicina, Universidad Nacional Aut6noma de Mexico; Senior Pathologist, Instituto Nacional de Ciencias Medicas y Nutrici6n Salvador Zubiran, Mexico City, Mexico Parathyroid Embryology, Anatomy, and Pathology Helene Gilbelin, MD Consultant Surgeon, Endocrine Surgery, Jean Bernard Hospital, Poitiers, France Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes Glenn Gibson, BA Senior Scientist, Pfizer Global Research and Development, Ann Arbor; Michigan Cryopreservation of Parathyroid Tissue
tDeceased
Peter E. Goretzki, MD Professor of Surgery, Heinrich Heine University, DUsseldorf, Germany Oncogenes in Thyroid Tumors Clive S. Grant, MD Professor of Surgery, Mayo Clinic, Rochester, Minnesota Pheochromocytoma Staffan Grandal, MD, PhD Associate Professor of Surgery, Karolinska Institutet; Consultant, Department of Surgery, Danderyds Hospital, Stockholm, Sweden Adrenal Physiology Bertil Hamberger, MD, PhD Professor of Surgery, Department of Surgical Sciences, Karolinska Institutet; Consultant; Department of Surgery, Karolinska Hospital, Stockholm, Sweden Adrenal Physiology J. F. Hamming, MD, PhD Surgeon, St. Elisabeth Hospital, Tilburg; The Netherlands Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer Jay K. Harness, MD Medical Director, St. Joseph Hospital Comprehensive Breast Center, Orange, California Childhood Thyroid Carcinoma Susannah E. Harte, MD, MRCPI University College, Dublin, Ireland Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Nils-Erik Heldin, PhD Associate Professor in Experimental Pathology, University, Hospital, Uppsala, Sweden Growth Factor, Thyroid Hyperplasia, and Neoplasia Jean-Francois Henry, MD Professor of Surgery, University of Marseilles; Chief, Department of General and Endocrine Surgery, University Hospital La Timone, Marseilles, France Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands and Recurrent and External Laryngeal Nerves; Endoscopic Parathyroidectomy
viii - - Contributors
Miguel F. Herrera, MD, PhD Associate Professor of Surgery, Facultad de Medicina, Universidad Veracruzana; Staff Surgeon, Instituto Nacional de Ciencias Medicas y Nutrici6n Salvador Zubiran, Mexico City, Mexico Parathyroid Embryology, Anatomy, and Pathology Shih-ming Huang, MD Professor, Department of Surgery, Buddhist Tzu-Chi University; Professor and Consultant Surgeon, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan Familial Hyperparathyroidism
Electron Kebebew, MD Assistant Professor of Surgery, University of California, San Francisco/Mt, Zion Medical Center, San Francisco, California Thyroid Oncogenesis Rachel R. Kelz, MD Assistant Professor of Clinical Surgery, University of Pennsylvania, Philadelphia, Pennsylvania Factors that Predispose to Thyroid Neoplasia
Maurizio Iacobone, MD Assistant Professor, Clinical Research, University of Padua, School of Medicine; Endocrine Surgery Unit, Department of General and Gastroenterological Sciences, University of Padua, Italy Cushing's Syndrome
Job Kievit, MD, PhD Professor of Clinical Decision Analysis and Associate Professor of Surgery, Leiden University Medical Center; Chief, Section of EndocrinelHead and Neck Surgery, Department of Surgery, Leiden University Medical Center, Leiden, Germany Occurrence and Prevention of Complications in Thyroid Surgery
Masatoshi Iihara, MD Assistant Professor, Department of Endocrine Surgery, Tokyo Women's Medical University; Assistant Professor, Department of Endocrine Surgery, Tokyo Women's Medical University Hospital, Shinjuku-ku, Tokyo, Japan Hyperaldosteronism
Barbara K. Kinder, MD William H. Carmalt Professor of Surgery, Yale University, School of Medicine; Attending Surgeon, Yale-New Haven Hospital, New Haven, Connecticut Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises
Silvio E. Inzucchi, MD Professor of Medicine, Section of Endocrinology, Yale University School of Medicine; Director, Yale Diabetes Center, Yale-New Haven Hospital, New Haven, Connecticut Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises
Jean-Louis Kraimps, MD Professor, Poitiers University Medical School; Professor of General Surgery, Jean Bernard Hospital, Poitiers, France Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes
George L. Irvin III, MD Professor of Surgery, University of Miami School of Medicine, Miami, Florida Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism Yukio Ito, MD Associate Professor, Department of Endocrine Surgery, Tokyo Women's Medical University; Associate Professor, Department of Endocrine Surgery, Tokyo Women's Medical University Hospital, Shinjuku-ku, Tokyo, Japan Hyperaldosteronism Suzanne Jan de Beur, MD Director, Division of Endocrinology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Hypoparathyroidism and Pseudohypoparathyroidism Edwin L. Kaplan, MD Professor of Surgery, The University of Chicago, Pritzker School of Medicine; Attending Physician, The University of Chicago Hospitals, Chicago, Illinois Insulinomas
Kanji Kuma, MD Honorary Director, Kuma Hospital, Kobe, Japan Hypothyroidism Geeta Lal, MD, MSc, FRCS(C) Assistant Professor of Surgery, University of Iowa; Staff Surgeon, Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa Thyroiditis; Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy Anne C. Larkin, MD Director of Undergraduate Surgical Education, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts Chemotherapy for Unresectable Endocrine Neoplasms Chen-Hsen Lee, MD Professor of Surgery, National Yang-Ming University; Team Leader of Endocrine Surgery and Vice Superintendent, Taipei Veterans General Hospital, Taipei, Taiwan Thyroid Emergencies: Thyroid Storm and Myxedema Coma Sten Lennquist, MD, PhD Professor Emeritus, University of Linkoping; Former Chairman, Department of Surgery, University Hospital, Linkoping, Sweden Thyroidectomy
Contributors - - ix
Hong-Da Lin, MD Clinical Professor, Taipei Medical University, School of Medicine; Chief, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan Thyroid Emergencies: Thyroid Storm and Myxedema Coma
Christopher R. McHenry, MD Professor of Surgery, Case Western Reserve University School of Medicine; Vice Chairman, Department of Surgery, and Director, Division of General Surgery, MetroHealth Medical Center, Cleveland, Ohio Anatomy and Embryology of the Pancreas
Dimitrios A. Linos, MD Associate Professor of Surgery, Athens Medical School, and Director of First Surgical Clinic, Hygeia Hospital Athens, Greece; Lecturer in Surgery, Harvard Medical School, and Consultant in Surgery, Massachusetts General Hospital, Boston, Massachusetts Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma)
Paolo Miccoli, MD Professor of Surgery, and Chairman, Department of Surgery, Universita Studi di Pisa, Pisa, Italy Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases; Minimally Invasive Parathyroid Surgery
Chung Yau Lo, MB BS(HK), MS(HK), FRCS(Edin), FACS Associate Professor, Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital; Associate Professor and Chief of Endocrine Surgery, Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong Parathyroid Reoperations Franco Lumachi, MD Assistant Professor, Clinical Research, University of Padua, School of Medicine; Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Padova, Italy Cushing's Syndrome Ewa Lundgren, MD, PhD Associate Professor, Uppsala University, Medical Faculty; Consultant and Head of the Surgery Department, Institution of Surgical Sciences, University Hospital, Uppsala, Sweden Natural History of Untreated Primary Hyperparathyroidism Andreas Machens, MD Department of General, Visceral, and Vascular Surgery, University of Halle, Halle, Germany Surgical Management ofAdvanced Thyroid Cancer Invading the Aerodigestive Tract Lloyd A. Mack, MD, FRCSC Assistant Professor, Department of Surgery and Oncology, Division of General Surgery, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid Paul R. Maddox, BSc, MCh, FRCS(Ed), FRCS(Eng) Consultant Surgeon, Royal United Hospital, Bath, England, United Kingdom Approach to Thyroid Nodules
Raducu Mihai, MD, PhD, MRCS Lecturer in Surgery, University of Bristol; Specialist Registrar in Endocrine Surgery, Bristol Royal Infirmary, Bristol, United Kingdom Surgical Embryology and Anatomy of the Adrenal Glands Craig A. Miller, MD Director of Vascular Services, St. Joseph Hospital, Kokomo, Indiana Multiple Endocrine Neoplasia Type 2B Daishu Miura, MD Staff, Department of Endocrine Surgery, Toranomon Hospital, Tokyo, Japan Comparative Genomic Hybridization in Thyroid Neoplasms Jeffery F. Moley, MD Associate Professor of Surgery, Washington University School of Medicine; Associate Chief of Surgery, St. Louis Veterans Administration Medical Center, St. Louis, Missouri Medullary Thyroid Carcinoma Jack M. Monchik; MD, FACS Clinical Professor of Surgery, Brown University School of Medicine, Chief, Endocrine Surgery, Rhode Island Hospital, Providence, Rhode Island Normocalcemic Hyperparathyroidism Bruno Niederle, MD Professor of Surgery, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna; Chief, Endocrine Surgery, General Hospital of Vienna, Vienna, Austria Metabolic Complications of Primary Hyperparathyroidism Ronald H. Nishiyama, MD Chief Emeritus, Department of Pathology, Maine Medical Center, Portland, Maine Pathology of Tumors of the Thyroid Gland Shiro Noguchi, MD, PhD, FJCS, FACE Chief Executive Officer, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita, Japan Localization Tests in Patients with Thyroid Cancer
x - - Contributors
Jeffrey A. Norton, MD Professor of Surgery, Stanford University Medical Center; Chief of Surgical Oncology, Stanford University, Department of Surgery, Stanford, California Somatostatinoma and Rare Pancreatic Endocrine Tumors Patricia J. Numann, MD The Lloyd S. Rogers Professor of Surgery, SUNY Distinguished Teaching Professor, and SUNY Distinguished Service Professor, State University of New York, Upstate Medical University; Medical Director, University Hospital, Syracuse, New York Addison's Disease and Acute Adrenal Hemorrhage Takao Obara, MD, PhD Professor and Chief, Department of Endocrine Surgery, Tokyo Women's Medical University, Tokyo; Director, Institute of Clinical Endocrinology, Tokyo Women's Medical University Hospital, Tokyo, Japan Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy; Hyperaldosteronism Niall O'Higgins, MCh, FRCSI, FRCS(Edin), FRCS(Eng) Professor and Head, Department of Surgery, University College, Dublin; Professor of Surgery, St. Vincent's University Hospital, Dublin, Ireland Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Takahiro Okamoto, MD, PhD Assistant Professor, Department of Endocrine Surgery, Tokyo Women's Medical University, Tokyo, Japan Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy Furio Pacini, MD Professor of Endocrinology, Universita di Siena, Siena Italy Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases Kevin Packman, MD Department of Surgery, Froedtert Memorial Lutheran Hospital and Medical College of Wisconsin, Milwaukee, Wisconsin Mechanisms and Regulation of Invasion in Thyroid Cancer P. Parrilla, MD Professor of Surgery, Department of Surgery, School of Medicine, University of Murcia; Chairman, Department of General Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain Localization Studies in Persistent or Recurrent Hyperparathyroidism Jin-Woo Park, MD, PhD Associate Professor, College of Medicine, Chungbuk National University, Cheongju, Korea Potentially New Therapies in Thyroid Cancer
Janice L. Pasieka, MD Clinical Professor of Surgery and Oncology, Faculty of Medicine, Department of Surgery, University of Calgary; Regional Division Chief, Division of General Surgery, Calgary Health Region and University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid; Asymptomatic Primary Hyperparathyroidism Fran~ois N. Pattou, MD Associate Professor of Surgery, Medical School of Lille; Senior Surgeon, Department of General and Endocrine Surgery, Lille University Hospital-Huriez, Lille, France Advenocortical Carcinoma: Nonfunctioning and Functioning
Nilima A. Patwardhan, MD Professor of Surgery, University of Massachusetts Medical Center, Worcester, Massachusetts Chemotherapy for Unresectable Endocrine Neoplasms Nancy Dugal Perrier, MD FACS Associate Professor of Surgery, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Graves' and Plummer's Diseases: Medical and Surgical Management Gerhard Prager, MD Assistant Professor, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna; Senior Resident, General Hospital of Vienna, Vienna, Australia Metabolic Complications of Primary Hyperparathyroidism Richard A. Prinz, MD Helen Shedd Keith Professor and Chairman, Department of General Surgery, Rush University; Chairman, Department of General Surgery, Rush University Medical Center, Chicago, Illinois Open Operative Approaches to the Adrenal Gland Charles A. G. Proye, MD Professor and Chairman of Surgery, Medical School of Lille; Head of the Department of General and Endocrine Surgery, Lille University Hospital-Huriez, Lille, France Adenocortical Carcinoma: Nonfunctioning and Functioning Roderick M. Quiros, MD General Surgery Resident, Rush University Medical Center, Chicago, Illinois Open Operative Approaches to the Adrenal Gland Jonas Rastad, MD, PhD Associate Professor, Department of Surgery, Uppsala University Hospital, Uppsala, Sweden Parathyroid Hormone: Regulation of Secretion and Laboratory Determination
Contributors - - xi
Peter Ridefelt, MD, PhD Associate Professor, Department of Surgery, Uppsala University Hospital, Uppsala, Sweden Parathyroid Hormone: Regulation of Secretion and Laboratory Determination
Andrew Saxe, MD Associate Program Director, Michigan State University, East Lansing; Director, Surgical Education, McLaren Regional Medical Center, Flint, Michigan Cryopreservation of Parathyroid Tissue
Jose M. Rodriguez, MD Professor of Surgery, Department of Surgery, School of Medicine, University of Murcia; Endocrine Surgery Unit, Department of Surgery, Virgen de la Arrixaca, II University Hospital, Murcia, Spain Localization Studies in Persistent or Recurrent Hyperparathyroidism
Frederic Sebag, MD Medical School, Mediterranean University; Attending Surgeon in Endocrine Surgery, Department of Endocrine Surgery, University Hospitalla Timone, Marseilles, France Endoscopic Parathyroidectomy
Hans-Dietrich Roeher, MD Professor of Surgery, Heinrich Heine University, Dusseldorf, Germany Oncogenes in Thyroid Tumors; Neuroendocrine Tumors
Wen T. Shen, MD Fellow, Endocrine Surgical Oncology Program, Department of Surgery, University of California, San Francisco, San Francisco, California Parathyroid Hormone: Regulation of Secretion and Laboratory Determination
Irving B. Rosen, MD, FRCS(C) Professor, Department of Surgery, University of Toronto, Toronto; Attending Surgeon, Mt. Sinai Hospital, Toronto, Ontario, Canada Anaplastic Carcinoma of the Thyroid Gland
Nina Shervin, MD Resident in Surgery, Harvard Combined Orthopaedic Residency Program, Massachusetts General Hospital, Boston, Massachusetts Medullary Thyroid Carcinoma
Matthias Rothmund, MD Professor of Surgery, Philipps University; Professor of Surgery and Chairman of the Department of Visceral, Thoracic, and Vascular Surgery, Klinikum der Philipps-Universitat, Marburg, Germany Adrenal Imaging Procedures; Localization of Endocrine Pancreatic Tumors
Mauricio Sierra, MD Fellow in Endocrine Surgery, Jean Bernard Hospital, Poitiers, France Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes
J. A. Roukema, MD, PhD Surgeon, St. Elisabeth Hospital, Tilburg, The Netherlands Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer
Dietmar Simon, MD Professor of Surgery, Heinrich Heine University, Dusseldorf, Germany Neuroendocrine Tumors; Oncogenes in Thyroid Tumors
Mary Ruppe, MD Senior Fellow, Division of Endocrinology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland Hypoparathyroidism and Pseudohypoparathyroidism
Antonio Sitges-Serra, MD Professor of Surgery, Universedad Aut6noma de Barcelona; Head, Department of Surgery, Hospital del Mar, Barcelona, Spain Surgical Management of Recurrent and Intrathoracic Goiters; Metabolic Complications of Secondary Hyperparathyroidism; Surgical Approach to Secondary Hyperparathyroidism
David E. Sahar, MD Resident, University of California San Francisco-East Bay Program, San Francisco, California Childhood Thyroid Carcinoma Juan J. Sancho, MD Associate Professor, Universidad Aut6noma de Barcelona; Staff Surgeon; Hospital del Mar, Barcelona, Spain Surgical Management ofRecurrent and Intrathoracic Goiters; Metabolic Complications of Secondary Hyperparathyroidism; Surgical Approach to Secondary Hyperparathyroidism Kerstin Sandelin, MD, PhD Associate Professor of Surgery, Department of Surgical Sciences, Korolinska Institutet, Stockholm; Senior Staff Surgeon, Karolinska University Hospital, Solna, Stockholm, Sweden Parathyroid Carcinoma
Allan E. Siperstein, MD Professor of Surgery and Section Head, Endocrine Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio Signal Transduction in Thyroid Neoplasms Staffan Smeds, MD, PhD Professor of Surgery, University Hospital, Linkoping, Sweden Growth Factor, Thyroid Hyperplasia, and Neoplasia Ilfet Songun, MD, PhD Surgeon, University Hospital, Maastricht, The Netherlands Occurrence and Prevention of Complications in Thyroid Surgery
xii - - Contributors
Maria Sorhede-Winzell, PhD Department of Medicine, Lund University, Lund, Sweden Pancreatic Endocrine Physiology Gordon J. Strewler, MD Professor of Medicine, Harvard Medical School; Vice Chairman, Department of Medicine, Brigham and Women's Hospital; Chief of Medical Service, Brockton/ West Roxburg, Veterans Administration Medical Center, Boston, Massachusetts Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein Masahiro Sugawara, MD Professor of Medicine, University of California, Los Angeles, School of Medicine; Staff Physician, Greater Los Angeles VA Medical Center, Los Angeles, California Hypothyroidism Hiroshi Takami, MD Professor of Surgery, Teiko University School of Medicine, Tokyo,Japan Hypercalcemic Crisis Serdar T. Tezelman, MD Professor of Surgery, Department of Surgery, Istanbul Faculty of Medicine, Istanbul University; Attending Surgeon, International Hospital, Istanbul, Turkey Signal Transduction in Thyroid Neoplasms Geoffrey B. Thompson, MD Professor of Surgery, Mayo Graduate School; Consultant, Department of Surgery, Division of Gastroenterologic and General Surgery, Mayo Clinic, Saint Mary's and Rochester Methodist Hospitals, Rochester, Minnesota Multiple Endocrine Neoplasia Type 1 Norman W. Thompson, MD Emeritus Professor of Surgery, University of Michigan, Ann Arbor, Michigan Pancreatic Surgery for Endocrine Tumors Sten A. G. Tibblin, MD, PhDt Formerly Associate Professor and Consultant Surgeon, Department of Surgery, University Hospital, Lund, Sweden Surgical Approach to Primary Hyperthyroidism (Unilateral Approach) Lars-Erik Tisell, MD, PhD Retired Chief of Endocrine Surgery, Department of Surgery, Sahlgrenska University Hospital, Sahlgrenska, Sweden Natural History of Treated Primary Hyperparathyroidism Robert Udelsman, MD, MBA, FACS Lampman Professor of Surgery and Oncology, and Chairman, Department of Surgery, Yale University School of Medicine; Chief of Surgery, Yale New Haven Hospital, New Haven, Connecticut Hiirthle Cell Adenoma and Carcinoma
tDeceased
John A. van Heerden, MB, ChB, MS(Surg) (Minn), FRCS (C), FACS, Hon FCM(SA), Hon FRCS(Edin), FRCPS (Glasg) Fred C. Anderson Professor of Surgery, Mayo Graduate School; Consultant in General Surgery, Mayo Clinic, Rochester, Minnesota Parathyroid Reoperations Cornelis J. H. van de Velde, MD, PhD Professor of Surgery, Leiden University Medical Center, Leiden, Germany Occurrence and Prevention of Complications in Thyroid Surgery Nobuyuki Wada, MD, PhD Assistant Professor, Department of Surgery, Yokohama City University School of Medicine, Yokohama City, Japan Comparative Genomic Hybridization in Thyroid Neoplasms Jeffrey D. Wayne, MD Assistant Professor of Surgery, Northwestern University, Feinberg School of Medicine; Attending Physician, Northwestern Memorial Hospital, Chicago, Illinois Insulinomas Malcolm H. Wheeler, MD, FRCS Professor of Surgery, University Hospital of Wales, Cardiff, Wales, United Kingdom Approach to Thyroid Nodules Scott M. Wilhelm, MD Assistant Professor of Surgery, University Hospital of Cleveland, Case Western Reserve University; Staff Surgeon, University Hospitals of Cleveland, Cleveland, Ohio Open Operative Approaches to the Adrenal Gland Stuart D. Wilson, MD Professor and Chief, Division of PancreatobiliarylEndocrine Surgery, Medical College of Wisconsin; Senior Attending Surgeon, Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin Gastrinoma Michael W. Yeh, MD Fellow, University of California, San Francisco, San Francisco, California; Endocrine Surgical Unit, Royal North Shore Hospital, St. Leonards, New South Wales, Australia Mechanisms and Regulation of Invasion in Thyroid Cancer William F. Young, Jr, MD, MSc Professor of Medicine, Mayo Clinic College of Medicine; Consultant, Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota Multiple Endocrine Neoplasia Type 1 Rasa Zarnegar, MS Surgical Resident, Case Western Reserve University Cleveland, Ohio Sodium-Iodide Symporter and Radioactive Iodine Therapy
Contributors - - xiii
Andrew P. Zbar, MB, BS University of the West Indies, Queen Elizabeth Hospital, St. Michael, Barbados Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Martha A. Zeiger, MD Associate Professor of Surgery, Division of Endocrine and Oncologic Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Hypoparathyroidism and Pseudohypoparathyroidism; Transplantation of Endocrine Cells and Tissues
Andreas Zielke, MD Department of Surgery, Endocrine Research Group, Philipps University, Marburg, Germany Adrenal Imaging Procedures
Since the first edition of the Textbook of Endocrine Surgery there have been considerable changes in the clinical management of patients with endocrine surgical problems, as well as advances in basic science regarding endocrine neoplasms. Many colleagues have asked Drs. Duh and Clark whether another edition will be published because of numerous recent changes in endocrine surgery. Major changes have occurred regarding the indications for parathyroidectomy in patients with primary hyperparathyroidism based on the natural history of the disease. The surgical approach for patients with primary hyperparathyroidism has also changed as more surgeonsare now recommending a selective approach rather than a bilateral approach. Much of this change is due to better preoperative localization studies and the use of intraoperative parathyroid hormone assays to determine when all abnormal parathyroid tissue has been removed. Some experts are also recommending a minimally invasive approach via small == 2.S-cm incisions or by using an endoscopic approach with I.S-cm incisions for patients with primary hyperparathyroidism. Substantial changes have also occurred regarding indications for adrenalectomy for patients with incidentally discovered adrenal neoplasms. More accurate localization studies and improved testing have made the diagnosis easier and tumor identification more precise. Most endocrine surgeons are now recommending laparoscopic removal of non-malignant-appearing adrenal tumors under 6 em in maximal diameter. Such treatment has dramatically reduced the duration of hospitalization and has also increased the referral of such patients to endocrine surgical units that are proficient in laparoscopic operations. There have been numerous other advances in using genetic testing to diagnose patients with multiple endocrine neoplasia types I and II. Children who are ret oncogene positive usually receive prophylactic thyroidectomy before age 6 and before they develop medullary thyroid cancer. More information is also available regarding genotype-phenotype relationships in predicting tumor behavior. Familial nonmedullary thyroid cancer with or without other syndromes has recently become a recognized clinical syndrome, and the thyroid cancers in these patients are somewhat more aggressive than are sporadic thyroid cancers. Papillary thyroid cancer in children and after radiation are frequently
associated with ret/PTC rearrangements and other papillary thyroid cancers with BRAF mutations, whereas follicular cancers are more often associated with PAX-S/PPARy and ras mutations. Since the Chemobyl nuclear accident in 1986, considerably more information has become available relating to the association of radiation exposure and thyroid cancer. Many other advances or consensus of opinion have also become available regarding the diagnosis, localization, and treatment of endocrine neoplasms, including endocrine tumors of the pancreas. New or revised areas in the second edition of Textbook of Endocrine Surgery include: (l) recent advances in the etiology and molecular biology of endocrine neoplasms; (2) methods used to diagnose patients with sporadic and familial thyroid cancers and the risks and benefits of prophylactic operations; (3) the association of low-dose therapeutic radiation, RET/PTC rearrangements, and surgical management of thyroid tumors; (4) current information regarding the adverse effects of primary hyperparathyroidism and related symptoms, associated conditions, and survival, as well as the indications for parathyroidectomy (this will include the usefulness of the follow-up information regarding the NIH consensus criteria and newer studies regarding quality of life improvement after parathyroidectomy); (5) the changing selective surgical approach for patients with primary hyperparathyroidism based on preoperative localization tests and intraoperative PTH testing; (6) the indications for operations for patients with incidentally discovered adrenal neoplasms; and (7) the use of laparoscopic adrenalectomy to remove most adrenal tumors under 6 em in maximal diameter. In summary, during the past several years there have been improved methods for diagnosing and treating patients with endocrine neoplasms, including screening for familial disease, more precise diagnostic tests, better preoperative localization studies, and new surgical instrumentation, as well as a better understanding of the natural history of many of these disorders. Orlo H. Clark, MD
Quan- Yang Duh, MD Electron Kebebew, MD
xv
Table of Contents 1
Thyroid physiology
3
2
Surgical anatomy and embryology of the thyroid and parathyroid glands and recurrent and external laryngeal nerves
9
3
Medical and surgical treatment of endemic goiter
16
4
Sporadic nontoxic goiter
24
5
Thyroiditis
34
6
Hypothyroidism
44
7
Graves' and Plummer's diseases : medical and surgical management
54
8
Use and abuse of thyroid-stimulating hormone suppressive therapy in patients with nodular goiter and benign or malignant thyroid 68 neoplasms
9
Approach to thyroid nodules
85
10
Childhood thyroid carcinoma
93
11
Papillary thyroid carcinoma : rationale for hemithyroidectomy
102
12
Papillary thyroid carcinoma : rationale for total thyroidectomy
110
13
Follicular neoplasms of the thyroid
115
14
Hurthle cell adenoma and carcinoma
123
15
Medullary thyroid carcinoma
129
16
Localization tests in patients with thyroid cancer
142
17
Papillary and follicular carcinoma : surgical and radioiodine treatment 152 of distant metastases
18
Anaplastic carcinoma of the thyroid gland
159
19
Unusual thyroid cancers, lymphoma, and metastases to the thyroid
168
20
Recurrent thyroid cancer
181
21
Thyroidectomy
188
22
Management of regional lymph nodes in papillary, follicular, and medullary thyroid cancer
195
23
Occurrence and prevention of complications in thyroid surgery
207
24
Thyroid emergencies : thyroid storm and myxedema coma
216
25
Pathology of tumors of the thyroid gland
223
26
Factors that predispose to thyroid neoplasia
240
27
Predictors of thyroid tumor aggressiveness
248
28
Growth factor, thyroid hyperplasia, and neoplasia
256
29
Signal transduction in thyroid neoplasms
265
30
Oncogenes in thyroid tumors
280
31
Thyroid oncogenesis
288
32
Mechanisms and regulation of invasion in thyroid cancer
295
33
Surgical management of recurrent and intrathoracic goiters
304
34
Surgical management of advanced thyroid cancer invading the aerodigestive tract
318
35
Potentially new therapies in thyroid cancer
334
36
Comparative genomic hybridization in thyroid neoplasms
344
37
Sodium-iodide symporter and radioactive iodine therapy
355
38
Parathyroid embryology, anatomy, and pathology
365
39
Parathyroid hormone : regulation of secretion and laboratory determination
372
40
Diagnosis of primary hyperparathyroidism and indications for parathyroidectomy
384
41
Natural history of untreated primary hyperparathyroidism
393
42
Metabolic complications of primary hyperparathyroidism
402
43
Natural history of treated primary hyperparathyroidism
413
44
Asymptomatic primary hyperparathyroidism
419
45
Normocalcemic hyperparathyroidism
424
46
Localization studies in persistent or recurrent hyperparathyroidism
430
47
Technique of parathyroidectomy
439
48
Surgical approach to primary hyperparathyroidism (bilateral approach)
449
49
Surgical approach to primary hyperparathyroidism (unilateral approach)
456
50
Minimally invasive parathyroid surgery
462
51
Endoscopic parathyroidectomy
467
52
Intraoperative parathyroid hormone assay as a surgical adjunct in patients with sporadic primary hyperparathyroidism
472
53
Parathyroid hyperplasia : parathyroidectomy
481
54
Familial hyperparathyroidism in multiple endocrine neoplasia syndromes
489
55
Familial hyperparathyroidism
493
56
Metabolic complications of secondary hyperparathyroidism
502
57
Surgical approach to secondary hyperparathyroidism
510
58
Parathyroid reoperations
518
59
Hypoparathyroidism and pseudohypoparathyroidism
527
60
Cryopreservation of parathyroid tissue
530
61
Hypercalcemia of malignancy and parathyroid hormone-related protein
536
62
Hypercalcemic crisis
543
63
Parathyroid carcinoma
549
64
Surgical embryology and anatomy of the adrenal glands
557
65
Adrenal physiology
571
66
Adrenal imaging procedures
576
67
Clinically inapparent adrenal mass (incidentaloma or adrenaloma)
586
68
Hyperaldosteronism
595
69
Adrenocortical carcinoma : nonfunctioning and functioning
604
70
Cushing's syndrome
612
71
Pheochromocytoma
621
72
Addison's disease and acute adrenal hemorrhage
634
73
Open operative approaches to the adrenal gland
641
74
Laparoscopic adrenalectomy
647
75
Anatomy and embryology of the pancreas
665
76
Multiple endocrine neoplasia type 1
673
77
Transplantation of endocrine cells and tissues
691
78
Pancreatic endocrine physiology
701
79
Insulinomas
715
80
Localization of endocrine pancreatic tumors
730
81
Pancreatic surgery for endocrine tumors
737
82
Gastrinoma
745
83
Multiple endocrine neoplasia type 2B
757
84
Somatostatinoma and rare pancreatic endocrine tumors
764
85
Non-multiple endocrine neoplasia endocrine syndromes
773
86
Neuroendocrine tumors
780
87
Endocrine emergencies : hypoglycemic and hyperglycemic crises
789
88
Chemotherapy for unresectable endocrine neoplasms
800
Thyroid Physiology Roderick Clifton-Bligh, MB, BS, PhD • Leigh Delbridge, MD, FRCS
The thyroid gland contains two separate physiologic endocrine systems: one responsible for the production of the thyroid hormones thyroxine (T4 ) and triiodothyronine (T3) , and the other responsible for the production of the hormone calcitonin. The functional unit for thyroid hormone production is the thyroid follicle. This is composed of a single layer of cuboidal follicular cells surrounding a central space filled with colloid. The average size of a follicle varies from 100 to 300 urn, each of which is surrounded by a network of capillaries. The primary function of the thyroid follicle is to make and store thyroid hormones. Calcitonin is produced by C cells within the thyroid. These cells, of neural crest origin, lie in a parafollicular position in direct contact with the follicular basement membrane.
Thyroid Embryogenesis Thyroid primordial cells develop from pharyngeal ectoderm, forming a visible medial anlage by human gestational days 16 to 17.1 The thyroid diverticulum then migrates caudally to reach its final position in the thyroid primordial body anterior to the cricoid cartilage (Fig. 1-1). Subsequently, these cells begin to express markers of mature thyrocyte differentiation, including proteins that are intrinsic to thyroid secretory function (thyroglobulin, thyroperoxidase, and the sodiumiodide symporter [NIS]), and the thyroid-stimulating hormone (TSH) receptor that controls both thyroid growth and secretory function. The foramen caecum, at the junction between the anterior two thirds and posterior third of the tongue base, remains as an embryologic reminder of thyroid origin. Thyrocytes form thyroid follicles, while intervening cells derived from the ultimobranchial body within the fourth pharyngeal pouch develop into calcitonin-secreting C cells (see Fig. 1-1). The parathyroid glands develop from the third and fourth pharyngeal pouches and migrate to the posterior surface of the thyroid gland. The thyroid gland begins to trap iodide between gestational weeks 10 and 12.1 Several transcription factors involved in the development of the thyroid gland have been identified. Three such factors-thyroid transcription factors (TTFs)-1 2•3 and _24 and the paired homeodomain factor Pax-85.6-were identified and isolated by their binding to specific regulatory elements
within the promoters of thyroid-specific genes (e.g., thyroperoxidase and thyroglobulin). Mutation of any of these transcription factors leads to thyroid dysgenesis, together with other phenotypic features specific to each transcription factor (TTF-l, pulmonary disease; Pax-8, renal hemiagenesis; TTF-2, cleft palate).7-9 The transcription factor GATA3 has been shown to be important in parathyroid gland development since mutations in this gene are associated with HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal aplasia).'? Failure of parathyroid gland development is also a feature of DiGeorge syndrome, in which parathyroid and thymic aplasia are variably accompanied by cardiac defects and facial malformations owing to microdeletion or rearrangement of the short arm of chromosome 22. 11 Several transcription factors involved in the development of the parathyroid glands in mouse models have been identified," including Gcm2 and Hoxa3.
Thyroid Hormone Physiology Iodide Metabolism and Uptake Iodine usually enters the body as the result of dietary and water uptake, but it can also be found in various drugs, such as cough medicines, and in diagnostic agents. Dietary iodine intake varies widely throughout various parts of the world. The relationship between iodine intake and thyroid disease was first demonstrated by Chatin in 1852, but the practice of iodine supplementation of food and water, which he recommended, fell into disrepute and was not revived until the large-scale experiments of Marine and Kimball in Ohio in 1917.14 Even in areas where endemic goiter is not a problem, iodine intake and excretion vary considerably with urinary excretion, ranging from as little as 40 ug/day up to 400 ug/day." Iodine deficiency is associated with nodular goiter, hypothyroidism, and cretinism" as well as the development of follicular thyroid carcinoma.!? In areas of the world where iodine deficiency is still a problem, a variety of measures are being introduced to increase iodine intake, such as iodination of salt, bread, and water to treat entire population groups and injections of iodized oil for target groups such as pregnant women.P Iodine excess, on the other hand, is associated
3
4 - - Thyroid Gland
FIGURE 1-1. Thyroid embryogenesis. Left, Coronal section through the pharyngeal arch region in a late-somite embryo. The thyroid diverticulum forms from a thickening in the midline of the anterior pharyngeal floor. The two lateral anlagen (ultimobranchialbodies) are derived from the fourth or fifth pharyngeal pouch; the thymus and inferior parathyroids are derived from the third pouch, whereas the superior parathyroid glands form from the fourth pharyngeal pouch (not shown). Right, Ventral view of the pharyngeal organ derivatives following migration toward their ultimate positions.The thyroid diverticulumhas caudally migrated anterior to the cricoid cartilage, where it is infiltrated by cells from the ultimobranchial bodies that will form parafollicular C cells. The superior and inferior parathyroid glands are positioned on the posterolateral surface of the thyroid gland. The two thymic primordia will fuse to become a single gland anterior to the trachea. (Adapted from Manley NR, Capecchi MR. The role of Hoxa-3 in mouse thymus and thyroid development. Development 1995;12l:l989.)
with an increased incidence of autoimmune thyroid disease such as Graves' disease and Hashimoto's thyroiditis'S" as well as papillary thyroid carcinoma. I? Iodine, in the form of inorganic iodide, is rapidly and efficiently absorbed from the gastrointestinal tract and enters the extracellular iodide pool, where it is joined by iodide derived from the breakdown of previously formed thyroid hormone. Less than 10% of total body iodide is contained in the extracellular pool; the remaining 90% is stored in the thyroid gland as either preformed thyroid hormone or iodinated amino acids.'? Iodide is taken up from the extracellular space into the follicular cells by an active transport process. The major source of loss of iodide from the extracellular space, in addition to uptake by the thyroid gland, is renal excretion. Small quantities of iodide are also lost through the skin, through the saliva, or in expired air. The active transport of iodide into the cells results in a significant intrathyroidal iodide gradient. The NIS is part of a family of membrane-associated transport glycoproteins that probably contain 12 membranespanning domains. 2o•21 Iodide is actively transported using energy from the coupled inward sodium transport. Mutations in the NIS gene are associated with goitrous congenital hypothyroidism.P Iodide transport into the follicular cells is influenced by TSH levels as well as by the glandular content of iodide.
Synthesis of Thyroid Hormone After uptake into the follicular cells through the basal membrane (Fig. 1-2), inorganic iodide is rapidly oxidized. Thyroid hormones are then synthesized by the combination of iodine with tyrosyl residues within the protein thyroglobulin. This reaction is catalyzed by thyroperoxidase in two principal steps. In the first reaction, iodide reacts with
FIGURE 1-2. Uptake of iodide into the follicular cell by active transport, with subsequent iodide oxidation, tyrosine iodination, and iodotyrosine coupling occurring at the apical membrane, catalyzed by thyroid peroxidase. DIT = diiodotyrosine; MIT = monoiodotyrosine; T3 = triiodothyronine; T4 = thyroxine.
Thyroid Physiology - -
tyrosyl residues in thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). In the second reaction, MIT and DIT condense to form 3,5,3'-triiodothyronine (T 3) or the inactive 3,3',5'-triiodothyronine (rT3) , whereas two molecules of DIT condense to form T 4 • T 3 and rT 3 are also formed by intrathyroidal deiodination of thyroxine, catalyzed by deiodinase enzymes.P In conditions of iodine-sufficient intake, the predominant iodothyronine synthesized by the thyroid gland is T 4 •24 Once formed, the thyroid hormones, covalently bound to thyroglobulin, are stored in colloid within the center of the follicle. The thyroid gland contains a very large store of thyroid hormone, which lasts for several weeks in the absence of the formation of new hormone. 19 Thyroid peroxidase (TPO) is a membrane-bound glycoprotein that is localized to the apical membrane of the follicular cell; the peroxidase reactions occur at the cell-colloid interface.f TPO has now been cloned and has been shown to have a hydrophobic signal peptide at its aminoterminus and a hydrophobic region with the characteristics of a transmembrane domain near the carboxylterminus.P This structure is consistent with TPO being a membrane-associated protein. The synthesis of thyroglobulin occurs exclusively in the thyroid gland, where homodimers are formed in the endoplasmic reticulum before being transported into the apical lumen of thyroid follicles.P Defects in thyroglobulin synthesis usually cause moderate to severe hypothyroidism in association with low circulating thyroglobulin levels." A partial organification defect and goiter (with or without overt hypothyroidism) is associated with sensorineural deafness in Pendred's syndrome. Mutations in a putative sulfate transporter gene (PDS) have recently been associated with this disorder," Although the precise mechanisms by which the pendrin protein causes the phenotype is unclear, it is proposed that defective sulfation of thyroglobulin impairs its subsequent iodination." Release of thyroid hormone into the peripheral blood occurs as the result of lysosomal hydrolysis within the follicular cells (Fig. 1-3). Pseudopodia form at the apical membrane
5
of the thyroid cell, and multiple vesicles containing thyroglobulin are incorporated into the follicular cell by endocytosis. Lysosomal hydrolysis of the thyroglobulin, with reduction of disulfide bonds, leads to release of both T3 and T 4 through the basement membrane into the circulation. The ratio of the levels of these two hormones released into the peripheral blood approximates their levels in stored thyroglobulin (T3:T4 is "" 1:13). Very little thyroglobulin reaches the peripheral circulation; however, when sensitive immunoassay procedures are used, small quantities can be detected in normal individuals.P Iodotyrosines released from thyroglobulin undergo deiodination and are recycled, with the iodide so released available for new thyroid hormone synthesis.
Peripheral Transport and Metabolism of Thyroid Hormones More than 99% of circulating thyroid hormones are bound to serum proteins, including thyroxine-binding globulin (TBG), transthyretin, and albumin." TBG is a glycoprotein that contains only one binding site per molecule. TBG is responsible for the transport of more than three fourths of thyroid hormone in the blood, and its levels are significantly increased by elevated levels of estrogens, as occurs in pregnancy. Dissociation of the free hormone from its binding proteins is rapid and efficient. Thyroid hormones are lipophilic and are capable of passive diffusion into cells, although specific transporters may also regulate intracellular thyroid hormone content." T 3 synthesized directly by the thyroid forms a relatively small proportion of the effective T 3 concentration in tissues, which is mainly derived from peripheral deiodination of T4 . This reaction is catalyzed by two deiodinases with characteristic tissue distributions. Type I deiodinase (5'DI) is predominant in liver, kidney, and thyroid, whereas type II deiodinase (5'DII) is present in the central nervous system, pituitary, placenta, brown adipose tissue, cardiac and skeletal muscle, and thyroid.'? A third deiodinase (5'DIII) catalyzes deiodination of T 4 to rT 3 or T 3 to diiodothyronine (T 2) and is found in the placenta and central nervous system." These differences in distribution and regulation may explain some tissue-specific variation in thyroid hormone action. Peripheral conversion of T 4 to T 3 may be impaired in a number of situations, including systemic illness, malnutrition, and trauma or by various drugs. The thyroid hormones generally have slow turnover times in the peripheral circulation. In adults, the half-life of T 4 is about 7 days, presumably because of the high degree of binding of T4 to its carrier proteins, whereas the half-life of T, is approximately 8 to 12 hours.
Peripheral Action of Thyroid Hormones
FIGURE 1-3. Lysosomal hydrolysis of pinocytotic vesicles containing stored colloid, with subsequent release of thyroid hormone into the peripheral circulation. T 3 = triiodothyronine; T4 = thyroxine.
The major effects of thyroid hormone action occur through the intranuclear action of Tj, with T4 being largely a prohormone." It remains controversial as to whether T 4 might also regulate non-nuclear biologic responses in some contexts, for instance, the activation of certain mitochondrial or cellmembrane enzymes." In the 1960s, Tata and associates observed that T3 treatment resulted in the rapid synthesis of nuclear RNA, which preceded increases in protein synthesis
6 - - Thyroid Gland and mitochondrial oxygen consumption." Subsequently, subcellular fractionation demonstrated specific nuclear binding sites for T 3 and identified the anterior pituitary, liver, brain, and heart as having high binding capacity for T 3.3! Thus, the current concept of thyroid hormone action is that its nuclear receptor binds to specific regulatory regions in target genes and regulates gene transcription in response to T 3.32-34 Thyroid hormone receptors (TRs) are members of the steroid hormone receptor superfamily. There are two TR genes, a and ~, located on chromosomes 17 and 3, respectively, and differential splicing of both these genes yields a total of four isoforms, denoted as TRal, TRa2, TRf3I, and TRf32 (Fig. 1_4).32 The expression of the various TR isoforms is both developmentally regulated and tissue specific, such that TRa is widely expressed at all stages of development, preceding the appearance of endogenous thyroid hormone, whereas TR~ begins to be expressed as thyroid hormone-dependent processes occur," An aminoterminal is specifically splice variant of the TR~ receptor, TR~2 expressed in the hypothalamus and pituitary and may therefore be the critical subtype involved in negative-feedback effects of T 3.32 In the adult, TRal may be the predominant isoform in myocardium, skeletal muscle, and fat, whereas TR~l and TR~2 predominate in the pituitary and liver." TRa2 does not bind ligand and its function is poorly understood, although it may function as an inhibitor of thyroid hormone action in some contexts.F TRs bind to specific regulatory DNA sequences usually within gene promoters.P A consensus regulatory binding site, termed the thyroid hormone response element (TRE), consists of a pair of hexanucleotide half-sites. Natural TREs present in gene promoters are commonly degenerate variations of these consensus sequences. Biochemical evidence suggests that on many TREs, the receptor complex is most active when bound to DNA as a heterodimer with the retinoid X receptor."
FIGURE 1-4. Multiple human thyroid hormone receptor (TR) isoforms, TRa and TR~ receptors are transcribed from different genes on chromosomes 17 and 3, respectively. Different isofonns are then generated from differential splicing of the primary messenger RNA transcripts in each case, such that TRal and TRa2 isofonns and TR~2 isofonns differ in their carboxytennini, whereas TR~I differ in their aminotermini, as shown. (Adapted from Lazar MA. Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr Rev 1993;14:184.)
The clinical manifestations of thyroid hormone action are the net result of the actions of the products of the various genes whose expression is regulated by T 3. For example, thyroid hormones affect cardiac contractility by affecting the transcription of, and subsequent relative proportions of, the various myosin heavy chains in cardiac muscle.P'" In the pituitary, T 3 regulates the transcription of the genes for both ex and ~ subunits of TSH, thus affecting the level of TSH secretion.'?
Thyroid Hormone Regulation Thyroid hormone production and release are under the control of the hypothalamic-pituitary-thyroid axis (Fig. 1-5), acting in a negative-feedback cycle. TSH is the major regulator of thyroid gland activity. Increased levels of TSH lead to hypertrophy and increased vascularity of the gland, whereas decreased levels of TSH lead to gland atrophy. A glycoprotein secreted by the anterior pituitary, TSH is composed of an a subunit and a ~ subunit. The ex subunit is common to a family of glycoprotein hormones, including
FIGURE 1-5. Negative-feedback regulation of thyroid hormone production. TRH = thyrotropin-releasing hormone; TSH = thyroidstimulating hormone; T 3 = triiodothyronine; T 4 = thyroxine.
Thyroid Physiology - - 7
follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin (hCG). TSH binds to a specific receptor on the surface of the thyroid cell. The TSH receptor is a G protein-coupled receptor. After activation by TSH, the receptor interacts with a guanine nucleotide-binding protein (G protein), which induces the production of cyclic adenosine monophosphate (cAMP).4o This cAMP then stimulates the synthesis and secretion of thyroid hormones. Receptors that are linked to G proteins are characterized by the presence of seven transmembranespanning domains linked by cytoplasmic and extracellular loops. The first cytoplasmic loop, as well as the carboxylterrninal residues in the second and third cytoplasmic loops, are important in mediating a TSH-dependent increase in intracellular cAMP production." The TSH receptor has been cloned.f and specific mutations have been identified in association with hyperfunctioning follicular thyroid neoplasms.tv" TSH is secreted from the anterior pituitary in response to thyrotropin-releasing hormone (TRH) and to reduced pituitary levels of T; TRH acts to directly stimulate the thyrotropic cells to increase both the synthesis and the release of TSH. TRH is a tripeptide synthesized in the paraventricular nucleus of the hypothalamus, and, after synthesis, it passes to the median eminence and down the pituitary stalk in the hypophysial portal system. It is thought that the principal function of TRH is to set the ambient level of regulatory control whereby thyroid hormone levels are mediated by negative feedback. TRH secretion itself is also under negative-feedback control in response to peripheral thyroid hormone levels. T 3, on the other hand, derived principally from the local deiodination of peripheral T 4 in the pituitary, directly inhibits the release and synthesis of TSH. It is also thought that peripheral thyroid hormone levels may regulate TRH receptor numbers on the surface of the pituitary thyrotropic cells, thus decreasing their responsiveness to TRH. A number of other factors affect thyroid hormone synthesis in addition to the hypothalamic-pituitary feedback cycle. Other hormones can have a direct effect on the thyroid gland. Catecholamines are thought to have a direct stimulatory effect on thyroid hormone release. hCG also stimulates thyroid hormone production, with free levels of thyroid hormone increasing during pregnancy and in the presence of hydatidiform moles." Glucocorticoids, on the other hand, act to reduce thyroid hormone production by suppressing pituitary TSH secretion. The thyroid also obtains direct adrenergic innervation, and there is some evidence that sympathetic stimulation can increase thyroid hormone synthesis. Other external factors that can affect thyroid regulation include nonthyroidal illness, starvation, and temperature changes. A variety of disorders, especially severe illness, lead to reduced levels of peripheral thyroid hormone in the absence of a compensatory rise in TSH (the so-called sick euthyroid syndrome). Starvation also leads to markedly reduced levels of both T 4 and T 3 , as does exposure to high temperatures.
Autoregulatory Mechanisms The thyroid can also control its own stores of thyroid hormone by intrinsic autoregulatory mechanisms. These mechanisms are principally seen in response to alterations in
iodide availability. For example, an excess of dietary iodide leads to autoregulated inhibition of iodide uptake into the follicular cells, whereas iodide deficiency results in increased iodide transport and uptake. Large doses of iodide have more complex effects, including an initial increase followed by a decrease in organification, the so-called Wolff-Chaikoff effect." Excess iodide also inhibits, at least initially, the release of stored thyroid hormone from the thyroid follicle.
Calcitonin Physiology Calcitonin Secretion Calcitonin is secreted by the parafollicular C cells located in the lateral lobes of the thyroid. This hormone is a 32-amino acid polypeptide with an NH-terminal 7-member disulfide ring."? Calcitonin acts to lower serum calcium concentration, principally by inhibition of bone resorption. Secretion of the hormone is increased in the presence of elevated levels of serum calcium. In the clinical context, calcitonin secretion can be stimulated by a number of techniques, including calcium infusion, pentagastrin infusion, and alcohol.t''
Peripheral Action of Calcitonin Calcitonin acts via specific cell surface receptors located predominantly on the surface of osteoclasts." These receptors have also been found in renal tubular epithelium, neural tissue, and lymphocytes.t" The predominant action of calcitonin is to inhibit osteoclast action, although in the physiologic situation calcitonin does not actually cause a lowering of s~rum calcium levels. Indeed, in patients with medullary carcinoma of the thyroid, in which calcitonin levels may be many thousands of times the normal level, hypocalcemia is not seen. Similarly, patients who have had a total thyroidectomy, with removal of all known C cells, maintain normal calcium metabolism.
Summary In summary, the thyroid gland contains two separate functioning units. The follicular cells produce T 4 and T 3, which regulate growth and metabolism, whereas the parafollicular cells produce the antihypercalcemia hormone calcitonin. Iodine is required for the synthesis of thyroid hormone, and iodine deficiency can result in endemic goiter and cretinism. Circulating levels of thyroid hormone depend on a negative feedback between T 3 and T 4 and TSH secretion as well as a positive action of TSH. Thus, medications and other factors can influence ambient thyroid hormone levels and, consequently, the metabolic state.
REFERENCES 1. Pintar JE. Normal development of the hypothalamic-pituitary-thyroid
axis. In: Braverman LE, Utiger RD (eds), Werner and Ingbar's The Thyroid, 7th ed. Philadelphia, Lippincott-Raven, 1996, p 6. 2. Guazzi S, Price M, De Felice M, et al. Thyroid nuclear factor I (ITF-I) contains a homeodomain and displays a novel DNA-binding specificity. EMBO J 1990;9:3631.
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Thyroid Gland
3. Mizuno K, Gonzalez FJ, Kimura S. Thyroid-specific enhancer-binding protein (TIEBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. Mol Cell Bioi 1991;11:4927. 4. Zannini M, Avantaggiato V, Biffali E, et al. TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J 1997;16:3185. 5. Plachov D, Chowdhury K, Walther C, et al. Pax-8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development 1990;110:643. 6. Zannini M, Francis-Lang H, Plachov D, Di Lauro R. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters. Mol Cell Bioi 1992;12:4230. 7. Devriendt K, Vanhole C, Matthijs G, de Zegher F. Deletion of thyroid transcription factor 1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med 1998;338: 1317. 8. Macchia PE, Lapi P, Krude H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 1997;19:83. 9. Clifton-Bligh RJ, Wentworth JM, Heinz P, et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate, and choanal atresia. Nat Genet 1998;19:399. 10. Van Esch H, Groenen P, Nesbit MA, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 2000;406:419. 11. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863. 12. Gunther T, Chen Z-F, Kim J, et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 2000;406: 199. 13. Manley NR, Capecchi MR. The role of Hoxa-3 in mouse thymus and thyroid development. Development 1995;121:1989. 14. Medvei Vc. The birth of endocrinology: Part I. In: Medvei VC (ed), A History of Endocrinology. Hingham, MA, MTP Press, 1982, p 213. 15. Laurence P. Iodine intake: What are we aiming at? [Editorial] J Clin Endocrinol Metab 1994;79: 17. 16. Boyages Sc. Iodine deficiency disorders. J Clin Endocrinol Metab 1993;77:587. 17. Livoisi VA, Asa SL. The demise of follicular carcinoma of the thyroid gland. Thyroid 1994;4:233. 18. Braverman LE. Iodine and the thyroid: 33 years of study. Thyroid 1994;4:351. 19. Larsen PR, Ingbar SH. The thyroid gland. In: Wilson DJ, Foster DW (eds), Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, p 357. 20. Dai G, Levy 0, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature 1996;379:458. 21. Smanik PA, Liu Q, Furminger TL, et al. Cloning of the human sodiumiodide symporter. Biochem Biophys Res Commun 1996;226:339. 22. Fujiwara H, Tatsumi K-I, Miki K, et al. Congenital hypothyroidism caused by a mutation in the Na+/I- symporter. Nat Genet 1997;16:PI24. 23. McLachlan SM, Rapoport B. The molecular biology of thyroid peroxidase: Cloning, expression, and role as autoantigen in autoimmune thyroid disease. Endocr Rev 1992;13:192. 24. Bjorkman U, Ekholm R, Denef F. Cytochemical localization of hydrogen peroxide in isolated thyroid follicles. J Ultrastruct Res 1981; 74:105. 25. Taurog A. Hormone synthesis. In: Braverman LE, Utiger RD (eds), Werner and Ingbar's The Thyroid, 7th ed. Philadelphia, LippincottRaven, 1996, p 47. 26. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997;17:411.
27. Refetoff S, Nicoloff JT. Thyroid hormone transport and metabolism. In: DeGroot LJ, Besser M, Burger HG, et al (eds), Endocrinology, 3rd ed. Philadelphia, WB Saunders, 1995, p 560. 28. Freake HC, Mooradian AD, Schwartz HL, Oppenheimer JH. Stereospecific transport of triiodothyronine to cytoplasm and nucleus in GHI cells. Mol Cell Endocrinol 1986;44:25. 29. Oppenheimer JH, Schwartz HL, Strait KA. The molecular basis of thyroid hormone actions. In: Braverman LE, Utiger RD (eds), Werner and Ingbar's The Thyroid, 7th ed. Philadelphia, Lippincott-Raven, 1996, p162. 30. Tata JR, Ernster L, Lindberg 0, et al. The action of thyroid hormones at the cell level. Biochem J 1963;86:408. 31. Oppenheimer JH, Schwartz HL, Surks MI. Tissue differences in the concentration of triiodothyronine nuclear binding sites in the rat: Liver, kidney, pituitary, heart, brain, spleen, and testis. Endocrinology 1974; 95:897. 32. Lazar MA. Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr Rev 1993;14:184. 33. Brent GA. The molecular basis of thyroid hormone action. N Engl J Med 1994;331:847. 34. Chin WW. Molecular mechanisms of thyroid hormone action. Thyroid 1994;4:389. 35. Glass CK. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev 1994;15:391. 36. Yu VC, Delsert C, Andersen B, et al. RXR~: A coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 1991;67:1251. 37. Dillman WHo Biochemical basis of thyroid hormone action in the heart. Am J Med 1990;88:626. 38. Morkin E. Regulation of myosin heavy chain genes in the heart. Circulation 1993;87: 1451. 39. Chin WW, Can FE, Burnside J, et al. Thyroid hormone regulation of thyrotropin gene expression. Rec Prog Horm Res 1993;48:393. 40. Wess J. Mutational analysis of muscarinic acetylcholine receptors: Structural basis of ligandlreceptor/G protein interactions. Life Sci 1993;53: 1447. 41. Chazenbalk GD, Nagayama Y, Russo D, et al. Functional analysis of the cytoplasmic domains of the human thyrotropin receptor by site directed mutagenesis. J Bioi Chern 1990;265:20970. 42. Parmentier M, Libert F, Maenjhaut C, et al. Molecular cloning of the thyrotropin receptor. Science 1989;246: 1620. 43. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene causing hyperfunctioning thyroid adenomas. Nature 1993;365:649. 44. Porcellini A, Ciullo I, Laviola L, et al. Novel mutations of thyrotropin receptor gene in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 1994;79:657. 45. Yoshikawa N, Nishikawa N, Horimoto M, et al. Thyroid-stimulating activity in sera of normal pregnant women. J Clin Endocrinol Metab 1989;69:74. 46. Wolff J. Physiological aspects of iodide excess in relation to radiation protection. J Mol Med 1980;4:151. 47. Aurbach GD, Marx J, Spiegel AM. Parathyroid hormone, calcitonin, and the calciferols. In: Wilson OJ, Foster DW (eds), Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, p 1397. 48. Ewins DL, McGregor AM. Medical aspects of thyroid disease. In: Lynn J, Bloom SR (eds), Surgical Endocrinology. Oxford, England, Butterworth Heinemann, 1993, p 294. 49. Takahashi N, Akatsu T, Sasaki T, et al. Induction of calcitonin receptors by l-o, 25-dihydroxyvitamin D3 in osteoclast-like multinucleated cells formed from mouse bone marrow cells. Endocrinology 1988; 123:1504. 50. Body JJ, Gilbert F, Nejal S, et al. Calcitonin receptors on circulating normal human lymphocytes. J Clin Endocrinol Metab 1990;71:675.
Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands and Recurrent and External Laryngeal Nerves Jean-Francois Henry, MD
The surgical anatomy of the thyroid, parathyroid glands, and recurrent and external laryngeal nerves should be considered as a whole. A thorough knowledge of the anatomy and an understanding of the embryonic development of the thyroid and parathyroid glands are the keys to successful surgery.
Thyroid Embryology and Developmental Abnormalities The thyroid gland has a double origin from the primitive pharynx and the neural crest. The main body of the thyroid gland is derived from epithelial cells of the endoderm of the primitive pharynx. These cells will form the greater portion of the follicular elements of the thyroid tissue. They arise as a diverticulum from the midline of the pharyngeal floor. It soon develops as a bilobed, encapsulated structure that descends in the midline of the neck. With further development, this diverticulum remains attached to the buccal cavity by a narrow tract-the thyroglossal duct. Its distal end may become the pyramidal lobe. The neural crest is the source of the parafollicular cells, or C cells, which secrete calcitonin. 1,2 These C cells migrate from the neural crest of the ultimobranchial bodies of the fourth branchial pouch (P IV) and the fifth branchial pouch. The incorporation of the fifth pouch with the P IV leads to the formation of the caudal-pharyngeal complex, which includes not only the ultimobranchial bodies (lateral thyroids) but also the parathyroid glands arising from the endoderm of the P IV. Eventually, C cells populate the thyroid tissue by way of its lateral lobes, which join the main body on each side (Fig. 2-1).
The normal adult thyroid gland is composed of two lateral lobes connected by an isthmus. Anomalies of embryonic development of the two lobes result in a large variety of shapes and sizes. Rarely, in fewer than 0.1 % of cases, the isthmus or one lobe may not develop. The thyroglossal duct may persist or may differentiate into thyroid tissue at any level. Normally, the epithelium of the thyroglossal duct disappears. Occasionally, the epithelium and the duct may form thyroglossal cysts or fistulas, which usually present above the hyoid bone but may occur at any site along the duct between the base of the tongue and the suprasternal notch. These are essentially midline structures. Because the duct passes through or anterior or posterior to the hyoid bone, excision of the midsection of the hyoid bone is necessary for complete excision of the entire cyst and thyroglossal duct up to the foramen cecum. Midline ectopic thyroid rests are the result of the failure of or incomplete descent of the thyroglossal duct and of abnormal development of its epithelium. The most common example is the pyramidal lobe, which extends upward from the isthmus or from either lateral lobe in about 30% of patients. It may be considerably enlarged in patients with endemic goiters and in Graves' disease. In the latter case, if overlooked, it may be responsible for recurrent hyperthyroidism. Complete failure of descent of the thyroglossal duct results in a lingual thyroid, located at the base of the tongue. A lingual thyroid may be the only functioning tissue and may be responsible for lingual goiter; symptoms depend on its size. Other midline ectopic thyroid rests of the thyroglossal duct may be found below or above the hyoid bone. Usually asymptomatic, they are demonstrated on radioiodine scanning after total thyroidectomy. Carcinomas may rarely arise in median ectopic thyroid tissue.
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Thyroid Gland
FIGURE 2-1. Schematic view of embryonic migrations of parafolIicular andparathyroid tissues. At the 13- to l4-mm stage, the P III and P IV migrate together with the thymus and ultimobranchial
bodies, respectively.
About I % of thyroglossal cysts contain papillary thyroid cancers. Aberrant thyroid tissue has also been identified lateral or inferior to the main body of the thyroid gland and in the superior anterior mediastinum. When aberrant thyroid tissue is situated lateral to the jugular vein and is unassociated with lymph node tissue, it may rarely be a developmental anomaly deriving from the fourth pouch. Ectopic intrathoracic thyroid tissue may also be found in the periaortic region and the pericardium. It is the result of the displacement of thyroid rests into the mediastinum by the descent of the heart and great vessels. Because their blood supply is from intrathoracic vessels, tumors arising from these thyroid remnants usually cannot be removed by cervicotomy and require a sternum-splitting incision. In contrast with the former rare situations, what appears on histologic examination to be normal thyroid tissue within lymph nodes lateral to the jugular vein in fact represents metastatic papillary thyroid carcinoma. On the other hand, on rare occasions, a few follicles of normal thyroid tissue are observed within the capsule of medially located lymph nodes. They do not necessarily represent metastases, provided that the follicular cells appear normal and the follicles are limited to the periphery of the lymph node. It has been demonstrated that in these rare cases, the thyroid gland is entirely normal at meticulous histologic examination.' Thyroid tissue may also rarely be found in ovarian teratomas. In rare instances, when thyroid tissue is the main component, struma ovarii may arise and be responsible for thyrotoxicosis or malignancy with peritoneal metastases.
it as the origin of the thymus IV (rudimentary thymus IV), which rapidly undergoes involution. The fatty lobules sometimes found at the site of the upper parathyroid (P IV) may well constitute the vestigial remnants of this thymus IV. At the 13- to 14-mm stage, the P III and P IV migrate together with the thymus and ultimobranchial bodies, respectively. The P III-thymus complex separates from the pharyngeal wall and moves toward the caudal and medial regions. Because of the extension of the cervical spine and the descent of the heart and great vessels, the thymus and the P III are drawn toward the superior mediastinum. At the 20-mm stage, the cephalic regression of the thymus brings about its separation from the P III, which are thus abandoned at the level of the anterior or posterolateral region of the inferior poles of the thyroid lobes or at the level of thyrothymic ligaments, vestigial structures indicative of their former connections. This embryologic migration results in an extensive area of dispersal of the normal P III. In 61% of cases, they are situated at the level of the inferior poles of the thyroid lobes on the posterior, lateral, or anterior aspects. In 26% of cases, they are situated in the thyrothymic ligaments or on the upper cervical portion of the thymus. More rarely, in 7% of cases, they are situated higher up, at the level of the middle third of the posterior aspect of the thyroid lobes, and may then be confused with P IV (Fig. 2-2). The P IV follow the thyroid migration of the ultimobranchial bodies, which travel toward the lateral part of the main median thyroid rudiment. Their descent in the neck is thus relatively limited. They remain in contact with the posterior part of the middle third of the thyroid lobes. The short course of embryonic migration of P IV explains why they remain relatively stable in their topography when they are not pathologic. Thus, in 85% of cases, they are grouped at the posterior aspect of the thyroid lobes, in an area 2 em in diameter, whose center is situated about 1 em above the
Parathyroid Embryology and Developmental Abnormalities The inferior parathyroid glands arise from the dorsal part of the P III. The thymus arises from the ventral portion of the same pouch. This common origin justifies labeling P III and thymus as parathymus. The dorsal part of the P IV gives rise to the superior parathyroids. The fate of the ventral portion of the P IV is little understood in humans. Gilmour" regarded
FIGURE 2-2. The embryonic migration of the third branchial
pouch (P III)-thymus complex results in an extensive area of the normal P III from the angleof the mandible to pericardium.
Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - -
FIGURE 2-3. The short course of embryonic migration of the fourth branchial pouches explains why they remain relatively stable in the topography when they are not pathologic. In 85% of cases, they are grouped at the junction of the middle and superior thirds of the posterior aspect of the thyroid lobe.
crossing of the inferior thyroid artery and the recurrent nerve (Fig. 2_3).4.6 Thus, the P IV are crossed by the P III during the descent of the parathymus. This embryonic crossing of P III and P IV explains why their grouping at the level of the inferior thyroid artery, at the junction of the middle and inferior thirds of the thyroid lobe, is more or less close, depending on the migration of P III. Because the area of dispersal of the P IV is limited by their short migratory course, a congenital ectopic position of P IV is unusual. In 12% to 13% of cases, the glands are on the posterior aspect of the superior pole of the thyroid lobe in a laterocricoid, lateropharyngeal, or intercricothyroid position, and, exceptionally, in less than 1% of cases, they are above the upper pole of the lobe. In 1% to 4% of cases, they are frankly posterior behind the pharynx or esophagus. Because the embryonic descent of the thymus extends from the angle of the mandible to the pericardium, anomalies of migration of the parathymus, whether excessive or defective, are responsible for high or low ectopias of P III. The incidence of high ectopias, along the carotid sheath, from the angle of the mandible to the lower pole of the thyroid, does not seem to exceed 1% to 2%.5.8 Conversely, if their separation from the thymus is delayed, the P III may be dragged down into the anterior mediastinum to a varying degree. They are then usually in the thymus, at the posterior aspect of its capsule, or still in contact with the great mediastinal vessels. These low ectopias are found in 3.9% to 5% of cases.v" Parathyroid glands found in the posterosuperior mediastinum are usually tumoral P IV that have migrated subsequently because of gravity." The strictly intrathyroid localization of some parathyroids is explicable only on embryologic grounds. According to Wang,1O the P IV may become included within the thyroid at the time of fusion of the ultimobranchial bodies with the median thyroid rudiment. Although the P III do not arise from the P IV, undeniable cases of a normal or pathologic P III included in the lower poles of the thyroid lobes have been reported.t'! According to Gilmour," intrathyroid inclusion of parathyroid tissue may be found with the same incidence as inclusions of thymic tissue. Overall, the incidence of intrathyroid ectopias that seem to involve both P III and P IV is between 0.5% and 3.5%.4,8-11 Other embryologic cervical or mediastinal ectopic glands are more rare and usually related to supernumerary glands. 13, 14 These develop from accessory parathyroid debris
11
arising from fragmentation of the pharyngotracheal duct when the pharyngeal pouches separate from the pharynx. The incidence of these supernumerary glands is relatively high at 13%.5 Akerstrom and colleagues' distinguish between accessory parathyroid glands containing simple tissue debris and weighing less than 5 mg, found very close to the main glands, and true supernumerary glands weighing more than 5 mg (average weight, 24 mg) situated apart from the other glands. Ectopic or supernumerary parathyroids may also be situated in quite exceptional positions. They are then revealed by tumoral formations developing from them and are responsible for hyperparathyroidism: in the middle mediastinum (0.3%) at the level of the aortopulmonary window," lateral to the jugulocarotid axis." The migration of pathologic parathyroid tissue seems highly improbable in such cases. In both cases, the embryologic hypotheses suggest a precocious fragmentation of P Iy' 15.16 Parathyroid tissue'? and parathyroid adenomas" have also been described within the vagus nerve. In the latter case, it has been hypothesized that parathyroid tissue arises from the P III, which is closely related to the vagus nerve during embryogenesis.'? A case of a parathyroid located in the mucosa of the piriform sinus has even been reported. 19
Surgical Anatomy of the Thyroid and Parathyroid Glands The normal adult thyroid gland weighs about 17 g. It is wrapped around the anterolateral portion of the upper tracheal rings and larynx. Each lobe occupies a bed between the trachea and the esophagus medially; the carotid sheath posteriorly; and the sternocleidomastoid, the sternohyoid, and the sternothyroid muscles laterally and anteriorly. If the sternothyroid and sternohyoid muscles are to be divided transversely, they must be transected high, at the cricoid level, to preserve their motor nerve, the ansa hypoglossi. Section of the strap muscles has no clinical functional consequence. The normal thyroid is soft, dark wine-red in color, and covered with a thin capsule. It is loosely attached to neighboring structures. The variations in fixation of the gland may arouse suspicion of pathologic change, particularly when the history suggests acute thyroiditis or cancer. Normally, the gland adheres only to the cricoid cartilage and the upper tracheal rings. This is the posterior suspensory, or Berry's, ligament. The superior and inferior thyroid arteries are derived from the external carotid arteries and the thyrocervical trunks, respectively. Occasionally, a branch from the innominate artery or aorta, the arteria thyroidea ima, may be present. It passes directly upward in front of the trachea to enter the lower border of the isthmus. Its frequency of occurrence has been greatly overemphasized. The superior thyroid artery is the first branch of the external carotid artery. It arises just above the thyroid cartilage. It gives off the superior laryngeal artery and then descends on the surface of the inferior constrictor of the pharynx, deep to the sternothyroid muscle. It enters the upper pole of the thyroid on its anterosuperior surface. It gives off a relatively
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Thyroid Gland
FIGURE 2-4. Relation between the external branchof the superior laryngeal nerve and the thyroid artery. The nerve may run partly to or around the artery or its branches.
large branch to the pyramidal lobe and isthmus. The superior thyroid artery, via its posterior branch, feeds the superior parathyroid or P IV. There is an extremely close relationship between the superior thyroid artery and the external branch of the superior laryngeal nerve (Fig. 2_4).20.2\ This nerve is the motor nerve to the cricothyroid muscle, which produces tension of the vocal cord and makes possible the production of high-pitched voice sounds. Injuries to the nerve, in particular bilateral injuries, are easily overlooked at postoperative laryngoscopy. In 6% to 18% of cases, the external branch of the superior laryngeal nerve runs with or around the superior thyroid artery or its branches. Therefore, the nerve is highly vulnerable during ligation of the superior thyroid artery. Nevertheless, routine identification of the nerve during thyroid surgery is usually not advocated. Indeed, in 20% of cases, the nerve is not located in the surgically accessible area around the superior thyroid pole. It cannot be identified without dissection into or through the fibers of the pharyngeal constrictor muscle. To avoid nerve injury when ligating the superior thyroid vascular pedicle, one may recommend first identifying the branches of the artery to avoid ligation of its main trunk. This identification is particularly recommended during excision of pathologically enlarged thyroid glands. The superior thyroid arteries should be ligated as low as possible on the thyroid gland. Second, it is advisable to dissect the superior thyroid vessels away from the nerve by opening up a space between the cricothyroid muscle and the upper pole of the thyroid. This dissection requires strong downward and outward traction on the upper pole of the gland. During this traction, the nerve should be sought more or less transversely between the superior thyroid vessels and the pharyngeal constrictor muscle or the cricothyroid muscle. Finally, the dissection must be performed from medial to lateral. Moreover, small vessels run from the superior thyroid artery into the pharyngeal constrictor and the cricothyroid muscles. As the nerve slips under these muscles, there is a risk of heat injury to the nerve during cauterization of these little muscular vascular branches. The inferior thyroid artery arises from the thyrocervical trunk. It runs upward behind the carotid sheath to about the
level of the cricoid cartilage, loops medially and downward to a level above the inferior pole of the thyroid, crossing the sympathetic trunk or its branches, and then runs upward again to reach the gland at its midportion. For the surgeon, the inferior thyroid artery appears from beneath the carotid artery only when the thyroid gland is retracted medially and the jugular vein laterally. This maneuver puts tension on the artery and makes it easier to identify. Before entering the thyroid, the artery usually divides into three branches: inferior, posterior, and internal. One branch or sometimes the trunk itself supplies the inferior parathyroid or P III. The inferior thyroid artery and its terminal branches are intimately associated with the recurrent laryngeal nerve at about the level of the junctions of the lower and middle thirds of the thyroid gland (Fig. 2-5). The left recurrent laryngeal nerve ascends at the depth of the tracheoesophageal groove or just lateral to it at the lower pole of the thyroid. Usually it crosses deep to the inferior thyroid artery, sometimes between the terminal branches of the artery, rarely superficially. The right recurrent laryngeal nerve courses more obliquely, being somewhat more lateral in position caudally. It rarely crosses deep to the artery, usually between its terminal branches. Innumerable variations have been described.F This is one of the most vulnerable areas for injury to the recurrent laryngeal nerve. From a practical point of view, it is safer to search for the nerve below the artery. Identification of the inferior thyroid artery and careful ligation of its branches close to the gland is an excellent means of preserving the nerve and the inferior parathyroid. The recurrent nerve may be mistaken for one branch of the artery and especially for the inferior laryngeal artery. The nerve is somewhat less regular, rounded, and elastic than the artery. A small, red, sinuous vessel, a vasa nervorum, is always observed on it. The tortuousity of this small vessel is reduced when retraction of the thyroid puts the nerve under tension. Rarely, the nerve branches below the inferior thyroid artery. In any case, the surgeon must consider each extralaryngeal branch of the recurrent nerve as the possible motor branch and make every attempt to preserve them all.
FIGURE 2-5. Recurrent laryngeal nerve and its relationship to the
inferior thyroid arteryandto Berry's ligament. The nerve is embedded in the posterior portion of Berry's ligament. It is accompanied by the inferiorlaryngeal artery, whichgivesoff a small branch that crosses the nerve internally.
Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - -
The recurrent laryngeal nerve continues upward and medially at the posterolateral aspect of the middle third of the thyroid gland. It is extremely close to the capsule of the gland. In a few cases, particularly in pathologically enlarged glands, it may appear to penetrate or may actually penetrate the thyroid gland itself before entering the larynx. At the two upper tracheal rings, the nerve is embedded in the posterior portion of Berry's ligament (see Fig. 2-5). This ligament extends posteriorly behind the recurrent nerve and loosely attaches the thyroid to the esophagus. Vessels and connective tissue are more condensed anteriorly at the level of the tracheal rings. The nerve commonly divides before the point at which it enters the larynx, posterior to the cricothyroid muscle. The nerve is accompanied by the inferior laryngeal artery. At the site of Berry's ligament, this artery, usually just posterior to the recurrent nerve, gives off a small branch that crosses the nerve to enter the thyroid glands. Therefore, bleeding vessels in this portion of the ligament should never be clamped until the nerve has been identified. It is in this area that the recurrent nerve is most vulnerable to injury. Medial retraction on the thyroid lobe makes the nerve more vulnerable to injury during lobectomy. Indeed, this maneuver puts tension on the inferior thyroid artery and its branches and on Berry's ligament; consequently, the nerve is displaced anteriorly on the lateral aspect of the trachea. Moreover, the posterior fibers of Berry's ligament press the nerve against the lateral aspect of the tracheal rings, increasing the difficulties of dissection. Instead of medial retraction, it is preferable to retract the lobe upward after complete dissection of its lower pole. With this maneuver, it is easier to follow the nerve until its entry in the larynx at the level of the cricoid cartilage. The recurrent laryngeal nerve is the motor nerve to the intrinsic muscles of the larynx." Injury to the motor trunk causes paralysis of the vocal cord on the ipsilateral side. The other extralaryngeal branches are sensory. On rare occasions (0.63%), the right inferior laryngeal nerve does not recur'" On the left side, this anomaly is quite exceptional (0.04%). As a rule, the origin of the nonrecurrent laryngeal nerve is cervical. Depending on its level of origin, the nerve runs more or less down along the vagus nerve and more or less across the jugulocarotid groove, making a downward curve. It always passes behind the common carotid artery. In one third of cases, it is in close contact with the trunk or the branches of the inferior thyroid artery; it enters the larynx at the usual level. Nonrecurrence of the inferior laryngeal nerve results from a vascular anomaly during embryonic development of the aortic arches: no innominate artery, but an aberrant subclavian artery (arteria lusoria). Nerve anomaly on the left side requires, in addition, a right aortic arch associated with situs inversus viscerum. A nonrecurrent laryngeal nerve has been also reported in association with an ipsilateral recurrent laryngeal nerve.25-28 Curiously, in some cases, no vascular anomaly has been demonstrated." The supposed coexistence of a recurrent and a nonrecurrent laryngeal nerve is questionable. First, an enlarged anastomotic branch between the cervical sympathetic system and the recurrent laryngeal nerve may be mistaken for nonrecurrent laryngeal nerve." Second, in the reported cases, it has never been demonstrated that the recurrent branch originated from the vagus nerve.
13
The nervous branch has only been described running in the usual pathway of a recurrent laryngeal nerve and having a small caliber. Whether this branch really originates from the vagus nerve and not from the sympathetic system, for example, the stellate ganglion, has not been proved." During thyroid lobectomy, if the nerve is not found at its usual place, before it crosses the inferior thyroid artery, it should be sought more or less transversely between the laterally retracted carotid sheath and the medially retracted thyroid in a plane that, in the case of nerve anomaly, cannot be cleaved as easily as usual, because the nonrecurrent inferior laryngeal nerve links the two structures. Other aberrant pathways for the recurrent laryngeal nerve are observed only with pathologically enlarged thyroids and particularly with large posterior nodules and in substernal multinodular goiters. In these cases, if it is not possible to search for the nerve at its usual place, below the inferior thyroid artery, it should be located superiorly near to where it enters the larynx at the level of the cricoid cartilage. This maneuver requires previous dissection of the upper pole of the gland, or an "inside-out" approach, after section of the isthmus. Then the nerve should be dissected in a downward direction. The venous drainage is more variable than the arterial supply. The capsular veins vary in size and may be enormous in pathologic glands. These are thin-walled structures that intercommunicate freely among themselves, forming a characteristic capsular network. The vessels within the gland itself are relatively small. Consequently, hemorrhage from capsular vessels may be important, but, provided that the vessels are clamped, subtotal resection of a lobe is a relatively bloodless procedure. The capsular network is schematically drained by three pedicles. The superior thyroid veins, just anterior and lateral to the superior thyroid artery, empty directly or indirectly into the internal jugular vein. The lateral or middle veins vary greatly in number. They pass directly from the anterolateral border of the lobe into the internal jugular vein. Careful lateral retraction of the carotid sheath facilitates their identification and their ligation, especially in enlarged glands where they may be mistaken for capsular veins. The inferior thyroid veins leave the lower pole and the isthmus in several trunks, frequently forming a plexus. They empty into the internal jugular vein and directly into the innominate vein. Ligation of the most lateral inferior thyroid veins requires previous identification of the recurrent nerve. The nerve may be anterior and, particularly when the thyroid lobe is medially retracted, could be mistaken for a vein. Follicular carcinomas, because of their high tendency for vascular invasion, may spread directly through veins into the internal jugular veins and sometimes downward into the innominate vein. In such cases, previous distal control of these veins is mandatory before thyroidectomy. Lymphatic drainage of the thyroid is extensive and may flow practically in all directions. Capsular lymph channels, draining the intraglandular capillaries, may even crosscommunicate with the isthmus and opposite lobe. Therefore, it is technically impossible to remove all the potential lymph node metastases in thyroid cancers. Nevertheless, and from a practical point of view, the surgeon must consider two zones of lymphatic drainage for the
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Thyroid Gland
FIGURE 2-6. The two sites of lymphatic drainage of the thyroid. The first site is the visceral compartment of the neck. The second site is the lateral cervical region. The boundary between the two sites is the carotid sheath.
thyroid (Fig. 2-6). The first site is the paraglandular space or middle or visceral compartment of the neck. The second site is the lateralcervical region. The boundary between the two sites is the carotid sheath. In the visceral compartment, there are two groups: (l) the prelaryngeal and pretracheal and (2) the paratracheoesophageal. The prelaryngeallymphatic vessels lie anterior to and above the isthmus and merge superiorly and laterally with the lymphatic vessels of the superior pole of the thyroid along the superior thyroid vessels to drain into the nodes of the lateral neck. The pretracheal lymphatic vessels lie below the isthmus and merge inferiorly with the lymphatic vessels of the anterior and superior mediastinum. The anterior boundary of the visceral compartment is the posterior surface of the prethyroid muscles, but sometimes node metastases may be found very anteriorly in the midline, particularly just above the isthmus (Delphian lymph nodes). The paratracheoesophageal lymphatic vessels lie along the lateral and posterior aspects of the thyroid gland and along the course of the recurrent laryngeal nerves. They communicate laterally with the lymphatic vessels in the supraclavicular triangles and posteriorly with those around and behind the trachea, the larynx, the pharynx, and the esophagus. Lymphatic drainage of the isthmus flows down into the mediastinal nodes and upward into the paralaryngeal nodes. The normal flow direction from the central and lower parts of the lateral lobes is toward the tracheoesophageal nodes. Only lymphatic drainage of the superior poles of the lobes may flow directly into the lateral neck nodes. This may explain why papillary thyroid carcinomas revealed by metastatic laterocervical lymph nodes are located in the upper pole of thyroid lobes in nearly two thirds of cases.'? Therefore, the central neck area is the primary zone of lymphatic drainage for all thyroid cancers except those located in upper poles of the glands. Lateral neck areas (internaljugular chains and posterior triangles) are secondary
zones of lymphatic drainage. Some of the involvement probably is brought about by retrograde extension resulting from obstruction of the lymph flow route in the central neck area." Because the visceral or central compartment of the neck is the primary zone of involvement, many surgeons advocate prophylactic neck dissection in this area in cases of papillary and medullary thyroid carcinomas. Indeed, even if metastatic nodal recurrences are rare, reoperations in the central neck area are difficult and increase the risk of injury to the recurrent laryngeal nerve and parathyroid glands. Just as embryology helps the surgeon understand where the parathyroid glands are positioned, their gross appearance makes it possible to identify them and to differentiate them from other structures. The parathyroid glands vary in shape but remain compact in 94% to 98% of cases.' Their color depends on their adipocyte content and vascularization: light brown or coffee colored when the gland is very fatty, and darker, buff, or reddish brown when the gland is more cellular or has a richer blood supply. They are soft and supple and retain their original shape during dissection. If flattened by the development of a thyroid nodule, they can become rounded again when detached from its surface. Their average size varies from 5.25 x 3 x 1.28 mm to 5 x 3 x 1 mm, as reported by Gilmour and Martin'? and Wang,6 respectively. The average weight of a normal gland is 40 mg (range, 10 to 78 mg). They are encapsulated and have sharp outlines and a smooth, glistening surface. Parathyroid glands have a particular affinity for fat and are often found completely or partially embedded in a fatty globule. They often have a fatty capsule over their surface like the crest of a helmet. Characteristically, they can be separated easily from the adjacent fatty structures. Whatever their size, shape, or color, the parathyroid glands always share an encapsulated appearance, which gives them a proper shape, an ocher tint, and a soft elastic consistency. Fat is softer, paler, and straw colored, with no definite shape. Thyroid tissue is firmer, less homogeneous, darker wine-red in color with bluish-gray tints, and often embedded in "padding." Lymph nodes are firmer, more rounded, less homogeneous, and white, dirty gray, or putty colored, with black dots. Nodes are separated from the adjacent fat with greater difficulty. Lymph nodes are usually multiple. Thymic tissue is paler, grayish yellow or grayish pink, granular, and adherent to the fat. The arterial supply of the parathyroid glands is terminal in type; the artery is solitary in two thirds of cases. The length of the artery varies (l to 40 mm), but in cases of thyroidectomy, even if the parathyroid is pedicled, its preservation depends primarily on the distance between the origin of its artery and the thyroid capsule. The vascularization of P III depends primarily on the inferior thyroid artery. The P IV are supplied by the inferior thyroid artery, by the posterior branch of the superior thyroid artery, or by the posterior marginal arch of Evans. Both P III and P IV may be entirely dependent on the inferior thyroid artery. Therefore, during thyroid lobectomy, the inferior thyroid artery must never be ligated at the level of its main trunk. Similarly, the preservation of P IV requires separate ligation of the branches of the superior thyroid artery so as to preserve the posterior branch. At the lower poles of the thyroid lobes, the preservation of P III is ensured by the technique of ultraligation
Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - - 15
advised by Halsted and Evans." When the lower parathyroid glands (P III) are situated in the thyrothymic ligaments or in the upper poles of the thymus, they are supplied by the inferior thyroid artery. Venous drainage occurs by three methods: (1) by the capsular network of the thyroid, (2) by the venous pedicles of the thyroid body, or (3) by a combination. Thyroid lobectomy may render the ipsilateral parathyroid glands ischemic. Hemostasis of a parathyroid vein generally should be avoided because of the risk of glandular infarction. Parathyroid ischemia is often evidenced by progressive darkening of the gland. Incision of the capsule and superficial parenchyma may prevent venous stasis and allow the gland to recover its normal color.
Summary The thyroid gland is made up of follicular and parafollicular cells of endoderm and neural crest origin, respectively. The lower parathyroid glands and thymus arise from the dorsal part of the P III, and the upper parathyroid glands arise from the P IV. The lower parathyroid glands are usually situated caudal to where the inferior thyroid artery and recurrent laryngeal nerve cross. If not situated here, they are usually in the thymus. The upper parathyroid glands are more dorsal or posterior, more consistent in position at the level of the cricoid cartilage. When not situated here, they may descend along the esophagus into the posterior mediastinum. An understanding of the embryonic formation of the thyroid and parathyroid glands as well as experience helps the surgeon recognize not only the normal relationship of the thyroid and parathyroid glands with the adjacent structures but also the aberrant development or position of these glands. This knowledge is of paramount importance for successful operations.
REFERENCES I. Le Douarin N, Le Lievre c. Embryologie experimentale: Demonstration de I'origine neurale des cellules a calcitonine du corps uItimobranchial chez I'embryon de poulet. Comptes rendus de l'Academie des Sciences 1970;270:2857. 2. Pearse AGE, Cavalheira AE Cytochemical evidence for an ultimobranchial origin of rodent thyroid C cells. Nature 1967;214:929. 3. Meyer JS, Steinberg LS. Microscopically benign thyroid follicles in cervical lymph nodes. Cancer 1969;24:302. 4. Gilmour JR. The gross anatomy of the parathyroid glands. J Pathol Bact 1938;46:133. 5. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:14. 6. Wang CA. The anatomic basis of parathyroid surgery. Ann Surg 1976; 183:271. 7. Fraker DL, Doppman JL, Shawker TH, et al. Undescended parathyroid adenoma: An important etiology for failed operations for primary hyperparathyroidism. World J Surg 1990;14:342.
8. Henry JF, Denizot A. Anatomic and embryologic aspects of primary hyperparathyroidism. In: Barbier J, Henry JF (eds), Primary Hyperparathyroidism. Paris, Springer-Verlag, 1992, p 5. 9. Thompson NW. Surgical anatomy of hyperparathyroidism. In: Rothmund M, Wells SA Jr (eds), Parathyroid Surgery. Basel, Switzerland, Karger, 1986, p 59. 10. Wang CA. Hyperfunctioning intra-thyroid parathyroid gland: A potential cause of failure in parathyroid surgery. J R Soc Med 1981;74:49. I I. Wheeler MH, Williams ED, Wade JSH. The hyperfunctioning intrathyroid parathyroid gland: A potential pitfall in parathyroid surgery. World J Surg 1987;11:110. 12. Gilmour JR. The embryology of the parathyroid glands, the thymus, and certain associated rudiments. J Pathol Bact 1937;45:507. 13. Numano M, Tominaga Y, Uchida K, et al. Surgical significance of supernumerary parathyroid glands in renal hyperparathyroidism, World J Surg 1998;22:1098. 14. Pattou NF, Pelissier LC, Noel C, et al. Supernumerary parathyroid glands: Frequency and surgical significance in treatment of renal hyperparathyroidism. World J Surg 2000;24: I330. 15. Curley IR, Wheeler MH, Thompson NW, Grant CS. The challenge of the middle mediastinal parathyroid. World J Surg 1988;I2:8 I8. 16. Udekwu AG, Kaplan EL, Wu TC, et al. Ectopic parathyroid adenoma of the lateral triangle of the neck: Report of two cases. Surgery 1987;101:114. 17. Lack EE, Delay S, Linnoila RI. Ectopic parathyroid tissue within the vagus nerve. Arch Pathol Lab Med 1988;112:304. 18. Raffaelli M, Defechereux T, Lubrano D, et al. Intravagal ectopic parathyroid gland. Ann Chir 2000;125:961. 19. Joseph MP, Nadol JB, Goodman ML. Ectopic parathyroid tissue in the hypopharyngeal mucosa (pyriform sinus). Head Neck Surg 1982;5:70. 20. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in thyroid surgery. Surgery 1987;102:999. 21. Cernea CR, Ferraz AR, Cordeiro AC. Surgical anatomy of the superior laryngeal nerve. In: Randolf GW (ed), Surgery of the Thyroid and Parathyroid Glands. Philadelphia, WB Saunders, 2003, p 293. 22. Reed AE Relations of inferior laryngeal nerve to inferior thyroid artery. Anat Rec 1943;85:17. 23. Randolf WR. Surgical anatomy of the recurrent laryngeal nerve. In: Randolf GW (ed), Surgery of the Thyroid and Parathyroid Glands. Philadelphia, WB Saunders, 2003, p 300. 24. Henry JF, Audiffret J, Denizot A. The nonrecurrent inferior laryngeal nerve: Review of 33 cases, including two on the left side. Surgery 1988;104:977. 25. Katz AD, Nemiroff P. Anastomoses and bifurcations of the recurrent laryngeal nerve: Report of II 77 nerves visualized. Am Surg 1993; 59:188. 26. Thompson NW. In discussion of article Reference 24. Surgery 1988;104:983. 27. Proye CAG, Carnaille BM, Goropoulos A. Nonrecurrent and recurrent inferior laryngeal nerve: A surgical pitfall in cervical exploration. Am J Surg 1991;162:495. 28. Sanders G, Uyeda RY, Karlan MS. Nonrecurrent inferior laryngeal nerves and their association with a recurrent branch. Am J Surg 1983;146:501. 29. Raffaelli M, Iacobone M, Henry JE The false nonrecurrent inferior laryngeal nerve. Surgery 2000; I28: 1082. 30. Henry JF, Denizot A, Bellus JE Papillary thyroid carcinomas revealed by metastatic cervical lymph nodes. Endocr Surg 1992;9:349. 31. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid: I. Developing pattern of metastasis. Cancer 1970;2:1053. 32. Gilmour JR, Martin WJ. The weight of the parathyroid glands. J Pathol Bact 1987;34;431. 33. Halsted WS, Evans HM. The parathyroid glandules: Their blood supply and preservation. Ann Surg 1907;46:489.
Medical and Surgical Treatment of Endemic Goiter Polly S-Y Cheung, MBBS(HK)
Endemic goiter is a preventable disease caused by iodine deficiency. According to statistics from the World Health Organization (WHO) in 1999, a total of 740 million people-about 13% of the world's population-are affected by endemic goiter alone. ' Clinically, the individual with endemic goiter may present with a diffuse to multinodular goiter. Biochemically, the urinary iodine excretion level is low, and the serum thyroxine (T4) level may be low or normal with an elevated thyroidstimulating hormone (TSH) level. Long-standing goiters may become autonomous in function and produce toxicity. Mechanical obstruction to the trachea and the thoracic inlet and malignant changes are possible sequelae of endemic goiters. The occurrence of endemic goiter is preventable by an adequate supply of iodine in the diet. Universal salt iodination is the goal of WHO in an attempt to eliminate the disease by the year 2000. Data from WHO in 1999 showed that 68% of the total population in countries affected by iodine deficiency disorders (IDDs) have access to iodized salt. Existing endemic goiters are currently treated with iodine supplementation to reverse hypothyroidism and to reduce the size of the goiters. For long-standing goiters, the treatment is the same as that for sporadic goiter: T4 therapy and thyroidectomy are used for treatment; radioiodine therapy is used selectively. Goiter, an enlargement of the thyroid gland, is conventionally called an endemic goiter when it occurs in more than 10% of the population in a defined geographic area; the area is called an endemic area? A total goiter rate of 5% or higher is now recommended as the cut-off point to indicate a public health problem, following a decision made by the WHOlUnited Nations International Children's Emergency Fund (UNICEF)/lnternational Council for the Control of Iodine Deficiency Disorders (ICCIDD) Consultation on IDD Prevalence in November 1992.3 This recommendation is based on the observation that goiter prevalence rates between 5% and 10% may be associated with a range of abnormalities, including inadequate urinary iodine excretion or subnormal levels of T4 among adults, children, and neonates. Epidemiologic studies are usually carried out in school-age children (6 to 12 years of age) because of their high physiologic vulnerability and their accessibility
16
through school for studies on baseline health parameters and results of public health programs. Endemic goiter is the chief consequence of iodine deficiency, resulting from either low iodine intake or ingestion of goitrogens. The effects of iodine deficiency on human growth and development are denoted collectively as IDDs (Table 3-1). 4 It affects all stages of development from fetus and neonate to infant, child, and adolescent. Severe iodine deficiency affects the developing central nervous system. In the fetus, it causes abortion, stillbirth, congenital anomalies, or cretinism. In children and adolescents, it produces problems ranging from mild intellectual impairment to mental retardation to full-blown endemic cretinism. It is well recognized that a marginal iodine intake is associated with some degree of motor deficit or developmental delays, such as poor hand-eye coordination and impaired intellectual performance exemplified by a reduction in IQ scores by as much as 10 to 15 points in tests of mental development.'
Prevalence According to a global review in 1999, more than 2 billion people are at risk for iodine deficiency, this number representing 38% of the world's population. Approximately 741 million people from 130 countries have endemic goiter, representing 13% of the world population (Table 3-2).' Most of the world's natural supply of iodine exists in the ocean as iodide. In high, mountainous areas and inland waters, the soil becomes leached of iodine by snow water and glaciation. Lowlands with heavy rainfall or flooding can also become iodine deficient. The most important goitrous areas historically include the northern and southern slopes of the Himalayas, the Andean region of South America, the European Alps, and the mountainous areas of China. Goiters also occur in lowlands far from the oceans, such as the central part of Africa and, to a lesser extent, in the coastal areas of Europe." The global prevalence of goiter has hardly increased at the global level from 1990 to 1998 (Table 3-3),1 This figure was thought to reflect the vigorous efforts in survey and
Medical and Surgical Treatment of Endemic Goiter - - 17
increased data, especially in countries in the Eastern Mediterranean, Africa, and Europe, where the total goiter rate is high. The Eastern Mediterranean region has the highest goiter prevalence rate, with 74% of the population at risk for iodine deficiency. On the other hand, IDD prevalence has decreased slightly in the Americas, Southeast Asia, and the Western Pacific, reflecting the impact of IDD control programs, especially salt iodization, on the population. Southeast Asia and the Western Pacific (including China) together account for more than 50% of the world's total population at risk for IDD (Fig. 3-1). Countries in this region, including India, Pakistan, Bangladesh, Nepal, Myanmar (Burma), Vietnam, and Thailand, share a large rate of prevalence of IDD; 599 million people are at risk and 172 million are goitrous. China alone has 300 million people at risk of IDD because of the extensive mountainous areas in that country, with 109 million suffering from goiter.8 Iodine deficiency persists mostly in developing countries despite the established benefits of iodine supplementation in the prevention of endemic goiter. In decreasing order of magnitude, the number of people at risk of IDD is largest in the Eastern Mediterranean, followed by Africa, Southeast Asia, Europe, Western Pacific, and the Americas (see Table 3-2).
18 - - Thyroid Gland
FIGURE 3-1. Prevalence of iodine deficiency disorders (IDDs)-global distribution. TGR = total goiter rate. (From WHOIUNICEFI International Council for the Control of Iodine Deficiency Disorders. Global Prevalence of Iodine Deficiency Disorders. Geneva, Switzerland, World Health Organization, 1996.)
Mild to moderate iodine deficiency still persists in a number of European regions, namely Italy, Spain, Germany, Greece, Romania, Hungary, Poland, and the former Yugoslavia." Continuous measures to provide iodine are required to overcome the socioeconomic and cultural limitations in different regions. The prevalence of endemic goiter is influenced by age and gender. In severely iodine-deficient areas, goiter appears at an early age, and the prevalence increases markedly during childhood and attains its peak during puberty. From the age of 10 years, the prevalence is higher in girls than in boys, probably because of the difference in metabolism of iodine during adolescent growth. In both sexes, goiter prevalence decreases during adulthood, but the decline is sharper in men than in women. 10
Etiology of Iodine Deficiency Iodine is an essential substrate in the synthesis of the thyroid hormones i.-thyroxine (T4) and t-triiodothyronine (T 3) . The normal human thyroid gland releases about 65 ug of hormonal iodine to the circulation per day, which represents the minimum daily requirement of iodine. Iodine requirements increase during puberty, pregnancy, and lactation.
Iodine intake is considered adequate when it is between 100 and 200 ug/day (Table 3-4). The principal source of iodine intake is from diet or pharmaceuticals. I I The highest amounts of iodine in food are found in fish, seafood, and seaweed. Iodine is also found to a lesser extent in milk, eggs, and meat from animals whose diet contained sufficient amounts of iodine. Fruits and vegetables, except spinach, generally have very low iodine contents. The iodine content of drinking water is too low to serve as a consistent contributor to iodine supply.12 In an iodine-deficient environment, the locally grown food will also have a low iodine content. Some foods, beverages, and drugs, such as multivitamins, minerals, and antacids, have coating or coloring agents that contain iodine.
Medical and Surgical Treatment of Endemic Goiter - - 19 Low supply of dietary iodine is the main cause of development of endemic goiter. Because it is difficult to measure the iodine content of foods, the adequacy of dietary iodine is usually determined by the measurement of urinary excretion of iodine. This measurement represents the ratio between concentrations of iodine and creatinine in casual urine samples. 13 Two or more casual urine samples from the same individual taken on consecutive days are recommended to allow for variation in creatinine content." Experience has shown that the iodine concentration in early-morning urine specimens adequately reflects an individual's iodine status. In addition, iodine concentration per liter of urine bears a 1:I relationship with iodine per gram of creatinine and is now adopted as the standard in field studies by WHO.3 Measuring iodine concentration per liter of urine helps avoid the cumbersome measurement and calculation of the iodinecreatinine ratio. In nonendemic areas, the urinary iodine measurement is at least 100 ug/L. Severe iodine deficiency is considered to occur with a daily iodine excretion of less than 20 IlgIL; moderate deficiency, 20 to 49 IlglL; and mild deficiency, 50 to 99 IlgIL.15.16 The prevalence of endemic goiter varies with the severity of iodine deficiency (Table 3-5). Increasing iodine consumption in endemic areas has resulted in a reduction in goiter prevalence. The persistence of goiter in some areas with adequate iodine prophylaxis and the unequal geographic distribution of goiter in iodine-deficient areas suggest the existence of other goitrogenic factors. Natural goitrogens were first found in vegetables of the Brassica family, including cabbage, turnips, and rutabagas. Their antithyroid action is related to the presence of thioglucosides, which, after digestion, release thiocyanate and isothiocyanate. These compounds have goitrogenic actions by inhibiting iodide transport in the thyroid gland. A particular thioglucoside, goitrin, is also found in the weeds growing in pastures in Finland and Tasmania. 17 Cyanoglucosides are another important group of naturally ?ccurring goitrogens found in several staple foods in the tropICS, namely cassava, maize, bamboo shoots, and sweet potatoes. They are converted to the goitrogen thiocyanate after digestion. Flavonoids from millet, a staple food in Sudan, are also known to have antithyroid activity. IS The consumption of millet in Sudan and cassava in Zaire was found to aggravate the severity of the goiter endemism in these places.'? Protein malnutrition coexists frequently with endemic goiter. Studies of malnourished individuals in endemic areas show alterations in thyroid morphology and functions, suggesting that malnutrition has a goitrogenic effect.P
Pathophysiology of Endemic Goiter Endemic goiter is the end result of the physiologic and morphologic changes in the thyroid gland as an adaptation to an insufficient supply of dietary iodine. When iodine intake is low, thyroid hormone synthesis is impaired. This impairment leads to an increased thyroidal clearance of iodide from the plasma and decreased urinary excretion of iodide, an adaptation toward iodine conservation. T3, being three to four times more potent than T 4 but containing only three fourths as much iodine as T 4, is preferentially synthesized over T 4 . There is also increased peripheral conversion of T 4 to T321 Clinical euthyroidism is thus maintained, but biochemically the pattern of low serum T4, elevated TSH, and normal or supranormal T 3 is often found. 22 . 24 In severe thyroid failure, such as that in endemic cretinism, serum T3and T 4 concentrations are low and serum TSH concentration is markedly elevated. In less severe thyroid endemism, serum T3 and T 4 concentrations may remain normal. The serum TSH level may also be normal or moderately elevated, and there may be an exaggerated TSH response to thyrotropin-releasing hormone (TRH) simulation, implying an increase in the pituitary reserve of TSH and subclinical hypothyroidism. Such changes are thought to be mediated through an elevation in the serum TSH level. However, a wide variation in the level of TSH has been observed in normal and goitrous individuals in endemic areas.P Such dissociation between goiter size and biochemical findings suggests the po~sible role of circulating thyroid growth factors, such as epidermal growth factors, or an autoimmune process in the pathogenesis of goiter." Activity of thyroid growth-promoting i~unoglo~ulin (TGI) has been demonstrated in patients With sporadic and endemic goiter.'? However, conflicting results were obtained, and the methods of detection of such activity have been criticized, with this uncertainty leaving an unsettled role of TGI in goitrogenesis.P-"
Morphologic Changes in Endemic Goiter An increase in thyroid gland mass often accompanies the physiologic changes in response to iodine deficiency. Generalized epithelial hyperplasia occurs, with cellular
20 - - Thyroid Gland hypertrophy and reduction in follicular spaces. In chronic iodine deficiency, the follicles become inactive and distended with colloid accumulation. These changes persist into adult life, and focal nodular hyperplasia may develop, leading to nodule formation." Some nodules retain the ability to secrete thyroid hormone and form hot nodules. Others do not retain this ability, become inactive, and form cold nodules. Necrosis and scarring result in fibrous septa, which contribute to the formation of multinodular goiter.
Clinical Presentation and Diagnosis Goiter is classified according to the size of the thyroid gland on inspection and palpation, and the following grading system was proposed by WHO in 196032 : Stage 0: no goiter Stage Ia: goiter detectable only by palpation and not visible even when the neck is fully extended Stabe Ib: goiter palpable but visible only when the neck is fully extended Stage II: goiter visible with the neck in the normal position; palpation is not needed for diagnosis
FIGURE 3-2. Classification of goiter size. 1, Stage Ia: goiter palpable but not visible. 2, Stage Ib: goiter visible when neck extended. 3, Stage II: goiter visible in normal neck extension. 4, Stage III: goiter visible at a distance. (From Perez C, Scrimshaw NS, Munoz JA. Technique of endemic goitre surveys. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 369.)
Stage III: very large goiter that can be recognized at a considerable distance (Fig. 3-2) Because of observer variation in the measurement of goiter by inspection and palpation, the WHOIUNICEFI ICCIDD Consultation on IDD indicators in November 1992 recommended a simplified classification of goiter by combining the previous stages la and Ib into a single grade (grade 1) and combining stages II and III into grade 2. 3 The sum of grades 1 and 2 is taken as the total goiter rate. The simplicity of this assessment allows for easy training of field staff in public health surveys. • Grade 0: no palpable or visible goiter • Grade 1: a mass in the neck that is consistent with an enlarged thyroid that is palpable but not visible when the neck is in the neutral position; it also moves upward in the neck as the subject swallows • Grade 2: a swelling in the neck that is visible when the neck is in a neutral position and is consistent with an enlarged thyroid when the neck is palpated In areas of mild endemicity where the goiter rate is low and goiters are generally small (i.e., grade 1 or bordering on either grade 0 or 2), interobserver variations can be as high as 40%. Ultrasonography is therefore recommended by WHO as a safe, noninvasive method for providing a more precise and objective measurement of thyroid volume than inspection and palpation." The most common form of goiter in children is a diffuse thyroid enlargement. Nodularity may occur at a young age, and the finding of a small, solitary, palpable nodule in adolescence is common. Some diffuse goiters persist into adulthood, or the main bulk of the goiter may be replaced by multiple nodules that form a multinodular goiter, simulating a bag of marbles on palpation. Functionally, the individual often remains clinically euthyroid despite biochemical evidence of hypothyroidism, with low or normal serum T4 concentrations and minimally elevated serum TSH levels. Scintigraphy of the thyroid in endemic areas may show marked heterogeneity in the uptake of radioiodine and formation of hot or cold nodules. Autonomous function of the nodules leads to failure of 1311 or 1231 suppression with T 3 and absence of TSH response to TRH. Hyperthyroidism in older patients with endemic goiter may be precipitated by iodination and cause Jodbasedow hyperthyroidism.>' Endemic cretinism is a sequela of severe iodine deficiency in which intrauterine growth is affected by deficiencies of maternal T4 and dietary iodine. The infant is born with mental retardation and either (1) a predominantly neurologic syndrome of hearing and speech defects and varying degrees of characteristic stance and gait disorders or (2) predominant hypothyroidism and stunted growth. These changes are preventable with iodine prophylaxis but are not curable once they have occurred. Mechanical problems often arise in patients with huge goiters that cause tracheal deviation and compression. Large, substernal, or retrosternal goiter can cause venous congestion and the development of collateral venous circulation on the chest wall (Fig. 3-3). Surgical treatment is indicated in such patients. The presence of hard nodules suggests possible malignant disease, although an increase in the number of thyroid cancers in endemic goiter remains controversial.v-"
Medical and SurgicalTreatment of Endemic Goiter - - 21
FIGURE 3-3. Large goiter with thoracic inlet obstruction. (From
DeSmetMP. Pathological anatomy of endemic goiter. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 338.)
Follicular and anaplastic carcinoma are more common in areas of endemic goiter. The diagnosis is often delayed in such patients because goiters are so common in iodine-deficient areas. Fine-needle aspiration biopsy helps select patients for
thyroidectomy.'?
Treatment and Prophylaxis The occurrence of endemic goiter can be prevented by supplying an adequate amount of iodine in the diet and eliminating goitrogens and malnutrition. Iodination of salt is the preferred method of prophylaxis because salt consumption is consistent and universal, the technology of iodination is simple, and its production is easy to regulate. It was first successfully introduced in Switzerland and in the state of Michigan in 1921.38 Iodine in the form of potassium iodide is added to table salt in varying amounts ranging from 1 to 10,000 parts of salt to 1 to 200,000 depending on local factors such as customary consumption of salt. Potassium iodate is preferred in humans because of its increased stability." Epidemiologic surveys have confirmed that there is a dramatic reduction in the prevalence of goiter and progressive disappearance of endemic cretinism within several years after introduction of salt iodination programs."
Countries such as the United States, the United Kingdom, New Zealand, Australia, the Netherlands, Norway, and Sweden have completely eliminated IDDs.41 Difficulties in implementation occur in countries where locally inexpensive noniodized salt is available and government programs to increase iodine consumption are lacking. Iodination of vegetable oil is the principal alternative used in developing countries and in areas where salt is not customarily used, such as the New Guinea highlands.f It is also used as a short-term intervention while an iodized-salt program is being established. One intramuscular injection containing 480 mg of iodine provides adequate amounts of iodine for up to 3 years. Oral administration of iodized oil has the advantage of avoiding injections, but its duration of action is shorter and more variable, depending on absorption of iodine through the gastrointestinal tract." An oral dose of 1 mL (containing 480 mg of iodine) provides adequate iodine for 1 to 2 years after a single administration. An increased incidence of thyrotoxicosis occurs after increased iodine consumption. This increase was observed in Tasmania after bread iodination in 1966 and was most evident in older people." The thyrotoxicosis was attributed to the presence of autonomous nodules or underlying hyperthyroidism in persons with long-standing endemic goiters. Overall, however, the long-term correction of iodine deficiency not only abolishes endemic goiter but also reduces the incidence of toxic nodular goiters. Therefore, the occurrence of thyrotoxicosis does not outweigh the enormous benefits of iodine prophylaxis in endemic regions. However, iodination does have some risk in individuals older than 45 years with goiter, because hyperthyroidism may develop. At the World Summit for Children in 1990, which was attended by 71 heads of state and government, WHO, UNICEF, and ICCIDD established the target of virtual elimination of IDDs by the year 2000 and universal salt iodination in affected countries by the end of 1995.45 Efforts have been made to reduce the cost of salt iodination by reducing the price of potassium iodate and the manufacturing cost of the spray-mixing equipment for salt iodination. At present, the cost of salt iodination is approximately $0.05 per person per year. Campaigns have been launched in affected countries to analyze the existence and the severity of the problem and to convince governments, salt producers, and other relevant bodies of the costeffectiveness and benefits of salt iodination. Funds have been raised to help developing countries start programs of salt iodination.i" A 1998 global survey by WHO reported that 85% of the total number of countries affected by IDD have either formed legislation on salt iodization to start implementing national plans for iodination of all salt and introducing legislation to prohibit the sale of uniodized salt'? or have plans of action for controlling IDD. Data also showed that of the 5 billion people living in countries with IDD, 68% have access to iodized salt and 65% of these countries have laboratory facilities to monitor urinary iodine status and salt iodine levels. America is the region that is closest to virtual elimination of IDD, with more than 90% of the total population consuming iodized salt. For the patient with hypothyroidism and endemic goiter, the functional and neurologic changes are irreversible.
22 - - Thyroid Gland Iodine supplementation during the first 6 months of life, however, has been shown to prevent some of the neurologic problems and also to cause regression in the size of endemic goiter in young children and adolescents.f In adults with large, diffuse, or nodular goiters, T4 therapy suppresses TSH secretion and in 50% to 87% of patients causes involution of the hyperplastic tissue and a 20% decrease in goiter size." Surgical treatment is indicated in diffuse or nodular goiters in the following situations: (1) large size or increase in size while the individual is receiving TSH suppression treatment; (2) mechanical obstruction to the trachea, esophagus, or thoracic inlet, such as in retrostemal or intrathoracic goiter; (3) toxic change; (4) suspected or proven malignant change; and (5) cosmetic reasons. Subtotal thyroidectomy, near-total, and total thyroidectomy are acceptable operations, and the indications are the same as those for patients with sporadic goiters.P Radioiodine therapy has been used to reduce the size of euthyroid goiters and to control toxicity in the presence of autonomously functioning tissue in multinodular goiters.51•52 However, large doses of radioiodine are usually required because of the low levels of uptake in these large multinodular goiters, which are also more radioresistant than diffuse toxic goiters." Surgical treatment is preferred for most patients because it eliminates the bulk of the goiter, corrects the functional abnormality, removes possible malignant neoplasms, and avoids long-term complications of radioiodine therapy.
Conclusion In conclusion, endemic goiter is preventable and is a public health problem worldwide, affecting 13% of the world's population. Iodination is cost-effective, and although it results in a transient increase in hyperthyroidism, overall the benefits greatly outweigh the risks. Significant progress has been achieved in a global effort in eliminating IDD in the last decade, with 68% of the 5 billion people living in countries with IDD having access to iodized salt. The global rates of goiter, mental retardation, and cretinism are falling. For established goiters, treatment with thyroid hormone is helpful in some patients in stabilizing or decreasing goiter size. Thyroidectomy becomes indicated for mechanical and cosmetic reasons or because of possible or documented malignancy.
Acknowledgment The author is grateful to Mrs. Pat Soong for providing technical assistance in the preparation of the chapter and Ms. Veronica Chan for typing the manuscript.
REFERENCES I. WHOfUNICEFIICCIDD. Progress Towards the Elimination of Iodine Deficiency Disorders (lDD). Document WHOINHD/99.4. Geneva, Switzerland, World Health Organization, 1999. 2. Delange F, Bastani S, Benmiloud M, et aI. Definitions of endemic goiter and cretinism, classification of goiter size and severity of endemias, and survey techniques. In: Dunn IT, Pretell EA, Daza CH, et aI (eds), Towards the Eradication of Endemic Goiter, Cretinism, and Iodine Deficiency, No. 502. Washington,DC, Pan American Health Organization, 1986,p 373.
3. WHOfUNICEFIICCIDD. Indicators for assessing iodine deficiency disorders and their control through salt iodization. Document WHOI NUT/94.6. Geneva, Switzerland, World Health Organization, 1994. 4. Hetzel BS, Dunn IT, Stanbury 18 (eds), The Prevention and Control of Iodine Deficiency Disorders. Amsterdam, Elsevier, 1987. 5. Fierro-Benitez R, et al. Long-term effects of correction of iodine deficiency on psychomotor and intellectual developments. In: Dunn IT, Pretell EA, Daza CH, et al (eds), Towards the Eradication of Endemic Goiter, Cretinism, and Iodine Deficiency. Washington DC, Pan American Health Organization, 1986, p 182. 6. Kelly FC, Snedden WW. Prevalence and geographical distribution of endemic goiter. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 27. 7. WHOfUNICEFIICCIDD. Global Prevalence of Iodine Deficiency Disorders. In: Micronutrient Deficiency Information System (MDIS), No.1. Geneva, Switzerland, World Health Organization, 1993. 8. Ma T, et al. The present status of endemic goiter and endemic cretinism in China. Food Nutr Bull 1982;4:13. 9. Gaitan E, Nelson NC, Poole GV. Endemic goiter and endemic thyroid disorders. World 1 Surg 1991;15:205. 10. Clements FW. Health significance of endemic goiter and related conditions. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 235. II. World Health Organization. Trace Elements in Human Nutrition and Health. Geneva, Switzerland, World Health Organization, 1996. 12. Koutras DA, Papapetrou PD, Yataganas X, et al. Dietary sources of iodine in areas with and without iodine deficiency goiter. Am 1 Clin Nutr 1970;23:870. 13. Bourdoux P, Thilly C, Delange F, et al. A new look at old concepts in laboratory evaluation of endemic goiter. In: Dunn IT, Pretell EA, Daza CH, et aI (eds), Towards the Eradication of Endemic Goiter, Cretinism, and Iodine Deficiency, No. 502. Washington, DC, Pan American Health Organization, 1986, p 115. 14. Furnee CA, van der Haar F, West CE, et al. A critical appraisal of goiter assessment and the ratio of urinary iodine to creatinine for evaluating iodine status. Am 1 Clin Nutr 1994;59: 1415. 15. Stanbury IB, Hetzel B. Endemic Goiter and Endemic Cretinism. New York, Wiley, 1980. 16. Gaitan E. Iodine deficiency and toxicity. In: White PL, Selvey N (eds), Proceedings of the Western Hemisphere Nutrition Congress IV. Acton, MA, Publishing Sciences, 1975, p 56. 17. Gaitan E. Environmental Goitrogenesis. Boca Raton, FL, CRC Press, 1989. 18. Gaitan E, Lindsay RH, Reichert RD, et al. Antithyroid and goitrogenic effects of millet: Role of C-glycosylflavones. 1 Clin Endocrinol Metab 1989;68:707. 19. Vanderpas 1, Bourdoux P, Lagasse R, et al. Endemic infantile hypothyroidism in a severe endemic goiter area of Central Africa. Clin Endocrinol 1984;20:327. 20. Ingenbleek Y, Luypaert B, De Nayer P. Nutritional status and endemic goiter. Lancet 1980;I :388. 21. Greer MA, Grimm Y, Studer H. Qualitative changes in the secretion of thyroid hormones induced by iodine deficiency. Endocrinology 1968;83:1193. 22. Delange F, Camus M, Ermans AM. Circulating thyroid hormones in endemic goiter. 1 Clin Endocrinol Metab 1972;34:891. 23. Pharoah POD, Lawton NF, Ellis SM, et al. The role of triiodothyronine (T3 ) in the maintenance of euthyroidism in endemic goiter. Clin Endocrinol 1973;2:193. 24. Bachtarzi H, Benmiloud M. TSH regulation and goitrogenesis in severe iodine deficiency. Acta Endocrinol (Copenh) 1983;103:21. 25. Weber P, Krause U, Gaffga G, et al. Unilateral pulsatile and circadian TSH release in euthyroid patients with endemic goiter. Acta Endocrinol (Copenh) 1991;124:386. 26. Tseng YC, Burman KD, Schaudies RP, et al. Effects of epidermal growth factor on thyroglobulin and adenosine 3',5'-monophosphate production by cultured human thyrocytes. 1 Clin Endocrinol Metab 1989;69:771. 27. Medeiros-Neto GA, Halpern A, Cozzi ZS, et al. Thyroid growth immunoglobulins in large multinodular endemic goiters: Effect of iodized oil. 1 Clin Endocrinol Metab 1986;63:644. 28. Vitti P, Chiovato L, Tonacchera M, et al. Failure to detect thyroid growth-promoting activity in immunoglobulin G of patients with endemic goiter. 1 Clin Endocrinol Metab 1994;78:1020. 29. Zakarija M, McKenzie 1M. Do thyroid growth-promoting immunoglobulins exist? 1 Clin Endocrinol Metab 1990;70:308.
Medical and Surgical Treatment of Endemic Goiter - - 23 30. Weetman AP. Is endemic goiter an autoimmune disease? J Clin Endocrinol Metab 1994;78:1017. 31. Studer H, Peter HJ, Gerber H. Natural heterogeneity of thyroid cells: The basis for understanding thyroid function and nodular goiter growth. Endocr Rev 1989;10:125. 32. Perez C, Scrimshaw NS, Munoz JA. Technique of endemic goiter surveys. In: Endemic Goiter, Monograph Series No. 44. Geneva, Switzerland, World Health Organization, 1960, p 369. 33. World Health OrganizationlInternational Council for Control of Iodine Deficiency Disorders. Recommended normative values for thyroid volume in children aged 6-15 years. Bull WHO 1997;75:95. 34. Steward JC, Vidor GI, Butterfield IH, et al. Epidemic thyrotoxicosis in northern Tasmania. Aust N Z J Med 1972;3:203. 35. Wahner HW, Cuello C, Correa P, et al. Thyroid carcinoma in an endemic goiter area--Cali, Columbia. Am J Med 1966;40:58. 36. Harach HR, Escalante DA, Onativia A, et al. Thyroid carcinoma and thyroiditis in an endemic goiter region before and after iodine prophylaxis. Acta Endocrinol (Copenh) 1985;108:55. 37. Lowhagen T, Granberg PO, Lundell G, et aI. Aspiration biopsy cytology (ABC) in nodules of the thyroid gland suspected to be malignant. Surg Clin North Am 1979;59:3. 38. Marine D, Kimball OP. Prevention of simple goiter in man. JAMA 1921;77: I 068. 39. Sooch SS, Deo MG, Karmarkar MG, et al. Prevention of endemic goiter with iodized salt. Bull WHO 1973;49:307. 40. Aykroyd WR. Endemic goiter. In: Conquest of Deficiency Disease: Achievements and Prospects. Geneva, Switzerland, World Health Organization, 1970, p 78. 41. UNICEF. Nutrition. In: Adamson P (ed), The Progress of Nations1994. New York, UNICEF, 1994, P 8. 42. Hetzel BS, Thilly CH, Fierro-Benitez R, et al. Iodized oil in the
43. 44. 45. 46. 47. 48.
49.
50. 51. 52. 53.
prevention of endemic goiter and cretinism. In: Stanbury JB, Hetzel BS (eds), Endemic Goiter and Endemic Cretinism. New York, Wiley, 1980, p 513. Bautista S, Barker PA, Dunn JT, et al. The effects of oral iodized oil on intelligence, thyroid status, and somatic growth in school-aged children from an area of endemic goiter. Am J Clin Nutr 1982;35:127. Connolly RJ, Vidor GI, Stewart JC. Increase in thyrotoxicosis in endemic goiter area after iodination of bread. Lancet 1970; 1:500. United Nations. World Declaration on the Survival, Protection, and Development of Children, and Plan of Action. New York, United Nations, 1990. Grant JP. Iodine Deficiency Disorders on the Run. New York, UNICEF, 1994. UNICEF. The State of the World's Children, 1995. Oxford, England, Oxford University Press for UNICEF, 1995. Hintze G, Emrich K, Kobberling J. Treatment of endemic goiter due to iodine deficiency with iodine, levothyroxine, or both: Results of a multi centre trial. Eur J Clin Invest 1989; 19:527. Wilders-Truschning MM, Warnkrob H, Leb G, et al. The effect of treatment with levothyroxine or iodine on thyroid size and thyroid growth-stimulating immunoglobulins in endemic goiter patients. Clin Endocrinol 1993;39:281. Roher HD, Goretzki PE. Management of goiter and thyroid nodules in an area of endemic goiter. Surg Clin North Am 1987;67:233. Bockisch A, Jamitzky T, Derwanz R, et al. Optimized dose planning of radioiodine therapy of benign thyroidal disease. J Nucl Med 1993;34:1632. Nygaard B, Hegedus L, Gervil M, et al. Radioiodine treatment of multinodular nontoxic goiter. BMJ 1993;307:828. Shapiro B. Optimization of radioiodine therapy of thyrotoxicosis: What have we learned after 50 years? J Nucl Med 1993;34: 1638.
Sporadic Nontoxic Goiter Maha AI-Fehaily, MD • Orlo H. Clark, MD
The term goiter (L. guttur, throat) refers to an enlarged thyroid gland, but what constitutes "enlargement" is often not clearly defined.' Goiters can be classified according to prevalence of the disease, thyroid function, location of the thyroid (neck or mediastinum), morphology, or underlying etiology (Table 4-1). Sporadic nontoxic goiter (SNG) may be diffuse or nodular, is associated with normal thyroid function, develops in subjects living in an iodine-sufficient area, and does not result from an inflammatory or neoplastic process.' Endemic goiter is present when more than 10% of the population living in a specific geographic area have a goiter. The term sporadic goiter is used in regions with normal iodine intake and a lower prevalence of goiter. Worldwide, endemic goiter is the most common endocrine disorder, occurring in more than 850 million people, or 7% of the world population. It occurs almost exclusively in the iodine-deficient areas. Sporadic goiter affects about 5% of the adult population in the United States.' Sporadic nodular goiter is a common clinical entity. Patients often present with small, diffuse, or nodular goiters or have a solitary palpable nodule. In addition, recent studies using high-resolution ultrasonography and previous autopsy studies document that up to 50% of the general population have thyroid nodules, even when the thyroid gland is normal to palpation. In addition, about 50% of individuals with a solitary thyroid nodule to palpation have other smaller thyroid nodules by ultrasound examination." There are numerous unresolved issues regarding the etiology, natural history, evaluation, and optimal management of persons with goiter' Goiter represents an impairment of the thyroid gland's function, growth, and size. The problems that arise in patients with goiter include the following: • Growth of the gland causing compressive symptoms or cosmetic problems (Fig. 4-1) • Development of subclinical or overt thyrotoxicosis or hypothyroidism • Risk of malignancy in nodular goiter • Cretinism or congenital hypothyroidism, as occurs in as many as 10% of infants born in areas of severe iodine deficiency'
24
Causes of Goiter Several mechanisms, including the interplay of intrinsic and extrinsic factors in the thyroid, cause goiter. The goitrogenic process involves genetic, environmental, dietary, endocrine, and other factors. The most common worldwide cause of endemic nontoxic goiter, as mentioned earlier, is iodine deficiency. In patients with sporadic goiter, the cause is usually unknown. Sporadic goiter is a result of environmental or genetic factors that do not affect the general population. The various types of goiter are listed in Table 4-1.
Genetic Factors The thyroid gland contains a series of enzymes that are essential for the biosynthesis and secretion of thyroid hormones. A defect in any of these hormones can result in diminished hormone synthesis and a condition of goiter formation known as dyshormonogenesis. Because the defects are inherited disorders, dyshormonogenesis is also known as familial goiter. These enzyme defects may be partial or complete. Patients with a more severe enzymatic defect may develop goiter and cretinism early in life. When the defect is partial or less severe, goiter often develops during adolescence or later in life, and these individuals are usually euthyroid. Although familial clustering of goiter is well recognized, no simple mode of inheritance has been recognized. Familial euthyroid goiter has recently been linked to a multinodular nontoxic goiter (MNG1) locus on chromosome 14q.6,7 Concordance rates for simple goiter in female monozygotic twins have been reported higher than in female dizygotic twins (42% and 13%, respectively)." The ageadjusted cumulative risk for simple goiter from birth to age 43 years was 0.53 for female monozygotic twins and 0.18 for female dizygotic twins." These facts provide evidence of a genetic component of the etiology of goiter. Tissue refractoriness to thyroid hormones due to a thyroid-stimulating hormone receptor (TSHR) defect is a rare cause of familial goiter. A germline mutation on codon 727 of the TSHR gene on chromosome 14q31 is specifically
Sporadic Nontoxic Goiter - -
associated with toxic multinodular goiter.1O•11 Similar somatic cell mutations may activatean intrinsic growth control system leading to goiter.
Environmentally Induced Goiter IODINE DEFICIENCY
Endemic goiter is discussed in Chapter 3. An inadequate adaptive mechanism of the thyroid to protect from severe iodine deficiency results in the development of goiter. These adaptive mechanisms include increased iodide clearance, increased production of triiodothyronine (T3) relative to thyroxine (T4 ) , and increased mass of thyroid follicular cells. I Pregnancy increases the need for iodine and T4, which results from significant transfer of thyroid hormone from the mother to the fetus and also increased iodide loss in the urine. 12 Iodine-deficient thyroid tissue is more growth responsive to thyroid-stimulating hormone (TSH) than is iodine-replete thyroid tissue." Thyroid cellular growth is also influenced by the higher human chorionic gonadotropin serum concentrations that occur during pregnancy.14 ENVIRONMENTAL AND OTHER FACTORS
The development of sporadic goiter is influenced by many factors. Thiocyanate is a well-known goitrogen produced from cigarette smoke and vegetable foods such as cassava and cabbage. These goitrogens, however, seem to be of clinical importance only in areas of iodine deficiency.
The intake of an excessive amount of iodine inhibits thyroid peroxidase and results in the Wolff-Chaikoff effect. The normal gland is usually able to escape from this effect by inhibition of iodide uptake so that the intrathyroidal iodide level falls and organification resumes. However, in some patients with underlying thyroid disorders, the thyroid is unable to adapt to iodide excess and goiter and hypothyroidism ensue (iodide-induced myxedema). Patients at risk of goiter and or hypothyroidism due to failure to escape from iodine inhibition of thyroid hormonogenesis are those with Hashimoto's thyroiditis or those with reduced or damaged thyroid tissue after thyroidectomy or after radiation exposure to the neck. 15•16 Excess iodine intake in contrast media may also cause goiter with hyperthyroidism (Jodbasedow hyperthyroidism). Numerous medications also have antithyroid and goitrogenic effects. Amiodarone, which is rich in iodine (37%), has been associated with induction of hypothyroidism and hyperthyroidism. Lithium causes hypothyroidism by inhibiting (1) colloid formation stimulated by cyclic adenosine monophosphate and (2) the release of thyroid hormone from the gland. Contrast media used for imaging are rich in iodine and may cause transient hypothyroidism but not goiter. Ionizing radiation, either externally or with therapeutic doses of radioactive iodine (1 311), usually destroy thyroid tissue, causing hypothyroidism, but smaller doses (200 to 1500 rad) increase the risk of developing nodular goiter, thyroiditis, or thyroid cancer. I
Pathogenesis Goiter Growth Goiters result from focal follicular cell hyperplasia at one or multiple sites within the thyroid gland. Iodine deficiency works synergistically with other causes of goiter but does not appear to change the basic mechanisms of goitrogenesis. There is a positive correlation between the total DNA content of the goiter and goiter weight. The increased amount of interstitial tissue and colloid formation usually contributes little to the total goiter growth. An intrinsically abnormal growth pattern of some thyroid cells is usually the driving force behind goiter growth. Heterogeneous subpopulations of thyrocytes proliferate at different rates. Both extrathyroidal and intrathyroidal growth factors modulate goiter formation. Under physiologic in vivo conditions, TSH is the most important stimulator of thyroid growth and function. A decrease in iodine intake leads to decreased synthesis and
FIGURE 4-1. Frontal (A) and side (B) views of a 45-year-old man with long-standing multinodular goiter in an endemic area.
A
25
B
26 - - Thyroid Gland secretion of thyroid hormones. As a result, the serum TSH level increases, stimulating thyroid growth.'? The increase must be relatively short lived and intermittent because most patients have normal serum TSH levels. Other growth factors are obviously involved since the sizes of various nodules vary considerably in the same patient. Furthermore, goiters may grow despite administration of T 4 in doses that reduce the serum TSH level to a subnormal level or in patients with toxic nodular goiter. Thus, thyroid growth-modulating factors in addition to TSH are involved in thyroid growth. Some growth factors (e.g., insulin-like growth factor 1, epidermal growth factor, and fibroblast growth factor) have a growth-promoting effect, whereas others (e.g., transforming growth factor [TGF]-~ and activin A) inhibit growth.l" Increased expression of ras and other protooncogenes may also contribute to goiter growth.'?
Nodule Formation With increasing age, most thyroid glands and goiters become nodular. Initially, many goiters are diffuse; however, with intermittent stimulation, some diffuse goiters outgrow their blood supply and become nodular (Fig. 4_2).20,21 Some thyroid cells are more sensitive to growth factors and become larger nodules. If these nodules trap and organify iodine, the nodule may be "hot" or autonomous rather than "cold." Hot nodules are associated with TSHR and gsp mutations. In general, formation of thyroid nodules can be explained by the following mechanisms.
Heterogeneous Subpopulation of Thyrocytes with Different Proliferation Rates that Cause Focal Hyperplasia or Nodular Transformation Time. Derwahl and Studer investigated the pathogenesis of this heterogeneity and suggested that multinodular goiters are "true" benign neoplasms due to intrinsically higher growth rates of some thyrocytes.Pr" However, most, but not all, nodules in a multinodular goiter are polyclonal when compared to true neoplasms." Kopp and associates have also documented that both monoclonal and polyclonal nodules can be present within the same multinodular thyroid gland."
Somatic Mutations and Clonality of the Thyroid Nodules. Different somatic mutations of the TSHR have been identified." Mutations in oncogenes such as ras appear
to be early mutations because they are present in both benign and malignant thyroid nodules. Scarring, Necrosis, and Hemorrhage. For thyroid nodules to grow, angiogenesis and new vessel formation are required. These newly formed capillary vessels are often fragile and are sometimes unable to adequately supply the growing thyroid tissue, This may result in areas of ischemic necrosis and hemorrhage within the goiter. Inflammation and granulation tissue replace the necrotic areas, ultimately resulting in fibrosis, scarring, and calcification. The resulting network of inelastic fibrous bands' connective tissue leads to nodularity because it interferes with smooth growth of thyroid parenchyma. 1
Autonomy Thyroid nodules that. function in the presence of a suppressed blood TSH level are referred to as autonomous or hot nodules. Autonomous function and autonomous growth mayor may not be related. Thus, cold nodules and hot nodules within a nodular goiter may have exactly the same growth potential and may respond or be refractory to TSHsuppressive T 4 treatment." Some thyroid follicular cells take up and organify iodine in the absence of TSH, causing hot or autonomous nodules. As previously mentioned, these nodules usually have either TSHR mutations or, less commonly, gsp mutations. When these nodules reach a certain size and secrete increased amounts of thyroid hormone, the patient develops subclinical and then overt hyperthyroidism. This may occur either spontaneously or after exposure to an excessive amount of iodine (Jodbasedow hyperthyroidismj.F
Natural History The natural history of nontoxic goiter varies. Children in endemic areas generally have diffuse goiters, whereas sporadic goiters tend to develop at an older age and tend to be nodular. Patients with multinodular goiter are usually older and have larger goiters than do patients with diffuse or uninodular goiters. The growth rate of thyroid nodules is usually slow, but some goiters increase up to 20% yearly." Rapid growth of a nodule is usually caused by hemorrhage or cyst formation. One must also be concerned about malignant tumors such as a thyroid lymphoma or a poorly differentiated or anaplastic cancer. Patients with goiters appear to have a slightly higher risk of thyroid malignancy (discussed later). Patients with multinodular goiters and suppressed TSH levels are generally older and have a higher plasma-free T 4 level and larger goiters than those with multinodular goiters and a normal TSH. Up to 10% of patients with euthyroid nodular goiter eventually develop hyperthyroidism.P-'?
Intervention Versus Observation FIGURE 4-2. Nodular goiter can involve either one or both lobes of the thyroid gland.
Clear indications for operation (whether the patient is symptomatic or potentially symptomatic) include the following: 1. Large goiter with obstructive symptoms such as shortness of breath and dysphagia
Sporadic Nontoxic Goiter - - 27 2. Substernal goiter, especially with abnormal flow-loop study 3. Large nodule (>4 em), because patients with large solitary or dominant nodules are more likely to be symptomatic and have an increased risk of cancer" 4. Disfigurement 5. Family history of thyroid cancer or exposure to lowdose therapeutic radiation Patients with a family history of thyroid cancer are much more likely to develop thyroid cancer. Familial medullary thyroid cancer, with or without multiple endocrine neoplasia, should always be excluded. Familial non-medullary thyroid cancer, with or without Cowden's syndrome (multiple hamartomas, breast cancer, colon cancer, and nodular goiter), Gardner's syndrome,familial polyposis coli, or Carney's syndrome (schwannomas, myxomas, adrenal tumors, pigmented skin lesions), should also be considered. Exposure to low or moderate doses of therapeutic radiation also dramatically increases the risk of thyroid cancer." Previous investigations document that exposure to as little as 6 cGy radiation increases the risk of thyroid cancer sixfold.33 The risk increases as the dose of radiation increases to 2000 cGy. Higher doses of radiation, such as 5000 to 6000 cGy, result in hypothyroidism, but thyroid cancer does not appear to increase appreciably, probably because the thyroid cells are destroyed." Younger children who receive radiation are most likely to develop thyroid cancer. A genetic predisposition to developing thyroid cancer after exposure to low-dose therapeutic radiation or radiation fallout may be present.34,35 Other factors that increase the risk of thyroid cancer include rapid enlargement of the thyroid nodule, presence of a dominant firm or hard nodule, ipsilateral vocal cord paralysis, fixation to adjacent structures, ipsilateral enlarged lymph nodes, and development of new thyroids nodule in young «20-year-old) or older (>60-year-old) individuals. When two of these factors suggest a possible cancer, the likelihood of thyroid malignancy approaches 100%.36 Fineneedle aspiration (FNA) biopsy for cytology often confirms the diagnosis but should be done only when it will alter therapy. Computed tomography (CT) scanning should be used selectively in patients with very large, fixed, or substernal goiters when the limits cannot be determined clinically. CT scanning is also indicated in patients with dysphagia, dyspnea, or hemoptysis. In patients with small to moderate-sized nodular goiters without other risk factors for malignancy, an ultrasound of the thyroid gland may be helpful for subsequent comparison regarding growth, but CT or magnetic resonance imaging (MRI) scanning is not neccessary." Although the risk of malignancy in unselected patients with multinodular goiter has been considered to be about I % to 3%, there are several studies that suggest thyroid nodules within a multinodular goiter harbor malignancy at a rate similar to those with solitary thyroid nodule (5% to 10%).38-40 These figures, however, include small papillary carcinomas of questionable clinical significance. Evidence suggests that clinically important thyroid carcinoma occurs in fewer than I% of patients, given the high prevalence of multinodular goiter and the very low incidence of clinical thyroid carcinoma."
Studies indicated that about 4% of the population in the United States has multinodular goiters and that 4% of these patients harbor thyroid cancer; therefore, the estimated prevalence would be around 1.6 per 1000. However, the estimated incidence of clinical thyroid cancer is only 0.025 to 0.05 cases per 1000, suggesting that less than I of 30 histologic microcarcinomas leads to clinically relevant disease each year." In other investigations, occult thyroid cancers have been found at autopsy in up to 36% of patients.v" The clinical significance of latent cancers (autopsy studies) and incidental occult cancers «I em in diameter) found by histologic examination after removal of benign thyroid tissues has been questioned" The incidence of clinical thyroid cancer (>10 mm) obtained in mass screening is about 0.2%, and in some investigations, only about 2% or 3% of these thyroid microcancers «10 mm) ever develop into clinical thyroid cancer." Thus, occult thyroid cancers do not represent an appreciable risk to an individual when found incidentally and confined to the thyroid gland. Recent clinical studies document that about 4% to 6% of nonpalpable nodules biopsied under ultrasound guidance are malignant.Fv' To date, there are, to our knowledge, no longitudinal studies that document any clinical benefit to performing a biopsy of nonpalpable nodules less than I em in diameter; however, occult thyroid tumors are presumably of more concern in high-risk individuals with a family history of thyroid cancer or individuals with a history of exposure to low-dose therapeutic radiation.P
How Patients with Sporadic Nontoxic Goiter Should be Managed Ultrasound examination is helpful for establishing the presence of multiple, nonpalpable, and cystic nodules and provides a baseline for subsequent comparison regarding nodule growth. Certain ultrasonic features in nodular goiter may suggest malignancy. Several groupS54.56,57 have recommend performing an ultrasound-guided FNA biopsy of any nodule that is I em or larger, hypoechoic, or solid or has microcalcifications, irregular borders, central blood flow, or an absent halo. Some clinicians suggest performing a biopsy on the dominant nodule. Papini and colleagues'? have documented invasive cancers (T4) in nodules smaller than I em; thus, the size cutoff may not be accurate in predicting the malignant potential of all nodules, and suspicious nodules on ultrasound examination should be considered for biopsy. A selective approach seems to be indicated; that is, most occult nodules can be followed by ultrasound examination, but biopsy should be performed in suspicious occult nodules or nodules in high-risk patients.
Clinical Evaluation History Patients with nontoxic goiter are usually asymptomatic and seek medical advice because of a thyroid mass. Goiters are more common in women than men (,.,4:1). Sporadic goiters from dyshormonogenesis and endemic goiter due to iodine deficiency are usually first noted during childhood and
28 - - Thyroid Gland
continue to grow with age. Other causes of sporadic goiter rarely occur before puberty and do not have a peak age of occurrence. Thyroid nodules increase in incidence with age. The natural history of nontoxic goiter is characterized by slow, often progressive or intermittent growth, with many patients eventually becoming symptomatic. Although most goiters are present for years, sudden, rapid growth of a discrete nodule or thyroid lobe, as previously mentioned, should suggest possible hemorrhage into a nodule or dedifferentiation to a poorly differentiated thyroid carcinoma, anaplastic carcinoma, or possible lymphoma. Benign goiters are rarely painful or grow quickly unless recent hemorrhage into a nodule has occurred. Some goiters, especially in patients with chronic lymphocytic thyroiditis, may cause a choking sensation or pain radiating to the ear. Symptoms may be caused by compression of structures in the neck and superior mediastinum. Obstructive symptoms are more likely to occur in patients with a substernal goiter. As the substernal goiter continues to grow, the thoracic inlet may become occluded, a phenomenon known as the thyroid cork. This is because substernal goiter is confined between the sternum and the vertebral bodies and may displace or impinge on the trachea, esophagus, recurrent laryngeal nerve, and, rarely, the superior vena cava or the cervical sympathetic chain. Tracheal compression is generally asymptomatic until critical narrowing has occurred (""75% of cross-sectional area) to about 4 mm. Nocturnal or positional dyspnea and dyspnea with exertion suggest that they are caused by substernal goiter. Anxiety when raising one's arm above one's head with a reddened face and distended neck veins (positive Pemberton sign) suggests superior mediastinal obstruction. Upper respiratory tract infection or hemorrhage into a nodule or cyst may exacerbate upper airway obstruction and result in acute respiratory distress. Dysphagia occurs in about 20% of patients with substernal goiters. Ischemia and stretching of the recurrent laryngeal nerve with vocal cord dysfunction may cause hoarseness in about 4% of patients with benign substernal goiters, but cancer is more likely in these patients. Compression of the venous outflow through the thoracic inlet and sympathetic chain, causing Homer's syndrome, may rarely occur.58.59 Review of the possible causative factors of goiter and the differential diagnosis of nontoxic goiter include family history of benign or malignant thyroid disorder, a history of living in an endemic goiter area or of intake of goitrogens, a history of radiation exposure or, rarely, metastases from other organs to the thyroid gland. The last one occurs most often in patients with lung cancer, breast cancer, hypernephroma, and melanoma.
Physical Examination In general, the size of a smaller goiter is overestimated, whereas the size of larger goiters is underestimated. Thyroid enlargement is often best observed when the patient swallows. A visible goiter has usually reached a size of 30 to 40 mL (""1.5- to 2-fold increase in the size of a normal thyroid gland). One should determine whether the thyroid gland is symmetrical or a solitary nodule, a multinodular goiter, or a dominant nodule in a multinodular goiter. Does the goiter
move with swallowing, or is the goiter fixed? Are the nodules hard, firm, or soft? Is there associated lymphadenopathy? One should also determine whether there is any tracheal deviation. As previously mentioned, one can document whether there is venous obstruction by having the patient elevate his or her arms above the head. If the neck veins become prominent or the face become flushed, this is a positive Pemberton sign. 60.61 One should also evaluate the patients for signs of hypothyroidism, hyperthyroidism, or possible other medical disorders. Features that suggest malignancy include vocal cord paralysis, fixed firm nodules, or associated lymphadenopathy.F Occasionally, a patient with recurrent laryngeal nerve palsy can have a benign nodule.P
Diagnosis The differential diagnosis of a patient with nodular goiter includes benign nodular goiter, Hashimoto's thyroiditis, follicular adenoma, and carcinoma. The laboratory evaluation of a patient with a thyroid nodule or a nodular goiter should begin with a TSH measurement to determine whether the patient is euthyroid, hypothyroid, or hyperthyroid. The degree of thyroid dysfunction is often mild or subclinical, with only an isolated TSH abnormality. The diagnosis of thyrotoxicosis should be considered in all, but particularly in elderly, patients with long-standing nodular goiter and/or atrial fibrillation. In some, usually elderly, patients, the diagnosis of hyperthyroidism is not clinically apparent (apathetic hyperthyroidism). TSH is suppressed to a variable degree, and characteristically the plasma T 3 level is elevated, whereas the plasma T4level is normal (T 3 thyrotoxicosis). When the thyroid gland is only moderately enlarged and firm, Hashimoto's thyroiditis should be considered. A blood test documenting increased levels of antithyroid peroxidase antibodies or thyroglobulin antibodies helps confirm the diagnosis. Ultrasound often reveals a heterogeneous thyroid gland. FNA is helpful when there is a discrete nodule within the firm thyroid gland. Some clinicians recommend evaluating calcitonin levels in patients with nodular goiter, but most believe it is not cost-effective.v' A chest radiograph often brings attention to cervical or substernal goiter due to tracheal deviation. Occasionally, fine calcifications in a nodular goiter suggest the presence of a papillary carcinoma. Ultrasound, as previously mentioned, is particularly helpful in patients who are to be followed to assess and monitor the size of a nodule or the goiter. Some clinicians recommend treating patients with small or moderate-sized euthyroid goiter with thyroid hormone. In about 25% of these patients, the goiter decreases in size, and in others, the growth rate may decrease (see Chapter 8). CT or MRI scanning of the neck and superior mediastinum in patients with substernal or fixed goiters may reveal tracheal deviation or compression (Fig. 4_3).65.66 Thyroid scintigraphy is not indicated for the assessment of nodular goiter unless the patient has a suppressed TSH or treatment with 1311 is being considered. Euthyroid patients with large goiters usually have low iodine uptake so that a large dose of radioiodine is required.
Sporadic Nontoxic Goiter - - 29
FIGURE 4-3. CT scan of a patient with a large goiter. Note the evidence of severe tracheal compression and deviation to the right side (arrow),
Such treatment is only rarely indicated but has recently been reported to be more effective than TSH suppression." Evidence of airway obstruction can be obtained by a flowvolume loop tracing. A barium swallow is rarely indicated unless other causes of dysphagia are considered. The role of FNA has previously been discussed. We recommend FNA for selected patients with multinodular goiter who have a dominant nodule within a multinodular goiter, a large (>4 ern) nodule, nodules with ultrasonic features suggestive of malignancy, a rapidly enlarging nodule, and suspicious complex thyroid nodules (biopsy the solid component).
Treatment The available treatment options are thyroidectomy, treatment with T4, and radioiodine (Table 4_2).68,69 The treatment goals for a patient with a nodular goiter include relief of local compressive symptoms or cosmetic deformity, prevention of progressive thyroid enlargement, and removal of possible but uncommon coexistent thyroid cancer, Asymptomatic euthyroid patients with moderate-sized goiters can be safely observed. When there is any concern about malignancy, patients should have an FNA. T4 therapy is effective in reducing the size of goiters in patients with iodine deficiency or those with subclinical hypothyroidism. About half of the clinicians in the United States and Europe use TSH suppression therapy in patients with euthyroid goiters. The benefits of such therapy are disputed.P?' T4 therapy seems to be more efficacious in patients with small goiters." T4 therapy carries the risk of inducing thyrotoxicosis, especially when there is autonomy of the thyroid gland. In addition, T4 administration to the elderly may predispose to cardiac arrhythmias and cardiovascular insufficiency.P"? Long-term T4 therapy with hyperthyroidism
is also associated with reduction in bone density, especially in postmenopausal women. 78-81 This does not appear to be a problem in euthyroid patients with low-normal or minimally suppressed TSH levels. Radioiodine therapy of nontoxic goiters is used primarily in Europe. It is not standard practice in the United States unless a patient is a poor surgical risk or has chemical evidence of thyrotoxicosis. Radioiodine therapy does, however, result in goiter reduction, producing a 40% to 60% decrease in volume within 2 years. Such studies have led to an increased use of 1311 in euthyroid or hyperthyroid elderly patients with multinodular goiter, to both decrease the size and, in the latter, to treat the hyperthyroidism.P:" Prior administration of human recombinant TSH may reduce the dose of radioactive iodine required for successful therapy. 1311therapy may be particularly helpful in selected patients (see Table 4_2).84-86 Side effects of radioiodine therapy include the following: 1. Hypothyroidism (20% to 30% at 5 years)" 2. Radiation thyroiditis-the symptoms are usually mild and transient but may be devastating due to acute thyroid swelling in patients with large substernal goiters83,87 3. Induction of Graves' disease in about 5% of patients, presumably due to release of antigens stimulating an autoimmune responsev" 4. Temporary thyrotoxicosis-to avoid this possibly catastrophic complication in poor-risk patients, antithyroid drugs should be administered to patients with hyperthyroidism several weeks before the administration of 1311and/or treatment with ~-adrenergic blocking agents after 1311 administration The potential risk of radiation-associated thyroid cancer is low when 1311 therapy is used in elderly patients. Recent evidence suggests that radioiodine therapy in patients with hyperthyroidism slightly increases the risk of thyroid cancer. Unfortunately, these thyroid cancers appear to be more aggresslve.v" Younger patients with large goiters should be treated surgically because this provides definitive therapy and rapid resolution of the problem. We recommend radioiodine ablation therapy only in selected patients with nodular goiter such as those who are poor surgical risks.A prospective trial comparing the results of surgery and 1311therapy in elderly patients would be of interest. Thyroidectomy offers a rapid reduction in goiter and resolution of the problem with minimal risk when the operation is done by an experienced thyroid surgeon. Thyroidectomy also provides tissue for histologic examination and radiation exposure is not necessary. The procedure is the preferred treatment for patients with substernal goiter because goiter may swell after 1311 therapy, and there appears to be a higher risk of cancer in substernal goiters; such goiters are generally not accessible for FNA. 65,93,94 The indications of thyroidectomy in patients with goiter are listed in Table 4-2.
Extent of Surgery The extent of thyroidectomy depends on the type of goiter. For patients with unilateral goiter, lobectomy-isthmectomy is sufficient. When the goiter is bilateral, we recommend total lobectomy on the side with the largest mass and subtotal, near-total, or total lobectomy of the contralateral side.
30 - - Thyroid Gland
The reason for this recommendation is that 10% to 20% of patients develop recurrent goiter.95,96 However, when the surgeon is not completely happy about the status of the parathyroid glands and/or recurrent laryngeal nerve on the initial side, less than total thyroidectomy is recommended on the contralateral side. Total thyroidectomy has been suggested to be as safe as subtotal thyroidectomy when the operation is performed by an experienced thyroid surgeon, with a 1% to 2% incidence of injury to the recurrent laryngeal nerve and 0.5% to 5% of hypoparathyroidism. Surgical morbidity is highest in patients with very large goiters, those with invasive cancers with extensive lymphadenopathy, those with substernal goiter, and those who undergo reoperation because of recurrent goiter,97-100 Proponents of subtotal thyroidectomy believe that leaving about 2 to 4 g of thyroid tissue results in little risk of recurrence.'?' Proponents of total thyroidectomy suggest that there is a low morbidity rate of total thyroidectomy, that there
is no risk of recurrence, and that patients after total or neartotal thyroidectomy should take thyroid hormone. 102-104 We believe that total lobectomy on one side and subtotal resection on the other side, leaving a small ("'4- to 5-g) remnant of thyroid tissue posteriorly (Hartley-Dunhill operation) is the preferred operation. If recurrence were to occur after the Hartley-Dunhill operation. reoperation would be required only on one side. The administration of iodide in sporadic multinodular goiter is not recommended and may result in thyrotoxicosis (Jodbasedow phenomenon). 105
Summary Sporadic nontoxic goiter is a relatively common problem. Iodine deficiency is the most common cause of goiter worldwide. Sporadic goiter due to environmental or genetic factors is also relatively common. Nontoxic goiter can be
SporadicNontoxic Goiter - - 31 caused by iodine excess, goitrogens, genetic defects, and other unknown factors. Determination of the serum TSH level is essential in all patients with thyroid enlargement. Imaging of the thyroid gland by ultrasonography to document baseline characteristic for future comparison is helpful and FNA is recommended selectively. CT or MRI scanning is recommended only for substernal goiters or fixed lesions. Patients with a family history of thyroid cancer, those with a history of radiation exposure, and patients with large clinically suspicious nodules suggesting cancer may be treated surgically without further investigation. Patients with clinically important compressive symptoms or cosmetic concern should be managed by surgery. Radioiodine can be helpful in poor-risk patients and those with toxic nodular goiter. Asymptomatic low-risk patients should be observed. We recommend doing total lobectomy on one side and subtotal lobectomy on the other side (Hartley-Dunhill operation) to minimize complications, yet avoid recurrent goiter.
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32 - - Thyroid Gland 44. Park SH, Suh EH, Chi JG. A histopathologic study on 1,095 surgically resected thyroid specimens. Jpn J Clin OncoI1988;18:297. 45. Mitselou A, Vougiouklakis T, Peschos D, et al. Occult thyroid carcinoma: A study of 160 autopsy cases. The First Report for the Region of Epirus-Greece. Anticancer Res 2002;22:427. 46. Yamamoto Y, Maeda T, Izumi K, Otsuka H. Occult papillary carcinoma of the thyroid: A study of 408 autopsy cases. Cancer 1990;65: 1173. 47. Lang W, Borrusch H, Bauer L. Occult carcinomas of the thyroid: Evaluation of 1,020 sequential autopsies. Am J Clin PathoI1988;90:72. 48. Komorowski RA, Hanson GA. Occult thyroid pathology in the young adult: An autopsy study of 138 patients without clinical thyroid disease. Hum PathoI1988;19:689. 49. Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid: A "normal" finding in Finland-a systematic autopsy study. Cancer 1985;56:531. 50. Chong PY. Thyroid carcinomas in Singapore autopsies. Pathology 1994; 26:20. 51. Yamashita H. Occult microcancer and clinical cancer. In: Clark OH, Noguchi S (eds), Hyoid Cancer: Diagnosis and Treatment. St. Louis, Quality Medical, 2000, p 105. 52. Hagag P, Strauss S, Weiss M. Role of ultrasound-guided fine-needle aspiration biopsy in evaluation of nonpalpable thyroid nodules. Thyroid 1998;8:989. 53. Khurana KK, Richards VI, Chopra PS, et al. The role of ultrasonographyguided fine-needle aspiration biopsy in the management of nonpalpable and palpable thyroid nodules. Thyroid 1998;8:511. 54. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: Predictive value of ultrasound and color-Doppler features. J Clin Endocrinol Metab 2002;87:1941. 55. Lupoli G, Vitale G, Caraglia M, et al. Familial papillary thyroid microcarcinoma: A new clinical entity. Lancet 1999;353:637. 56. Nakhjavani M, Gharib H. Diffuse nontoxic and multinodular goiter. Curr Ther Endocrinol Metab 1997;6:109. 57. Peccin S, de Castro JA, Furlanetto TW, et al. Ultrasonography: Is it useful in the diagnosis of cancer in thyroid nodules? J Endocrinol Invest 2002;25:39. 58. Rios Zambudio A, Rodriguez Gonzalez JM, Carrasco Prats M, et al. Superior vena cava syndrome caused by multinodular goiter. Rev Clin Esp 2000;200:208. 59. Anders HJ. Compression syndromes caused by substernal goitres. Postgrad Med J 1998;74:327. 60. Anders H, Keller C. Pemberton's maneuver-a clinical test for latent superior vena cava syndrome caused by a substernal mass. Eur J Med Res 1997;2:488. 61. Auwaerter PG. The Pemberton and Maroni signs. Ann Intern Med 1997;126:916. 62. Lassaletta Atienza L, Melchor Diaz MA, Gavilanes Plasencia J, et al. [Thyroid nodules: Factors suggestive of malignancy). Acta Otorrinolaringol Esp 1997;48:220. 63. Cerise EJ, Randall S, Ochsner A. Carcinoma of the thyroid and nontoxic nodular goiter. Surgery 1952;31:552. 64. Niccoli P, Wion-Barbot N, Caron P, et al. Interest of routine measurement of serum calcitonin: Study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab 1997;82:338. 65. Netterville JL, Coleman SC, Smith JC, et al. Management of substernal goiter. Laryngoscope 1998;108:1611. 66. Jennings A. Evaluation of substernal goiters using computed tomography and MR imaging. Endocrinol Metab Clin North Am 2001;30:401. 67. Wesche MF, Tiel VB, Lips P, et al. A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter. J Clin Endocrinol Metab 2001 ;86:998. 68. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996;29:527. 69. Arici C, Dertsiz L, Altunbas H, et al. Operative management of substernal goiter: Analysis of 52 patients. Int Surg 2001;86:220. 70. Gharib H, Mazzaferri EL. Thyroxine-suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998;128:386. 71. Ross DS. Thyroid hormone suppressive therapy of sporadic nontoxic goiter. Thyroid 1992;2:263. 72. Lima N, Knobel M, Cavaliere H, et al. Levothyroxine suppressive therapy is partially effective in treating patients with benign, solid thyroid nodules and multinodular goiters. Thyroid 1997;7:691.
73. Glueck CJ, Streicher P. Cardiovascular and medical ramifications of treatment of subclinical hypothyroidism. Curr Atheroscler Rep 2003;5:73. 74. Burmeister LA, Flores A. Subclinical thyrotoxicosis and the heart. Thyroid 2002;12:495. 75. Mercuro G, Panzuto MG, Bina A, et al. Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropinsuppressive therapy with levothyroxine: Effect of individual dose tailoring. J Clin Endocrinol Metab 2000;85:159. 76. Shapiro LE, Sievert R, Ong L, et al. Minimal cardiac effects in asymptomatic athyreotic patients chronically treated with thyrotropinsuppressive doses of t-thyroxine. J Clin Endocrinol Metab 1997;82:2592. 77. Perk M, O'Neill B1. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol 1997; 13:273. 78. Sijanovic S, Kamer I. Bone loss in premenopausal women on longterm suppressive therapy with thyroid hormone. Medscape Women's Health 2001;6:3. 79. Jodar E, Martinez-Diaz-Guerra G, Azriel S, Hawkins F. Bone mineral density in male patients with t-thyroxine suppressive therapy and Graves' disease. CalcifTissue Int 2001;69:84. 80. Nuzzo V, Lupoli G, Esposito Del Puente A, et al. Bone mineral density in premenopausal women receiving levothyroxine suppressive therapy. Gynecol Endocrinol 1998;12:333. 81. Knudsen N, Faber J, Sierbaek-Nielsen A, et al. Thyroid hormone treatment aiming at reduced, but not suppressed, serum thyroid-stimulating hormone levels in nontoxic goiter: Effects on bone metabolism amongst premenopausal women. J Intern Med 1998;243: 149. 82. Bonnema SJ, Knudsen DU, Bertelsen H, et al. Does radioiodine therapy have an equal effect on substernal and cervical goiter volumes? Evaluation by magnetic resonance imaging. Thyroid 2002;12:313. 83. Huysmans D, Hermus A, Edelbroek M, et al. Radioiodine for nontoxic multinodular goiter. Thyroid 1997;7:235. 84. Huysmans DA, Buijs WC, van de Ven MT, et al. Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters. J Nucl Med 1996;37:2072. 85. Beckers C. \311 therapy of toxic and non-toxic goiters. Q J Nucl Med 1999;43:291. 86. Maurer AH, Charkes ND. Radioiodine treatment for nontoxic multinodular goiter. J Nucl Med 1999;40:1313. 87. Nygaard B, Faber J, Hegedus L. Acute changes in thyroid volume and function following IJI I therapy of multinodular goitre. Clin Endocrinol (Oxf) 1994;41:715. 88. Nygaard B, Knudsen JH, Hegedus L, et al. Thyrotropin receptor antibodies and Graves' disease, a side effect of 13\1 treatment in patients with nontoxic goiter. J Clin Endocrinol Metab 1997;82:2926. 89. Hall P, Lundell G, Holm LE. Mortality in patients treated for hyperthyroidism with iodine 131. Acta Endocrinol (Copenh) 1993; 128:230. 90. Franklyn JA, Maisonneuve P, Sheppard M, et al. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: A populationbased cohort study. Lancet 1999;353:2111. 91. Franklyn JA, Maisonneuve P, Sheppard MC, et al. Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med 1998;338:712. 92. Tezelman S, Grossman RF, Siperstein AB, Clark OH. Radioiodineassociated thyroid cancers. World J Surg 1994;18:522. 93. Nervi M, Iacconi P, Spinelli C, et al. Thyroid carcinoma in intrathoracic goiter. Langenbecks Arch Surg 1998;383:337. 94. Torre G, Borgonovo G, Amato A, et al. Surgical management of substernal goiter: Analysis of 237 patients. Am Surg 1995;61:826. 95. Rojdmark J, .Jarhult J. High long-term recurrence rate after subtotal thyroidectomy for nodular goitre. Eur J Surg 1995;161:725. 96. Cohen-Kerem R, Schachter P, Sheinfeld M, et al. Multinodular goiter: The surgical procedure of choice. Otolaryngol Head Neck Surg 2000; 122:848. 97. Thomusch 0, Machens A, Sekulla C, et al. Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: Prospective multicenter study in Germany. World J Surg 2000; 24:1335. 98. Wilson DB, Staren ED, Prinz RA. Thyroid reoperations: Indications and risks. Am Surg 1998;64:674; discussion, 678. 99. Makeieff M, Rubinstein P,Youssef B, et al. Repeat surgery for thyroid nodules (excluding cancer and hyperthyroidism). Ann Chir 1998; 52:970.
Sporadic Nontoxic Goiter - 100. Shen W, Kebebew E, Duh QY, Clark OH. Substernal goiter. Arch Surg 2004; 139:656. 101. Mattioli FP, Torre GC, Borgonovo G, et al. Surgical treatment of multinodular goiter. Ann Ital Chir 1996;67:341. 102. Gough IR, Wilkinson D. Total thyroidectomy for management of thyroid disease. World J Surg 2000;24:962. 103. Delbridge L, Guinea AI, Reeve TS. Total thyroidectomy for bilateral benign multinodular goiter: Effect of changing practice. Arch Surg 1999;134:1389. 104. Marchesi M, Biffoni M, Tartaglia F, et aJ. Total versus subtotal thyroidectomy in the management of multinodular goiter. Int Surg 1998;83:202.
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105. Vagenakis AG, Wang CA, Burger A, et aJ. Iodide-induced thyrotoxicosis in Boston. N Engl J Med 1972;287:523. 106. Robbins J, Schneider AB. Thyroid cancer following exposure to radioactive iodine. Rev Endocr Metab Disord 2000; 1:197. 107. Hahn K, Schnell-Inderst P, Grosche B, Holm LE. Thyroid cancer after diagnostic administration of iodine 131 in childhood. Radiat Res 2001;156:61. 108. Hall P, Holm LE. Late consequences of radioiodine for diagnosis and therapy in Sweden. Thyroid 1997;7:205.
Thyroiditis Geeta Lal, MD • Orlo H. Clark, MD
Thyroiditis is defined as an inflammatory disorder of the thyroid gland. It may result from a myriad of etiologies and is usually classified into acute, subacute, and chronic forms (Table 5-1). Each of these is associated with a distinct clinical presentation and histology. Medical therapy remains the mainstay of management of thyroiditis, but surgical treatment is warranted in certain specific circumstances.
Eikenella corrodens, and Corynebacterium species have also been cultured. Rare other implicated organisms include Mycobacteria, Salmonella, Aspergillus, and Actinomycoses species. J In general, (X- and p-hemolytic Streptococcus and anaerobes account for about 70% of cases. Pneumocystis carinii has been identified as the causative organism in patients with AIDS. HISTOLOGIC FEATURES
Acute (Suppurative) Thyroiditis Acute thyroiditis was first described by Bauchet in 1857 and accounted for approximately 0.1 % of thyroid surgeries before the advent of antibiotic therapy. J ETIOLOGY AND PATHOGENESIS
The thyroid gland has an innate resistance to infection due to its extensive blood and lymphatic supply, high iodide content, and fibrous capsule.' Despite these protective mechanisms, acute thyroiditis may be caused by infectious agents that seed the thyroid gland (1) by the hematogenous or lymphatic route, (2) by direct spread from persistent pyriform sinus fistulas or thyroglossal duct cysts, or (3) as a result of penetrating trauma to the thyroid gland.' Takai and associates first demonstrated that acute suppurative thyroiditiscan result from persistent pyriform sinus fistulas." Since then, several investigators have demonstrated that pyriform sinus fistulas are responsible for a large proportion of cases of recurrent acute thyroiditis. These fistulas are commonly believed to be fourth branchial pouch remnants and originate at the apex of the pyriform fossa.t The tract courses in an anteroinferior direction to end blindly in the perithyroidal space or the thyroid parenchyma-? as shown in Figure 5-1. As a result, infection may lead to acute thyroiditis or soft tissue abscesses, which can secondarily extend to the thyroid. Immunosuppression may be another risk factor for the disease and acute suppurative thyroid infections and necrosis have been described in patients with acquired immunodeficiency syndrome (AIDS)8 and those undergoing aggressive chemotherapy for hematologic malignancies." Oral cavity bacteria such as Staphylococcus and Streptococcus species and anaerobes are the most common causative organisms. Other bacteria such as Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae,
34
Acute thyroiditis usually arises in a normal thyroid gland, although occurrence in a multinodular gland is not uncommon.'? Histologically, the gland demonstrates an intense inflammatory response with numerous polymorphonuclear leukocytes and lymphocytes. II Necrosis of the thyroid gland and abscess formation often ensue. CLINICAL PRESENTATION
Acute suppurative thyroiditis is more common in children and young adults and occurs equally in both sexes. The disease is often preceded by an upper respiratory tract infection or otitis media. It is characterized by severe neck pain radiating to the jaws or ear, fever, chills, odynophagia, and dysphonia. Infants may present with respiratory distress and stridor secondary to tracheal compression caused by a thyroid abscess.'? Rarely, acute suppurative thyroiditis may cause transient vocal cord palsy.'? On physical examination, erythematous skin usually overlies an extremely tender thyroid gland. The patient holds the neck in a flexed position to avoid stretching the overlying strap muscles. Fluctuance indicates an underlying abscess. These findings are more frequent on the left side and reflect the left-sided predominance of pyriform sinus fistulas.'? This is thought to be due to embryologic asymmetry of the transformation of the fourth branchial arch to form the aortic and innominate arteries or to poor development of the ultimobranchial body on the right side of the embryo.i-" Acute suppurative thyroiditis can be complicated by systemic sepsis, tracheal or esophageal rupture, jugular vein thrombosis, laryngeal chondritis and perichondritis, or sympathetic trunk paralysis.!' DIFFERENTIAL DIAGNOSIS
Several other conditions that must be considered in the differential diagnosis include subacute painful thyroiditis,
Thyroiditis - -
Hashimoto's thyroiditis, suppurative lymphadenitis, thyroid carcinoma, thyroglossal duct or branchial cleft cyst, Ludwig's angina, and dissecting retropharyngeal abscess. Laryngeal and esophageal carcinomas have also been reported to present as acute thyroiditis.P'P These disorders can often be distinguished by clinical history, physical examination, and various diagnostic tests described in the following section. Lin and colleagues studied the clinical features that may help distinguish acute thyroiditis from aggressive malignant thyroid tumors and concluded that patients with malignancy were older and more likely to have a history of dysphonia, right thyroid lobe involvement, larger lesions, anemia, and sterile thyroid aspirates." DIAGNOSTIC TESTS
Blood tests reveal leukocytosis and an elevated erythrocyte sedimentation rate (ESR). Blood cultures are useful to identify
35
the causative organisms. Thyroid function tests are usually normal, although transient elevations of triiodothyronine (T3) and thyroxine (T4 ) may occur as a result of release of preformed hormone from the inflamed gland.'? Radioactive iodine uptake (RAIU) scans are usually normal, or there is decreased uptake due to suppression of thyroid-stimulating hormone (TSH) by the release of thyroid hormones. However, if a thyroid abscess is present, an area of decreased uptake will be seen on the scan. Ultrasound is helpful to distinguish solid from cystic lesions. Fine-needle aspiration (FNA) biopsy for Gram stain, culture, and cytology confirms the diagnosis and helps guide antibiotic therapy and diagnose underlying malignancy. Computed tomography scans not only aid in the diagnosis of acute thyroiditis but also help delineate the extent of infection. 18.19 If a persistent pyriform sinus fistula is suspected, a barium swallow demonstrates the anomalous tract with 80% sensitivity. False-negative results are usually due to edema around the tract orifice during acute infection. Hence, contrast studies should be performed after antibiotic therapy during the quiescent phase.P Direct laryngoscopy is also helpful in identifying the tract. TREATMENT
Patients should be treated with parenteral antibiotics based on the results of the Gram stain and culture. Abscesses are treated by drainage, either by aspiration with a wide-bore needle or open surgical drainage. In patients with pyriform sinus fistulas, complete resection of the sinus tract, including the area of the thyroid where the tract ends, is recommended. Miyauchi and coworkers have demonstrated that complete fistulectomy is essential for cure.? Methylene blue infiltration via a Fogarty catheter is sometimes used to cannulate the tract and facilitate its identification and dissection.P
Subacute Thyroiditis Painful (de Quervain's) Thyroiditis Painful thyroiditis is a transient inflammatory thyroid disorder that was first described by de Quervain in 19042 1 and is the most common cause of a painful thyroid gland. Other eponyms for this condition include granulomatous thyroiditis. subacute granulomatous thyroiditis. or pseudogranulomatous thyroiditis. ETIOLOGY AND PATHOGENESIS
FIGURE 5-1. Gastrografin swallow showing a fistula originating in the left pyriform sinus. The arrows indicate the fistula.
Painful thyroiditis is thought to be viral in origin or result from a post-viral inflammatory response. This theory is supported by the following observations: 1. The disorder is frequently preceded by a respiratory infection, is usually self-limiting, and has a seasonal distribution (summer and fall). 2. It is often associated with specific viral infection outbreaks such as coxsackievirus, mumps, measles, adenovirus, and infectious mononucleosis. 3. Cytopathic viruses have been cultured from thyroid tissue. 4. Viral antibodies have been detected in the sera of patients with the disease.F
36 - -
Thyroid Gland
There is also evidence for a genetic predisposition, manifested by its strong association with the HLA-B35 haplotype." A model of pathogenesis suggests that antigens (either directly from viruses or from damaged thyroid tissue) are presented by macrophages in the context of HLA-B35 and stimulate cytotoxic T lymphocytes. These lymphocytes proceed to damage thyroid follicular cells. This autoimmune process, however, is self-limiting. Antibodies directed against the TSH receptor have also been described, but they seem to be related to the inflammatory process and are not believed to cause the disease. HISTOLOGIC FEATURES
The inflammatory process may involve the entire gland or a single lobe. On cut section, the involved areas are firm and yellow-white. Microscopically, the changes vary with the stage of the disease and may overlap. Microabscesses, which result from neutrophil replacement of disrupted follicles, are commonly seen during the early inflammatory stage. Later, lymphocytes, histiocytes, and plasma cells are seen to accumulate around damaged follicles. Colloid (or fragments thereof) are surrounded by multinucleated giant cells, giving this disorder the designation of granulomatous thyroiditis, as shown in Figure 5-2. 11
high fever, tOXICIty, and pronounced edema leading to obstructive symptoms. The disorder classically progresses through four stages." The initial hyperthyroid phase, due to release of thyroid hormone, lasts 3 to 6 weeks and may be accompanied by symptoms such as tremors, sweating, palpitations, and heat intolerance in 50% to 70% of patients. Patients then progress to the second or euthyroid phase. Hypothyroidism, which is the hallmark of the third phase, occurs in about 20% to 30% of patients and lasts from weeks to months. The last phase is characterized by resolution of the disease and returns to the euthyroid state in more than 90% of patients. Of note, some patients may progress directly from the hyperthyroid phase to the recovery phase, without the intervening hypothyroid phase. A few patients develop recurrent disease. DIFFERENTIAL DIAGNOSIS
Disorders that mimic the presentation of subacute thyroiditis include hemorrhage into a thyroid nodule or cyst, acute suppurative thyroiditis, painful Hashimoto's thyroiditis, infected thyroglossal duct or branchial cleft cyst, and pseudothyroiditis." The last entity is produced by rapid growth of anaplastic or poorly differentiated thyroid malignancies.
CLINICAL PRESENTATION
DIAGNOSTIC STUDIES
Painful thyroiditis occurs more commonly in women (malefemale ratio of 1:3 to I :6) between 30 and 40 years of age. It is characterized by the sudden or gradual onset of unilateral or bilateral pain in the neck, which may radiate toward the mandible or ear and is exacerbated by swallowing or neck movement. Many patients report a preceding upper respiratory tract infection with low-grade fever, neck pain, dysphagia, and flu-like symptoms with malaise and myalgias. Physical examination reveals an enlarged, exquisitely tender thyroid gland that is firm, particularly in the acute phase. The overlying skin may be erythematous if the inflammation is severe. Rarely, patients may present with
In the early stages of the disease, TSH is decreased, and thyroglobulin, T 4, and T 3 levels are elevated due to the release of preformed thyroid hormone and colloid from destroyed follicles. In contrast with Graves' disease, T 4 and T 3 are elevated in proportions reflecting their intrathyroidal content." Thyroid antibody titers (antithyroglobulin, antimicrosomal, and TSH receptor antibody) are also elevated in 10% to 20% of patients, although they bear no relationship to the state of thyroid function. The most characteristic abnormality is an elevation of the ESR greater than 100 mm/hr. In fact, a normal ESR rules out active subacute thyroiditis.F RAID is also decreased «2% at 24 hours) even in euthyroid patients due to the destruction of the thyroid parenchyma and iodine-trapping mechanism and release of thyroid hormones with TSH suppression. RAID returns to normal as the process resolves. FNA biopsy may be useful in equivocal cases or to rule out malignancy or acute thyroiditis. Thyroid ultrasound shows areas of hypoechogenicity that disappear as the disease process resolves-" as demonstrated in Figure 5-3, and thyroid ultrasound has demonstrated usefulness in predicting autoimmune thyroid disease in a multicenter study. 29 TREATMENT
FIGURE 5-2. Histologic features of subacute granulomatous thyroiditis. The thyroidparenchyma contains a chronic inflammatoryinfiltrate with a multinucleate giantcell (upper left corner) and a colloid follicle (lower right corner). (From Cotran R, KumarY, Collins T, RobbinsSL reds], Robbins Pathologic Basis of Disease, 6th ed. Philadelphia, WB Saunders, 1999, p 1135.)
Painful thyroiditis is self-limited and usually resolves within a few months without specific therapy. Therefore, treatment is primarily symptomatic. Aspirin and other nonsteroidal anti-inflammatory drugs are often the initial medications of choice for pain relief. However, prednisone (40 mg/day) may be indicated for early relief of pain and swelling in more severe cases." These drugs suppress the inflammatory response but do not alter the underlying disease process. The dose is usually tapered after a week and then discontinued within 2 to 4 weeks. If pain and swelling recur during the taper or after withdrawal, the treatment is restarted.
Thyroiditis - - 37
A
B
FIGURE 5-3. Thyroid ultrasound (transverse) showing normal thyroid echogenicity (A) and subacute thyroiditis (B). In B, the thyroid is enlarged and shows reduced echogenicity, similar to surrounding strap muscles. Arrows indicate the thyroid surface. M = muscle; T = thyroid parenchyma; C = common carotid artery; TR = trachea; VC = vertebral column. (A and B, From Pedersen OM, Aardal NP, Larssen TH, et al. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid 2000; 10:251.)
Hyperthyroidism may rarely require treatment with Pblockers. Thyroid replacement may be needed in the hypothyroid phase, if patients are symptomatic. Therapy should be withdrawn and the patient re-evaluated after 6 months. Externalbeam radiation therapy was used to treat subacute thyroiditis in the past. However, this modality as been abandoned due to a slower and less predictable response than steroids, an approximately 25% failure rate, and the risk of thyroid cancer formation." Thyroidectomy is reserved for the rare patient who has a prolonged course not responsive to medical measures.
titers are typically higher than in patients with the sporadic variant. Postpartum thyroiditis is more likely to occur in successive pregnancies. Familial clustering of cases has also been reported," and a positive family history for postpartum thyroiditis can be elicited in up to 50% of patients.t'' Silent thyroiditis can also develop after exposure of the thyroid gland to therapeutic doses of external-beam radiation" or drugs such as interferon IX used in the management of chronic hepatitis."
Painless Thyroiditis Painless thyroiditis is also known as lymphocytic thyroiditis with spontaneously resolving hyperthyroidism, subacute lymphocytic thyroiditis, painless lymphocytic thyroiditis, painless thyroiditis, or silent thyroiditis. Painless thyroiditis may occur sporadically or in the postpartum period.
The thyroid gland may be asymmetrically enlarged on gross inspection. Microscopic examination reveals a multifocal inflammatory infiltrate, consisting chiefly of smalllymphocytes. Scattered areas of disrupted and collapsed thyroid follicles are also present. Unlike Hashimoto's thyroiditis, plasma cells and germinal centers are not conspicuous, and this feature is helpful in distinguishing the two conditions."
ETIOLOGY AND PATHOGENESIS
CLINICAL PRESENTATION
Both variations of subacute painless thyroiditis are considered to be autoimmune in origin. Like Hashimoto's thyroiditis, patients with painless thyroiditis have a high prevalence of anti-thyroid peroxidase (anti-TPO or antimicrosomal) antibodies and lymphocytic infiltration of the thyroid gland. 3D Furthermore, painless thyroiditis is also associated with other autoimmune conditions such as Sjogren's syndrome," autoimmune Addison's disease.F Graves' disease." and Hashimoto's thyroiditis." There is also evidence for a genetic predisposition with an association with HLA-DR3, -DR4, and -DR5 haplotypes.Y" The evidence supporting an autoimmune origin for postpartum thyroiditis is much stronger. This variant typically occurs at about 6 weeks' postpartum in women with high TPO antibody titers in early pregnancy. This timing is thought to coincide with a decrease in the normal immune tolerance of pregnancy and consequent rebound elevation of antibody titers.'? TPO antibodies mediate thyrocyte destruction via complement activation.t" Furthermore, the antibody
Painless thyroiditis is also more common in women (malefemale ratio, 1:1.5 to 3) and occurs between 30 and 60 years of age. The clinical course parallels painful thyroiditis and is characterized by four stages-thyrotoxic (occurs 1 to 3 months' postpartum), euthyroid, hypothyroid (occurs at 3 to 6 months' postpartum), and euthyroid again (occurs by 1 year). However, only about 30% of all patients follow this classic sequence of events. Thyrotoxicosis or hypothyroidism alone is the presenting features in about 35% and 40% of patients, respectively." When hyperthyroid symptoms occur, they are transient and characterized by tachycardia, palpitations, heat intolerance, nervousness, and weight loss. The hypothyroid phase is more pronounced in terms of symptoms. Physical examination demonstrates a normalsized or slightly enlarged, slightly firm, nontender gland.
HISTOLOGIC FEATURES
DIAGNOSTIC TESTS
The results of thyroid function studies correlate with the clinical stage of disease. In the early phases, TSH is
38 - -
Thyroid Gland
suppressed and T 4 and T 3 levels are elevated, similar to painful thyroiditis. In contrast with subacute painful thyroiditis, the ESR is normal or only mildly elevated (usually - 0.10
a..
-----
Antibody-positive (fitted model)
='0 .0 ._ III 0 .0'" (5
~ :::c 0.02
0.2
0.5
1
2
Observed data (smoothed) Antibody-negative (fitted model)
5
10
20
50
Thyrotropin (mU per liter)
FIGURE 5-6. Probability of developing overt hypothyroidism in women within 20 years of initial measurement of serum thyrotropin (follow-up of the Whickham survey). (From Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol [Oxf] 1995;43:55.)
of female patients became hypothyroid (a progression of 4.3% per year)."? The probability of developing overt hypothyroidism in these patients is shown in Figure 5-6. Male patients and those with higher initial TSH levels had an even higher rate of progression. However, patients who had slightly elevated TSH levels but no antibodies did not progress to hypothyroidism. Rarely, patients may develop Graves' disease'!" or lymphoma. Thyroid lymphoma is a well-recognized, ominous complication of chronic autoimmune thyroiditis and has a prevalence 80 times higher than the expected frequency in this population than in a control population without thyroiditis. Most thyroid lymphomas are of the non-Hodgkin's B cell type and tend to occur in older female patients.l'" TREATMENT
Thyroid hormone replacement therapy is indicated in overtly hypothyroid patients with a goal of normal TSH levels. The management of patients with subclinical hypothyroidism (normal T 4 and elevated TSH) is controversial. Since these patients do progress to overt disease, treatment is generally recommended, especially for male patients and those with TSH higher than 10 mUlL. 57 Treatment is also indicated in euthyroid patients to shrink large goiters.P? Surgery is occasionally indicated for suspicion of malignancy or for goiters causing compressive symptoms or cosmetic deformity.
Riedel's Thyroiditis Riedel's thyroiditis is a rare variant of thyroiditis that was initially described in two patients by Riedel in 1896 and subsequently in a third patient in 1897. 103•104 It is also known as Riedel's struma or invasive fibrous thyroiditis and leads to a wood-like thyroid gland. A review of the Mayo Clinic experience disclosed 37 cases in 56,700 thyroidectomies over a 64-year period. ros
Thyroiditis - -
ETIOLOGY AND PATHOGENESIS
Riedel's thyroiditis is characterized by the replacement of thyroid parenchyma by fibrous tissue, which also invades into adjacent tissues. The etiology of this disorder is controversial and has not been resolved. This disorder has been reported to occur in patients with other autoimmune diseases such as pernicious anemia and Graves' disease. This association, coupled with the presence of lymphoid infiltration and response to steroid therapy, led some investigators to suggest a primary autoimmune etiology.l06,107 Riedel's thyroiditis is also associated with other focal sclerosing syndromes, including mediastinal, retroperitoneal, periorbital, and retro-orbital fibrosis and sclerosing cholangitis,108 suggesting that it may be a primary fibrotic disorder. HISTOLOGIC FEATURES
The histologic criteria for the diagnosis of Riedel's thyroiditis were first described by Woolner and coworkers in 1957. The thyroid is typically involved with a fibrotic process consisting of fibroblasts and collagen. The chief light microscopic features that enable this entity to be distinguished from Hashimoto's thyroiditis are (1) extension of the fibrotic ~rocess through the strap muscles and other surrounding tissue, (2) phlebitis with luminal distention by fibrous or lymphoid tissue, and (3) relatively normal remnant thyroid tissue.P? Tissue eosinophil infiltration is also a characteristic finding in fibrous thyroiditis.!'? CLINICAL FEATURES
The disease occurs predominantly in women (male-female ratio, I :3) between the ages of 30 and 60 years. It typically presents as a painless, hard anterior neck mass that progresses over weeks to years to produce symptoms of compression including dysphagia, dyspnea, choking, and hoarseness. Patients may present with symptoms of hypothyroidism as the gland is replaced by fibrous tissue. Extension of the process can also l~ad to hypoparathyroidism and, rarely, vocal cord paralysis.U'{'? Physical examination reveals a ~ard, "woo~y" thyroid gland with fixation to surrounding tIs~ues. TYPI~ally, the thyroid is diffusely involved, although unilobular disease has been described. DIFFERENTIAL DIAGNOSIS
The. differential diagnosis includes lymphoma, poorly or undifferentiated thyroid cancer, chronic thyroiditis, and granulomatous thyroiditis. DIAGNOSTIC STUDIES
An. elevate? TSH and hypocalcemia may be present in patIent~ WIth hypothyroidism and hypoparathyroidism, respectively, Antithyroid antibodies and a mild eosinophilia ~e diagnosis needs to be confirmed by open may ~e p~esent. thyroid bIOpSY, WhICh also helps exclude carcinoma. The firm and fibrous nature of the gland renders FNA inadequate. I 13 TREATMENT ~urgery is ~e mainstay of the treatment of Riedel's thyroiditis. The chief goal of operation is to decompress the trachea by wedge excision of the thyroid isthmus and to make a tissue diagnosis. More extensive resections are not advised
41
owing to the infiltrative nature of the fibrotic process that obscures usual landmarks and structures (recurrent laryngeal nerves, parathyroids, carotid arteries). Hypothyroid patients are treated with thyroid hormone replacement. External-beam radiation therapy is not usually effective. 114 Some patients remain symptomatic even after these treatment modalities. These patients have been reported to experience dramatic improvement after treatment with corticosteroids.l" In another study, these patients experienced subjective and objective relief of symptoms after several weeks of treatment with the antiestrogen medication tamoxifen (20 mg twice a dayj.!" Although estrogen receptors have been identified in normal and neoplastic thyroid tissue,'!" tumors from these patients were not positive for estrogen, and the mechanism underlying the response to tamoxifen has been postulated to be related to transforming growth factor (TGF)-~I' TGF-~I is a potent growth inhibitor of immature fibroblasts and epithelial cells!" and has been shown to be upregulated by tamoxifen.I'v!"
Summary Surgeons are rarely in the frontline of the diagnosis and management of patients with the different variants of thyroiditis. However, an understanding of these disorders is an important component of the endocrine surgeon's armamentarium in the unusual situations when surgical invention is required for localized symptoms and diagnosis. FNA biopsy for cytology and culture is helpful for diagnosis in many patients, as is careful analyses of laboratory tests.
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4 I. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 1991;325:599. 42. Roti E, Minelli R, Giuberti T, et ai. Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon a. Am J Med 1996;101:482. 43. Adams H, Jones MC, Othman S, et ai. The sonographic appearances in postpartum thyroiditis. Clin Radiol 1992;45:311. 44. Nikolai TF, Coombs GJ, McKenzie AK, et ai. Treatment of lymphocytic thyroiditis with spontaneously resolving hyperthyroidism (silent thyroiditis). Arch Intern Med 1982;142:2281. 45. Agarwal A, Mishra A, Mishra SK, et ai. Recurrent painless thyroiditis requiring total thyroidectomy. J Assoc Physicians India 2000;48:367. 46. Choe W, McDougall IR. Ablation of thyroid function with radioactive iodine after recurrent episodes of silent thyroiditis. Thyroid 1993; 3:31 I. 47. Nikolai TF, Coombs GJ, McKenzie AK. Lymphocytic thyroiditis with spontaneously resolving hyperthyroidism and subacute thyroiditis: Long-term follow-up. Arch Intern Med 1981;141:1455. 48. Tachi J, Amino N, Tamaki H, et ai. Long term follow-up and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 1988;66:480. 49. Othman S, PhiIIips 01, Parkes AB, et ai. A long-term follow-up of postpartum thyroiditis. Clin Endocrinol (Oxf) 1990;32:559. 50. Premawardhana LD, Parkes AB, Ammari F, et ai. Postpartum thyroiditis and long-term thyroid status: Prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;85:71. 51. Kuijpens JL, Vader HL, Drexhage HA, et ai. Thyroid peroxidase antibodies during gestation are a marker for subsequent depression postpartum. Eur J Endocrinol 2001;145:579. 52. Balazs C, Farid NR. Soluble CD4 concentrations predict relapse of postpartum thyroiditis. J Endocrinol Invest 2002;25: II. 53. de Bruin TW, RiekhoffFP, de Boer 11.An outbreak of thyrotoxicosis due to atypical subacute thyroiditis. J Clin Endocrinol Metab 1990;70:396. 54. Daniels GH. Atypical subacute thyroiditis: Preliminary observations. Thyroid 2001;11:691. 55. Hashimoto Z. Zur Kenntniss der Iymphomatosen veranderung der schiiddruse (struma lymphomatosa). Arch Klin Chir 1912;97:219. 56. Roitt 1M, Doniach D, Campbell PN, Hudson RY. Autoantibodies in Hashimoto's disease (lymphadenoid goitre). Lancet 1956;2:820. 57. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99. 58. WiIIiams ED, Doniach I. The postmortem incidence of focal thyroiditis. J Pathol Bacteriol 1962;83:255. 59. Okayasu I, Hara Y, Nakamura K, Rose NR. Racial and age-related differences in incidence and severity of focal autoimmune thyroiditis. AmJ Clin PathoI1994;101:698. 60. Yoshida H, Amino N, Yagawa K, et ai. Association of serum antithyroid antibodies with lymphocytic infiltration of the thyroid gland: Studies of seventy autopsied cases. J Clin Endocrinol Metab 1978; 46:859. 61. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol ImmunopathoI1997;84:223. 62. Weetman AP, McGregor AM. Autoimmune thyroid disease: Further developments in our understanding. Endocr Rev 1994;15:788. 63. Valtonen VV, Ruutu P, Varis K, et ai. Serological evidence for the role of bacterial infections in the pathogenesis of thyroid diseases. Acta Med Scand 1986;219:105. 64. Tomer Y, Davies TF. Infection, thyroid disease, and autoimmunity. Endocr Rev 1993;14: 107. 65. Volpe R. A perspective on human autoimmune thyroid disease: Is there an abnormality of the target ceIl which predisposes to the disorder? Autoimmunity 1992;13:3. 66. Hanafusa T, Pujol-Borrell R, Chiovato L, et ai. Aberrant expression of HLA-DR antigen on thyrocytes in Graves' disease: Relevance for autoimmunity. Lancet 1983;2: I II I. 67. Todd I, Pujol-Borrell R, Hammond LJ, et ai. Interferon y induces HLA-DR expression by thyroid epithelium. Clin Exp Immunol 1985; 61:265. 68. Dayan CM, Londei M, Corcoran AE, et ai. Autoantigen recognition by thyroid-infiltrating T cells in Graves' disease. Proc Natl Acad Sci USA 1991;88:7415. 69. Raspe E, Costagliola S, Ruf J, et ai. Identification of the thyroid Nat/l cotransporter as a potential autoantigen in thyroid autoimmune disease. Eur J Endocrinol 1995;132:399.
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70. Chin HS, Chin DK, Morgenthaler NG, et al. Rarity of anti-Na'/I" symporter (NIS) antibody with iodide uptake inhibiting activity in autoimmune thyroid diseases (AITD). J Clin Endocrinol Metab 2000;85:3937. 71. Salmaso C, Bagnasco M, Pesce G, et al. Regulation of apoptosis in endocrine autoimmunity: Insights from Hashimoto's thyroiditis and Graves' disease. Ann NY Acad Sci 2002;966:496. 72. Laurberg P. Iodine intake-what are we aiming at? J Clin Endocrinol Metab 1994;79: 17. 73. Harach HR, Escalante DA, Onativia A, et al. Thyroid carcinoma and thyroiditis in an endemic goitre region before and after iodine prophylaxis. Acta Endocrino! (Copenh) 1985; 108:55. 74. Boukis MA, Koutras DA, Souvatzoglou A, et al. Thyroid hormone and immunological studies in endemic goiter. J Clin Endocrinol Metab 1983;57:859. 75. Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev 2001;22:240. 76. Gisslinger H, Gilly B, Woloszczuk W, et al. Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinant interferon IX. Clin Exp ImmunoI1992;90:363. 77. Atkins MB, Mier JW, Parkinson DR, et al. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 1988;318:1557. 78. Hoekman K, von Blomberg-van der Flier BM, Wagstaff J, et al. Reversible thyroid dysfunction during treatment with GM-CSF. Lancet 1991;338:541. 79. Bagchi N, Brown TR, Urdanivia E, Sundick RS. Induction of autoimmune thyroiditis in chickens by dietary iodine. Science 1985;230:325. 80. Fritz TE, Norris WP, Kretz ND, et al. Thyroiditis in a closed colony of beagle dogs: Nondestructive methods for diagnosis. ANL-7535. ANL Rep 1968:173. 81. Barbesino G, Chiovato L. The genetics of Hashimoto's disease. Endocrinol Metab Clin North Am 2000;29:357. 82. Doniach D, Roitt 1M. Taylor KB. Autoimmunity in pernicious anemia and thyroiditis: A family study. Ann NY Acad Sci 1965;124:605. 83. Phillips D, McLachlan S, Stephenson A, et al. Autosomal dominant transmission of autoantibodies to thyroglobulin and thyroid peroxidase. J Clin Endocrinol Metab 1990;70:742. 84. Fleming S, Cowell C, Bailey J, Burrow GN. Hashimoto's disease in Turner's syndrome. Clin Invest Med 1988; I I :243. 85. Friedman DL, Kastner T, Pond WS, O'Brien DR. Thyroid dysfunction in individuals with Down syndrome. Arch Intern Med 1989;149:1990. 86. Irvine WJ, Gray RS, Morris PJ, Ting A. HLA in primary atrophic hypothyroidism and Hashimoto goitre. J Clin Lab Immunol 1978;1:193. 87. Farid NR, Sampson L, Moens H, Barnard JM. The association of goitrous autoimmune thyroiditis with HLA-DR5. Tissue Antigens 1981;17:265. 88. Stenszky V, Balazs C, Kraszits E, et al. Association of goitrous autoimmune thyroiditis with HLA-DR3 in eastern Hungary. J Immunogenet 1987; 14:143. 89. Roman SH, Greenberg D, Rubinstein P, et al. Genetics of autoimmune thyroid disease: Lack of evidence for linkage to HLA within families. J Clin Endocrinol Metab 1992;74:496. 90. Hayashi Y, Tarnai H, Fukata S, et al. A long-term clinical, immunological, and histological follow-up study of patients with goitrous chronic lymphocytic thyroiditis. J Clin Endocrinol Metab 1985;61: 1172. 91. Vickery AL, Hamblin EJ. Struma Iymphomatosa (Hashimotos's thyroiditis): Observations on repeated biopsies in sixteen patients. N Engl J Med 1961;264:226. 92. Fatourechi V, McConahey WM, Woolner LB. Hyperthyroidism associated with histologic Hashimoto's thyroiditis. Mayo Clin Proc 1971; 46:682. 93. Amino N, Hagen SR, Yamada N, Refetoff S. Measurement of circulating thyroid microsomal antibodies by the tanned red cell haemagglutination technique: Its usefulness in the diagnosis of autoimmune thyroid diseases. Clin Endocrinol (Oxf) 1976;5: 115. 94. Czarnocka B, Ruf J, Ferrand M, et al. Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in autoimmune thyroid diseases. FEBS Lett 1985; 190:147. 95. Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71 :661.
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96. Cho BY, Kim WB, Chung JH, et al. High prevalence and little change in TSH receptor-blocking antibody titres with thyroxine and antithyroid drug therapy in patients with nongoitrous autoimmune thyroiditis. Clin Endocrinol (Oxf) 1995;43:465. 97. Ajjan RA, Kemp EH, Waterman EA, et al. Detection of binding and blocking autoantibodies to the human sodium-iodide symporter in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2000;85:2020. 98. Ramtoola S, Maisey MN, Clarke SE, Fogelman I. The thyroid scan in Hashimoto's thyroiditis: The great mimic. Nucl Med Commun 1988;9:639. 99. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55. 100. Kurihara H, Sasaki J, Takamatsu M. Twenty cases with Hashimoto disease changing to Graves' disease. In: Nagataki S, Mori T, Torizuka K (eds), Eighty Years of Hashimoto Disease. Amsterdam, Elsevier Science, 1993, p 249. 101. Matsuzuka F, Miyauchi A, Katayama S, et al. Clinical aspects of primary thyroid lymphoma: Diagnosis and treatment based on our experience of 119 cases. Thyroid 1993;3:93. 102. Hegedus L, Hansen JM, Feldt-Rasmussen U, et al. Influence of thyroxine treatment on thyroid size and antithyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf) 1991;35:235. 103. Riedel BMCL. Die chronische, zur Bildung eisenharter Tumoren fuhrende entzundung der schilddruse. Verhandlung der Deutsche Gesellschaft fur Chirugerie 1896;25: 101. 104. Riedel BMCL. Bortellung eines Kranken mit chrinischer Strumitis. Verhandlung der Deutsche Gesellschaft fur Chirugerie 1897;26:127. 105. Hay ill. Thyroiditis: A clinical update. Mayo Clin Proc 1985;60:836. 106. Heufelder AE, Hay ill. Evidence for autoimmune mechanisms in the evolution of invasive fibrous thyroiditis (Riedel's struma). Clin Invest 1994;72:788. 107. Zimmermann-Belsing T, Feldt-Rasmussen U. Riedel's thyroiditis: An autoimmune or primary fibrotic disease? J Intern Med 1994;235:271. 108. Dehner LP, Coffin CM. Idiopathic fibrosclerotic disorders and other inflammatory pseudotumors. Semin Diagn Pathol 1998;15:161. 109. Harach HR, Williams ED. Fibrous thyroiditis-an immunopathological study. Histopathology 1983;7:739. 110. Heufelder AE, Goellner JR, Bahn RS, et al. Tissue eosinophilia and eosinophil degranulation in Riedel's invasive fibrous thyroiditis. J Clin Endocrinol Metab 1996;81 :977. Ill. McRorie ER, Chalmers J, Campbell IW. Riedel's thyroiditis complicated by hypoparathyroidism and hypothyroidism. Scott Med J 1993; 38:27. 112. Yasmeen T, Khan S, Patel SG, et al. Riedel's thyroiditis: Report of a case complicated by spontaneous hypoparathyroidism, recurrent laryngeal nerve injury, and Horner's syndrome [Clinical Case Seminar]. J Clin Endocrinol Metab 2002;87:3543. 113. Tseleni-Balafouta S, Kyroudi-Voulgari A, Paizi-Biza P, Papacharalampous NX. Lymphocytic thyroiditis in fine-needle aspirates: Differential diagnostic aspects. Diagn Cytopathol 1989;5:362. 114. Amorosa LF, Shear MK, Spiera H. Multifocal fibrosis involving the thyroid, face, and orbits. Arch Intern Med 1976;136:221. 115. Bagnasco M, Passalacqua G, Pronzato C, et al. Fibrous invasive (Riedel's) thyroiditis with critical response to steroid treatment. J Endocrinol Invest 1995;18:305. 116. Few J, Thompson NW, Angelos P, et al. Riedel's thyroiditis: Treatment with tamoxifen. Surgery 1996;120:993. 117. Clark OH, Gerend PL, Davis M, et aI. Estrogen and thyroid-stimulating hormone (TSH) receptors in neoplastic and non-neoplastic human thyroid tissue. J Surg Res 1985;38:89. 118. Arteaga CL, Tandon AK, Von Hoff DD, Osborne CK. Transforming growth factor ~: Potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells. Cancer Res 1988;48:3898. 119. Colletta AA, Wakefield LM, Howell FV, et al. Anti-oestrogens induce the secretion of active transforming growth factor ~ from human fetal fibroblasts. Br J Cancer 1990;62:405. 120. Mirza MR. Anti-estrogen induced synthesis of transforming growth factor ~ in breast cancer patients. Cancer Treat Rev 1991; 18:145. 121. Butta A, MacLennan K, Flanders KC, et al. Induction of transforming growth factor ~I in human breast cancer in vivo following tamoxifen treatment. Cancer Res 1992;52:4261.
Hypothyroidism Kanji Kuma, MD • Shuji Fukata, MD • Masahiro Sugawara, MD
Hypothyroidism is the state of decreased thyroid hormone action at the target tissue. There are two types of hypothyroidism, on the basis of thyroid function tests: (1) clinical or overt and (2) subclinical. Patients with the former show elevated serum thyroid-stimulating hormone (TSH) and reduced serum thyroid hormone levels, which are the characteristic laboratory findings of primary hypothyroidism. The latter disorder is characterized by a mildly elevated serum TSH concentration and normal serum thyroid hormone levels. Subclinical hypothyroidism is the most common thyroid dysfunction nationwide, with a marked increase in prevalence in the elderly population.l-' Hypothyroidism, including subclinical hypothyroidism, can cause cardiovascular problems, lipid disorders, cognitive dysfunction, neurologic abnormalities, and a high rate of abortion. An extreme case of untreated hypothyroidism is myxedema coma. The timely detection of hypothyroidism and appropriate therapy with thyroid hormone are beneficial for patients and reduce perioperative morbidity as well as mortality.
Prevalence and Subclinical Forms The prevalence rates of overt hypothyroidism and subclinical hypothyroidism in the general population are 0.4% and 9%, respectively, based on the Colorado Thyroid Disease Prevalence Study.' The National Health and Nutrition Examination Survey (NHANES) III in the United States showed overt hypothyroidism of 0.3% and subclinical hypothyroidism of 4.3% in the general population in all ages.? Thus, subclinical hypothyroidism is 16 to 20 times more common than overt hypothyroidism. The prevalence of subclinical hypothyroidism increases with age and is more common in women than in men. In groups older than 70 years of age, a steep increase in prevalence of subclinical hypothyroidism is apparent; it reaches to 14% in the white population and 5% in the black population.? Subclinical hypothyroidism, therefore, should always be suspected whenever elderly patients undergo surgical procedures. Most patients with subclinical hypothyroidism have either mild symptoms of hypothyroidism or nonspecific symptoms. Before making the diagnosis of subclinical hypothyroidism, it is important to exclude other causes of elevated serum TSH concentration, such as the recovery stage from a nonthyroidal illness (serum TSH concentration can be
44
mildly elevated during the recovery stage), intermittent thyroid hormone ingestion for treatment of hypothyroidism, TSH-secreting tumor, and thyroid hormone resistance.' The causes of subclinical hypothyroidism are the same as those for overt hypothyroidism listed in a later section. Patients with subclinical hypothyroidism previously were considered as having a mild form of hypothyroidism, and no clear treatment has been established. Chu and Crapo claimed that thyroid hormone treatment is seldom needed unless the serum TSH concentration exceeds 10 mU/mL,4 but these patients have more chance of myocardial infarction,' hyperlipidemia," and hyperhomocysteinemia.? The trend is to treat patients with subclinical hypothyroidism to reduce these complications; in fact, most members of the American Thyroid Association choose thyroid hormone treatment for patients with subclinical hypothyroidism."
Causes and Clinical Features Hashimoto's Thyroiditis Hashimoto's thyroiditis, known as an autoimmune or chronic lymphocytic thyroiditis, is the leading cause of hypothyroidism. The pathogenesis of hypothyroidism is complex. Three mechanisms have been proposed: (1) thyroid cell damage by the thyroid antibody-mediated complement attachment; (2) T-cell-mediated cytotoxicity; and (3) enhanced apoptosis (programmed cell death). The initial event is the formation of antibody in response to self-antigen such as thyroid peroxidase (TPO) and thyroglobulin; this event does not normally happen. If self-antigen is falsely recognized by the immune system, antibody formation takes place to the specific self-antigen, creating organ-specific autoimmunity. This leads to immune complex deposition in the basement membrane of follicular cells and complement activation, as suggested in 1977.9 Weetman and associates confirmed the presence of terminal complement complexes around thyroid follicles.'? Thyrocytes attacked by complement through antibodies were shown to release cytokines interleukin (lL)-l and IL-6," which may promote infiltration and autoactivation of lymphocytes, subsequently leading to cell destruction. However, anti-TPO titers do not always correlate with the degree of thyroid cell destruction. Thus, thyroid antibodies should not be the sole cause of cell destruction. T-cellmediated cytotoxicity then came to attention. T lymphocytes originating from the bone marrow are differentiated in the
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thymus and become T cells (thymus-derived lymphocytes). One population of T cells expresses the surface molecule CD8, called cytotoxic T cells, and recognizes antigen that is associated with class I major histocompatibility complex (MHC) molecules. These class I MHC molecules are present in all cells and permit the CD8 cells to recognize and destroy foreign tissues, infected cells, or tumor cells. There are two pathways to destroy thyroid cells by cytotoxic T cells. One mechanism is to release lytic granules that contain perforin and granzyme.F'" These molecules enter the target cells and activate apoptosis pathways (caspase or cytochrome c release from the mitochondria). The other mechanism is an involvement of binding of Fas ligand (CD 178, expressed on the surface of T cells and thyrocytes) to the Fas death receptor (CD95/APO) of thyrocytes. This binding (dimerization of Fas and Fas ligand) triggers activation of the intracellular apoptosis pathway using adapter protein (Fas-associated protein death domain), Whatever the initial events are, the final immune reaction is cell destruction. In 1997, Giordano and colleagues first described the presence of Fas (CD95) in thyrocytes of Hashimoto's thyroiditis and not in normal thyroid gland,!" raising the possibility of Fas-mediated apoptosis in Hashimoto's thyroiditis. Since then, cell destruction by apoptosis has been studied intensely. Details of apoptosis in Hashimoto's thyroiditis have been reviewed by Baker" and Stassi and De Maria.16 The apoptosis in Hashimoto's thyroiditis involves complex linkages among thyrocytes, cytokines, CD4 cell, and death receptors/ligand. The interactions of these factors lead to either cell death or cell survival. Cytokines-biochemical signals that help coordinate immune responses-playa particularly central role in autoimmune diseases. The most important final event is activation of cytosolic cell lysis by expression of either Fas receptor-Fas ligand and/or tumor necrosis factor (TNF)-a and the TNF-related apoptosis-inducing ligand in thyrocytes.!? How does it happen? T-helper (TH) cells expressing CD4 playa critical role in cell death and survival in autoimmune diseases. CD4 T cells recognize antigen present on the surface of antigen-presenting cells (APCs) in association with class II MHC molecules. Unlike class I MHC molecules, class II MHC molecules are expressed only on APCs such as macrophages, B cells, and dendritic cells. There are two functionally distinct subsets of TH cells based on cytokine production: Tw land T w2. Twi cells secrete interferon (INF)-y and other cytokines that are associated with inflammation and cell-mediated immune responses. Tw2 cells promote humoral immune responses and inhibit Twi cell-mediated responses by the release of IL-4, IL-5, and IL_1O.18,19 TH-l cells are predominant in Hashimoto's thyroiditis, whereas Tw2 cells are prevalent in Graves' disease, Cytokines from Twi cells, such as INF-y and to a lesser extent IL-l~, stimulate the appearance of Fas death receptor in thyrocytes.'? Thus, cytokine-mediated reactions in Hashimoto's thyroiditis favor cell death by overcoming cell survival signals of cytokines from TH-2 cells and antiapoptotic proteins, Clinical features of Hashimoto's thyroiditis include the presence of goiter and variable thyroid functional status, Most patients with Hashimoto's thyroiditis have a small goiter. On palpation, the goiter can be felt as lobulated or multinodular; the consistency varies from rubbery to firm to stony hard. The surface of the Hashimoto's
45
thyroid gland is often described as bosselated. Thyroid function can be euthyroid, hypothyroid, or hyperthyroid depending on the stage of Hashimoto's thyroiditis and its associated conditions, For instance, at the beginning of this disease, most patients are euthyroid. As the disease progresses, patients become hypothyroid. If silent thyroiditis occurs in the thyroid gland of patients with Hashimoto's thyroiditis, patients may have transient hyperthyroidism due to thyroid cell destruction. Also, true hyperthyroidism can occur if Graves' disease and Hashimoto's thyroiditis coexist. The presence of antithyroid antibodies is the hallmark of this disorder; antirnicrosomal antibodies or anti-TPO antibodies are positive in more than 95% of cases. 19 Therefore, the presence of thyroid antibodies is used exclusively as the diagnostic test of Hashimoto's thyroiditis. Antibodies against thyroglobulin, sodium-iodide symporter, and TSH receptor may be detected. Also, ultrasound findings of hypoechogenicity of the thyroid gland should assist in the diagnosis of Hashimoto's thyroidiris-" and thyroid dysfunction." The clinical conditions described in the following sections need special attention in patients with Hashimoto's thyroiditis, Pregnancy. All pregnant women should have thyroid function tests and a TPO antibody test. If pregnant women have Hashimoto's thyroiditis, postpartum thyroid dysfunction is expected in 5% to 70%.22,23 This disorder can cause a transient hypothyroidism or hyperthyroidism in the postpartum period. If hypothyroidism or subclinical hypothyroidism is discovered during pregnancy, thyroid hormone treatment must be started as soon as possible. This is because of a high spontaneous abortion rate of 60% to 70%24 and adverse effects of hypothyroidism on the neuropsychological development of children, including IQ score." Also, thyroid hormone deficiency during early fetal life (first 12 weeks of pregnancy) leads to psychomotor development abnormality in infancy/"; the fetus is dependent on maternal thyroid hormone until 12 weeks' gestation. Smoking. Smoking is a risk factor for hypothyroidism in patients with Hashimoto's thyroiditis. Fukata and coworkers showed an increased prevalence of subclinical hypothyroidism in patients with Hashimoto's thyroiditis who smoke cigarettes because of an increased serum level of thiocyanate from smoking.?" This relationship between hypothyroidism and smoking has also been described by others.28.29 In addition to hypothyroidism, smoking is associated with the development of Graves' disease, Graves' ophthalmopathy, nodular goiter, and antithyroid antibodies.P Iodine. Iodine is needed for thyroid hormone formation. However, patients with Hashimoto's thyroiditis are known to have increased sensitivity to excessive iodine causing reversible hypothyroidism.v-" although the exact mechanism is unclear. Amiodarone. One of the common sources of excessive iodine is arniodarone; this antiarrhythmic drug contains 75 mg of iodine in a 200-mg tablet. Therefore, iodine-induced hypothyroidism is a possible side effect of this medication, particularly in patients with Hashimoto's thyroiditis.'? Also, amiodarone can cause destructive hyperthyroidism followed by transient hypothyroidism.>' An elevated serum level of IL-6 is a marker of amiodarone-induced thyroditis." Lithium. This medication is used for the treatment of bipolar disorder. Lithium has multiple actions in the thyroid
46 - - Thyroid Gland gland, including inhibition of thyroid hormone secretion." thyroid hormone formation," and activation of the protein kinase C pathway.'? If the thyroid gland has marginal function (i.e., Hashimoto's thyroiditis), lithium treatment can cause hypothyroidism. In fact, lithium-induced hypothyroidism is more commonly seen in patients with Hashimoto's thyroiditis than in people without underlying thyroid disease." suggesting that the effect of lithium on the normal thyroid gland is subtle. Cytokines. INF-a and IL-2 treatment for malignant disease or hepatitis C can cause hypothyroidism in patients with Hashimoto's thyroiditis. The mechanism of induction of hypothyroidism by cytokines is still unclear, and addition of ribavirin, an antiviral therapeutic agent, to INF increases the chance of hypothyroidism.'? The development of thyroid dysfunction does not appear to be dependent on the dose of INF.40 Also, INF-a treatment can induce anti-TPO antibodies in some patients during hepatitis C treatment." The outcome of hypothyroidism in these patients seems to be partly dependent on the persistence or disappearance of anti-TPO antibodies. If anti-TPO antibodies disappear at the end of INF-a treatment, patients' thyroid status also improves."
Association with Other Autoimmune Endocrine Disorders. A small number of patients with Hashimoto's
thyroiditis may have autoantibodies to other endocrine organs, such as the pancreas, adrenal gland, and ovary, causing diabetes mellitus, adrenal insufficiency, or premature ovarian failure, respectively (polyglandular autoimmune syndrome). The association of Hashimoto's thyroiditis with adrenal insufficiency has been previously referred to as Schmidt's syndrome. Thyroid Lymphoma. Thyroid lymphoma accounts for 2% to 5% of malignant thyroid tumors and occurs exclusively in the thyroid gland of Hashimoto's thyroiditis. 42,43 When a goiter develops rapidly in an elderly patient with Hashimoto's thyroiditis, thyroid lymphoma should be suspected. This is a potentially curable malignant tumor as long as it is discovered at an early stage."
Hypothyroidism Caused by Iodine Therapy Radioactive iodine (l3II) is one of the common methods of treating patients with Graves' disease. This treatment leads to the development of hypothyroidism in most patients. The dose of l311 administered affects the onset of hypothyroidism. Of patients who receive 370 MBq (10 mCi) or more (>5.55 MBq/g of thyroid tissue), about 50% of patients become hypothyroid 1 year after treatment and about 70% of patients are hypothyroid 10 years after treatment.v-" Euthyroidism can initially be attained by treatment with a low dose of radioactive iodine (l.48 to 2.59 MBq/g of thyroid tissue delivered); however, most patients subsequently develop hypothyroidism by 10 years or later,"
Hypothyroidism Caused by External Radiation to the Neck External radiation to the neck is known to cause thyroid disorders, including hypothyroidism.f? Radiation doses of 4500 cGy or more cause hypothyroidism by 20 years in approximately 50% of patients of all ages," and more cases
occur thereafter. The effect of radiation therapy on the development of hypothyroidism is dose and duration dependent. The higher the dose and the longer the observation period, the higher the incidence of hypothyroidism. The timing of development of hypothyroidism after the initial radiation therapy can be 4 months to years, depending on the dose and duration received." Ionized radiation releases reactive oxygen species from the water molecule. 50 This appears to be the mechanism of radiation-induced hypothyroidism. In addition to hypothyroidism, radiation therapy to the neck also predisposes to hyperthyroidism, thyroid cancer, Hashimoto's thyroiditis, and benign thyroid nodules.tv" Lifelong observation is needed in patients who received external radiation therapy to the neck.
Hypothyroidism after Subtotal or Total Thyroidectomy Subtotal thyroidectomy is still an excellent form of treatment for patients with Graves' disease, particularly when antithyroid drugs and 131 1 therapy are not suitable." Surgical approach has three advantages over radioactive iodine therapy. First, the incidence of overt hypothyroidism is considerably less than after radioactive iodine therapy. Second, the incidence of hypothyroidism does not increase as much in later years. Third, patients with Graves' ophthalmopathy are less likely to develop progression than after radioactive iodine therapy. Kuma and associates characterized the type of postoperative hypothyroidism after surgery in patients with Graves' disease who underwent subtotal thyroidectomy. 52 Nearly 40% to 50% of patients experienced subclinical hypothyroidism during the first 4 years after surgery, and the incidence correlates inversely with the size of the thyroid remnant. Palit and colleagues reviewed 35 published papers regarding subtotal thyroidectomy for Graves' disease and found a 25.6% prevalence of postoperative hypothyroidism." The most important aspect of the outcome of surgery is the remnant size of thyroid tissue. The average weight of remnant tissue is 6.1 g, and the increment of each gram of thyroid tissue decreases the prevalence of hypothyroidism by 8.9% but increases the risk of recurrent hyperthyroidism." Other factors, such as the degree of lymphocyte infiltration, iodine deficiency, and medications, may affect the outcome of thyroid surgery and thyroid function.
Iodine Deficiency Iodine deficiency is a serious worldwide problem, particularly in Africa, China, southern Asia, and Europe. It is estimated that about 1 billion people are iodine deficient. About 20 million people have endemic goiter and 2 million people have endemic cretinism. 53 To form adequate amounts of thyroid hormone, 100 to 150 ug/day of iodine is needed.P If iodine intake is less than 100 ug/day, endemic goiter may develop. Further decrease in iodine intake of less than 25 Ilg/day may cause endemic cretinism.P Most patients with endemic goiter have normal thyroid function; however, hypothyroidism develops when iodine deficiency is severe. Endemic cretinism is divided into two types: neurogenic and myxedematous. 54 The former is more common than the myxedematous type and is characterized by irreversible neurologic deficits such
Hypothyroidism - -
as deafness, gait abnormality, squint, and spasticity. Curiously, neurogenic cretins are euthyroid, despite severe iodine deficiency. Myxedematous cretinism is relatively rare and is limited to parts of central Africa, Nepal, and western provinces of China. The clinical manifestation of myxedematous cretinism is attributed to hypothyroidism.
Iodide-Induced Hypothyroidism Hypothyroidism caused by excessive iodine intake has also been observed in patients having the following conditions or underlying diseases: history of postpartum thyroiditis, after a previous episode of subacute thyroiditis, and recombinant INF-a treatment.P The hypothyroidism is transient, and thyroid function returns to normal 2 to 3 weeks after iodide withdrawal; however, long-term follow-up is needed for these patients because some subsequently develop permanent primary hypothyroidism/"
Central Hypothyroidism Abnormalities of the pituitary gland, such as pituitary tumor, ischemic lesion (Sheehan's syndrome), and iatrogenic events (surgical removal or radiation therapy), can cause central hypothyroidism with decreased pituitary TSH secretion. Other rare causes of pituitary lesions include tuberculosis, syphilis, hemochromatosis, sarcoidosis, histiocytosis, and aneurysms of the internal carotid artery. Hypothalamic lesions, such as suprasellar extension of pituitary tumors or craniopharyngioma, meningioma, glioma, and metastatic tumors, can damage the hypothalamus and decrease thyrotropin-releasing hormone (TRH) secretion. This event leads to decreased TSH secretion and subsequent hypothyroidism. Chronic head trauma (e.g., in boxers) can also be the cause of hypothalamic dysfunction. Bexarotene, a retinoid X receptor-selective ligand used for treatment of T-cell lymphoma, has been shown to suppress TSH secretion and cause reversible central hypothyroidism." Hereditary central hypothyroidism is rare, and two types have been described: (1) isolated cases caused by alteration of TSH-~ and TRH receptors and (2) combined pituitary hormone deficiency caused by inactivating mutations of different pituitary transcription factors." It is important to diagnose central hypothyroidism and start treatment at an early stage.
Congenital Hypothyroidism Congenital hypothyroidism is a rare cause of hypothyroidism. There are three different etiologies: (1) athyreosis (absent thyroid); (2) dysgenesis (hypoplastic or lingual thyroid); and (3) dyshormonogenesis (congenital defect in the steps of thyroid hormone synthesis). The importance of identifying the etiology for treatment and follow-up planning has been described previously. 58
Generalized Thyroid Hormone Resistance Hypothyroidism resulting from generalized thyroid hormone resistance is a rare familial disorder. This is caused by a mutation of thyroid hormone receptor ~. Because the thyroid
47
hormone receptor does not function normally, tissues do not get messages of thyroid hormone. Thus, clinical features of hypothyroidism appear in the presence of elevated serum thyroid hormone levels.
Increased Thyroid Hormone Destruction as a Cause of Hypothyroidism Huang and coworkers first reported an infant with hepatic hemangioma who had severe hypothyroidism despite vigorous thyroid hormone treatment. The study revealed increased type 3 deiodinase activity in the liver, causing degradation of thyroid hormone by increased deiodination."
Symptoms and Signs Symptoms of hypothyroidism are listed in Table 6-1. Figure 6-1 shows the characteristic facial expression of primary hypothyroidism and secondary hypothyroidism (Sheehan's syndrome). Prominent periorbital edema is seen in patients with primary hypothyroidism, and this sign is usually absent or minimal in patients with secondary hypothyroidism. Patients with the latter disorder present with a pale face, increased wrinkles, and loss of eyebrow, particularly the lateral portions. In general, patients with overt hypothyroidism have more symptoms than those with subclinical hypothyroidism. Also, the number of symptoms and hypothyroid signs increase as they progress from subclinical hypothyroidism to overt hypothyroidism. In 1969, Billewicz and associates described a scoring system of hypothyroid symptoms and signs to assist in diagnosing hypothyroidism, because no TSH assay was available at that time/" This scoring system was re-evaluated by analyzing symptoms and signs based on modem thyroid function tests in 1997. 61 Delayed relaxation of ankle reflex is the most prominent sign of hypothyroidism with the highest specificity" ; this is
48 - - Thyroid Gland Primary hypothyroidism
A
Secondary hypothyroidism
B
FIGURE 6-1. Characteristic facial expression in primary hypothyroidism (A) and central (secondary) hypothyroidism (B).
consistent with the finding of the Billewicz group. Periorbital puffiness, slow movements, and hearing loss should be sought as hypothyroid signs because of the specificity of these signs in hypothyroidism.w-" Some patients have only mild symptoms and signs of hypothyroidism despite profound biochemical hypothyroidism, and some patients have marked symptoms despite only mild thyroid dysfunction. The discrepancy between symptoms and thyroid function tests indicates that tissue responsiveness and not serum TSH levels determines the symptoms and signs of hypothyroidism." In addition, hypothyroid patients may have many atypical clinical signs and manifestations such as sleep apnea, galactorrhea, respiratory failure, pericardial effusion, pleural effusion, dementia, depression, psychosis, adynamic ileus, and anemia. Therefore, judicious judgment is required when patients show atypical symptoms or signs of hypothyroidism. Even though these symptoms and signs suggest hypothyroidism, the final diagnosis should be made based on laboratory tests.
single test, but the accuracy of the test eventually turns out to be more cost-effective because it avoids frequent repeat testing. In summary, if thyroid status is to be screened as a routine test without clinical signs of thyroid dysfunction, serum TSH alone is acceptable. If one suspects thyroid dysfunction, both TSH and Ff4 testing should be done. Radioactive iodine uptake or thyroid scan is not needed for diagnosing hypothyroidism.
Nonthyroidal Illness as a Diagnostic Dilemma Nonthyroidal illness is an alteration of serum thyroid hormone levels due to the presence of medical illness or fasting or after surgery. The nature of this disorder and a practical approach to this disorder have been well described.F'''? Initially, these patients present with low serum triiodothyronine (T 3) levels due to decreased deiodinase 1 activity that converts T 4 to T 3 • As the disease progresses, total T 4 concentrations are reduced. When Ff4 was measured by equilibrium dialysis, FT 4 levels were usually normal/" whereas FT 4 measured by the analog method is low.68 The analog method is used in automated thyroid testing in most clinical laboratories and is significantly altered by high or low serum protein levels." Serum TSH levels vary depending on the stage of nonthyroidal illness. During the recovery stage of illness, serum TSH levels tend to be elevated. This causes difficulty in determining whether patients are hypothyroid. History of medical illness, careful physical examination, and selection of the right laboratory tests can be helpful. For instance, the presence of goiter, positive TPO antibody, and a long history of hypothyroid symptoms favor a diagnosis of hypothyroidism. Also, the level of serum TSH is known to be helpful. When serum TSH levels are higher than 20 IlIU/mL, primary hypothyroidism is likely, with a few exceptions.s?
Laboratory Testing for Detection of Hypothyroidism
Thyroid Hormone Treatment
The diagnosis of hypothyroidism is now focused on a single or most cost-effective test. A single TSH test was advocated for screening of thyroid dysfunction in 1993. 62 Serum TSH measurements use highly sensitive second- and thirdgeneration assays, based on lower limits of detection of 0.1 and O.OlIlU/mL, respectively. The TSH test accurately measures thyroid function and helps provide accurate thyroid hormone treatment. The limitation of the single TSH test is missing central hypothyroidism, since serum TSH concentrations in most patients with central hypothyroidism are normalP In addition, some patients have elevated serum TSH concentrations (immunologically active and biologically inactive TSH) despite the presence of central hypothyroidism.P Using serum free thyroxine (Ff4) alone as a diagnostic test of hypothyroidism detects hypothyroidism and monitors rapidly changing function better, but it cannot detect subclinical hypothyroidism. Also, low Ff4 alone is not sufficient to make the diagnosis of central or primary hypothyroidism. The combination of serum TSH and Ff4 is the most accurate test for detecting central as well as primary hypothyroidism/" Addition of serum Ff4 to TSH costs more than the
There are three thyroid hormone preparations: L-thyroxine (T 4) , T 3 , and combined T 4 and T 3 (desiccated thyroid [Thyrolar]). Synthetic levothyroxine (L-T4 ) is used most often and has distinct advantages: long half-life of 7 days and efficient conversion to T 3 • Thus, this medication is given once a day, and missing a dose for 1 to 2 days is not harmful. L-T4 also generates T 3 in the liver, the kidney, the brain and other tissues, providing tissue T 3 . The dose of L-T4 of 1.7 ug/kg (0.075 to 0.15 mg/day) should normalize the serum TSH level in most patients with hypothyroidism."? The daily requirement of T4 is 100 to 150 ug for adults, 50 to lOOllg for children, and 50 ug for infants. These are commonly used doses; the dose may need to be adjusted for some patients depending on body weight and severity of hypothyroidism. Patients with myocardial ischemia or cardiac arrhythmia, such as atrial fibrillation, should be treated using a small starting dose of thyroxine (0.0125 to 0.025 mg once a day)." Because of the long half-life of T 4 , once-a-week dosing is also recommended for patients who are not compliant." If L-T4 is to be given once a week, the weekly dose should be slightly higher than seven times the usual daily dose.
Hypothyroidism - -
Is additional T 3 to L-T4 beneficial? The study by Bunevicius and coworkers showed improvement in neuropsychological behavior and mood by combined T 4 and T 3 treatment in hypothyroid patients." In animal models of thyroidectomized rats, the addition of T3 to T 4 normalized plasma and tissue levels of thyroid hormone; T 4 treatment alone did not achieve such normal levels." However, the addition of T, may cause palpitations and worsening angina, particularly in elderly patients. Therefore, T 3 treatment should be used carefully if it is to be employed. Follow-up of patients who are receiving thyroid hormone replacement is critically important. It is now known that about 60% of patients receive an appropriate amount of thyroid hormone and the remaining 40% of patients take too little or too much, based on serum TSH levels in the Colorado Thyroid Disease Prevalence Study. 1 This finding is probably relevant to other geographic areas. It is now known that subclinical hyperthyroidism and subclinical hypothyroidism are risk factors for cardiovascular complications and that strictly controlling thyroid status is beneficial. To achieve normal thyroid status, serum TSH levels should be measured periodically and the thyroid hormone dose should be adjusted accordingly. The only exception is central hypothyroidism, in which a serum TSH level is not helpful; serum Ff4 and Ff3 should be used to determine the thyroid status. Ordering serum Ff3 is important because Ff4 level alone is not sufficient to determine the adequacy of thyroid hormone dose, and normalization of serum FT3 level is also needed in patients with central hypothyroidism." A biologic marker of thyroid hormone action should also be useful when serum TSH levels do not accurately determine thyroid status. Resting energy expenditure has been reported to be a sensitive marker of thyroid hormone replacement." Clinical use of this method seems to be of interest.
Conditions that Affect the Maintenance Dose of T4 Several conditions require increasing the dose of T 4 . Pregnancy is the most important because more T 4 is needed during pregnancy in patients with hypothyroidism based on serial serum TSH measurements." Similarly, patients with hypothyroidism who take estrogen require more thyroid hormone due to increased thyroid-binding protein by estrogen and subsequent decrease in available FT 4.78 Medications to decrease T4 absorption include cholestyramine, sucralfate, ferrous sulfate, aluminum hydroxide, and calcium carbonate.Ys? Increased thyroid hormone replacement should be considered if patients are on these medications. Patients should also take these medications at a different time than when they take their thyroid hormone. Measurement of serum TSH levels is an excellent method to determine the appropriate T4 dose in patients with primary hypothyroidism. In contrast, some conditions require decreased thyroid hormone dose. Androgen therapy decreases T 4-binding globulin and increases Ff4 hormone." Delayed degradation of thyroid hormone can be expected in elderly patients. Thus, patients with androgen therapy for breast cancer and elderly patients (>65 years of age) may need less thyroid hormone.
49
Adverse Effects of T4 and Bone Mineral Density Sodium levothyroxine is not recognized as a foreign antigen; thus, allergic reactions to levothyroxine should not occur. However, an allergic reaction to the coloring agents of levothyroxine has been reported.F In this situation, taking a noncolored tablet prevents an allergic reaction. Thyroid hormone is known to increase osteoclastic activity.83 It is documented that patients with untreated Graves' disease will develop bone 10ss.84 This is because of persistently high levels of circulating thyroid hormone levels for prolonged periods. There is controversy regarding how patients who have had thyroidectomy for thyroid cancer should be managed. In general, TSH suppression with high-normal T3and T 4 levels is recommended. There are conflicting opinions about the risks and benefits when patients' serum TSH levels are chronically suppressed.v-" Recently, Quan and associates analyzed the effect of thyroid hormone on bone mineral density in 11 studies that also describe confounding factors relevant to bone loss." They concluded that thyroid hormone suppression treatment does not affect bone mineral density in premenopausal women and in men. However, the effect of TSH suppression in postmenopausal women remains controversial.
Surgery in Patients with Hypothyroidism Surgery in patients with undiagnosed hypothyroidism may cause a catastrophic outcome. It is essential for surgeons to know the precise approach and management of patients with hypothyroidism who may have to undergo surgery in the hypothyroid state. In this section, we describe a practical approach as well as potential problems that may occur during surgery in patients with untreated hypothyroidism.
Approach The following considerations should be taken into account: 1. Does your patient have hypothyroidism or nonthyroidal illness? 2. Does your patient require urgent or elective surgery? 3. Is your patient's cardiac condition stable? 4. Are there any significant complications of hypothyroidism that may cause problems during surgery (anemia, hyponatremia, respiratory failure, signs of adrenal insufficiency)? The first step is to make sure that patients are actually hypothyroid and not in the category of nonthyroidal illness. Patients who undergo surgery often have a picture similar to nonthyroidal illness, which is sometimes difficult to distinguish from primary hypothyroidism. The diagnosis of hypothyroidism should be established as outlined earlier in this chapter by laboratory testing. After the diagnosis is made, one needs to determine whether patients need elective or emergency surgery. If elective surgery is indicated, patients should be treated with thyroid hormone to restore the euthyroid state. This eliminates some of the hypothyroid-related surgical complications. However, difficulty arises if patients
50 - -
Thyroid Gland
have to undergo emergency surgery in the hypothyroid state. At present, there is a general consensus that emergency surgery can be done in patients with mild to moderate hypothyroidism as long as potential perioperative problems and complications are appreciated (Table 6-2). In particular, cardiopulmonary complications (hypotension, respiratory failure, heart failure), hypothermia, hyponatremia, bleeding tendency, and adrenal insufficiency should be the main concerns during and after surgery." Chronic thyroid hormone deficiency affects cardiac function by prolonging systolic and diastolic function, as seen by echocardiography.'" Even patients with subclinical hypothyroidism have an increased risk of myocardial infarction.?" hyperlipidemia," and byperhomocysteinernia,? Therefore, patients' cardiac status needs to be carefully evaluated before surgery. Because of these complications, thoughtful planning for surgery and special preoperative and postoperative management of these patients become critically important. There are three control studies in which surgery was performed on patients in the hypothyroid state. 88.91,92 Problems and complications during and after surgery were then compared with those of euthyroid patients. On the basis of these studies, we have established guidelines for the care of patients in a hypothyroid state who may have to undergo surgery (Table 6-3). Before surgery, all surgical patients in a hypothyroid state should have glucocorticoid administered because hypothyroidism can be of central origin, and even primary hypothyroid patients may experience adrenal insufficiency during surgery.92.93 It is appropriate to administer 50 to 100 mg hydrocortisone every 8 hours during the preoperative period. The normal adrenal gland produces as much as 300 mg hydrocortisone a day; thus, 100 mg of hydrocortisone given every 8 hours should be sufficient to cover all surgical stress. The dose of preoperative medications, such as sedatives, should be reduced or avoided. During intubation, one may encounter difficulty controlling the airway because of a goiter or vocal cord edema. Deep anesthesia should be avoided by adjusting the amount of anesthetic agents administered. During the operation, blood pressure and cardiac function should be monitored carefully. It is highly advisable that inotropic agents and vasopressors be ready for use should these complications arise. One should be aware that patients with severe hypothyroidism may be refractory to the administration of cathecolamines.?" After surgery, extubation may be delayed because of a combination of respiratory failure from hypothyroidism and respiratory depression caused by anesthetic agents. Therefore, monitoring of arterial blood levels is essential.
During the postoperative period, the dose of postoperative sedatives should be reduced. Complete blood count, electrolytes, and cardiopulmonary status need to be routinely checked. Infection may be more difficult to diagnose because some patients with hypothyroidism fail to become febrile. The most difficult case for physicians involves the patient with untreated or profound hypothyroidism who needs emergency surgery. The question is whether such patients should be treated with intravenous T 4 before and during surgery. To our knowledge, no comprehensive study is available in regard to the outcome of surgery with and without T4 therapy. However, surgical procedures are a precipitating cause of myxedema coma, so that patients with severe hypothyroidism should receive intravenous T 4 before surgery (i.e., 200 to 500 ug L-T4 used for myxedema coma). An electrocardiogram should be obtained prior to T 4 treatment. What should be done in patients with ischemic heart disease and profound hypothyroidism who need surgery? If elective surgery is possible, patients should be treated slowly, starting with a low dose of thyroid hormone to restore a near-euthyroid state before surgery. If emergency surgery is required in such patients, 100 to 200 ug of t,- T 4 intravenously is needed, depending on the patient's condition.
Coronary Bypass Surgery Coronary artery bypass graft surgery (CABO) is one of the conditions in which intravenous T 3 may be beneficial and has potential application. CABO can produce a picture of nonthyroidal illness with low serum T 3.95 It is speculated that this low T 3 state may have significant hemodynamic consequences
Hypothyroidism - -
similar to those seen with chronic hypothyroidism. In fact, diminished cardiac contractility altered gene expression similar to that seen in hypothyroidism developed in animals." Also, T 3 treatment increased left ventricular function in patients with congestive heart failure who also exhibited the picture of nonthyroidal illness.97•98 There have been several investigations showing the beneficial effects of T3 treatment given before and after CABG in adults and children by demonstrating increased cardiac outpUt. 99- 103 Administration of T3 had no adverse effects in most studies99•IOO,102 and even lowered the incidence of atrial fibrillation after cardiac surgery.l'" The dose of T3 administered intravenously by Klemperer and colleagues was 1.4 ug/kg of body weight over a period of 6 hours (average total dose of 110 ug) starting immediately after surgery.103 If hypothyroid patients need bypass surgery, the same strategy of intravenous T 3 treatment should be considered, but such management remains controversial. In fact, one investigation failed to find any change in outcome when Tj-treated bypass patients were compared to those receiving dopamine and to placebo groups."
Prevention Neonatal screening must be done for all infants because mental retardation and growth abnormality caused by hypothyroidism can be prevented by thyroid hormone treatment. Because serum TSH levels in normal newborns are elevated immediately after birth, blood samples should be obtained 4 to 6 days after birth. Neonatal screening is generally performed by spotting blood from the heel onto filter paper. Measurement of T, and TSH is done in the eluate from the filter paper. T4 therapy should be started immediately after the diagnosis of hypothyroidism is established. For newborn infants, the dosage is 25 to 50 ug/day: for infants 6 to 12 months old, 50 to 75 ug/day is commonly used. T4 should be crushed and mixed with milk for administration. Early treatment of infants in whom hypothyroidism was discovered 3 to 6 days after birth was associated with a normal IQ and normal growth. !04
Iodine Deficiency Iodine is an important precursor of thyroid hormone. Thus, iodine deficiency leads to impaired production of thyroid hormones that are essential for prenatal and postnatal brain development for normal cognitive and neurologic function. The importance of iodine deficiency was addressed by the Rome Conference on Nutrition and the 1990 World Summit for Children, which called for the virtual elimination of iodine deficiency by the year 2000,105 There are three methods of iodine prophylaxis: iodinated salt, iodized oil, and iodinated water. Iodinated salt is the most inexpensive and most suitable for the general population. Iodinated salt is designed to provide more than 100 ug of iodine per day, assuming that daily intake of salt is 2 to 5 g. However, iodine content in salt varies in each country. Iodized oil is a longacting iodine and can be given orally or intramuscularly. One dose of 1 mL of iodized oil contains 480 mg of iodine. If given intramuscularly, it provides enough iodine for 2 to 3 years in children and 7 years in adults. Duration of oral
51
iodized oil is 1 to 2 years. Iodination of drinking water is not widely practiced except in Italy. Iodine prophylaxis is an important project to be carried out nationwide to save many children and adults from endemic goiter and cretinism.
Prevention of Hypothyroidism after Subtotal Thyroidectomy Approximately 25% of patients develop hypothyroidism after subtotal thyroidectomy for Graves' disease." Prevention of postoperative hypothyroidism has been attempted by changing the size of remnant tissues. Increasing remnant tissue size decreases the incidence of hypothyroidism,' 1 but recurrent Graves' disease is a problem. S2.106 Shimizu and coworkers tried autotransplantation of cryopreserved thyroid tissues in four patients who developed postoperative hypothyroidism after subtotal thyroidectomy for Graves' disease.P? About 2.5 to 3.5 g of cryopreserved thyroid tissues at -80°C were autotransplanted into the muscle of the forearm, and three of the four patients were able to discontinue thyroid hormone medications.I'" This interesting technique may be applicable for the prevention of postoperative hypothyroidism in some cases.
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52 - - Thyroid Gland 17. Bretz JD, Rymaszewski M, Arscott PL, et aI. Death pathway expression and induction in thyroid follicular cells. J BioI Chern 1999;274:23627. 18. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787. 19. Van der Veen RC, Stohlman SA. Encephalitogenic THI cells are inhibited by TH2cells with related peptide specificity: Relative roles of interleukin (IL)-4 and IL-lO. J Neuroimmunol 1993;48:213. 20. Rago T, Chiovata L, Grasso L, et aI. Thyroid ultrasonography as a tool for detecting thyroid autoimmune diseases and predicting thyroid dysfunction in apparently healthy subjects. J Endocrinol Invest 2001;24:763. 21. Premarwardhana LD, Parkes AB, Ammari F, et aI. Postpartum thyroiditis and long-term thyroid status: Prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;85 :71. 22. Bagis T, Gokcel A, Saygill ES. Autoimmune thyroid disease in pregnancy and the postpartum period: Relationship to spontaneous abortion. Thyroid 2001;11:1049. 23. Amino N, Tada H, Hidaka Y. Postpartum autoimmune thyroid syndrome: A model of aggravation of autoimmune disease. Thyroid 1999;9:705. 24. Abalovich M, Gutierrez S, Alcaraz G, et aI. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12:63. 25. Haddow JE, Palomaki GE, Allan WC, et aI. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549. 26. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149. 27. Fukata S, Kuma K, Sugawara M. Relationship between cigarette smoking and hypothyroidism in patients with Hashimoto's thyroiditis. J Endocrinol Invest 1996;19:607. 28. Nystrom E, Bengtsson C, Lapidus L, et aI. Smoking-a risk factor for hypothyroidism. J Endocrinol Invest 1993;16:129. 29. Vestergaard P, Rejnmark L, Weeke J, et aI. Smoking as a risk factor for Graves' disease, toxic nodular goiter, and autoimmune hypothyroidism. Thyroid 2002;12:69. 30. Muller B, Zulewski H, Huber P, et aI. Impaired action of thyroid hormone associated with smoking in women with hypothyroidism. N Engl J Med 1995;333:964. 31. Braverman LE, Ingbar SH, Vagenakis AG, et aI. Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J Clin Endocrinol Metab 1971;32:515. 32. Tajiri J, Higashi K, Morita M, et aI. Studies of hypothyroidism in patients with high iodine intake. J Clin Endocrinol Metab 1986;63:412. 33. Franklyn JA, Sheppard Me. Amiodarone and thyroid dysfunction. Trends Endocrinol Metab 1993;4:128. 34. Roti E, Minelli R, Gardini E, et aI. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone: A possible consequence of a destructive process in the thyroid. Arch Intern Med 1993;153:886. 35. Bartalena L, Grasso L, Brogioni S, et aI. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994;78:423. 36. Mori M, Tajima K, ada Y, et aI. Inhibitory effect of lithium on the release of thyroid hormones from thyrotropin-stimulated mouse thyroids in a perfusion system. Endocrinology. 1989;124:1365. 37. Urabe M, Hershman JM, Pang XP, et aI. Effect of lithium on function and growth of thyroid cells in vitro. Endocrinology 1991; 129:807. 38. Myers DH, Carter RA, Bums BH, et aI. A prospective study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies. Psychol Med 1985;15:55. 39. Carella C, Mazziotti G, Morisco F, et aI. The addition of ribavirin to interferon-a therapy in patients with hepatitis C virus-related chronic hepatitis does not modify the thyroid autoantibody pattern but increases the risk of developing hypothyroidism. Eur J EndocrinoI202;146:743. 40. Dalgard 0, Bioro K, Helium K, et aI. Thyroid dysfunction during treatment of chronic hepatitis C with interferon a: No association with either interferon dosage or efficacy of therapy. J Intern Med 2002;251 :400. 41. Carella C, Mazziotti G, Morisco F, et al. Long-term outcome of interferon-a-induced thyroid autoimmunity and prognostic influence of thyroid autoantibody pattern at the end of treatment. J Clin Endocrinol Metab 2001 ;86: 1925. 42. Aozasa K, Inoue A, Tajima A, et aI. Malignant lymphoma of thyroid gland: Analysis of 79 patients with emphasis on histologic prognostic factors. Cancer 1986;58: 100.
43. Matsuzuzka, F, Miyauchi A, Katayama S, et aI. Clinical aspects of thyroid lymphoma: Diagnosis and treatment based on our experience of 119 cases. Thyroid 1993;3:93. 44. Nofal MM, Beierwaltes WH, Patno ME. Treatment of hyperthyroidism with sodium. JAMA 1996;197:605. 45. Cunnien AJ, Hay 10, Gorman CA, et aI. Radioiodine-induced hypothyroidism in Graves' disease: Factors associated. J Nucl Med 1982;23:978. 46. Sridama V, McCormick M, Kaplan EL, et aI. Long-term follow-up study of compensated low-dose 1311 therapy for Graves' disease. N Engl J Med 1984;311 :426. 47. Tell R, Sjodin H, Lundell G, et aI. Hypothyroidism after external radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 1997;39:303. 48. Sklar C, Whitton J, Mertens A, et aI. Abnormalities of the thyroid in survivors of Hodgkin's disease: Data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 2000;85:3227. 49. Mercado G, Adelstein OJ, Saxton JP, et aI. Hypothyroidism: A frequent event after radiotherapy and after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer 2001 ;292:2892. 50. Little JB. Cellular, molecular, and carcinogenic effects of radiation. Hematol Oncol Clin North Am 1993;7:337. 51. Palit TK, Miller CC III, Miltenburg DM. The efficacy of thyroidectomy for Graves' disease: A meta-analysis. J Surg Res 2000;90: 161. 52. Kuma K, Matsuzuka F, Kobayashi A, et aI. Natural course of Graves' disease after subtotal thyroidectomy and management of patients with postoperative thyroid dysfunction. Am J Med Sci 1991;302:8. 53. Medeiros-Neto G. Iodine deficiency disorders. Thyroid 1990;1:73. 54. Boyages SC, Halpern JP. Endemic cretinism: Toward a unifying hypothesis. Thyroid 1993;3:59. 55. Markou K, Georgopoulos N, Kyriazopoulou V, et aI. Iodine-induced hypothyroidism. Thyroid 2001;11:501. 56. Sherman SI, Gopal J, Haugen BR, et aI. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 1999;340: 1075. 57. Asteria C, Persani L, Beck-Peccoz P. Central hypothyroidism: Consequences in adult life. J Pediatr Endocrinol Metab 2001;14 (SuppI5):1263. 58. Hanukoglu A, Perlman K, Sharnis L, et al. Relationship of etiology to treatment in congenital hypothyroidism. J Clin Endocrinol Metab 2001 ;86: 186. 59. Huang SA, Tu HM, Harney JW, et aI. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;343:185. 60. Billewicz WZ, Chapman RS, Crooks J, et aI. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med 1969;38:255. 61. Zulewski H, Muller B, Exer P, et aI. Estimation of tissue hypothyroidism by a new clinical score: Evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771. 62. Becker DV, Bigos ST, Gaitan E, et al. Optimal use of blood tests for thyroid function. JAMA 1993;269: 2736. 63. Persani L, Ferretti E, Borgato S, et aI. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 2000;85:3631. 64. Wardle CA, Fraser WD, Squire CR. Pitfalls in the use of thyrotropin concentration as a first-line thyroid-function test. Lancet 2001; 357:1013. 65. De Groot LJ. Dangerous dogmas in medicine: The nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999;84:151. 66. Langton JE, Brent GA. Nonthyroidal illness syndrome: Evaluation of thyroid function in sick patients. Endocrinol Metab Clin North Am 2002;31:159. 67. Chopra 11. Clinical review 86: Euthyroid sick syndrome-is it a misnomer? J Clin Endocrinol Metab. 1997;82:329. 68. Wang R, Nelson JC, Weiss RM, et aI. Accuracy of free thyroxine measurements across natural ranges of thyroxine binding to serum proteins. Thyroid 2000;10:31. 69. Nicoloff JT, Spencer CA. Clinical review 12: The use and misuse of the sensitive thyrotropin assays. J Clin Endocrinol Metab 1990;7:553. 70. Weinberg AD, Brennan MD, Gorman CA, et aI. Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 1983; 143:893. 71. Ellyin PM, Kumar Y, Somberg JC. Hypothyroidism complicated by angina pectoris: Therapeutic approaches. J Clin PharmacoI1992;32:843. 72. Grebe SK, Cooke RR, Ford HC, et aI. Treatment of hypothyroidism with once-weekly thyroxine. J Clin Endocrinol Metab 1997;82:870.
Hypothyroidism - 73. Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424. 74. Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 1996;137:2490. 75. Ferretti E, Persani L, Jaffrain-Rea ML, Giambona S, et al: Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999; 84:924. 76. al-Adsani H, Hoffer LJ, Silva JE. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab 1997;82:1118. 77. Mandel SJ, Larsen PR, Seely EW, et al. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990;323:91. 78. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001 ;344: 1743. 79. Mandel SJ, Brent GA, Larsen PRo Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993;119:492. 80. Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000;283:2822. 81. Arafah BM. Decreased levothyroxine requirement in women with hypothyroidism during androgen therapy for breast cancer. Ann Intern Med 1994;121:247. 82. Magner J, Gerber P. Urticaria due to blue dye in Synthroid tablets. Thyroid 1994;4:341. 83. Britto JM, Fenton AJ, Holloway WR, Nicholson GC. Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption. Endocrinology 1994;134:169. 84. Riggs BL, Melton LJ III. Involutional osteoporosis. N Engl J Med 1986;314: 1676. 85. Jodar E, Martinez-Diaz-Guerra G, Azriel S, Hawkins F. Bone mineral density in male patients with L-thyroxine suppressive therapy and Graves' disease. CalcifTissue Int 2001;69:84. 86. Nuzzo V, Lupoli G, Esposito Del Puente A, et al. Bone mineral density in premenopausal women receiving levothyroxine suppressive therapy. Gynecol Endocrinol 1998;12:333. 87. Quan ML, Pasieka JL, Rorstad O. Bone mineral density in welldifferentiated thyroid cancer patients treated with suppressive thyroxine: A systematic overview of the literature. J Surg Oncol 2002;79:62. 88. Ladenson PW, Levin AA, Ridgway EC, et al.. Complications of surgery in hypothyroid patients. Am J Med 1984;77:261. 89. Vora J, O'Malley BP, Petersen S, et al. Reversible abnormalities of myocardial relaxation in hypothyroidism. J Clin Endocrinol Metab 1985;61:269. 90. Hak AE, Pols HAP, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med 2000;132:270.
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91. Drucker OJ, Burrow GN. Cardiovascular surgery in the hypothyroid patient. Arch Intern Med 1985;145:1585. 92. Weinberg AD, Brennan MD, Gorman CA, et al. Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 1983;143:89. 93. Finlayson DC, Kaplan JA. Myxoedema and open heart surgery: Anaesthesia and intensive care unit experience. Can Anaesth Soc J 1982;29:543. 94. Myerowitz PO, Karnienski RW, Swanson OK, et al. Diagnosis and management of the hypothyroid patient with chest pain. J Thorac Cardiovasc Surg 1983;86:57. 95. Bennett-Guerrero E, Kramer DC, Schwinn DA. Effect of chronic and acute thyroid hormone reduction on perioperative outcome. Anesth Analg 1997;85:30. 96. Ojamaa K, SabetA, Kenessey A, et al. Regulation of rat cardiac Kvl.5 gene expression by thyroid hormone is rapid and chamber specific. Endocrinology 1999; 140:3170. 97. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501. 98. Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;81 :443. 99. Cimochowski GE, Harostock MD, Foldes PJ. Minimal operative mortality in patients undergoing coronary artery bypass with significant left ventricular dysfunction by maximization of metabolic and mechanical support. J Thorac Cardiovasc Surg 1997;113:655. 100. Klemperer JD, Klein IL, Ojamaa K, et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323. 101. Bettendorf M, Schmidt KG, Grulich-Henn J, et al. Tri-iodothyronine treatment in children after cardiac surgery: A double-blind, randomized, placebo-controlled study. Lancet 2000;356:529. 102. Portman MA, Fearneyhough C, Ning XH, et al. Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart disease. J Thorac Cardiovasc Surg 2000;120:604. 103. Klemperer JD, Klein IL, Ojamaa K, et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323. 104. Moltz KC, Postellon DC. Congenital hypothyroidism and mental development. Compr Ther 1994;20:342. 105. UNICEF. The State of the World's Children. London, Oxford University Press, 1995, p 12. 106. Patwardhan NA, Moront M, Rao S, et al. Surgery still has a role in Graves' hyperthyroidism. Surgery 1993;114:1108. 107. Shimizu K, Kurnita S, Kitamura Y, et al. Trial of autotransplantation of cryopreserved thyroid tissue for postoperative hypothyroidism in patients with Graves' disease. J Am Coli Surg 2002;194:14.
Graves' and Plummer's Diseases: Medical and Surgical Management Michael Sean Boger, MD, PharmD • Nancy Dugal Perrier, MD
Historical Aspects The striking clinical malady of exophthalmic goiter, with its distinctive protruding eyes, tachycardia, nervousness, and enlarged thyroid, has been known for more than 150 years. Thyrotoxicosis was first described in 1786 by Parry, a physician in England, but was not reported until after his death in 1825. It was also noted by von Basedow and a handful of others. I To this day, on the continent of Europe, it is known as Basedow's disease. In the English-speaking world it is named for Robert James Graves because of a lucid monograph he wrote on the subject. As with many medical eponyms, however, he was not the first to describe the condition.' It was during the next century that Dr. Henry Plummer first described toxic nodular goiter, which came to be known as Plummer's disease. Both of these physicians made everlasting contributions to the field of endocrinology.
Robert James Graves (1796-1853) Robert James Graves (Fig. 7-1) was a descendant of a colonel in Cromwell's army. He was described as a brilliant student, highly cultured, handsome, and charming. In Dublin, Ireland, where he was born and trained in medicine, he received the highest educational award, the Golden Medal, for organizing medical education.' He introduced "clinical teaching," which has evolved into bedside teaching today, encouraging students to actually examine patients, present them to the professor, and write clinical histories-a novel idea at the time. 1,4 He insisted that his students attend autopsies to correlate findings there with the patient's state prior to death.' This was met with great opposition by the then current tradition that students have extensive book knowledge and little practical experience. I Dr. Graves' clinical lectures were the talk of the town, where he introduced many novel concepts including the pinhole pupil after pontine hemorrhage, timing the pulse by watch, and abandoning the practice of bleeding and starving
54
patients with pyrexia. i.as His book, Clinical Lectures on the Practice ofMedicine, is regarded as a medical masterpiece.' He was a pioneer in proper nutritional therapy for the sick and requested that his epitaph read: "He Fed the Fevers."! In 1835, he published his famous monograph, "A Newly Observed Affection of the Thyroid Gland in Females."
Three cases of violent and long continued palpitations in each of which the same peculiarity presented itself (with) enlargement ofthe thyroid gland ... the eyes assumed a singular appearance for the eye balls were apparently enlarged, so that when she slept or tried to shut her eyes, the lids were incapable of closing. When the eyes were open, the white sclerotic could be seen, to a breadth of several lines, all around the cornea. .. .The enlargement of the thyroid ... seems ... essentially different from goiter, in not attaining a size at all equal to that observed in the latter disease.6
Henry Plummer (1874-1937) The death rate in the United States from hyperthyroidism around 1908 was 25%. The extremely high mortality in goiter surgery was underscored by Samuel Gross, who stated the following:
Can the thyroid gland, when in a state of enlargement, be removed with a reasonable hope of saving the patient? Experience emphatically answers no... no sensible man will. ... Every stroke of a knife will be followed by a torrent of blood, and lucky will it be for him if his victim lives long enough to enable him to finish his horrid butchery/ By 1918, Charlie Mayo had performed his 5000th thyroidectomy. He had a personal death rate of 3%, a number touched by no one on the continent, in part due to Dr. Henry Plummer (Fig. 7-2).2 From Minnesota, Dr. Plummer was first consultant to Drs. Will and Charlie Mayo.? He developed a
Graves' and Plummer's Diseases: Medical and Surgical Management - -
55
clinical one. He was a pioneer in the development of radiographic diagnosis and therapy," His other achievements include designing the tube system for transporting patient records and the complex medical record system still in use at Mayo today." He later developed the first intercom system and irrigation system in the United States.' By 1922, Dr. Plummer was elaborating a theory about goiter disease. He led weekly "goiter lunches" to share his expertise.l When thyroxine (T4) proved to be 65% iodine, he posed the hypothesis that the extra toxic substance he postulated to be the cause of crises in exophthalmic goiter was a noniodinated molecule of T4, a compound discovered at the Mayo Clinic by Dr. Edward Kendall.s? He reasoned that a (then unknown) stimulus causes the thyroid gland to work too fast and if not enough iodine was readily available in the blood, the gland would tum out a half-finished product, a molecule of T4 with the essential iodine missing. At once, he believed that iodine should be tried on his goiter service at St. Mary's Hospital, and the results were miraculous.'
FIGURE 7-1. Dr. Robert James Graves. (From Jay V. Dr. Robert James Graves. Arch Pathol Lab Med 1999;123:284.)
special interest in the thyroid gland through his neighbor, Mr. Strain, the first goiter patient to be operated on by the Mayo brothers.' In 1913, Dr. Plummer first distinguished toxic adenomatous goiter from exophthalmic goiter. Until the availability of radioactive iodine, which made scintigraphy possible in the mid-1940s, this disease was an entirely
Against all tradition, every professor of medicine, every textbook ... following his own understanding of the function of the thyroid, [he] saved the life of a woman by injecting 5.0 mg of thyroxine intravenously/' At the Association of American Physicians in May 1923, he presented his results that administration of iodine preoperatively and postoperatively would prevent the crises that caused death after symptomatic treatment of exophthalmic goiter. He found that iodine in both nonoperative cases and as preoperative treatment significantly reduced mortality." His work turned the most treacherous operation known to surgery into one of the safest in the hands of any competent operator. It was hailed as one of medicine's greatest gifts to surgery and the Germans coined the fitting word for it-Plummerung. 2
Graves'Disease Epidemiology There are several subtle but distinct differences among patients with hyperthyroidism from Graves' and Plummer's diseases, as outlined in Table 7-1. 10-13 Graves' disease is the most prevalent autoimmune disorder in the United States and the most common cause of hyperthyroidism. The chief risk factor for Graves' disease is female gender, in part due to modulation of the autoimmune response by estrogen. Other potential precipitants of the autoimmune process
FIGURE 7-2. Dr. Henry Plummer. (From Clapesattle H. The Doctors Mayo. Rochester, MN, Mayo Foundation for Medical Education and Research, 1990.)
56 - - Thyroid Gland
FIGURE 7-3. A, Pathogenesis of Graves' hyper-
A
B
c
*
Propylthiouracil X Beta-blockers X Potassium iodide Potassium perchlorata Methimazole ~ Glucocorticoids { } Calcium channel blockers
*
thyroidism.IO·18.48,S3 Inflammatory cells infiltrate the thyroid, producing inflammatory mediators including various interleukins and tumor necrosis factor (TNF)-a. Such inflammatory mediators increase the production of stimulatory antibodies to the thyroglobulin receptor, leading to an increased production of cyclic adenosine monophosphate (cAMP) and, thus, thyroid hormones. They also bind to other receptors on thyroid follicular cells, including HLA class I, further increasing their production, and antithyroglobulin antibodies, producing a vicious cycle. B, Thyroid hormone synthesis. IO,18,48.53 The production of thyroid hormones involves (A) active transport of iodide into the follicular cell mediated by a sodium-iodide transporter in the basement membrane of the follicular cell and secretion across the apical membrane into colloid; (B) uptake of amino acids, which are then synthesized into thyroglobulin (TG) via the endoplasmic reticulum (ER), which is modified by the Golgi apparatus and secreted via exocytosis of secretory vesicles into colloid; (C) oxidation and organification of iodide into iodine via thyroperoxidase (TPO) and hydrogen peroxide; (D) iodination of TG via TPO to attach iodine to tyrosyl residues in the TG molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT); (E) coupling of two iodotyrosine residues via TPO produces thyroid hormones thyroxine (T4) and triiodothyronine (T3) that are incorporated in the TG molecule for storage in colloid; (F) endocytosis of colloid from the lumen back into the follicular cell; (G) TG proteolysis via lysozymes into T4, MIT, and DIT; (H) deiodination of MIT and DIT into iodide; and (I) deiodination of T4 into T3, which occurs, to a lesser extent, in the thyroid gland and, predominantly, in the periphery. C, Effects of antithyroidal therapies. l3,48.S1 Propylthiouracil (PTU) and methimazole (MTM) inhibit synthesis of T 3 and T4 by serving as preferential substrates for TPO, becoming iodinated and diverting oxidized iodine away from potential iodination sites in TG. They are actively trapped by the thyroid gland against a concentration gradient. They may also inhibit the oxidation and organification of iodine and the coupling reaction. PTU, but not MTM, inhibits deiodinase in both the thyroid gland and in peripheral tissues. Both agents appear to have direct effects on the disordered immunity in Graves' disease. ~ Blockers (BB) and calcium-channel blockers (CCB) reduce the vascularity of the gland; BBs control the peripheral manifestations of hyperthyroidism. Glucocorticoids in stress doses may help stabilize the vascular bed and block conversion of T4 to T3. Potassium iodide decreases iodine transport, iodine organification, TG proteolysis, and thyroid hormone secretion. It may also inhibit the ability of thyroid-stimulating hormone and cAMP to stimulate colloid endocytosis. Potassium perchlorate inhibits the iodine-trapping mechanism.
Graves' and Plummer's Diseases: Medical and Surgical Management - - 57
include infection, particularly Yersinia enterocolitica, stress, and iodine exposure. Smoking is weakly associated but strongly associated with the development of ophthalmopathy. There is no evidence that infection affects the susceptibility to Graves' hyperthyroidism or directly induces it. No single gene is known to cause the disease or to be necessary for its development, although there is a well-established association with certain human leukocyte antigen (HLA) alleles that vary among racial groups. Prevalence is similar among whites and Asians and lower in blacks. 14
Pathogenesis Graves' hyperthyroidism is caused by thyroid-stimulating antibodies that bind to and activate the thyrotropin receptor on thyroid follicular cells, stimulating the synthesis of cyclic adenosine monophosphate (cAMP) and, in tum, thyroid hormones (Fig. 7_3A).13.15-18 Inflammatory cells infiltrate the thyroid gland and produce inflammatory mediators including various interleukins and tumor necrosis factor (TNF)-a. These inflammatory mediators stimulate the production of stimulating antibodies to the thyrotropin receptor, leading to an increased production of cAMP and, thus, thyroid hormones. These inflammatory mediators bind to and stimulate various other receptors on the follicular cells of the thyroid, including HLA class I, causing a further increase in their production and a further increase in antithyrotropin antibodies, leading to a vicious cycle. Antibodies are also produced against thyroid peroxidase and thyroglobulin. This leads to abnormalities in most organ systems, including the cardiovascular and central nervous systems. The thyroid-stimulating antibodies not only cause thyroid hypersecretion but also hypertrophy and hyperplasia of the thyroid follicles, which have a columnar and folded epithelium and little colloid. The result is the characteristic goiter (Fig. 7-4A and B). This is due to the emergence of autoreactivity of T and B cells to the thyrotropin receptor. The exact mechanisms involved are unknown. As illustrated in Figure 7-3A, there are high circulating levels of various cytokines produced by lymphocytes in the thyroid gland. There is no direct correlation between serum concentrations of thyroid-stimulating antibodies and serum thyroid hormone. There is diffuse columnar epithelial hyperplasia and colloid excess. 14 Lymphocytic infiltration is often present, occasionally resulting in the formation of germinal centers.Iv'? These intrathyroidal lymphocytes are a major source of autoantibodies, with contributions from the cervical lymph nodes and bone marrow. 14
Clinical Manifestations The manifestations of Graves' disease can be marked or subtle, with periods of exacerbation or remission. It is now recognized as a multisystem disease characterized by diffuse goiter (see Fig. 7-4B), thyrotoxicosis, infiltrative ophthalmopathy and, occasionally, by infiltrative dermopathy?" The symptoms can be functional as a result of increased circulating levels of thyroid hormones or systemic as a result of autoantibodies directed against thyroid and extrathyroid organs such as the eye or skin. In an individual patient, these
features may occur singly or in varying combinations, such that the full syndrome may never develop. The most common symptoms are nervousness, fatigue, irritability, palpitations or rapid heartbeat, heat intolerance, weight loss, tremor, and decreased menstrual periods in women. These symptoms are present in more than half of all patients with the disease. With myxedema, the skin is warm and moist and has a silky texture. Patients may have graying of the hair, vitiligo, or onycholysis. The hair becomes thinner, and alopecia may develop.v" The classic goiter is one of the most consistent features of Graves' disease. Approximately 90% of patients younger than 50 years of age have a firm, diffuse goiter compared to 75% in older patients." It is usually symmetrical, smooth, firm, and rubbery and a bruit or thrill may be present in the gland. Graves' disease can also occur in normal-sized glands, especially in the elderly." Clinically evident ophthalmopathy occurs in 50% of patients, in 75% of whom the eye signs appear within a year before or after diagnosis of hyperthyroidism. There is an inflammatory infiltrate composed predominately of activated T cells in the extraocular muscles and orbital connective tissue. This infiltrate may localize in the orbit via recognition by T cells of an orbital antigen that cross-reacts with thyroid antigen, such as the thyrotropin receptor expressed in preadipocyte fibroblasts. Cytokines stimulate the production of glycosarninoglycans, leading to edema and fibrosis.Pv" These changes displace the eyeball forward due to increased volume of tissue within the orbit and may interfere with extraocular eye muscle function.P Patients may have photophobia, eye irritation, diplopia, and change in visual acuity. Most frequently, this presents as eyelid retraction or lag and periorbital edema. Proptosis (exophthalmos) occurs in up to one third of patients (Fig. 7-5A and B). Eyelid erythema, conjunctival injection, chemosis, swelling, and eyelid edema may occur. 13.20 Dermopathy occurs in 1% to 2% of patients, almost always in the presence of severe ophthalmopathy. In fact, there are close histologic similarities between the orbital connective tissue in Graves' ophthalmopathy and the pretibial connective tissue in pretibial dermopathy (Fig. 7-5C).22 Infiltrative skin manifestations are associated with eye changes in most cases. 13.20 It is most frequent over the anterolateral aspects of the shin but can occur in other sites.'? Pretibial myxedema presents as scaly, thickened, indurated skin, often with an orange-peel texture. 19.22
Diagnosis Features for the diagnosis of Graves' disease are shown in Table 7_2.13.20.23 The clinical triad of palpitations, weight loss, and heat intolerance plus diffuse bilateral goiter usually secures the diagnosis, but one must rule out subacute thyroiditis, thyrotoxicosis factitia, and other conditions. Radioactive iodine uptake studies can demonstrate a diffuse goiter (see Fig. 7-4C). Patients with increased thyroid hormone secretion have high uptake, whereas those with low uptake indicate suppression of thyroid-stimulating hormone (TSH) levels without increased thyroid-stimulating antibodies.P A radionuclide scan is essential if subacute thyroiditis is suspected to differentiate it from Graves' disease."
58 - - Thyroid Gland
B
A
FIGURE 7-4. The characteristic diffuse goiter in Graves' disease. A, Patient with a symmetrically diffusely enlarged thyroid gland. B, Surgical specimen reveals diffuse hypertrophy and hyperplasia with a smooth, rubbery yet lobular consistency. C, Homogeneous increased technetium (99mTc) uptake on radionuclide scan. (A, Courtesy of Ken Greer, MD, Charlottesville, VA.)
c Patients with low uptake do not need treatment, because low-uptake hyperthyroidism usually implies thyroiditis, which generally resolves spontaneously. Some argue for routine testing of antibodies, whereas others note that Graves' disease can nearly always be inferred correctly on the basis of clinical findings." Therapy
The ideal therapeutic agent for Graves' disease would offer (I) prompt control of disease manifestations, (2) return to and maintenance of euthyroidism, (3) minimal morbidity and mortality, and (4) reasonable COSt,20 The current therapeutic armamentarium remains empirical with antithyroid medications, radioactive iodine ablation, and subtotal or near-total thyroidectomy. Each option has advantages, disadvantages, and complications. Factors to consider when deciding on a treatment plan for thyrotoxicosis include patient age, associated ophthalmopathy, thyroid size, presence of compressive symptoms, substernal thyroid extension, contraindications to the use of radioiodine, intolerance to antithyroid drugs, presence of a dominant nodule, response to previous therapy, and patient preference. 12
Subtotal thyroidectomy was the standard of treatment in the early part of the 20th century. The goal was to eliminate the underlying pathology while leaving a tiny thyroid remnant to achieve a euthyroid state without causing recurrent hyperthyroidism. Eastern countries such as Japan continue to use surgery as first-line therapy today. In 1946, Hertz and Roberts described radioactive iodine therapy for hyperthyroidism, which has since gradually replaced surgery as firstline therapy because of the belief that it was safer and more effective. It is inexpensive and safer for debilitated patients who may be poor surgical candidates. However, since the introduction of radioactive iodine, surgery has improved with preoperativedrug treatment and modem operative techniques. There is a worldwide variation in the use of therapy. A recent questionnaire from the American Thyroid Association demonstrated what many believe-using a selective surgical approach is an underused treatment modality in the United States when an experienced surgeon is available. Radioactive iodine is widely used in North America, whereas antithyroid medications and surgery are more commonly used in Europe, China, and Japan. Radioactive iodine is used by most clinicians for patients with recurrent or persistent hyperthyroidism," A similar survey was
Graves' and Plummer's Diseases: Medical and Surgical Management - -
A
59
B
FIGURE 7-5. Systemic manifestations of Graves' disease. Graves' ophthalmopathy with characteristic wide, staring gaze, lid lag, significant periorbital edema (A), and proptosis (B). Dermopathy (C) presenting as pretibial myxedema with nonpitting edema over the shins, scaly thickening, and skin induration, creating the characteristic orange-peel texture. (Courtesy of Ken Greer, MD, Charlottesville, VA.)
c conducted by Soloman and associates in the United States using hypothetical cases of Graves' disease." Radioiodine therapy was chosen 70% of the time, with antithyroid drug therapy as the alternative. Surgery represented only 2% of the total options selected. ANTITHYROID MEDICATIONS
Indications of a favorable response to medical therapy include a small thyroid gland, reduction in goiter size with medical therapy, biochemical euthyroidism with normalization of TSH, and decreased antibody titers." Antithyroid medications interfere with one or more steps in the biosynthesis
and secretion of thyroid hormone, as illustrated in Figure 7-3B and C.13.16-18.27.28 Initial doses are methimazole 10 to 40 mg three times daily and propylthiouracil (PTU) 100 to 300 mg three times daily and subsequently decreased to oncedaily dosing once the patient is rendered euthyroid. The rapidity of response is influenced by the severity of the underlying disease, the size of the gland reflecting hormonal stress, and the dose and frequency of the agent used. Patients generally become euthyroid within 6 to 12 weeks after starting therapy. Methimazole has the advantage of once-daily dosing and improves compliance and side effects, particularly hepatotoxicity. Side effects are less common when used in low dose compared with PTU, where side effects are not dose dependent. PTU is preferred in pregnancy and lactation due to higher protein binding. Methimazole may cause aplasia cutis, a scalp defect, in newborns. PTU is also preferred in thyroid storm when rapid normalization of serum thyroid hormone levels is critical because it inhibits peripheral conversion of T4 to triiodothyronine (T3) . However, it may cause agranulocytosis." Potassium perchlorate is used with iodine-induced hyperthyroidism related to amiodarone exposure. Pretreatment with antithyroid medications before radioactive iodine
60 - - Thyroid Gland therapy reduces radiation-induced thyroiditis that could transiently exacerbate hyperthyroidism but also reduces the effectiveness of radiation therapy. Propranolol, 5 to 40 mg four times daily, can be given to control the catecholamine response of hyperthyroidism. Two drops of saturated solution of potassium iodide (SSKl, Lugol's solution) three times a day (48 ug/drop) can be added 10 to 14 days prior to surgery to decrease the vascularity of the gland" Although it rapidly decreases serum thyroid hormone levels, most patients treated with SSKI have a rapid "escape" within 1 to 2 weeks back to hyperthyroidism. Antithyroid medications are used for 12 to 24 months and should be slowly tapered.?? Because of the high failure rate, medical therapy with curative intent is primarily indicated in adults with small, nontoxic goiter «40 g), those with mildly elevated thyroid hormone levels, and those who exhibit rapid remission with reduction of gland size. Long-term therapy may lead to remission, but approximately 40% of patients fail a 2-year course." The recurrence rate of disease is 60% after 6 months of therapy, with a latent period of 2 to 6 weeks.'? The disadvantages of these agents are that multiple daily dosing requires strong patient compliance, and they often fail to produce a lasting remission. Predictors of poor response to oral medications are large goiter size and high thyroid hormone output. The disadvantages of the major treatment modalities for Graves' disease are outlined in Table 7_3. 21,27 For methimazole and PTU, the latent period is 2 to 6 weeks due to initial stores of hormone, and after 2 years of therapy, up to 69% have a recurrence." Side effects occur in up to 7% of patients; the most serious is agranulocytosis, occurring in approximately 0.3% of cases. Hypothyroidism develops in 15% of cases. For these reasons, antithyroid therapy is most useful in patients with mild disease, in those with small goiters, and in children and adolescents.?" RADIOACTIVE IODINE
Advantages of radioactive iodine therapy are avoidance of daily medications and symptoms of hyperthyroidism. The lifetime risk of early or late hypothyroidism with radioactive iodine necessitating, lifelong replacement therapy, is 3%
per year. Euthyroidism may take 4 to 6 months to achieve, and multiple doses may be required. Hyperparathyroidism may develop from radiation exposure. It is contraindicated in pregnancy, which should be avoided for a year, and in breastfeeding mothers. Factors to consider in therapy with radioactive iodine include increased risk of benign thyroid tumors, malignant transformation in young patients, thyroid cancers that develop are more aggressive, and ophthalmopathy is more likely compared with surgery.29,30 The effect of therapy for Graves' hyperthyroidism on the course of ophthalmopathy is controversial. A recent prospective, randomized study evaluated the effects of radioactive iodine versus antithyroid medications and the effects of glucocorticoids in patients with or without Graves' ophthalmopathy." Among those treated with radioactive iodine, ophthalmopathy developed or worsened in 15% of patients 2 to 6 months after therapy. None of the patients with baseline ophthalmopathy in this group had improved eye disease. Among patients treated with a combination of radioactive iodine and prednisone, 67% of patients with ophthalmopathy at baseline had improvement and no patients had progression. In the methimazole group, 92% of patients with baseline ophthalmopathy had improved eye disease, 3% had worsening of disease, and the remainder had no change. Since treatment with antithyroid medications such as methimazole is not often followed by development or progression of ophthalmopathy, it might be argued that patients with Graves' disease who have ophthalmopathy should be treated with these agents. However, antithyroid therapy may not give satisfactory control of hyperthyroidism and, more important, hyperthyroidism can recur after withdrawal of therapy. Therefore, it is best to achieve permanent control of hyperthyroidism in patients with ophthalmopathy, which can occur only with surgery. Total thyroidectomy has been recommended for patients with severe or progressive ophthalmopathy to completely remove the abnormal thyroid antigens serving as the stimulus for damage to the extraocular muscles and optic nerve. 12 If radioactive iodine is used, the best chance for preventing ophthalmopathy is with use of steroids, although their use also comes with significant side effects. There is an
Graves' and Plummer's Diseases: Medical and Surgical Management - -
unexplained increased mortality as compared to the general population. In a study evaluating the mortality in a cohort of 7209 patients with hyperthyroidism treated with radioactive iodine, mortality from all causes and mortality due to cardiovascular and cerebrovascular diseases and fracture was increased. For cerebrovascular disease, mortality was most marked in the first year and was confined to patients aged 50 years and 01der. 32 This may reflect diastolic hypertension or atrial fibrillation, and there appeared to be a relationship between the severity of hyperthyroidism and risk of cerebrovascular disease." Therefore, the role of radioactive iodine in the treatment of Graves' disease is controversial. Radioactive iodine is a good choice for patients with recurrence after surgery, since reoperation is more technically difficult" SURGERY
Surgery for Graves' disease is underused in the United States. The advantages are that treatment is rapid and stops hyperthyroidism, avoids the possible long-term risks of radioactive iodine, and provides tissue for histologic examination. The complication rate is low in experienced hands. The disadvantages are that hyperthyroidism may persist or recur if insufficient tissue is removed and hypothyroidism usually develops after near-total thyroidectomy. The absolute and relative indications for thyroidectomy are summarized in Table 7_4. 20,24 Five percent of patients with Graves' disease develop nodules, 20% of which are malignant. Thyroidectomy is useful in patients having serious allergic reactions during medical therapy. In pregnancy, surgery is usually performed during the second trimester. Surgery is not more technically difficult in patients who have been treated medically. There is a higher chance of hypothyroidism after radioactive iodine ablation than after subtotal thyroidectomy. Radioactive iodine therapy has a 6-week to 6-month latency of onset, during which patients need to be placed on antithyroid medications, whereas surgery results in rapid remission. Total or near-total thyroidectomy appears to stabilize or improve eye manifestations, whereas radioactive iodine tends to aggravate Graves' ophthalmopathy unless given with steroids." For substernal goiters, even in the absence of symptoms, surgery is always recommended, because most patients will likely develop
61
symptoms in the future as the gland enlarges, including acute respiratory distress.s' Surgery is particularly advantageous in juvenile Graves' disease, which primarily affects female children between 11 to 15 years of age. It is the leading cause of hyperthyroidism in childhood.v' Most children present with emotional lability, hyperactivity, nervousness, and learning disabilities. In this population, medical therapy has a failure rate approaching 60% to 80% due to poor compliance, side effects, and disease aggressiveness at this age.35 When compared to surgery, radioactive iodine has a higher incidence of recurrence, hypothyroidism, and subsequent hyperparathyroidism." Additionally, the risk of cancer in patients treated with radioactive iodine is greater than in the general population and is inversely related to age. Children treated with radioactive iodine are also more likely to experience hyperparathyroidism than adults. The recommendation is to leave one remnant less than 4 g on one side as relapse is more likely.34 The anatomy of the thyroid gland and surrounding arteries and nerves must be carefully considered during surgery (Fig. 7-6). While dissecting the upper pole of the gland, carefully avoid the external branch of the superior laryngeal nerve and superior thyroid artery. An approach via the avascular space between the cricothyroid muscle and the upper pole of the gland allows a medial approach to the superior pole vessels and early ligation of the vessels directly on the thyroid capsule." The external branch of the superior
thyroid a,
Inferior thyroid a.
Recurrent laryngeal n. Ligament of Berry
FIGURE 7-6. Important anatomic considerations during thyroid surgery. The recurrent laryngeal nerve is at greatest risk for injury at three key locations: at the ligament of Berry, during ligation of branches of the inferior thyroid artery, and at the thoracic inlet. The external branch of the superior laryngeal nerve is at greatest risk when dissecting the superior pole of the gland, whereas the internal branch would theoretically be damaged at the level of the thyrohyoid membrane,
62 - - Thyroid Gland laryngeal nerve is motor to the cricothyroid muscles, and the internal branch is purely sensory, innervating the mucosal lining of the supraglottic larynx. The external branch is intimately associated with the superior thyroid artery, and the relationship of these two structures is extremely variable. In up to 20% of normal individuals and in up to 56% of patients with large goiters, it crosses the avascular space below the tip of the superior pole of the thyroid. Damage to the external branch leads to an inability to reach high pitches or project the voice or to easy vocal fatigue during prolonged speech. Although this may be subtle in everyday conversation, such a disability is significant in patients whose voice is key to their career (e.g., singers). Damage to this nerve may be reduced by beginning dissection in the avascular cricothyroid space and proceeding cephalad. Ligating and dividing the vessels near the capsule reduces the chance of injury to the external branch when it is adherent to or passing between the branches of the superior thyroid artery, which occurs in approximately 15% of cases. 37,38 Damage to the internal branch leads to anesthesia of the superior laryngeal mucosa and loss of the protective mechanism for foreign bodies in the larynx. The reported incidence of permanent damage to the external branch of the superior laryngeal nerve after surgery is approximately 1% and of the recurrent laryngeal nerve is 0 to 4%.28 There are also many variations in the relationship of the recurrent laryngeal nerve (inferior laryngeal nerve) to the inferior thyroidal artery-it may pass superficial, deep to (most common), or within the terminal branches of the artery. Thus, it is extremely important to properly identify the branches of the inferior thyroid artery in relation to the end-arteries supplying the parathyroid glands and delineate their relationship to the recurrent laryngeal nerve." Passing superiorly and medially to enter the larynx along the posterior portion of the cricothyroid muscle, it is intimately related to the capsule of the thyroid and may be invisible. The most common regions where the recurrent laryngeal nerve is at risk of injury are near the inferior thyroid artery, near the ligament of Berry, and at the inferior pole of the gland (see Fig. 7-6). All of the intrinsic laryngeal muscles are supplied by the recurrent laryngeal nerve-the posterior cricoarytenoid muscle that abducts the vocal fold, the lateral cricoarytenoid muscle that adducts the vocal fold, the thyroarytenoid that relaxes the vocal fold, the transverse and oblique arytenoid muscles that close the intercartilaginous portion of the rima glottidis, and the vocalis muscles that relax the posterior vocal ligament and tense the anterior vocal ligament. Therefore, damage to the recurrent laryngeal nerve can lead to significant pathology. Unilateral recurrent nerve damage causes the vocal cord to be adducted toward the midline causing hoarseness, temporary aphonia, and laryngospasm. Bilateral damage may lead to respiratory distress, necessitating intubation." It is not unusual for the tubercle of Zuckerkandl to extend laterally over this nerve." Hypoparathyroidism after surgery may be temporary or permanent. It is most frequent with bilateral thyroid lobectomies. Once the superior pole is mobilized, the inferior pole vessels can be carefully mobilized with preservation of the lower parathyroids, which often lie in or near the thyrothymic ligament. The parathyroids are also at risk when
dissecting cervical lymph nodes. The incidence of permanent hypoparathyroidism after thyroid surgery should be less than 2%. Hematoma is a rare complication after thyroidectomy but has devastating consequences. An expanding hematoma can severely compromise the airway and become a medical emergency." The extent of thyroidectomy performed depends on several factors. A total thyroidectomy is indicated in patients with a coexisting malignancy such as thyroid cancer or multiple endocrine neoplasia, in those with severe ophthalmopathy, or in patients unwilling to undergo reoperation or radioactive iodine therapy. Subtotal thyroidectomy is useful for most patients. Factors associated with hypothyroidism after subtotal thyroidectomy include remnant size and autoimmune activity. If a euthyroid patient is the goal, some functioning thyroid tissue must be preserved. A 4- to 7-g remnant is the most appropriate size. The classic report by Mitchie illustrated that, in the range of 2 to 8 g, increasing the remnant size by 1 g decreases the rate of postoperative hypothyroidism by about 10%.38 Increasing the remnant size above 109 does not, however, lead to further appreciable decreases in hypothyroidism but, rather, leads to more recurrences. Remnants that are 8 g or larger decrease the risk of hypothyroidism but increase the incidence of persistent or recurrent disease. Three-gram remnants are suggested for children, a population that has a higher incidence of disease recurrence.A" Witte and colleagues performed a prospective, randomized trial to further examine the effects of total versus subtotal thyroidectomy." Patients were randomized to one of three interventions: bilateral subtotal thyroidectomy with less than 4-g remnant, unilateral hemithyroidectomy and contralateral subtotal thyroidectomy with less than 4-g remnant, and total thyroidectomy. Ophthalmopathy improved in 72% of all patients. The TSH receptor antibody level showed no difference in any group. Hypoparathyroidism was most common in total thyroidectomy (28% vs. 12%, P < 0.002). If the removal of thyroid tissue could reduce the antigenic load, one would expect total thyroidectomy to be more effective than subtotal thyroidectomy in preventing eye disease. Unfortunately, total thyroidectomy may be more likely than subtotal thyroidectomy to have operative complications and postoperative hypothyroidism. Therefore, given the lack of difference in postoperative outcome and increased chance of hypoparathyroidism, total thyroidectomy is not advocated. The upper limit of 4-g total thyroid remnant size was chosen in that study because of the higher incidence of recurrent Graves' disease in patients with larger thyroid remnants. Abe and coworkers assessed the influence of subtotal thyroidectomy compared to radioactive iodine therapy on the outcome of Graves' ophthalmopathy.t? Over a 5-year period, 287 cases were studied prospectively. All patients were treated initially with antithyroid medications to maintain euthyroidism, and those having a high titer of TSH receptor antibody were considered for thyroidectomy or radioactive iodine. Among patients who did not have proptosis at baseline, the incidence of eye disease occurrence was 7.1% in the surgically treated group, 9.2% in the medically treated group, and 11.9% in the radiation-treated group. In patients treated with surgery, ophthalmopathy
Graves' and Plummer's Diseases: Medical and Surgical Management - - 63
progressed in 5.6% and was alleviated in 16.7% compared with 10.4% and 3.0%, respectively, with radioactive iodine. Eye disease improved in 75% of patients treated with surgery, in 61.5% of patients treated medically, and in only 25% of patients treated with radioactive iodine. This study further supports that surgery is a better treatment than radioactive iodine in patients with Graves' disease with eye involvement. Gupta and associates examined the effect of 1311 therapy on Graves' ophthalmopathy in 20 newly diagnosed patients with Graves' hyperthyroidism.f Patients were followed with ophthalmologic evaluations and magnetic resonance imaging at baseline, 2, and 6 months and with examination alone at 6 years. At baseline, 50% of patients showed evidence of mild Graves' ophthalmopathy. There was no significant risk for radioiodine-induced initiation or progression of mild Graves' ophthalmopathy. However, this study did not assess patients with moderate to severe Graves' ophthalmopathy in whom radioiodine may have a more detrimental effect. Recent clinical studies of thyroidectomy for Graves' disease may not reflect outcomes accurately because of small sample size, especially when estimating ideal remnant size. A meta-analysis was performed by Palit and colleagues on studies in which patients underwent total or subtotal thyroidectomy.f The purpose of the study was to determine the overall efficacy and complication rates for both procedures in Graves' disease. There were 35 studies comprising 7241 patients with a median follow-up of 5.6 years. Overall, persistent or recurrent hyperthyroidism occurred in 7.2% of patients, and successful treatment of hyperthyroidism occurred in 92%. Hypothyroidism occurred in all patients receiving a total thyroidectomy. Subtotal thyroidectomy produced a euthyroid state in more than 60% of cases, with an 8% rate of persistent or recurrent hyperthyroidism. There was no statistical difference in complication rates of the two procedures, including permanent recurrent laryngeal nerve injury or permanent hypoparathyroidism. Andaker and coworkers examined the effects of two types of subtotal thyroidectomy: (1) bilateral subtotal with 2 g of remnant tissue left on both sides and (2) the HartleyDunhill procedure with a total lobectomy and isthmectomy on one side and a 4-g remnant on the other side, as illustrated in Figure 7_7.43 They found no differences in the results but preferred the Hartley-Dunhill procedure. A bigger remnant on one side allows dissection not to be carried far enough laterally to encounter the recurrent laryngeal nerves or parathyroid glands, thereby minimizing the risk of complications. If disease were to recur, only one side of the neck would need to be re-explored. The operation is more difficult than operating on patients with nontoxic goiter or thyroid neoplasms because of the extensive vascularity of the gland in Graves' disease. However, complication rates are still low. Patients should be rendered euthyroid before thyroidectomy to prevent thyroid storm. Preoperative iodine for patients with Graves' disease is useful in reducing intraoperative bleeding, allowing better visualization and preservation of the surrounding nerves, vasculature, and parathyroid glands. 12 Thyroid storm is a medical emergency and presents as central nervous system agitation or depression, cardiovascular
A
B FIGURE 7-7. Types of subtotal thyroidectomy. A, Bilateral subtotal, with remnant tissue left on both sides. B, Hartley-Dunhill procedure, with total lobectomy and isthmectomy on one side and remnant on other side.
dysfunction, fever, and hyperthyroidism. It is precipitated by surgery, trauma, infection, and administration of an iodine load as occurs with amiodarone or after radioactive iodine treatment. Signs and symptoms resemble severe thyrotoxicosis, with profound tachycardia, fever, and confusion. Disorientation may occur from dehydration, vomiting, diarrhea, and fever, and in extreme cases overt mania or coma may occur as a late sequela." The best management of thyroid storm is prophylaxis by rendering patients euthyroid prior to surgery. It should be treated immediately with hemodynamic support and oxygen. Oral Lugol's solution (potassium iodide, SSKI), 5 drops three or four times daily, or intravenous iodinated radiographic contrast agents such as sodium ipodate block iodine uptake and the secretion of thyroid hormones (see Fig. 7-3). Antithyroid therapy should be started at least 1 hour prior to SSKI to prevent eventual worsening of hyperthyroidism. PTU blocks the peripheral conversion of L-T4 to T 3, for rapid resolution of symptoms. Fever should be controlled with nonaspirin compounds and rapid cooling with ice or cooling blankets. Aspirin should be avoided because it increases free thyroid hormone levels. ~ Blockers in high doses, such as propranolol 480 mg/day in divided
64 - - Thyroid Gland doses or a 2- to 5-mg/hr infusion, control adrenergic manifestations. Calcium channel blockers are useful in patients intolerant to ~ blockers. Glucocorticoids in stress doses help stabilize the vascular bed, block peripheral conversion of T, to T3 , and prevent adrenal exhaustion." Dialysis may be necessary in some cases, such as thyroid storm induced by amiodarone. Sedation may be necessary in cases of agitation with hyperactivity."
Plummer's Disease (Toxic Multinodular Adenomatous Goiter) Toxic multinodular goiter was first described in 1913 by Dr. Henry Plummer (see Fig. 7-2), who believed that practically all adenomatous goiters would eventually become toxic given enough time. He noted that the average interval from first detection of the goiter to subsequent development of symptoms was 15 years.45.46
Pathogenesis Nodular goiters (Fig. 7-8A) occur when hyperplasia of a small subset of follicular cells with abnormal growth potential
A
occurs at multiple sites in the thyroid gland." In contrast with Graves' disease, where the thyroid follicular cells are hyperfunctional due to an external factor, IgG, which binds to and stimulates the TSH receptor, autonomous thyroid nodules develop hyperfunction through alterations in the cell biology of the follicular cell, possibly via a somatic mutation constitutively activating cAMP.47 The development of toxic multinodular goiter is a gradual process, as Plummer noted that goiters were present an average of 17 years before becoming toxic. 45.46 Plummer's disease occurs when one or more thyroid nodules become autonomous, trap and organify more iodine, and secrete more thyroid hormone independently of control by TSH stimulation." In the remainder of the gland, the normal feedback mechanism is operative. 11 As the adenomatous areas grow, their contribution to thyroid secretion increases and TSH secretion, therefore, decreases. This decrease in TSH results in decreased activity of the extranodular tissue. One or more follicles in a diffuse goiter has greater intrinsic growth and functional capability than the others and continues to grow and function despite declining TSH secretion, causing initially a nontoxic multinodular goiter and, ultimately, a toxic multinodular goiter." There is a gradual evolution of a sporadic diffuse goiter to a toxic one. A multinodular goiter occurs due to recurrent episodes of hyperplasia and involution and is considered toxic if it
B
FIGURE 7-8. Toxic multinodular goiter (Plummer's disease). A, Patient with a multilobulated, asymmetrically enlarged thyroid gland. B, The gland is inhomogeneous and coarsely nodular with areas of fibrosis and cystic change. C, Focal regions of increased 99mTc uptake on radionuclide scan revealing multiple functioning thyroid nodules with suppressed uptake in surrounding tissue. (B from Edis AJ, Grant CS, Egdahl RH: Surgery of the thyroid. In: Manual of Endocrine Surgery, 2nd ed. New York, Springer-Verlag, 1984.)
c
Graves' and Plummer's Diseases: Medical and Surgical Management - - 65
induces thyrotoxicosis. These multinodular goiters produce the most extreme enlargement of the thyroid, up to 2 kg, and are multilobulated and asymmetrically enlarged.'? Most "hot" or "autonomous" nodules have either TSH receptor mutations (most often) or gsp (less common) mutations." There is no correlation between morphology and function of the nodules.'? In contrast to the thyroid in Graves' disease, which is soft and resembles muscle, the thyroid in Plummer's disease on cut section has irregular nodules containing brown, gelatinous colloid.'? It most commonly occurs in areas of endemic goiter."
Clinical Manifestations Plummer's disease is more common than Graves' disease in elderly patients. It accounts for 15% of cases of hyperthyroidism in nonendemic goiter regions.'? The hyperthyroidism may be caused by multiple hyperfunctioning nodules or, less frequently, a single hyperfunctioning nodule. It is differentiated from Graves' disease in that extrathyroidal manifestations and thyroid autoantibodies are not present,20,44 Approximately 80% of patients with multinodular goiter are chemically euthyroid at initial presentation.'? Patients are more likely to have a prolonged course with weight loss, depression, atrial fibrillation, and muscle wasting than with Graves' disease and thyrotoxicosis is often less obvious and easily missed.P When it presents in the young, thyrotoxicosis is seen as weight loss, anxiety, tremor, insomnia, and heat intolerance, similar to Graves' disease." Atrial fibrillation in the setting of an enlarged goiter is often the only finding in the elderly." Symptoms of dysphagia, hoarseness, dyspnea, stridor, and cough may indicate a retrosternal or intrathoracic multinodular goiter.'? It is important to monitor T 3 carefully because these patients are more likely to have T 3 toxicosis, with high serum free T 3 and normal free T4 concentrations. This may be due to limited ability of the nodules to oxidize iodide or may be due to their preponderance in areas of relatively low iodine intake. On examination, the goiter has one or more palpable nodules. Compressive symptoms such as dysphagia or dyspnea may be present. Thyrotoxicosis may be exacerbated following iodine-containing contrast media, leading to the Jodbasedow phenomenon." Toxic multinodular goiter accounts for less than 5% of cases of thyrotoxicosis in iodine-sufficient areas but nearly half of cases in relatively iodine-deficient areas. Many patients have subclinical thyrotoxicosis with few, if any, symptoms and signs of thyrotoxicosis and normal thyroid hormone levels, but others have overt thyrotoxicosis. The incidence of thyroid cancer coexisting with multinodular goiter approaches 10%, similar to that in patients with a solitary thyroid nodule. Coexistent cancer is more common with nonfunctioning nodules and in men. 10
Diagnosis Patients with toxic multinodular goiter present with increased T 3 but a normal T 4 and free T4 index (T 3 thyrotoxicosis). A thyroid scintiscan (Fig. 7-8B) classically reveals one or more areas of increased uptake and suppressed areas in between. The hot nodules are identified as areas concentrating
radioactive iodine to a greater degree than the surrounding thyroid tissue. Technetium pertechnetate is preferred over radioiodide scanning and is useful in the differentiation of toxic nodular goiter from Graves' disease or to evaluate compressive symptoms.'? However, iodine is the preferred imaging agent for a toxic goiter with a substernal component due to its higher energy photons." Autonomous function of the nodules can be demonstrated by administering suppressive doses of T 3, which does not affect the function of the nodule but decreases the uptake of the extranodular tissue. Administration of TSH increases or restores the radionuclide uptake in the quiescent tissue." In contrast with Graves' disease, administration of exogenous T 3 or T 4 does not suppress the function of autonomous nodules because their secretory activity is, by definition, independent of stimulation with pituitary TSH. In addition, the secretions of the autonomous nodules suppress pituitary TSH, causing variable reduction of the function of the extrathyroidal tissue.
Therapy Similar to treatment of Graves' disease, there are three major classes of therapy: antithyroid medications, radioactive iodine ablation, and subtotal or near-total thyroidectomy. Antithyroid medications have not been widely accepted in the treatment of Plummer's disease because they are less effective and lifetime therapy would be necessary since, unlike the usual spontaneous remission of Graves' disease, the hyperthyroidism of toxic multinodular goiter continues indeflnitely.Pr" Their use is recommended only as adjunctive when needed for the initial control of hyperthyroidism. 10 As with Graves' disease, prior to surgery, patients should be rendered euthyroid with p blockers and thionarnides." Lugol's solution, in contrast with Graves' disease, should be avoided in pretreatment of Plummer's disease because it may significantly worsen thyrotoxicosis." Radioactive iodine therapy is inferior to its role in Graves' disease because the toxic multinodular goiter often persists after therapy.r' The goal of radiation therapy in Plummer's disease is destruction of autonomous tissue and restoration of euthyroidism.t? Erickson and associates evaluated medical records of 253 patients treated for toxic multinodular goiter between 1975 and 1993. 50 Of those treated with radioactive iodine, 20% required a second treatment, compared to zero patients treated with surgery. A latency of several months occurs before treatment is effective. In the report by Erickson and associates, half of surgically treated patients had achieved success within 3 days for surgical treatment versus 3 months for radioactive iodine treatment" Similar results were found in a report by Jensen and colleagues, who evaluated the records of 446 patients treated between 1950 and 1974. 51 The dose of radioactive iodine is variable, and several doses may be needed. Uptake is often relatively low, necessitating high doses to almost twice those given to Graves' patients for successful treatment. Uptake is localized to the autonomous toxic nodules and the remaining thyroid tissue is suppressed.r' The thyroid tissue adjacent to the thyroid nodule receives about 2000 rads, which is in the carcinogenic range for the surrounding normal tissue, enough to induce
66 - - Thyroid Gland subsequent thyroid cancer. Radioactive iodine therapy in large multinodular goiters extending substernally puts patients at risk for radiation-induced thyroiditis that can, although rare, cause acute thyroid enlargement and airway compression." A follow-up study assessed solitary autonomous thyroid nodules treated with iodine.P In this study of 23 patients, 54% of nodules were still palpable, 9% had increased in size, and 36% were hypothyroid. Goldstein and Hart concluded that iodine does not eradicate the nodule. The incidence of hypothyroidism in that study was not related to gland size, thyroid function, or total dose of radiation. Radioactive iodine is an effective therapy for hyperthyroidism caused by a single hot nodule, since the suppressed normal extranodular tissue should be protected via its inability to concentrate radioactive iodine. It is also suitable for patients with mild hyperthyroidism or those considered at high risk for surgical management" A recent study suggests that patients treated with high doses of 1311, such as those needed for Plummer's disease, may have xerostomia and xerophthalmia that persist for several years after therapy.53 Seventy-nine patients were treated between 1990 and 1995 with a dose ranging from 25 to 100 mCi. The numbers of patients who reported xerostomia 1, 2, and 3 years after therapy were 33%, 20%, and 15%, respectively. The most common symptoms were dry mouth and abnormal taste; oral ulcers and sialadenitis were also reported. One explanation is that salivary glands and lacrimal tissue have sodium-iodide transporters. Induction of an autoimmune lacrimal gland dysfunction, similar to that in Sjogren's syndrome, may also occur. For these reasons, surgery is the treatment of choice in Plummer's disease, particularly if patients have obstructive symptoms or if there is concern of carcinoma in the goiter. Surgery is immediate and certain, there is a low recurrence rate, and the patient is freed from the large goiter volume and its associated cardiac manifestations. The surgical approach varies depending on the type of nodule." For solitary nodules, nodulectomy or thyroid lobectomy is the treatment of choice because cancer is rare. For toxic multinodular goiter, lobectomy on one side and subtotal lobectomy on the other side is recommended in most cases to prevent the need for bilateral reoperation in cases of recurrence.>' The approach and precautions are similar to the surgical management of Graves' disease.
Conclusions There is a key role for both the endocrinologist and endocrine surgeon in the management of hyperthyroidism due to Graves' and Plummer's diseases, and therapy involves a team approach. The three basic treatment modalities-antithyroid therapy, radioactive iodine therapy, and surgery-each have their advantages and disadvantages. Surgery is an excellent therapy for both diseases because there is no mortality, and there are few complications or recurrences. It allows a rapid and consistent method of achieving euthyroidism and avoids the long-term risks of radioactive iodine. However, experience is important. The Hartley-Dunhill procedure is the treatment of choice.
Patients should be rendered euthyroid before operation. It can be technically difficult because of gland vascularity. Radioactive iodine ablation should be considered for disease recurrence after surgery.
Acknowledgments The authors owe many thanks to the following individuals, without whom preparation of this chapter would not have been possible: Gloria Graham, MD, Associate Professor, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, for her expert guidance on the dermatologic manifestations of thyroid diseases Kenneth Greer, MD, Associate Professor, Department of Dermatology, University of Virginia Health Systems, Charlottesville, Virginia, for generously providing prize photographs of the systemic manifestations of Graves' disease Nat Watson, Jr, MD, Associate Professor, Radiological SciencesRadiology, Wake Forest University School of Medicine, for his indispensable guidance on nuclear medicine and graciously providing radiologic images Paige Clark, MD, Associate Professor, Radiological Sciences-Radiology, Wake Forest University School of Medicine, for providing technetium 99m radionuclide scans Phyllis Easter, Secretarial Assistant, Department of Surgery, Wake Forest University School of Medicine, for her endless devotion in assisting with the preparation of this chapter Andrea Hassell, Secretarial Assistant, Division of Surgery, Wake Forest University School of Medicine, for her wonderful assistance
REFERENCES I. Jay V. Dr. Robert James Graves. Arch Pathol Lab Med 1999;123:284. 2. Clapesattle H. The Doctors Mayo. Rochester, MN, Mayo Foundation for Medical Education and Research, 1990. 3. Taylor S. Graves of Graves' disease: 1796-1853. J R Coli Physicians Lond 1986;20:298. 4. Havard CWH. Medical eponyms updated: Graves' disease. Br J Clin Pract 1990;44:409. 5. Whitehead RW. Robert James Graves, physician, educator, scientist. Circulation 1969;39:719. 6. Graves RJ. Clinical lectures. Lond Med Surg J 1835;7:516. 7. McConahey WM, Pady DS. Henry Stanley Plummer. Endocrinology 1991;129:2271. 8. Anonymous. Henry Stanley Plummer, MD, 1874-1937. Int Surg 1977;62:635. 9. Keys TE. Dr. Henry Stanley Plummer, 1874-1937. Minn Med 1972;55 :957. 10. Hurley DL, Gharib H. Evaluation and management of multinodular goiter. Otolaryngol Clin North Am 1996;29:527. II. Weiner JD. Plummer's disease: Localized thyroid autonomy. J Endocrinol Invest 1987; 10:207. 12. Mittendorf EA, McHenry CR. Thyroidectomy for selected patients with thyrotoxicosis. Arch Otolaryngol Head Neck Surg 2001;127:61. 13. Weetman AP. Graves' disease. N Engl J Med 2000;343: 1236. 14. McIver BM, Morris IC. The pathogenesis of Graves' disease. Endocrinol Metab Clin North Am 1998;27:73. 15. Felz MW. Stein PP. The many "faces" of Graves' disease: I. Postgrad Med 1999;106:57. 16. Carrasco N. Thyroid hormone synthesis. In: Braverman LE, Utiger RD (eds), Werner and Inghar's The Thyroid. Philadelphia, Lippincott Williams & Wilkins, 2000, p 52. 17. Dunn IT. Biosynthesis and secretion of thyroid hormones. In: DeGroot LJ, Iameson JL (eds), Endocrinology. Philadelphia, WB Saunders, 2000, p 1290. 18. Stevens A, Lowe I. Endocrine system. In: Human Histology, 2nd ed. Baltimore, Mosby, 1997, p 251. 19. Cotran R, Kumar S, Collins T: The endocrine system. In: Robbins Pathologic Basis of Disease. Philadelphia, WB Saunders, 1999, p 1121. 20. AIsanea 0, Clark O. Treatment of Graves' disease: The advantages of surgery. Endocrinol Metab Clin North Am 2000;29:321. 21. Felz MW, Stein PP. The many "faces" of Graves' disease: II. Postgrad Med 1999;106:45.
Graves' and Plummer's Diseases: Medical and Surgical Management - - 67 22. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993;329:469. 23. Dabon-Almirante CLM, Surks MI. Clinical and laboratory diagnosis of thyrotoxicosis. Endocrinol Metab Clin North Am 1998;27:25. 24. Alsanea 0, Clark OH. Benign disorders of the thyroid gland. World J Surg. In press. 25. Olinoer D, Hesch D, Lagasse R, et al. The management of hyperthyroidism due to Graves' disease in Europe in 1986: Results of an international survey. Acta Endocrinol Suppl 1987;285:3. 26. Soloman B, Glinoer D, Lagasse R, et al. Current trends in the management of Graves' disease. J Endocrinol Metab 1990;70:1518. 27. Cooper DS. Antithyroid drugs for the treatment of hyperthyroidism caused by Graves' disease. Endocrinol Metab Clin North Am 1998;27:225. 28. Udelsman R. Thyroid gland. In: Greenfield LJ, Mulholland MW, Oldham KT, et al (OOs), Surgery: Scientific Principles and Practice. Philadelphia, Lippincott Williams & Wilkins, 2001, p 1261. 29. Tezelman S, Grossman RF, Siperstein AE, et al. Radioiodine-associated thyroid cancers. World J Surg 1994;18:522. 30. Wood LC, Ingbar SH. Hypothyroidism as a late sequelae in patients with Graves' disease treated with antithyroid agents. J Clin Invest 1979;64:1429. 31. Bartalena L, Marocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med 1998;338:73. 32. Franklyn JA, Maisonneuve P, Sheppard MC, et al. Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med 1998;338:712. 33. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. N Engl J Med 1995;332:767. 34. Bergman P, Auldist AW, Cameron F. Review of the outcome of management of Graves' disease in children and adolescents. J Paediatr Child Health 2001;37:176. 35. Witte J, Goretzki PE, Roher HD. Surgery for Graves' disease in childhood and adolescence. Exp Clin Endocrinol Diabetes 1997;105 (SuppI4):58. 36. Cheetham TD, Wraight P, Hughes lA, et al. Radioiodine treatment of Graves' disease in young people. Hormone Res 1998;49:258. 37. Bliss R, Gauger PG, Delbridge LW. Surgeon's approach to the thyroid gland: Surgical anatomy and the importance of technique. World J Surg 2000;24:891. 38. Mitchie W. Whither thyrotoxicosis? Br J Surg 1975;62:673. 39. Witte J, Goretzki PE, Dotzenrath C, et al. Surgery for Graves' disease-
40. 41.
42. 43.
44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.
total versus subtotal thyroidectomy: Results of a prospective randomized trial. World J Surg 2000;24: 1303. Abe Y, Sato H, Noguchi M, et al. Effect of subtotal thyroidectomy on natural history of ophthalmopathy in Graves' disease. World J Surg 1998;22:714. Gupta MK, Perl J, Beham R, et al. Effect of 13l-iodine therapy on the course of Graves' ophthalmopathy: A quantitative analysis of extraocular muscle volumes using orbital magnetic resonance imaging. Thyroid 2001; 11:959. Palit TK, Miller CC, Miltenburg DM. The efficacy of thyroidectomy for Graves' disease: A meta-analysis. J Surg Res 2000;90:161. Andaker L, Johansson K, Smeds S, et al. Surgery for hyperthyroidism: Hemithyroidectomy plus contralateral resection or bilateral resection? A prospective randomized study of postoperative complications and long-term results. World J Surg 1992;16:765. Sadler GP, Clark OH, van Heerden JA, et al. Thyroid and parathyroid. In: Schwartz Sl, Shires GT, Spencer FC, et al (eds), Principles of Surgery. New York, McGraw-Hili, 1999, p 1661. Plummer HS. The clinical and pathologic relationships of hyperplastic and nonhyperplastic goiter. JAMA 1913;61:650. Plummer HS. The clinical and pathological relationship of simple and exophthalmic goiter. Am J Med Sci 1913;146:790. Siegel RD, Lee SL. Toxic nodular goiter: Toxic adenoma and toxic multinodular goiter. Endocrinol Metabol Clin North Am 1988; 27:151. Corvilain B, Dumont JE, Vassart G. Toxic adenoma and toxic multinodular goiter. In: Braverman LE, Utiger RD (eds), Werner and Inghar's The Thyroid. Philadelphia, Lippincott Williams & Wilkins, 2000, p 564. Mellen J, Wisheu S, Munzel U, et al. Radioiodine therapy for Plummer's disease based on the thyroid uptake of technetium-99m pertechnetate. Eur J Nucl Med 2000;27:1286. Erickson D, Gharib H, Li H, et al. Treatment of patients with toxic multinodular goiter. Thyroid 1998;8:277. Jensen MD, Gharib H, Naessens JM, et al. Treatment of toxic multinodular goiter (Plummer's disease): Surgery or radioiodine? World J Surg 1986;10:673. Goldstein R, Hart IR. Follow-up of solitary autonomous thyroid nodules treated with 13\1. N Engl J Med 1983;309:1473. Solans R, Bosh JA, Galofre P, et al. Salivary and lacrimal gland dysfunction after radioiodine therapy: Clinical thyroidology. J Nucl Med 2001;42:738. Edis AJ, Grant CS, Egdahl RH: Surgery of the thyroid. In: Manual of Endocrine Surgery, 2nd ed. New York, Springer-Verlag, 1984, p 210.
Use and Abuse of Thyroid-Stimulating Hormone Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms Niall O'Higgins, MCh • Andrew P. Zbar, MB • Susannah E. Harte, MD
Nodular disease of the thyroid gland is common. The medical suppressive treatment of goiter relies heavily on the ability to distinguish benign from malignant disease, largely through the use of high-resolution thyroid ultrasonography and fine-needle aspiration cytology of solitary and dominant thyroid masses. Thyroid nodules occur in approximately 0.8% of adult men and in as many as 5% of adult women in iodine-replete areas; there is a steady increase in detectable incidence after 45 years of age. 1 The prevalence of thyroid nodules is population dependent and is markedly higher in areas of endemic iodine deficiency? Exposure to low-dose ionizing radiation early in life increases the incidence of both benign and malignant nodules.v' Thyroid cancer is the most common endocrine malignancy, with an annual incidence of 10,000 new cases in the United States." Thyroid glands that are normal by palpation frequently have one or more nodules demonstrable at autopsy, and as many as 4% of patients at autopsy harbor microscopic, so-called occult, carcinomas of the thyroid.v? Ultrasonography in high-risk cases has produced a further dilemma in management with the discovery of impalpable nodules as small as 1 mm. The natural history and significance of these subclinical masses are unknown." Nodular goiter, on the other hand, is probably the most common endocrine "problem" in the world, and delineation of the value of thyroid suppression therapy in patients at low risk for carcinoma has significant implications for global health care costs.v'? The use of thyroid-stimulating hormone (TSH; thyrotropin) suppressive therapy after thyroidectomy
68
for benign and malignant disease remains controversial largely because of the heterogeneity of disorders for which it has been advocated and because the natural history of malignant disease is long. Unfortunately, few randomized, controlled clinical trials exist for specific disorders such as solitary nodular disease, multinodular goiter, and differentiated carcinoma to support unequivocally the value of long-term suppressive therapy. The failure to monitor adequately the suppression of TSH in patients, to establish the compliance with suppression medication, and to evaluate nodular size objectively have also contributed to difficulties in interpreting the results in patients receiving suppressive therapy. It is clear, however, that despite an overall increase in the detectable incidence of differentiated thyroid cancer over the last 30 years, there has been a steady decrease in mortality, and this may be explained by both earlier diagnosis and more widespread use of TSH suppressive treatment. I1,12 The introduction of highly sensitive thyrotropin immunoenzymometric assays has led to a standardization of TSH suppression and permitted closer monitoring of both the efficacy of and problems with thyroxine (T4 ) treatment. However, these assays, although sufficiently sensitive to allow more accurate quantification of subnormal values, are still not routinely used in certain parts of the United States." Measurement of serum TSH permits precise levothyroxine dosage in both replacement therapy and TSH suppressive therapy when supraphysiologic doses of levothyroxine are given to maintain TSH levels below normal. Evidence of the delayed complications of overzealous and minimally
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -
monitored T4 replacement in both overt and subclinical hypothyroidism, most notably in inducing bone demineralization, altering serum lipid profiles, and contributing to cardiac morbidity, particularly in elderly patients, has raised concerns about the dangers of T4 therapy when used in the long term in supraphysiologic doses to suppress TSH in both benign and malignant disease." Decreased bone mineral density and an accelerated rate of bone loss have been reported in the literature in both pre- and postmenopausal women who are receiving doses of levothyroxine sufficient to produce subnormal serum TSH levels.P:" A better understanding of growth factors that affect normal thyrocyte function and that may explain TSH independence of autonomous nodules, as well as a more selective individual approach to suppressive therapy of tumors in patients deemed to have a poor prognosis, will be of value in limiting the number of patients receiving long-term suppression. Excessive levothyroxine therapy, either intentional or inadvertent, is not as innocuous as once was supposed, and studies have shown that as many as 50% of patients treated with levothyroxine therapy, who were clinically euthyroid, were overtreated based on their serum TSH concentration. 19.20
Physiology and Pharmacology Levothyroxine treatment relies on a negative feedback on pituitary thyrotropin production. In euthyroid humans, 20% of circulating 3,5,3'-triiodothyronine (T3) is produced in the thyroid gland and 80% is formed extrathyroidally by monodeiodination of Tz, largely in the liver and kidney under the action of a selenium-dependent type I deiodinase, a selenoprotein." The presence of selenocysteine renders the conversion of T4 to T3 sensitive to dietary selenium levels.P T 3 is the principal functioning thyroid hormone binding to a nuclear receptor (T3 receptor) and regulating transcription of thyroid hormone-responsive genes.P Pituitary and cerebral cortical T 3 is, however, produced predominantly by local deiodinase II action, and thus central nervous system levels of active thyroid hormone depend on both circulating T 3 and T4. Conversion of T4 to T 3 in these tissues contributes equally to or even as much as 80% to levels of nuclear bound T3. Therefore, although most peripheral tissues depend primarily on circulating T 3 levels, the central nervous system is sensitive to both circulating T3and T4.24-26 In thyrotropin suppression treatment, the aim is not principally the physiologic replacement of T 4 (and T 3) as in hypothyroidism (although this may well be necessary in patients rendered hypothyroid after total or near-total thyroidectomy), but the use of T4 is to induce a particular level of TSH suppression by supraphysiologic dosing without rendering the patient clinically hyperthyroid. In this setting, the benefit-risk equation for TSH suppression therapy must be assessed for each patient on the basis of the likely hazards of untreated thyroid disease in benign cases or the likelihood of local or systemic recurrence in carcinoma as balanced against the potential complications of prolonged T4 overdosage. Precise feedback relations between circulating thyroid hormones and pituitary TSH secretion, along with exact measurement of serum TSH concentration, are essential in
69
the management of patients receiving suppressive levothyroxine therapy." Thyroid function and T 4 dosing can be monitored most accurately by new and highly sensitive immunometric assays for TSH that are sensitive for levels as low as 0.01 mUlL. The normal circulating TSH concentration is 0.5 to 3.5 mUlL, and the newer assays are at least 10 times more sensitive than the original TSH radioimmunoassays.P:" Basal TSH levels are directly proportional to the TSH response to thyrotropin-releasing hormone (TRH) stimulation, rendering this test virtually obsolete." Debate regarding the use of suppressive therapy centers on the role ofTSH as the principal growth-stimulating factor in benign and malignant disease and on the degree of TSH suppression needed. Thyroid suppression therapy has a very long history. It has been used as a treatment for goiter since the 12th century" and historically has had better clinical success in diffuse as opposed to nodular goiter." Its use was expanded by Crile to the treatment of patients with thyroid cancer using thyroid extract and desiccated animal thyroid.F Today, the principal TSH suppression agents used are levothyroxine and liothyronine. Levothyroxine is one of the most commonly prescribed medications; more than 15 million prescriptions are filled annually in the United States alone.P It is synthetically produced and is identical to T 4 secreted by the thyroid. It is the more frequently used agent and has a half-life of about 7 days. It is a more standardized preparation than Iiothyronine, being dose encoded by high-performance liquid chromatography," and its regular administration and compliance result in more stable serum levels ofT3.35 Gastrointestinal absorption is approximately 80%,36 with peak levels attained at between 2 and 4 hours, remaining above basal level for up to 6 hours.'? Liothyronine has a more powerful peripheral and central action and has a half-life of about 24 hours. It is used in emergency situations and when cessation of therapy should be limited, such as in the assessment of brittle-boned patients with thyroid cancer undergoing follow-up thyroid scanning. There is, however, considerable variation in T 4 dosing in patients during replacement and suppression" Combination preparations such as liotrix (T 4 plus T 3) and animal-derived products such as thyroid extract or thyroglobulin are rarely used today. These agents are less standardized and may lead to unwanted supraphysiologic rises in T 3, with clinically troublesome side effects for relatively low serum T 4 levels. The advantage of levothyroxine is a more controlled T 3 conversion in extrathyroidal sites, which is of value in fasting states and illness when peripheral generation of T3 is normally decreased, partly on the basis of variable absorption and bioavailability.v-" Several states, such as pregnancy, malabsorption, and caloric deprivation, and certain drugs alter levothyroxine needs, and these are of particular importance when supraphysiologic dosing is required (Table 8-1). During pregnancy, serum TSH levels increase largely as a result of an increase in T 4-binding globulins, with a consequent fall in circulating free T 4 and free T3. This is offset by a natural amelioration of such diseases as chronic autoimmune thyroiditis but, in general, T4 requirements tend to be greater. 39.40 Certain drugs may block T 4 absorption (e.g., cholestyramine." sucralfate," aluminum hydroxide," ferrous sulfate"), increase nondeiodinative T 4 clearance by pathways not leading to T 3 generation, such as
70 - - Thyroid Gland
sulfation and glucuronidation (e.g., rifampin.f carbamazepine." phenytoin [Dilantin]47), or inhibit the peripheral conversion of T, to T3 (e.g., amiodarone'v" and essential selenium deficiency'"), Conversely, levothyroxine dosage needs to be diminished in elderly persons in part because of a lower general requirement." The serum TSH levels should be monitored more often in these circumstances, with adjustment in levothyroxine dosage to maintain an appropriate therapeutic serum TSH level in those receiving suppressive therapy. Much of the concern about TSH suppressive therapy and supraphysiologic levothyroxine dosing has arisen from reports about the long-term complications of replacement therapy for primary and subclinical hypothyroidism.52 Does it matter whether thyrotropin levels are reduced below 0.1 mUlL in an otherwise healthy person with no clinical features of hyperthyroidism? There is increasing evidence that excessive levothyroxine administration, resulting in suppressed serum TSH levels, is associated with physiologic alterations in peripheral tissue. In several studies, as many as 50% of patients requiring levothyroxine replacement alone who were clinically judged to be euthyroid were actually deemed overtreated on the basis of TSH concentration.P Some evidence implicates overtreatment with harmful effects, particularly in elderly patients, most notably a sustained increase in nocturnal heart rate, a reduction in systolic ejection time, an increase in urinary sodium excretion, an increase in hepatic and muscular enzyme activity as well as serum ferritin level, and potentially hazardous alterations in blood lipid profile. In short, these are the metabolic effects of subclinical hyperthyroidism.54-56 It is becoming increasingly clear, however, that bone resorption is a significant problem in prolonged levothyroxine
usage, as indicated by an increase in serum and urinary calcium, a decrease in parathyroid hormone level, a rise in urinary excretion of pyridinium cross-links (specific markers for bone resorption), and a rise in serum osteocalcin (a peripheral marker for bone formation). These effects are not confined to postmenopausal women and are exaggerated when suppressive as opposed to replacement therapy is used,57-60 Premenopausal women treated with excess levothyroxine show a predominantly cortical bone loss, measured in wrist and hip, as opposed to trabecular bone loss, measured in the spine. 15-17 Postmenopausal women, on the other hand, show reductions in both cortical and trabecular bone mineral density.!"!? The risk is appreciably higher in patients who are already at risk for osteoporosis (heavy smokers and patients with inadequate calcium intake, steroid dependence, alcoholism, or prior hyperthyroidism), although this subclinical form of hyperthyroidism has not been associated with a clinical rise in symptomatic fractures." The development of osteopenia during TSH suppressive therapy is of increased concern because up to 70% of patients with nodular thyroid disease or thyroid cancer are female and have been receiving supraphysiologic suppressive treatment for decades. Conversely, undertreated patients (hormone replacement cases after thyroidectomy or iodine 131 therapy) suffer from subclinical hypothyroidism. Debate exists about the relative risks of this condition if left untreated, although on a background of impaired left ventricular function, the consequences are likely to be deleterious.f Overzealous TSH suppressive therapy may have major effects on lipid metabolism and cardiac function.
Thyroxine and Lipid Metabolism There is an overall increase in hyperlipidemia in overt hypothyroidism, and there have been claims of higher mortality from ischemic heart disease in undertreated patients. 63.64 In subclinical hypothyroidism the biologic efficacy of thyroid hormone replacement has been confirmed with observed changes in serum lipoprotein concentration, improvement in cognitive performance and indices of cardiac function, and reduction of subjective symptoms. The majority of patients show no fundamental changes in lipid profile during levothyroxine treatment for TSH suppression.f but occasional reports of deleterious changes in relative high-density lipoprotein (HDL)-low-density lipoprotein (LDL) cholesterol concentration have been documented.w'" Franklyn and colleagues''? have argued that supraphysiologic levothyroxine may be distinctly beneficial because of its effects on LDL cholesterol in reducing the number of cardiac events in those so treated, but it may not be possible to extrapolate the effects on lipid profile from replacement to suppressive therapy; this study was confined to women and showed a beneficial effect only in patients older than 35 years. The total cholesteroVHDL and LDL/HDL ratios, which are correlated with increased cardiovascular disease risk, have been shown to decrease with TSH suppressive therapy.70-72 That beneficial effects on lipids may be
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -
achievable only by inducing subclinical hyperthyroidism implies that the advantages of such deliberate treatment must be offset in each case against the expected delayed cardiac morbidity and the known consequences for bone metabolism.P
Thyroxine and Ischemic Heart Disease Clearly, T4 replacement is necessary to prevent the development of overt hypothyroidism in postsurgical patients. There is also an annual conversion rate of 3% from subclinical to clinical hypothyroidism after 131 1 therapy and slightly less than 1% per year after thyroidectomy. Post-thyroidectomy hypothyroidism is more likely in elderly patients and in those who have circulating thyroid auroantibodies.V" Myocardial infarction and angina are both recognized complications of levothyroxine therapy in hypothyroid patients, even in dosages as small as 25 ug/day. Forty percent of patients with a history of angina are unable to tolerate fully suppressive doses of T4 . 76 Patients with known cardiac disease who are older than 65 years should, therefore, be treated with caution. Substantial increases in both heart rate and left ventricular contractility tend to increase myocardial oxygen consumption, although slight reductions in ventricular afterload may offset this effect." It is likely that only a small percentage of patients will experience new-onset angina with TSH suppressive therapy; about 33% of patients will have significant improvement in preexisting angina, 50% will remain stable, and about 16% will worsen. Cardiac function was observed in a randomized l-year trial of levothyroxine therapy (mean dose 71 ug/day) in patients with subclinical hypothyroidism. There was no demonstrable difference in systolic time intervals between treatment and placebo groups. Abnormal values however, were restored to normal in the five patients with the most abnormal baseline values."? Other studies have shown improved cardiac contractility of up to a 10% mean increase in left ventricular ejection fraction with maximal exertion by the patient.?? Levothyroxine in such patients should be initiated at 50 ug, with 25-/lg increments at 3-month intervals until TSH is suppressed to one tenth of normal. In clinical practice, the vigor with which TSH suppression is undertaken is related more to the underlying condition for which it is prescribed than to the likelihood of worsening preexisting cardiovascular disease. Whether evidence exists for justification of suppressive therapy still remains unclear. In suppressive therapy, there remains a need (despite logistic difficulties in its conduct) for a longitudinal study to assess the effects of levothyroxine on bone metabolism in defined groups of patients. The theoretical advantages of a possible reduction in morbidity from cardiac disease must be balanced against the effects on a susceptible population of levothyroxine-induced osteopenia. However, there appears to be no difference in overall morbidity between the patients with normal TSH levels and those with mildly suppressed TSH levels." Clearly, although lessons can be learned from patients
71
treated with replacement T4 for hypothyroidism, the metabolic and systemic effects may not be readily extrapolated to patients in whom it is used for deliberate TSH suppression. In patients treated with T4 suppression, clinical judgment alone is insufficient to monitor cases."
Thyroid-Stimulating Hormone Suppression and the Solitary Thyroid Nodule Studies in this area are confusing in that they include a heterogeneous collection of goiters (such as nodules with functional autonomy or cystic degeneration), are frequently uncontrolled and poorly randomized, fail to establish compliance or consistent TSH suppression, and do not objectively evaluate nodule size and treatment response. Inclusion in a suppressive treatment arm relies on the absolute ability to distinguish a benign from a malignant nodule largely on the basis of accurate fine-needle aspiration cytology.82-86 TSH suppressive therapy is of unproven benefit in the solitary nodule. The reported incidence of reduction in thyroid nodule size varies from 9% to 68%,87.88 although disappearance of the nodule is rare. Several controlled, randomized, double-blind trials have failed to show significant reduction in nodular size on the basis of volumetric calculation by high-resolution ultrasonography, although most studies have shown a marked reduction in contralateral thyroid lobar volume during T4 therapy provided it is carried on for periods exceeding 6 months. 78,87-91.93-99 In three prospective randomized studies involving a total of 167 patients with mean treatment periods ranging from 6 months to 18 months, levothyroxine was shown to be no more effective than placebo in reducing nodule size. 93.97, l oo However, in other studies, nodule size decreased more than 50% in 56% of levothyroxine-treated patients with serum TSH suppression.f Both these studies lacked placebo control groups for comparison but still recorded a decrease in nodule size during levothyroxine therapy greater than the natural 15% to 30% observed spontaneous regression rate (Table 8-2). Further, some of these studies have confirmed that there is a natural tendency for up to one third of solitary nodules to regress spontaneously during follow-up beyond 1 year. In some, this is explained by hormonally insensitive events such as cystic degeneration, resorption of colloid, or necrosis of follicular epithelia, and in others, it is explained by regression of surrounding normal, hormonally responsive thyroid. Treatment of the solitary nodule medically in this way should be undertaken with caution; it must be remembered that fine-needle aspiration cytology has a false-negative rate of 5% and that up to 15% of solitary nodules continue to grow with adequate TSH suppressive treatment.101.I02 Studies suggest that the response of a nodule to T4 is independent of age, duration of nodule, pretreatment nodular size, TRH-TSH amplitudes, initial technetium uptake, and pretreatment thyroglobulin level. The large or complex nodule should not be medically treated because it is less likely on average to respond and because cytologic sampling error is always possible.
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Recommendations for the Use of Thyroxine in the Solitary Thyroid Nodule Given that the expected nodule response rate slightly exceeds the reported natural regression rate, suppression therapy may be considered to be of slight benefit. If it is to be used (perhaps in the context of an institutional trial), it must be for the proven solitary nodule that has unequivocally negativecytology,is homogeneously solid on ultrasonography, and has normal or reduced uptake on technetium 99m pertechnetate scanning (Fig. 8-1). These nodules ideally should be associated with a normal thyroid profile and negative thyroglobulin and thyroid peroxidase autoantibody status. Patients with a large nodule, particularly if it possesses echogenic heterogeneity or has been present for longer than 2 years, or in whom there is a history of head and neck irradiation, should not be treated in this manner. One may aim for a TSH suppression level of 0.05 to 0.10 mUlL in premenopausal patients without cardiac risk factors and for a level of 0.1 to 0.3 mUlL in postmenopausal women, particularly those with a known history of osteoporosis, and in men older than 65 years with a recognized cardiac history. Treatment is continued for 6 months to 1 year with clinical and ultrasonographically calculated nodular volume based on anteroposterior length and width, assuming the nodule to be a spherical ellipsoid. This is complemented by assessment of the contralateral thyroid lobar volume to gauge response to suppression.l'" Ultrasonography is essential in the follow-up of these patients because of its greater accuracy in nodule assessment and because it eliminates patients' and clinicians' bias.l'" If the nodule regresses, treatment may be stopped after 6 to 12 months of therapy and reinstituted if it remains stable or gradually enlarges after 6 months of therapy cessation. If the nodule actually enlarges with compliant therapy, repeated fine-needle aspiration cytology or thyroidectomy is mandatory to exclude
Clinical solitary nodule
~High-resolution
Ultrasonography
!
confirjmed solitary-
i: TSH Thyroglobulin autoantibodies
/FNA Negative TSH suppression
»> Premenopausal
----. Postmenopausal
Thyroid-Stimulating Hormone Suppressive Treatment of the Multinodular Goiter Sporadic, nontoxic multinodular goiters are pathologically diverse with cystic, colloid, hemorrhagic, fibrotic, and calcific components. Their natural history is characterized by unpredictable periods of stability in size and function and occasionally by rather sudden enlargement. There is considerable debate about the efficacy of levothyroxine suppressive treatment of the nonendemic, nontoxic multinodular goiter, and the results are even less satisfying in many cases than those for solitary nodular disease because of the greater amount of pathologic thyroid tissue that is likely to be hormonally insensitive, the variability of TSH dependence given the likelihood of multiple other thyroid growth factors, and the difficulty in objectively evaluating the response of dominant nodules. This should be coupled with the fact that up to 10% of dominant masses within multinodular goiters may actually spontaneously regress during follow-up.'!" A randomized study of 115 patients showed a total reduction in thyroid volume of more than 13% (by ultrasonographic measurement) in 58% of patients receiving TSH suppressive doses of levothyroxine for an average of 9 months. The thyroid volume was also shown to increase on cessation of levothyroxine therapy. I 19
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Evidence for the routine use of suppressive levothyroxine in multinodular goiter is varied. Two controlled clinical trials to assess this question demonstrated benefit in reduction in overall goiter size in about 50% of cases (Table 8_3).119.120 Accurate and consistent assessment of dominant nodules within an abnormal gland, along with a concern that malignancy may coexist in a small percentage of cases, makes the routine use of TSH suppressive therapy for this condition inappropriate except in patients for whom surgery is contraindicated.98,121 No clear response association exists with patient's age, duration of goiter, family history of thyroid disease, pretreatment thyroid volume, or preliminary radioactive iodine uptake.99.122-125 The mechanism in the patients who respond is unknown, but T4 has been shown to influence thyrocyte growth synergistically in the presence of other growthstimulating factors.!" Many questions remain concerning this type of treatment. What constitutes response? Is complete regres-sion necessary, and is uniform regression ever possible? Considering that a significant proportion of patients are never submitted for surgery, what is the true underlying incidence of carcinoma?
point in continuing treatment if an effect is not observed within this time. It should also be noted that after surgery for nodular nontoxic goiter, only 15% of patients experience recurrence; hence, potentially lifelong treatment is unnecessary in 85%. One randomized trial comparing levothyroxine therapy versus no therapy after thyroid lobectomy showed no difference in thyroid size after a follow-up of 1 year when the thyroid remnant size was recorded ultrasonographically.F' Several large retrospective studies, including a total of 656 patients and mean follow-up of 5 to 8 years, showed that postoperative levothyroxine therapy did not decrease the frequency of goiter recurrence, which on average was 10% at 8 years. 128 In many patients older than 50 years, dominant nodules never change in size after discovery. Because of the logistic difficulty in assessing response to suppressive treatment in multinodular goiter, we do not recommend its use, although other clinicians do.
Recommendations for the Use of Thyroxine in the Nontoxic Multinodular Goiter
Diffuse nontoxic goiter can be sporadic or endemic. Iodine treatment is clearly the treatment of choice over T4 therapy in endemic cases, as shown by Hintze and colleagues!" in a 1989 multicenter trial. The most common cause of adult diffuse nontoxic goiter in nonendemic areas is chronic autoimmune thyroiditis. Both microsomal cytoplasmic and thyroid peroxidase autoantibodies are evident in 10.3% of adult women and 2.7% of adult men in clinical surveys of sporadic goiter. Conversely, about one third of patients with detectable antibodies have clinical goiters. 1 Chronic autoimmune thyroiditis is also the most common cause of sporadic childhood and adolescent goiter, of which there is a spectrum of illness ranging from focal thyroiditis to Hashimoto's thyroiditis. Such patients typically have high titers of antimicrosomal antibodies and are often hypothyroid, either clinically or subclinically. Levothyroxine is given to both euthyroid and hypothyroid patients with chronic goitrous thyroiditis of this type and has been shown to be associated with a mean reduction in palpable thyroid volume.!" This type of treatment must be balanced against a small chance of spontaneous regression of active Hashimoto's
In practical terms, if TSH suppressive treatment is to be tried, it would be logical to give enough levothyroxine to reduce the TSH consistently to 0.5 mUlL. If the goiter decreases in overall size or remains static (both clinically and by ultrasonography), treatment may be continued indefinitely in a low dose (perhaps in patients younger than 60 years), with periodic monitoring of TSH and thyroglobulin levels to assess the patient for the likelihood of functional anatomy. If the goiter clinically enlarges, further evaluation for underlying carcinoma is necessary. If the serum TSH concentration is low in the clinically euthyroid case to begin with, levothyroxine is contraindicated because of the likelihood of subclinical incipient functional autonomy. The natural history of these glands is toward hyperthyroidism over a 15- to 25-year period of goiter follow-up. Goiters that respond usually do so within a period of 6 months of commencement of therapy, so there is little
Thyroxine Suppressive Therapy and Diffuse Goiter
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - - 75
disease in a subgroup of patients with detectable thyrotropinblocking antibodies, which inhibit the peripheral action of TSH.13J.l32 The natural history of autoimmune thyroiditis, however, is in general toward inexorable hypothyroidism at a rate of roughly 5% per year, especially in patients with very elevated antibody titers.73.133·134 Few trials of levothyroxine suppressive therapy in diffuse goiter have been conducted (Table 8_4).135-137 These suggest a reasonable response rate for adequately suppressive therapy over a 3- to 6-month period, although the level of TSH suppression required is not known. Clearly, if the gland is unresponsive after 6 months of compliant therapy, levothyroxine should usually be withdrawn. One study observed that a return to normal of the serum TSH resulted in a mean decrease of 32% in thyroid volume, with almost 50% attaining normal thyroid size after 2 years of therapy.138
Thyroid-Stimulating Hormone Suppression and the Post-Thyroidectomy Patient Levothyroxine may prevent clinical hypothyroidism after bilateral or subtotal thyroidectomy and occasionally after unilateral Iobectomy.P? In three randomized, controlled trials comparing levothyroxine with placebo, there was no demonstrable difference in nodular recurrence after a range of thyroid operations in the TSH-suppressed patients.14o-142 Miccoli and colleagues'< demonstrated an advantage for suppressive as opposed to substitutive T4 dosing on echographic follow-up at 3 years, but this was in an area of endemic goiter in northern Italy, where the rate of nodular recurrence postoperatively is normally relatively high. The particularly high early recurrence of echographically demonstrable postoperative recurrence after thyroidectomy in the latter article (78% on substitutive T4 therapy) may not be indicative of the general Western experience. Large, uncontrolled, retrospective series, however, with prolonged follow-up over periods ranging from 5 to 8 years, have failed to demonstrate an advantage for patients treated with levothyroxine after surgery.122,143,144 The role of T4 therapy in patients with normal serum TSH concentration who have had thyroid lobectomy only is debatable. Its use has mainly been advocated in cases in which preoperative autoantibody titers are high and postoperative hypothyroidism is anticipated rather than for prevention of recurrence,
although antibody titers do not clearly discriminate in untreated cases for the development of either overt or subclinical hypothyroidism. 145 After subtotal thyroidectomy, it is clearly recognized that with extended follow-up moderate hypothyroidism develops in about 20% of cases. This depends largely on the size of the thyroid remnant.!" the degree of lymphocytic infiltration of the gland,"? the preoperative level, if present, of complement-fixing thyroid antibody.l" and the original condition for which thyroidectomy was performed. 149 There is evidenceI43.150-154 from Westermark and colleagues that T4 dosage needs to be higher in the patients treated with subtotal thyroidectomy than in those treated by unilateral lobectomy to reduce TRH stimulation of TSH secretion, implying that pituitary TRH responsiveness needs a longer period of recovery after supraphysiologic T4dosing than basal TSH production.l" Because of the variability of goiter growth, both de novo and postoperatively, and the fact that a certain percentage of patients exhibit flat TRH-TSH responsiveness preoperatively, other mechanisms apart from the TSH receptor must be invoked, most notably the presence of TSIs. Because of the expression by thyroid tissue of human leukocyte antigen DR, it has been postulated that a secondary autoimmune process may be induced as part of the goitrous phenomenon.l" On balance, there is little evidence for the routine use of suppressive as opposed to replacement therapy after lobectomy or subtotal thyroidectomy. This must be weighed against the known hazards of secondary surgery to the thyroid in terms of recurrent laryngeal nerve injury and serious sustained hypoparathyroidism should reoperation be needed for recurrent goiter,157,158
Thyroid-Stimulating Hormone Suppression and Miscellaneous Benign Goiters Levothyroxine has been advocated for a variety of benign goitrous conditions, most notably in the follow-up of patients who have experienced irradiation to the head and neck in some cases of functionally autonomous nodules and in postpartum and neonatal goiter. Irradiation during childhood or adolescence for a range of benign conditions (tinea capitis, tonsillar and thymic enlargement, acne vulgaris, or head and neck vascular malformations) has been associated with a substantial increase
76 - - Thyroid Gland in both benign and malignant nodules of the thyroid as well as an increase in parathyroid adenomas.159-162 Controversy exists in regard to the optimal management of patients both with and without palpable thyroid nodules who have been exposed to low-dose irradiation to the thyroid area. Evidence suggests that thyroid suppressive therapy is as likely to be successful in this group of patients as in those with sporadic multinodular goiter, but the main difficulty seems to be in the delineation of underlying malignancy.95.163.164 Shimaoka and coworkers'P were the first to conduct a double-blind study of suppressive treatment using T3, desiccated thyroid, or both, in irradiated patients with measurable thyroid nodules. In 1500 patients exposed with a 34% incidence of nodules and an average interval between radiation exposure and nodule detection of 27 years, TSH suppression of nodules was possible in 18% of patients over 6 months of therapy. This approach was uncontrolled, however, and made no attempt to assess the efficacy of suppression in a heterogeneous group of patients. Clearly, there is a risk of underlying malignancy in this group on the order of 5% of those without clinical nodules and 40% of those with clinical nodules. Thus, and in the presence of a clinical nodule, because of this possibility as well as the potential for cytologic sampling error, total thyroidectomy is generally advocated. A question remains, however, regarding the role of suppressive therapy in patients without either clinical or subclinical nodules. The rationale for treating the latter group of patients is that an intact pituitary thyroid axis is needed for the production of thyroid tumors that are likely to be TSH sensitive, as has been demonstrated in rats by the protective effect of hypophysectomy on the irradiated thyroid.165.166 In a study by Fogelfeld and associates.P' 511 patients exposed were monitored for up to 40 years after irradiation following initial surgery for benign thyroid nodules, with an overall nodular recurrence rate of 19.5%. Thyroid hormone supplementation reduced the incidence of recurrent nodules from 35.8% in the untreated group to 8.4% in the treated group. TSH suppressive therapy, however, had no effect on the rate of underlying malignancy, which was 19.2%.151 The implication is that recurrent nodules of this type, which develop during TSH suppressive therapy, are much more likely to be malignant. Such a study should, however, be viewed with caution because of its lack of randomization, its failure to substantiate effective TSH suppression in many cases, and the nonstandardization of T4 dosage. Given that there is an increased incidence of hypothyroidism and thyroid nodules in children exposed to head and neck irradiation for such conditions as Hodgkin's disease, neuroblastoma, Wilms' tumor, and leukemia, as well as in adults irradiated for breast cancer and lymphoma, the role of TSH suppressive therapy in an expanding population of patients needs to be defined.167.168 The question remains whether patients who have been exposed should have suppressive treatment in the absence of nodules as well as the correct management of ultrasonographically demonstrable impalpable nodules. It should also be recognized that the rate of falsenegative fine-needle aspiration cytology is significantly higher in the irradiated gland. 169 What is also unknown is the role of TSH suppressive treatment during the time of neck irradiation.
Autonomously functioning nodules represent about 5% of all solitary or dominant nodules in the thyroid gland. Toxicity is more a feature of nodule size, with nodules smaller than 2.5 em in diameter rarely causing clinical hyperactivity. Young patients with functionally autonomous nodules with low TSH levels are more likely to experience clinical toxicity and have a slightly higher incidence of malignancy. 170 Functional status of such nodules with low TSH concentration is best assessed by both technetium 99m and iodine 123 scanning because the discordant nodule (hot on 99mTc, cold on 1231) is more likely to represent a carcinoma. Although the growth and function of many of these nodules appear to be TSH independent, the true incidence of hyperthyroidism over prolonged follow-up is only about 10%.171 These nodules may also be characterized by a relative increase in the T 3ff4 ratio (T 3 toxicosis). Furthermore, there is a moderate rate of spontaneous regression of these autonomous nodules with time, and their development may represent one part of the spectrum of multinodular goiter. 104 Because autonomous thyroid nodules are uncommon and because patients with these nodules are treated with either radioiodine or surgery, their true natural history remains unknown. The demonstration of a responsive TSH receptor mechanism in these cases, as evidenced by an intact TSH adenylate cyclase system in tissue culture.F? and the fact that exogenous T4 has been shown to reduce the radioiodine uptake and size in certain nodulesI73.174 imply that there is at best only partial autonomy from TSH influence. These more "dependent" cases are on average smaller with preserved and unsuppressed surrounding parenchyma and over time tend to involute or undergo degenerative change. However, the role of TSH suppression in such cases is quite unclear because there is a risk of rendering patients subclinically hyperthyroid if treatment is based merely on the presence of a low preliminary TSH concentration or if the nodule inadvertently undergoes spontaneous degeneration during suppressive treatment.!" It is likely that these so-called autonomous nodules represent a heterogeneous mix of thyroid tissues, with some follicles predisposed toward hyperfunction, autonomy, and TSH independence and others toward autonomous growth or function, or both, exhibiting some initial T 4 responsiveness but later undergoing degeneration and hypofunction. Because these features are essentially unpredictable, TSH suppressive therapy is usually not recommended. T 4 may also be of value in the treatment of transient goitrous hypothyroidism in infants exposed to the transplacental passage of thyrotropin receptor antibodies in maternal chronic autoimmune thyroiditis. Changes in T 4-binding globulins and relative subclinical reductions in circulating free T4 and T3 during pregnancy are not compensated for by increased thyroid hormone secretion by the gland because of lack of functioning thyroid tissue. Such patients, with Hashimoto's disease during pregnancy, tend to suffer from repeated episodes of transient postpartum thyroid dysfunction, which may require suppressive treatment in its own right and ultimately replacement therapy because of the small risk of clinical hypothyroidism in multiparous cases.l?"
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - - 77
Thyroid-Stimulating Hormone Suppression and Thyroid Cancer Controversy exists in thyroid cancer management about the extent of surgery, the use of 131 1 ablation therapy, the place of thyroglobulin assay in follow-up, and the role and level of TSH suppressant treatment. Further, there is debate about the degree of TSH dependence of differentiated thyroid carcinomas and the importance of other thyroid growth factors.
Thyroid Growth Factors and Thyroid Carcinoma Thyroid tumors vary markedly in prognosis, and the natural history of differentiated tumors is long. The control of thyroid cell growth is complex and is influenced by many hormones and growth factors operating through distinctly different cell signal transduction systems. Classically, TSH is considered the major thyroid growth hormone, and, although there is no dispute about its role in stimulating thyroid gland function, its effects on thyroid growth and particularly abnormal growth are in question. TSH stimulates "differentiated" thyroid functions, most notably iodine uptake and organification as well as thyroglobulin synthesis, by activating a membrane-bound adenylate cyclase system and increasing intracellular cyclic adenosine monophosphate; this results in cytoplasmic protein phosphorylation and increased nuclear transcription. I?? In general, follicular thyroid neoplasms have enhanced adenylate cyclase activity in response to TSH stimulation and tend to have an inverse correlation with the state of aggressiveness of the tumor.!" It is also evident that TSH functions through the phosphatidyl inositol phosphokinase C-intracellular calcium system because it is known that high dietary calcium, particularly in areas of endemic iodine deficiency, promotes goiter formation. I?9,180 Elevated levels of TSH promote thyroid tumors in rats, and these tumors can be prevented by treating with thyroid hormone (TSH suppressionj.l'" TSH is generally considered a relatively weak factor for human thyroid cell growth in tissue culture. 182 The cells tend to be very heterogeneous in their response, 183 and transplanted human thyroid tumors ultimately demonstrate TSH independence in vitro. 165 The fact remains that thyroid tumor tissue has demonstrable TSH receptor sites, although the importance of these sites clinically is another matter.P' The list of known thyroid growth factors is quite long (Table 8-5) and includes 'I'Sls, epidermal growth factor, epidermal growth factor receptor (EGFr), insulin-like growth factors, and prostaglandin E2. Inhibitors of thyroid growth in vitro include transforming growth factor ~, somatostatin, and vitamin A 185-187 EGF functions as a powerful thyroid growth stimulant, possibly more active than TSH and perhaps acting synergistically with TSH, promoting cell growth but inhibiting cellular differentiated functions.188.189 Further, EGFr expression has been shown to be associated with reduced disease-free survival in differentiated tumors. 190.J91 Thyroid cell proliferation is further affected by growthpromoting oncogenes and inhibited by tumor suppressor genes.
Their protein products presumably replace known specific growth regulators, growth factor receptors, and signal transducers. TSIs and fibroblast growth factor function as circulating growth factors. The protooncogene c-erb B2 (HER-2/neu) is a plasma membrane receptor and the ras oncogene a signal transducer for thyroid growth. 192 c-erb B2 is a surface growth receptor that has been shown to be frequently overexpressed in a proportion of breast and ovarian cancers and to correlate with poor prognosis. 193 Oncogenes, whether natural (protooncogenes) or viral, encode protein products, which act in either the nucleus or cytoplasm. Both ras and c-myc oncogenes are overexpressed in about 60% of differentiated thyroid neoplasms; prognosis is worse in the cases in which c-myc is heavily encoded. 194,195 Frauman, Lemoine, Wyllie, and Clarkl96-2oo and their colleagues have discussed the subject in great depth. Both the tumor suppressor gene p53, which has been heavily implicated in the tumorigenesis of colorectal carcinoma, and platelet-derived growth factor have been found to be overexpressed in anaplastic tumors. 201,202 It is evident then that TSH suppression in thyroid cancer is likely to have only a partial role in tumor control, perhaps similar to that of tamoxifen therapy in women with breast cancer.
Thyroid-Stimulating Hormone Suppressive Therapy in Thyroid Cancer TSH suppressive therapy was first advocated for thyroid carcinoma by Dunhill in 1937 203 and was used extensively in the treatment of disseminated differentiated thyroid cancer by Crile. 204 The rationale for its use has subsequently been the demonstration of TSH receptors in malignant tissue from differentiated thyroid cancers of follicular cell origin and the noted increase in adenylate cyclase activity in response to TSH stimulation in vitro. 205,2o6 Thyroid tumors, however, that already have increased basal TSH adenylate cyclase activity are unlikely to be particularly responsive to TSH suppression.P?
78 - - Thyroid Gland It is clear that 80% of patients with papillary thyroid cancer and many cases of follicular thyroid cancer do well almost regardless of how they are treated.208.209 TSH suppression has been shown to date to have no proven benefit in patients with medullary thyroid carcinoma. The use of TSH suppressive therapy has to show survival advantage over prolonged follow-up for the patients deemed to have poor prognoses and, in view of the potential side effects of long-term suppressive treatment, it seems sensible to individualize its use on the basis of expected likelihood of local or systemic recurrence. Factors associated with a particularly poor prognosis in differentiated thyroid cancer include poor 1311 uptake (such as Htirthle cell variantsj.i'? decreased adenylate cyclase response to TSH,178 DNA aneuploidy,"! the expression of EGFr,191 and the extent of initial surgical treatment. 212 This has been complemented by the AGES classification devised by Hay and colleagues to classify patients as high risk and low risk on the basis of age, histologic grade, extent of primary tumor, and primary size.213 Notably, patients older than 40 years at diagnosis with tumors larger than 4 em with marked DNA aneuploidy have been shown to have markedly worse disease-free and overall survival.i" In this sense, it is advocated that TSH suppressive therapy should be adjusted to individual prognostic factors to avoid unnecessary radical surgery, radiation exposure, and the costs associated with monitoring patients at minimal risk for recurrent disease. The use of TSH suppression is very much aligned with the view that differentiated thyroid carcinoma should be treated by total thyroidectomy. The advantage of total thyroidectomy in such cases is to permit both diagnostic and, where appropriate, ablative radioactive 131 1 to be administered without the problem of a competing thyroid lobe as well as to diminish the likelihood of troublesome recurrence in the central neck, which is difficult to treat and whose surgical therapy is fraught with considerable morbidity.215·216 Other advantages of total thyroidectomy in this setting include the removal of the contralateral lobe, which has as much as an 80% chance of containing a microscopic focus of carcinoma,"? as well as the elimination of the very small risk of a differentiated tumor dedifferentiating into an anaplastic cancer.t" Total thyroidectomy permits better potential ablation of metastatic disease and allows serum thyroglobulin levels to be more reflective of recurrence. The evidence for T 4 treatment actually improving survival in differentiated carcinoma is at best uncontrolled. Mazzaferri 219,220 and Massin-" and their coworkers showed the best long-term survival in the patients treated by total thyroidectomy, ablative radioiodine, and deliberate TSH suppression. A beneficial effect has been reported in both papillary and follicular cancer,222 in papillary cancer alone,22o and in neither.F' The most convincing evidence comes from Mazzaferri, who was able to show a cumulative recurrence rate for papillary carcinoma of 17% for patients receiving T 4 compared with 34% when no T 4 was used over a lO-year follow-up period.P' This retrospective series was neither controlled nor randomized. However, another large study failed to show any improvement in survival with thyroid hormone therapy.-" T 4 is probably tumor static and not tumoricidal. The dose requirements and level of required TSH suppression are
simply not known.F" No study has documented conclusively the optimal degree ofTSH suppression, and patients' compliance is an issue that remains largely unexplored. Because of the heterogeneity of thyroid cancers, their variable prognostic indicators, the required length of follow-up needed to demonstrate survival advantage, and a general failure to record uniformly both the presence and extent of TSH suppression, it seems unlikely that such a controlled, randomized, prospective trial assessing the value of levothyroxine, particularly in carcinoma subgroups, will ever be conducted.F' Suppression of TSH to less than 0.1 mUlL is recommended. The average daily dose of T 4 to achieve this level of suppression is usually 2.2 to 2.5 ug/kg. Because low-risk cases represent about 75% of all patients-" and the incidence of local recurrence is greatest within the first 5 years after thyroidectomy.-" it is recommended that high-level TSH suppression be used for this initial period, allowing the TSH concentration to rise to between 0.1 and 0.3 mUlL if no recurrences are demonstrable at 5 years.
Recommendations for the Use of Levothyroxine in Thyroid Cancer The consensus recommendation currently is that TSH suppressive therapy should be given postoperatively to all patients with differentiated thyroid cancer. The exact definition of appropriate TSH suppression to suppress tumor growth adequately remains unclear. Studies with very large numbers and follow-up would be required to detect significant differences. The true efficacy of ablative 131 1 has never been established in a controlled clinical setting. 228,229 In the postoperative setting in the cases believed to be high risk (the older male patient with a tumor larger than 4 em with either capsular or angioinvasion if follicular or extensive lymphadenopathy if papillary), T 4 replacement therapy is avoided for 4 to 6 weeks. This allows maximal TSH stimulation to occur and permits a valuable assessment of postoperative thyroglobulin levels (because thyroglobulin levels increase as serum TSH levels increase in patients with remnant normal thyroid tissue or metastatic thyroid cancer after thyroidectomyj.P" In some patients with rapidly growing metastases, it may be critical to minimize TSH stimulation of the tumor after thyroidectomy or 1311scanning or ablation, and this is best achieved by the use of T3, which, because of its shorter half-life, needs to be discontinued for only about 2 weeks to stimulate TSH for diagnostic or therapeutic purposes.P' It can be seen that radioiodine scanning and ablation are not trivial undertakings. The need to stop replacement therapy and to render the patient at least subclinically hypothyroid, along with the precautions necessary in the use of radiopharmaceuticals, must be coordinated by a nuclear medicine physician with a specific interest and experience in thyroid tumor treatment. The timing of the first scan, the indications for remnant removal or ablation, and the interval between scanning are all matters of controversy. Serum thyroglobulin determination is also comparable to or more sensitive than 131 1 scanning in the follow-up of
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -
patients with differentiated carcinoma. Thyroglobulin is a large glycoprotein synthesized by thyroid follicular cells and stored in colloid, providing the tyrosyl groups for iodination and coupling to form both T 3 and T 4. TSH stimulates thyroglobulin release, and thus serum thyroglobulin is elevated in any disease associated with an increased mass or activity of the gland. As a result, it is elevated in endemic and sporadic goiter, thyroiditis, and benign and malignant thyroid neoplasms.P? Its use in the assessment of patients after total thyroidectomy is roughly equivalent to that of radioiodine scanning. 233 -238 In 8% to 22% of cases of differentiated thyroid carcinoma, thyroglobulin measurement is difficult, however, because of circulating antithyroglobulin antibodies leading to spuriously high levels.P? although the newer use of monoclonal antibodies to thyroglobulin and immunometric assays will lessen this problem.s'" A serum concentration suppressed according to a second-generation assay with a TSH of less than 0.1 mUlL may be readily detectable by a third-generation assay with a limit of 0.01 mUlL. The term "undetectable" then becomes obsolete when assessing TSH suppression and is relative to the assay used. Equally, in a small group of patients with nonfunctioning but differentiated metastases (particularly elderly patients with invasive Hiirthle cell tumors), both thyroglobulin measurement and sestamibi or thallium scanning or technetium pyrophosphate bone scanning, or a combination, are superior to diagnostic 1311 scans. 24 1,242 TSH suppression has been shown to reduce recorded levels of thyroglobulin in patients with proven functional metastases, and thus thyroglobulin levels are best assessed with the patient not receiving replacement thyroid hormone. 243 ,244 An elevated thyroglobulin concentration with a normal 1311 diagnostic scan without thyroid hormone should alert the clinician to the possibility of nonfunctioning osseous or pulmonary metastases and result in careful clinical assessment with standard radiologic methods for detecting metastatic disease, such as computed tomography scanning, skeletal surveys, and magnetic resonance imaging. When treated with therapeutic doses of 1311, some of these patients have their thyroglobulin levels decrease to below 3 ng/mL, and metastatic tumor is seen on a follow-up scan (approximately 5 days after treatment). The value of thyroglobulin measurement after simple lobectomy in thyroid cancer is clearly debatable, but if it is elevated after such surgery in patients receiving levothyroxine suppression (i.e., above the normal range for an intact thyroid lobe), a search for metastatic disease should be initiated. 232,245 An algorithm for the use of TSH suppression therapy, based on data from Schlumberger and colleagues.s" is shown in Figure 8-2.
Conclusion Treatment by supraphysiologic dosing of levothyroxine is done to create adequate suppression of TSH without inducing clinical evidence of hyperthyroidism. The rationale is that TSH is one of the principal stimulants of thyroid growth. Its use is recommended in patients after a total thyroidectomy for differentiated carcinoma of the thyroid, particularly
79
After total thyroidectomy (wait 4-6 weeks off T4 or 2 weeks off T3)
!
131 1 total
body scan T4, TSH, TG, pregnancy test, if female Anti·TG antibody status
~
TG < 2.5
!
Annual clinical examination Every 5 years 131)
TG > 5
!
Annual clinical examination
scan
131 1 scan
TG TG
Chest x-ray film
Chest x-ray film
A
Low TG off T4
High TG off T4 Ablative
131 1
""T"
Ablative 131 1
CT scan of neck and chest Bone scan Thallium-201 scan
FIGURE 8-2. An algorithm for the use of thyroid-stimulating hormone (TSH) suppression in the follow-up of thyroid carcinoma. CT =computed tomography; 1311 =iodine 131; TG =thyroglobulin; T3 = triiodothyronine; T4 = thyroxine. (Data from Schlumberger M, Travagli JP, Fragu P, et al. Follow-up of patients with differentiated thyroid carcinoma: Experience at Institute Gustave-Roussy, Villejuif. Eur J Cancer Clin Oncol 1988;24:345.)
in the first 5 years after surgery when there are prognostic factors that imply a worse overall prognosis for the tumor. Suppressive therapy is not recommended in patients with multinodular goiter after thyroid resection for benign disease because of the difficulty in assessing dominant masses within an abnormal gland. Replacement therapy to avoid hypothyroidism may be useful. Suppression treatment must be stopped before diagnostic scanning and thyroglobulin assessment in malignant disease. Treatment with T4 to suppress TSH must be monitored closely because of the risks of subclinical hyperthyroidism and T4-induced osteopenia and cardiac dysfunction, particularly in elderly persons.
REFERENCES 1. Tunbridge WM, Exered DC, Hall R, et al. The spectrum of thyroid disease in a community: The Whickham survey. Clin Endocrinol (Oxf) 1977:7:481. 2. Scriba PC, Beckers C, Burgi H, et aJ. Goiter and iodine deficiency in Europe: Report of the Subcommittee for the Study of Endemic Goiter and Iodine Deficiency of the European Thyroid Association. Lancet 1985;1:1289. 3. Maxon HR, Thomas SR, Saenger EL, et aJ. Ionizing irradiation and the induction of clinically significant disease in the human thyroid gland. Am J Med 1977:63:967.
80 - - Thyroid Gland 4. De Groot U, Reilly M, Pinnameneni K, et al. Retrospective and prospective study of radiation-induced thyroid disease. Am J Med 1983;74:852. 5. Silverberg E. Cancer statistics, 1984. CA Cancer J Clin 1984;34:7. 6. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955;15:1270. 7. Fukunaga FH. Occult thyroid carcinoma. In: DeGroot U, Frohman LA, Kaplan EL, Refetoff S (eds), Radiation Associated Thyroid Cancer. New York, Grune & Stratton, 1977, p 161. 8. Scheible W, Leopold GR, Woo UL, et al. High resolution real-time ultrasonography of thyroid nodules. Radiology 1979;133:413. 9. Greenspan FS. The problem of multinodular goiter. Med Clin North Am 1991;75:195. 10. Horlocker IT, Hay Il), James EM, et al. Prevalence of incidental nodular thyroid disease detected by high resolution parathyroid ultrasonography. In: Medeiros-Neto G, Gartan E (eds), Frontiers in Thyroidology, Vol I. New York, Plenum Press, 1986, p 1309. II. dos Santos-Silva I, Swerdlow AJ. Thyroid cancer epidemiology in England and Wales: Time trends and geographical distribution. Br J Cancer 1993;67:330. 12. Adami HO, Wilander E, Coleman MP. Trends in thyroid cancer incidence in Sweden 1958-1981 by histopathologic type. Int J Cancer 1991;48:28. 13. Kaplan MM. Assessment of thyroid function during pregnancy. Thyroid 1992;2:57. 14. Toft AD. Thyroxine therapy. N Engl J Med 1994;331:174. 15. Ross DS, Neer RM, Ridgway EC, Daniels GH. Subclinical hypothyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary thyroid axis with t-thyroxine, Am J Med 1987;82: 1167. 16. Paul TL, Kerrigan J, Kelly AM, et al. Long-term i.-thyroxine therapy is associated with decreased hip bone density in premenopausal women. JAMA 1988;259:3137. 17. Taelman P, Kaufman JM, Janssens X, et al. Reduced forearm bone mineral content and biochemical evidence of increased bone turnover in women with euthyroid goitre treated with thyroid hormone. Clin Endocrinol (Oxf) 1990;33:107. 18. Adlin EV, Maurer AH, Marks AD, Channick BJ. Bone mineral density in postmenopausal women treated with i.-thyroxine. Am J Med 1991; 90:360. 19. Hennessey JV, Evaul JE, Tseng YC, et al. t-Thyroxine dosage. A reevaluation of therapy with contemporary preparations. Ann Intern Med 1986; 105: II. 20. Ross DS, Daniels GH, Gouveia D. The use and limitations of a cherniluminescent thyrotropin assay as a single thyroid function test in an outpatient endocrine clinic. J Clin Endocrinol Metab 1990;71 :764. 21. Larsen PRo Thyroid: pituitary interaction. Feedback regulation of thyrotropin secretion by thyroid hormones. N Engl J Med 1982;306:23. 22. Berry MJ, Banu L, Larsen PRo Type I iodothyronine deiodinase is a selenocysteine-containing enzyme. Nature 1991;349:438. 23. Brent GA, Moore DD, Larsen PRoThyroid hormone regulation of gene expression. Annu Rev Physiol 1991;53: 17. 24. Sawin CT, Herschman JM, Chopra IJ. The comparative effect of T4 and T3 on TSH response to TRH in young adult men. J Clin Endocrinol Metab 1978;44:273. 25. Brabant G, Brabant A, Ranft U, et al. Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration. J Clin Endocrinol Metab 1987;65:83. 26. Spencer CA, Lai-Rosenfeld AO, Guttier RB, et al. Thyrotropin secretion in thyrotoxic and thyroxine treated patients: Assessment by a sensitive immunoenzymometric assay. J Clin Endocrinol Metab 1986; 63:349. 27. Spencer CA, LoPresti JS, Patel A, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990;70:453. 28. Toft AD. Use of sensitive immunoradiometric assay for thyrotropin in clinical practice. Mayo Clin Proc 1988;63:1035. 29. Seth J, Killett HA, Caldwell G, et al. A sensitive immunoradiometric assay for serum TSH-A replacement for the TRH test. Br Med J (Clin Res Ed) 1984;289: 1334. 30. Greer MA, Astwood EB. Treatment of simple goiter with thyroid. J Clin Endocrinol Metab 1953;13: 1312.
31. Astwood EB, Cassidy LE, Aurbach GD. Treatment of goiter and thyroid nodules with thyroid. JAMA 1960;174:459. 32. Crile G Jr. Treatment of carcinoma of the thyroid with desiccated thyroid. Cleve Clin Q 1955;22: 161. 33. IMS America Ltd. National prescription audit: Basic data report. Ambler, Pa, IMS American Ltd, 1988. 34. U.S. Pharmacopoeial Convention. U.S. Pharmacopoeia: The National Formulary, 22nd ed. Easton, Pa, Mack Publishing, 1990, p 764. 35. Wermalund A. Variation in serum levels of T3, T4, free T4 and TSH during thyroxine replacement therapy. Acta Endocrinol (Copenh) 1986;113:47. 36. Fish LH, Schwartz HL, Cavanugh J, et al. Replacement dose metabolism and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med 1987;316:764. 37. Browning MC, Bennet WM, Krikaldy AJ, Jung RT. Intra-individual variation of thyroxin, triiodothyronine and thyrotropin in treated hypothyroid patients: Implications for monitoring replacement therapy. Clin Chern 1988;34:696. 38. LeBoff MS, Kaplan MM, Silva JE, et al. Bioavailability of thyroid hormones from oral replacement preparations. Metabolism 1982; 31:900. 39. Mandel SJ, Larsen PR, Seely EW, et al. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990;323:91. 40. Kaplan MM. Monitoring thyroxine therapy during pregnancy. Thyroid 1992;2:147. 41. Harmon SM, Seifert CF. Levothyroxine/cholestyramine interaction reemphasized. Ann Intern Med 1991;115:658. 42. Harrankova J, Lahaie R. Levothyroxine binding by sucralfate. Ann InternMed 1992;117:445. 43. Sperber AD, Liel Y. Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminium hydroxide. Arch Intern Med 1992;152:183. 44. Campbell NR, Hasinoff BB, Stalts H, et al. Ferrous sulphate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med 1992;117:1010. 45. Isky WL. Effect of rifampin treatment on thyroid function tests in a hypothyroid patient on levothyroxine. Ann Intern Med 1987; 107:517. 46. DeLuca F, Arrigo T, Pandullo E, et al. Changes in thyroid function tests induced by two months' carbamazepine treatment in levothyroxine substituted hypothyroid children. Eur J Paediatr 1986;145:77. 47. Faber J, Lumholtz lB, Kirkegaard C, et al. The effects of phenytoin (diphenylhydantoin) on the extrathyroidal turnover ofT4, 3, 5, 3'D, 3, 3'5'-T3 and 3'5' diiodothyronine in man. J Clin Endocrinol Metab 1985;61:1093. 48. Burger A, Dimichart D, Nicod P, et al. Effect of amiodarone on serum T3, reverse T3, T25 units/ml.), maximal stimulation of any residual thyroid tissue or thyroid cancer can be assumed. Patients are given a small dose of 1311 and a total-body scan performed to survey for areas of uptake. A substantial proportion of patients have residual uptake in the cervical region in spite of total anatomic thyroidectomy. This residual uptake in what is usually normal thyroid tissue can be subsequently ablated with an appropriate dose of 1311. After this dose (typically -30 mCi) has been administered, the patient can be started on thyroxine replacement. If there were no demonstrable extracervical metastatic lesions on the initial scan, the patient should be rescanned in 6 months to 1 year. If, however, the patient has had metastatic disease defined on the initial radioiodine scan, the patient should be treated with a substantial dose of radioiodine, typically 75 to 250 mCi. This cycle of radioiodine scanning and treatment for metastatic lesions can be repeated every 6 to 9 months as appropriate given the patient's physiologic status and tumor response. The efficacy of radioiodine in an adjuvant setting is variable. A study from Young and colleagues demonstrated clear improvement in the overall recurrence rate in patients with disease initially confined to the neck who were treated with surgery, radioiodine, and hormonal therapy compared with patients treated with only surgery and hormonal therapy." Overall, survival was improved; however, there may be subgroups that are at very low risk that do not benefit from radioiodine ablation. One of these groups was evaluated retrospectively in a study from the University of British Columbia. In 71 patients with follicular thyroid cancers and minimal invasion, this group saw no difference in survival or disease-free survival between the 46 patients who underwent hormonal suppression only and the 17 patients who had radioiodine ablation and hormonal suppression." With the data currently available, radioiodine ablation should be recommended for most patients with follicular carcinoma of the thyroid; however, there may be low-risk groups who will be more clearly defined in future studies as not benefitting from such treatment.
Management of Follicular Neoplasms A scheme for the management of patients with follicular neoplasms is presented in Figure 13-6. The typical euthyroid patient with a solitary nodule should be evaluated with
Follicular Neoplasms of the Thyroid - -
Solitary No Evidence of • Euthyroid Thyroid' Nodule Metastases Fineneedle aspiration
High Risk Size>3 em Age> 60 yr History of neck radiation Suspicious cytology
• Thyroxine suppression • Foilowsize each6 months
~
+
l
'--1
I No Growth I ~
Operation Thyroidlobectomy and isthmusectomy
FIGURE 13-6. Management scheme for patients with follicular neoplasms.
FNA of the nodule. Cytology cannot usually distinguish between follicular adenoma and follicular carcinoma because the diagnosis of carcinoma depends upon histologic features (vascular or capsular invasion) that are not demonstrable by FNA. The diagnosis then is follicular neoplasm. Patients who are at low risk for having thyroid carcinoma rather than adenoma, as well as low risk for a poor outcome if they do have carcinoma, can be managed conservatively. Conservative management consists ofTSH suppression with exogenous thyroxine to decrease the growth stimulus for the neoplasm. The value of suppression as a technique for distinguishing between carcinoma and adenoma has been questioned, and the potential downside of oversuppression (osteoporosis in particular) has been recognized. However, it seems reasonable to suppress TSH to a moderately low level (0.3 to 0.6 mU/mL) while patients are being observed conservatively. This is done not to decide that lesions that shrink are not cancers, as 2 of 19 follicular cancers shrank with suppression therapy in the University of California series," but to remove growth stimulation during the prolonged follow-up. If the lesion does grow during follow-up, the patient should have a thyroid lobectomy and isthmusectomy. Patients with thyroid nodules should be observed indefinitely for evidence of growth. Intermediate-risk patients include those whose lesions are I to 3 em in size and those who are older than 40 years. The patients should have a functional (1 231 or 99mTc04) scan to assess the nature of the nodule. Patients with functional nodules are unlikely to harbor cancer in that lesion; they can join the low-risk follow-up group with thyroxine suppression. Patients who have nonfunctioning nodules should have thyroid lobectomy and isthmusectomy for diagnosis, not only because they are at higher risk of having follicular
121
cancer but also because they are at higher risk of having an aggressive tumor if they do have thyroid cancer. Low-risk patients who are averse to the inherent risk of delaying treatment of a cancer, which is possible in the more conservative plan of follow-up, can be included with this group and assessed with a functional scan. The high-risk group includes patients who are older than 60 years and those with nodules greater than 3 em in size. These patients are at higher risk of having cancer in the nodule and of having an aggressive cancer. In addition, patients who have a history of neck irradiation, or whose cytology is suspicious for cancer (because of atypia or necrosis, for example), have a higher risk of cancer. These patients should have a diagnostic thyroid lobectomy and isthmusectomy without further evaluation because of their higher risk. The scheme outlined here is one of several possible designs for managing patients with follicular thyroid neoplasms. More important than the algorithm itself are the data that underlie it. If the clinician understands these data, individual algorithms can be constructed for each patient and new information incorporated into future plans.
REFERENCES 1. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5. 2. Pettersson B, Adami H-O, Wilander E, Coleman MP. Trends in thyroid cancer incidence in Sweden, 1958-1981, by histopathologic type. lnt J Cancer 1991;48:28. 3. Burgess JR, Dwyer T, McArdle K, et al. The changing incidence and spectrum of thyroid carcinoma in Tasmania (1978-1998) during a transition from iodine sufficiency to iodine deficiency. J Clin Endocrinol Metab 2000;85:1513. 4. Bisi H, Fernandes VSO, Asato De Camargo RY, et al. The prevalence of unsuspected thyroid pathology in 300 sequential autopsies, with special reference to the incidental carcinoma. Cancer 1989;64:1888. 5. Martinez-Tello FJ, Martinez-Cabruja R, Fernandez-Martin J, et al. Occult carcinoma of the thyroid. Cancer 1993;71:4022. 6. Davis NL, Gordon M, Germann E, et al. Clinical parameters predictive of malignancy of thyroid follicular neoplasms. Am J Surg 1991;161:567. 7. LiVolsi VA. Current concepts in follicular tumors of the thyroid. In: LiVolsi VA, DeLellis RA (eds), Pathobiology of the Parathyroid and Thyroid Glands. Baltimore, Williams & Wilkins, 1994, p 118. 8. Antonini P, Levy N, Caillou B, et al. Numerical aberrations, including trisomy 22 as a sole anomaly, are recurrent in follicular thyroid adenomas. Genes Chromosomes Cancer 1993;8:63. 9. Hicks DG, LiVolsi VA, Neidich JA, et al. Clonal analysis of solitary follicular nodules in the thyroid. Am J PathoI1990;137:553. 10. Roque L, Castedo S, Gomes P, et al. Cytogenetic findings in 18 follicular thyroid adenomas. Cancer Genet Cytogenet 1993;67:1. II. Aust G, Steinert M, Kiessling S, et al. Reduced expression of stromalderived factor 1 in autonomous thyroid adenomas and its regulation in thyroid-derived ceils. J Clin Endocrino! Metab 200 1;86:3368. 12. Persani L, Lania A, Alberti L, et al. Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas. J Clin Endocrinol Metab 2000; 85:2872. 13. Tonacchera M, Agretti P, Chiovato L, et al. Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter. J Clin Endocrinol Metab 2000;85:2270. 14. Tonacchera M, Vitti P, Agretti P, et al. Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms. J Clin Endocrinol Metab 1999;84:4155. 15. Hishinuma A, Takamatsu J, Ohyama Y, et al. Two novel cysteine substitutions (C1263R and C1995S) of thyroglobulin cause a defect in intracellular transport of thyroglobulin in patients with congenital goiter and the variant type of adenomatous goiter. J Clin Endocrinol Metab 1999;84: 1438.
122 - - Thyroid Gland 16. van Heerden JA, Hay ID, Goellner JR, et al. Follicular thyroid carcinoma with capsular invasion alone: A nonthreatening malignancy. Surgery 1992;112:1130. 17. Tielens ET, Sherman SI, Hruban RH, Ladenson PW. Follicular variant of papillary thyroid carcinoma. Cancer 1994;73:424. 18. Lin HS, Komisar A, Opher E, Blaugrund SM. Follicular variant of papillary carcinoma: The diagnostic limitations of preoperative fineneedle aspiration and intraoperative frozen section evaluation. Laryngoscope 2000;110:1431. 19. Evans HL, Vassilopoulou-Sellin R. Follicular and Hurthle cell carcinomas of the thyroid: A comparative study. Am J Surg Pathol 1998; 22:1512. 20. Ashfaq R, Vuitch F, Delgado R, Albores-Saavedra J. Papillary and follicular thyroid carcinomas with an insular component. Cancer 1994;73:416. 21. Pilotti S, Collini P, Mariani L, et al. Insular carcinoma: A distinct de novo entity among follicular carcinomas of the thyroid gland. Am J Surg Patho 1997;21:1466. 22. Gardner HAR, Ducatman BS, Wang HH. Predictive value of fineneedle aspiration of the thyroid in the classification of follicular lesions. Cancer 1993;71:2598. 23. Harach HR, Zusman SB. Necrotic debris in thyroid aspirates: A feature of follicular carcinoma of the thyroid. Cytopathology 1992;3:359. 24. Montironi R, Braccischi A, Scarpelli M, et al. Well differentiated follicular neoplasms of the thyroid: Reproducibility and validity of a "decision tree" classification based on nucleolar and karyometric features. Cytopathology 1992;3:209. 25. DeMicco C, Basko V, Garcia S, et al. Fine-needle aspiration of thyroid follicular neoplasm: Diagnostic use of thyroid peroxidase immunocytochemistry with monoclonal antibody 47. Surgery 1994;116:1031. 26. Saggiorato E, Cappia S, De Giuli P, et al. Galectin-3 as a presurgical immunocytodiagnostic marker of minimally invasive follicular thyroid carcinoma. J Clin Endocrinol Metab 2001;86:5152. 27. Kingston GW, Bugis SP, Davis N. Role of frozen sections and clinical parameters in distinguishing benign from malignant follicular neoplasms of the thyroid. Am J Surg 1992;164:603. 28. Iwasaki H, Matsumoto A, Ito K, et al. Prediction of distant metastasis in follicular adenocarcinoma of the thyroid. World J Surg 1990; 14:425. 29. Akslen LA, Haldorsen T, Thoresen SO, Glattre A. Survival and causes of death in thyroid cancer: A population-based study of 2479 cases from Norway. Cancer Res 1991;51:1234. 30. Balan KK, Raouf AH, Critchley M. Outcome of 249 patients attending a nuclear medicine department with well differentiated thyroid cancer; a 23 year review. Br J RadioI1994;67:283. 31. Hoie J, Stenwig AE. Long-term survival in patients with follicular thyroid carcinoma. The Oslo experience: Variations with encapsulation, growth pattern, time of diagnosis, sex, age, and previous thyroid surgery. J Surg Oncol 1992;49:226. 32. Beasley NJ, Walfish PG, Witterick I, Freeman JL. Cause of death in patients with well-differentiated thyroid carcinoma. Laryngoscope 2001;111:989.
33. Kitamura Y, Shimizu K, Nagahama M, et al. Immediate causes of death in thyroid carcinoma: Clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab 1999;84:4043. 34. Cady B, Rossi R, Silverman M, Wool M. Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 1985;98: 1171. 35. Cady B, Sedgwick CE, Meissner WA, et al. Risk factor analysis in differentiated thyroid cancer. Cancer 1979;43:810. 36. De Jong SA, Demeter JG, Lawrence AM, Paloyan E. Necessity and safety of completion thyroidectomy for differentiated thyroid carcinoma. Surgery 1992;112:734. 37. Emerick GT, Duh Q-Y, Siperstein AE, et al. Diagnosis, treatment, and outcome of follicular thyroid carcinoma. Cancer 1993;72:3287. 38. Harness JK, Thompson NW, McLeod MK, et al. Follicular carcinoma of the thyroid gland: Trends and treatment. Surgery 1984;966:972. 39. Samaan NA, Schultz PN, Hickey RC, et al. The results of various modalities of treatment of well differentiated thyroid carcinomas: A retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75:714. 40. Young RL, Mazzaferri EL, Rahe AJ, et al. Pure follicular thyroid carcinoma: Impact of therapy in 214 patients. J Nucl Med 1980;21 :735. 41. Ley PB, Roberts JW, Symmonds RE Jr, et al. Safety and efficacy of total thyroidectomy for differentiated thyroid carcinoma: A 20-year review. Am Surg 1993;59: 110. 42. DeGroot LJ, Kaplan EL. Second operations for "completion" of thyroidectomy in treatment of differentiated thyroid cancer. Surgery 1991;110:936. 43. Shaha AR, Jaffe BM. Completion thyroidectomy: A critical appraisal. Surgery 1992;112:1148. 44. Udelsman R, Westra WH, Donovan PI, et al. Randomized prospective evaluation of frozen-section analysis for follicular neoplasms of the thyroid. Ann Surg 2001;233:716. 45. Schneider AB, Recant W, Pinsky SM, et al. Radiation-induced thyroid carcinoma. Ann Intern Med 1986;105:405. 46. Smit JW, Vielvoye GJ, Goslings BM. Embolization for vertebral metastases of follicular thyroid carcinoma. J Clin Endocrinol Metab 2000;85:989. 47. Davis NL, Gordon M, Germann E, et al. Efficacy of 1311 ablation following thyroidectomy in patients with invasive follicular thyroid cancer. Am J Surg 1992;163:472. 48. Jorda M, Gonzalez-Campora R, Mora J, et al. Prognostic factors in follicular carcinoma of the thyroid. Arch Pathol Lab Med 1993;117:631. 49. Brennan MD, Bergstralh EJ, van Heerden JA, McConahey WM. Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970. Initial manifestations, pathologic findings, therapy and outcome. Mayo Clin Proc 1991;66:II. 50. Mueller-Gaertner HW, Grzac HT, Rehpenning W. Prognostic indices for tumor relapse and tumor mortality in follicular thyroid carcinoma. Cancer 1991;67:1903. 51. Crile G Jr, Pontius KI, Hawk WA. Factors influencing the survival of patients with follicular carcinoma of the thyroid gland. Surg Gynecol Obstet 1985;160:409.
Hurthle Cell Adenoma and Carcinoma Herbert Chen, MD, FACS • Robert Udelsman, MD, MBA, FACS
Few topics in endocrine surgery have been as controversial as Hiirthle cell neoplasms of the thyroid. Hiirthle cell neoplasms (adenomas and carcinomas) are "solitary masses in the thyroid comprised of Hiirthle cells exclusively, or at least over 50% so comprised, and confined by a capsule found in a gland not otherwise overcome by chronic thyroiditis.'" They comprise 3% to 10% of all epithelial thyroid tumors and have been reported to account for 15% to 20% and 2% to 8% of all follicular and papillary cancers, respectively.' Hurthle cell tumors are well differentiated and tend to be more aggressive than routine follicular thyroid cancers but less so than sporadic medullary thyroid cancers. Since their initial description, there has been debate about their origin, clinical behavior, classification, diagnosis, surgical management, and prognosis. Part of the difficulty in characterizing the behavior of these tumors is due to the relative low incidence of malignant Hiirthle cell lesions; therefore, experience obtained in any single institution is limited. In this chapter, we discuss the controversy surrounding Hiirthle cell neoplasms and outline our current management.
Historical Background The term Hiirthle cell tumor is a misnomer. In 1894, Hiirthle described intrafollicular cells of the thyroid in a normal dog that actually were parafollicular C cells.' True Hiirthle cells were first described in 1898 in a patient with thyrotoxicosis by Askanazy." In 1907, Langhans reported the first Hiirthle cell tumor, and Ewing, in 1919, described a true Hiirthle cell tumor and miscredited Hiirthle as the original discoverer.' Therefore, these tumors are occasionally referred to as Askanazy cell tumors or Langhans tumors; however, they are most commonly referred to as Hiirthle cell neoplasms.
Origin and Classification Controversy exists regarding the presumed origin of Hiirthle cells. Most believe that they originate from thyroid follicular cells. This conclusion is supported by the following: (1) histology from a single thyroid gland can show the
transition from follicular cells to Hiirthle cells; (2) Hiirthle cells can secrete thyroglobulin similar to thyroid follicular cells; (3) a high concentration of Hiirthle cells is seen in inflammatory diseases of the thyroid; and (4) a functional thyroid-stimulating hormone (TSH) receptor-adenylate cyclase system is present in Hiirthle cell neoplasms." There are some investigators, however, who suggest that Hiirthle cells are of parafollicular origin. This is based on the fact that Hiirthle cell cancers more often metastasize to lymph nodes, are less likely to trap radioactive iodine, and have a distinct oncogene expression profile as compared to follicular cancers.' The confusion surrounding the description of Hiirthle cell tumors continues today. The nomenclature is not standardized; Hi.irthle cell tumors (adenomas and carcinomas) are also referred to as oncocytomas, oxyphilic tumors, Askanazy cell tumors, Langhans tumors, and follicular Hiirthle cell tumors. In 1988, the World Health Organization formally classified Hiirthle cell carcinoma as an oxyphilic variant of follicular carcinoma. However, since then, several investigators have presented convincing evidence that these tumors should be classified separately as Hiirth1ecell carcinomas.
Clinical Characteristics Histology Hiirth1e cells are large polygonal, eosinophilic cells with pleomorphic, hyperchromatic nuclei and fine granular, acidophilic cytoplasm, representing an abundance of mitochondria (Fig. 14-1). The individual cells are 10 to 15 urn in diameter and can vary in shape and size from small dumbbells to bizarre giant cells. Hiirthle cell neoplasms are encapsulated collections of Hiirthle cells (Fig. 14-2). Therefore, the presence of nonencapsulated Hiirth1e cells does not signify a neoplastic process, because they are commonly associated with Hashimoto's thyroiditis, Graves' disease, and nodular goiters as well as with well-differentiated thyroid cancers. Hiirthle cell tumors continue to be classified as variants of follicular neoplasms. However, Hiirthle cell carcinomas
123
124 - -
Thyroid Gland
Risk Factors Up to 39% of patients with Htirthle cell neoplasms in one study reported previous childhood head and neck radiation. II Previous radiation exposure has also been correlated with an increase in bilaterality and multicentricity of Htirthle cell tumors, as well as an increased incidence of contralateral non-Htirthle cell malignant thyroid lesions. No genetic syndromes have been reported to be associated with Htirthle cell tumors. Other than radiation exposure and age, no other risk factors have been associated with Htirthle cell neoplasms.
Presentation
FIGURE 14-1. Fine-needle aspiration of a thyroid nodule showing an abundance of polygonal-shaped Hiirthle cells. Note the pleomorphic hyperchromatic nuclei and granular cytoplasm.
generally behave in a more aggressive manner, metastasizing more frequently, and are less likely to respond to radioactive iodine." In addition, Htirthle cell variants of papillary thyroid cancer have been reported with increasing frequency." These tumors behave in a manner more similar to Htirthle cell carcinomas, metastasizing and recurring more frequently than papillary carcinomas. Therefore, most believe that Htirthle cell tumors should be classified as a distinct category, with subgroups of follicular and papillary variants.
Demographics Htirthle cells neoplasms have a peak incidence in the fifth to sixth decades. With advancing age there is an increased chance of a malignancy. 10 There is a female preponderance, with reported ratios ranging from 2:1 to 10:1. However, male patients with Htirthle cell neoplasms have a higher relative incidence of carcinoma.
FIGURE 14-2. A Htirthle cell adenoma (A). Note the presence of a thin capsule (C) without any signs of capsular invasion. Most of this neoplasm is composed of Htirthle cells.
Most patients with Htirthle cell neoplasms present with a solitary thyroid nodule. Approximately 80% of these lesions are nonfunctioning and are therefore "cold" on nuclear scans. Approximately 5% to 60% (in most series, 10% to 35%) of Htirthle cell neoplasms are carcinomas. In patients presenting with malignant lesions, 70% to 80% are confined to the gland, 11% have lymph node metastasis, and 15% have distant metastasis, most commonly to bone or lung. Patients may also present with advanced local disease manifested by esophageal or airway obstructive symptoms.
Diagnosis Histopathology In 1974, Thompson and colleagues reported a series of 25 patients with Htirthle cell neoplasms in which 75% of these whose lesions were initially described as benign (i.e. adenomas) subsequently died of Htirthle cell carcinoma." This led to the suggestion that gross and histopathologic examination of Htirthle cell neoplasms could not reliably predict clinical behavior and that all lesions should be treated as malignant or potentially malignant. Since then, however, several studies have shown that histologic criteria can reliably differentiate between Htirthle cell adenomas and carcinomas. Grant and colleagues in 1988 reviewed 272 surgically resected Htirthle cell neoplasms at the Mayo Clinic that were deemed to be histologically benign and found that only 1 had an incorrect diagnosis manifested by tumor recurrence, with a mean follow-up of 4 years.13 The criteria currently used to diagnose Htirthle cell carcinoma are capsular or vascular invasion, invasion of adjacent structures, lymph node metastases, and distant metastases. Moreover, Carcangiu and associates found similar results in reviewing 153 cases of Htirthle cell neoplasms." In their study, patients were grouped into three categories: benign (90), indeterminate (35), and malignant (28). Malignant lesions had to demonstrate fullthickness capsular invasion, vascular invasion, or invasion into adjacent tissue. Indeterminate lesions had minimal capsular invasion, solid versus follicular growth pattern, marked nuclear atypia, and extensive necrosis. With up to 22 years of follow-up, no tumor recurrences or cause-specific death was seen in the benign or indeterminate groups. From these and other studies.v-" one can conclude that histologic examination can differentiate benign from malignant Htirthle cell neoplasms and that the sine qua non of Htirthle cell carcinoma is full-thickness capsular and/or vascular invasion (Figs. 14-3 and 14-4).
Htirthle Cell Adenoma and Carcinoma - - 125
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0%
1 em or less
>1 em and Preventive Surgery for Multiple Endocrine Neoplasia Type 2 Gene Carriers Individuals with MEN 2A, 2B and FMTC are virtually certain to acquire MTC at some point in their lives (usually before age 30 years). Therefore, at-risk family members who are found to have inherited the RET gene mutation are candidates for thyroidectomy regardless of their calcitonin levels. It has been shown in several series that RET mutation carriers often harbor foci of MTC in the thyroid gland even when stimulated calcitonin levels are normal. I4 , IS,33,34,45-47 In a series from Washington University in St. Louis reported in 1994, Wells and coauthors described the performance of preventive surgery in asymptomatic RET mutation carriers." Families of patients with MEN 2A were screened with genetic and biochemical testing. Thirteen children found to be asymptomatic RET mutation carriers were treated with total thyroidectomy, central lymph node dissection, and parathyroid autotransplantation (six with normal plasma calcitonin levels and seven with elevated levels). After surgery, patients received thyroid, calcium, and vitamin D supplementation. Approximately 8 weeks after the operation, the oral calcium and vitamin D were stopped. 1\\'0 weeks later the serum calcium concentration was within the normal range in each patient. All patients had microscopic foci of MTC or C-cell hyperplasia. In 1996, Wells and colleagues reported an updated series including 49 patients with similar results.f Lips and colleagues, in a series from the Netherlands reported in 1994, identified 14 young members of families affected by MEN 2A who had normal calcitonin testing but who were found to be MEN 2A gene carriers by DNA testing. IS Thyroidectomy was performed on 8 of these 14, and foci of MTC were identified in all 8. At Washington University in St. Louis, we have performed 85 such procedures to date. All patients had central neck node dissection and parathyroidectomy with autotransplantation. Two patients were found to have nodal metastases (one despite a normal stimulated calcitonin level), and calcitonin levels remain elevated in two. Three patients continue to receive calcium supplementation. There were no recurrent laryngeal nerve injuries. Follow-up testing is being carried out in all of these patients to determine the long-term outcome of such procedures. The finding of carcinoma in the glands of many young patients with normal stimulated calcitonin testing indicates that the operation is often therapeutic, not prophylactic. There is some urgency, therefore, to apply this genetic test to other at-risk individuals and to perform thyroidectomy on those who test positive genetically. The ideal age for performance of thyroidectomy in patients found to be genetically positive has not been determined unequivocally. We believe that 6 years of age is a reasonable time to perform surgery in patients with MEN 2A and FMTC. Patients with MEN 2B should undergo thyroidectomy during infancy because of the aggressiveness and earlier age of onset of MTC in these patients. Follow-up over the next decades
Medullary Thyroid Carcinoma - - 135 will determine whether there is a significant rate of recurrence after preventive thyroidectomy. At present, it is advisable to observe these patients with stimulated plasma calcitonin levels every 1 to 2 years. These patients must also continue to be observed for the development of pheochromocytomas and hyperparathyroidism.
Nonsurgical Treatment of the Patient with Persistent or Recurrent Medullary Thyroid Carcinoma Radiation Therapy
Persistent or Recurrent Hypercalcitoninemia After primary surgery for MTC, persistent or recurrent elevation of the basal or stimulated calcitonin levels indicates the presence of residual or recurrent tumor. Although longer follow-upof reported series is needed, it is likely that thyroidectomy is curative in children with MEN 2A and FMTC in whom the diagnosis of MTC is made by genetic testing or by detection of an elevated calcitonin level after previous negative yearly testing.lv" Patients in whom the diagnosis of hereditary MTC is made at an older age, however, when calcitonin levels are already high or a palpable tumor is present, are more likely to have residual disease after thyroidectomy. In one series, approximately 50% of these patients had persistent elevations of calcitonin levels postoperatively." In patients who present with a mass in the neck (this includes virtually all patients with sporadic MTC), lymph node metastases are present in more than 50%, and persistent elevation of calcitonin levels occurs in 50% to 100%.50,51 In one study of patients who presented with palpable tumors, 15 of 18 patients (83%) with hereditary disease and 11 of 20 patients (55%) with sporadic tumors had persistent disease as indicated by elevated calcitonin levels postoperatively. 50 The clinical course of patients with MTC who have positive nodes has been addressed in several studies. MTC can be a very indolent disease. Many patients with persistently high levels of calcitonin after thyroidectomy and node dissection continue to do well without evidence of disease for many years. In a study of 18 patients, 16 of whom had persistently elevated calcitonin levels after "adequate surgery," Block and coworkers found that calcitonin levels remained stable for up to 6 years and recommended observation in the absence of overt clinical disease. 52 These observations and this approach have been supported by other groups.v-" Other studies have indicated a poorer outcome in these patients. In a Norwegian study of 84 cases of MTC, it was noted that more than 50% of patients who presented with cervical node metastases eventually died of the disease.'? In a series of 139 patients operated on for MTC at Mayo Clinic, it was found that 59% of the patients with positive cervical lymph nodes experienced progression of disease.v In a subsequent report from Mayo Clinic, 66% of nodepositive patients with hereditary MTC died, and none of the patients with positive nodes had normal calcitonin levels after a median follow-up of 15.7 years." The variable outcome of patients with positive lymph nodes is explained by differences in the biologic virulence of the tumor, the extent of spread at the time of treatment, and the adequacy of surgical extirpation.
The thyroid C cells do not concentrate iodine, and reports of radioactive iodine treatment of metastatic MTC have indicated a lack of significant effect." Several reports have advocated the use of external beam radiation therapy for MTC.55-58 These retrospective studies involved small numbers of patients, and it is difficult to determine whether or not radiation treatment had a significant effect. Other studies have not supported the use of radiation therapy in MTC.23.24.59 In the report by Samaan and colleagues, 202 patients were studied retrospectively. Even though the authors believed that the characteristics of the two groups were comparable, it was found that the patients who received external beam radiation therapy had a worse outcome those who did not." A study from France in 1992 reported a series of 59 patients with MTC, all of whom received external beam radiation therapy to the neck and upper mediastinum after surgery.'" Of these 59 patients, 44 had positive nodes and 11 had residual tumor after surgery. After radiation therapy to a mean dose of 54 Gy, 18 patients (30%) experienced clinically evident local recurrences. Thirty-five patients were still alive (median follow-up, 65 months), and 24 had no clinical evidence of disease, although calcitonin levels were not available for all patients. These data indicate a high rate of clinically significant local recurrence, and without post-treatment calcitonin levels it is impossible to determine the actual response rate. Postradiation scarring, fibrosis, and vasculitis make further surgery for removal of metastatic deposits much more difficult and dangerous in the radiated patient. Further studies are needed to define the role of radiation therapy in this disease.
Chemotherapy In patients with advanced or metastatic MTC, chemotherapeutic regimens have not been extensively studied because of the relative rarity of the disease. Existing reports, however, have not shown any consistent benefit from either singleagent or combination chemotherapy regimens. Doxorubicin (Adriamycin) as a single agent was not noted to alter the progression ofMTC. 61A study of combination chemotherapy, using doxorubicin, cisplatin, and vindesine, resulted in one partial remission and three minor responses of 20 patients treated/? Another study used a combination of dacarbazine (dimethyl triazeno imidazole carboxamide, DTIC) and 5-fluorouracil (5_FU).61 In the five patients treated, there were three partial responses that lasted less than a year.63 In a study by Schlumberger and coworkers, combinations of 5-FU and streptozocin and 5-FU and dacarbazine were given alternately to 20 patients with metastatic MTC. Three partial responses and 11 long-term stabilizations were observed.P"
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The use of low-dose interferon-a was reported in two patients with MTC. 64,65 Both of these patients showed improvement in symptoms and in calcitonin level after treatment, Neither had a complete response, Juweid and colleagues reported the results of a phase I clinical trial in which 12 patients were treated with highdose 1311-MN-14F(abh anti-CEA monoclonal antibody combined with autologous hematopoietic stem cell rescue (AHSCR).66 Toxicity was acceptable, and one partial response was reported. Schott and coauthors reported treatment of seven patients with MTC by immunotherapy with calcitonin-pulsed dendritic cells."? One significant response was seen in this preliminary study. Chemoembolization of liver metastases from patients with MTC has been effective in reducing the size of lesions and in ameliorating symptoms (author, unpublished data). Studies with tyrosine kinase inhibitors have shown in vitro activity, and clinical trials to test these agents are under way.68-70
Localization of Persistent or Recurrent Medullary Thyroid Carcinoma Computed Tomography and Ultrasonography A number of methods have been used to localize residual or recurrent disease in patients with persistent or recurrent calcitonin elevation after surgery for MTC. Careful physical examination may reveal adenopathy in the jugular and paratracheal regions. Patients with advanced metastatic disease may acquire subcutaneous tumors of the trunk and extremities. Imaging studies that have been reported to be successful in localization include ultrasonography with fine-needle biopsy, computed tomography (CT) scanning, magnetic resonance imaging (MRI), selective venous catheterization (SVC), and nuclear imaging studies. Van Heerden and colleagues reported on high-resolution (lO-MHz) ultrasonography with ultrasound-guided fine-needle aspiration biopsy in patients with a negative clinical examination.P In a study of 47 patients with elevated calcitonin levels after primary surgery for MTC, Raue and associates evaluated ultrasonographic examination of the neck as well as physical examination, CT scan, SVC, fine-needle biopsy, and combinations of these modalities in localization of metastatic MTC.71 After reoperation in 14 patients, calcitonin levels were normalized in 2 patients. In a subsequent study they reported that SVC correctly localized tumor tissue in 89% of patients compared with 38% with CT scan and only 28% with ultrasonography."
Selective Venous Catheterization SVC facilitates detection of occult foci of metastatic MTC by determining basal or stimulated calcitonin levels in samples of venous blood drawn from sites in the neck, chest, and abdomen. This technique was used successfully by Norton and coworkers in seven patients." They reported that SVC correctly localized tumor to a surgically resectable
area of the neck in every case. In a study by Mrad and colleagues," localized disease in the neck was identified by SVC in six patients. In two patients the calcitonin levels were normal after operation guided by SVC data." In a study from France in 1994, SVC was performed in 19 patients, and calcitonin elevations suggestive of distant metastases were found in 5 patients." All five eventually acquired clinically apparent distant disease, recommending the usefulness of this technique in identifying distant metastases. In another series from Norway, elevated hepatic vein stimulated calcitonin levels were believed to indicate the presence of hepatic metastases. In this series, however, only three patients were demonstrated to have hepatic metastases by other means, and the significance of this finding is unclear," In our series, eight patients with hepatic vein calcitonin gradients were not found to have evidence of liver metastases by CT scanning and laparoscopy with liver biopsy." These patients underwent resection of metastatic MTC in the neck and two of the eight had subsequent normalization of stimulated calcitonin levels, indicating that the hepatic vein elevations may have been spurious. We no longer routinely use SVC in patients with occult MTC. The technique of SVC varies depending on the institution. At our institution, catheters are simultaneously placed in the right and left jugular veins and also in the left innominate vein and in a hepatic vein. Peripheral blood is drawn from a femoral catheter. After obtaining baseline values from these locations, a standard injection of calcium and pentagastrin is performed. Samples for calcitonin levels are drawn at I, 3, and 5 minutes from each of these locations. Values obtained are compared with simultaneously obtained baseline and stimulated peripheral values. Other authors do not use calciumpentagastrin stimulation during SVC but rather use sample basal levels from multiple sites in the neck, chest, and abdomen and determine gradients by comparing these with peripheral levels."
Nuclear Imaging Studies A number of different radiopharmaceuticals have been described to localize metastatic MTC. Thallium 201 (l0ITl) chloride and technetium 99m dimercaptosuccinic acid (99mTc DMSA) have been shown to be useful in evaluating hypercalcitoninemic patients. 78-8o Iodine 131 metaiodobenzylguanidine (MIBG) scintigraphy can be used to image MTC but is not consistent.v-" Octreotide scans with indium III CII In) have been used to localize metastatic disease, but these scans do not detect small liver metastases.Pv" Monoclonal anti-CEA antibodies labeled with iodine 131 ( 1311) or iodine 123 C231), 1111n, and 991l1Tc have been evaluated for localization of MTC. 85,86 Juweid and colleagues reported the largest series with 26 patients, but only 9 of those were identified as patients with occult disease.f'" Single-photon emission CT (SPECT) with labeled monoclonal anti-CEA antibodies was compared with ultrasonographic examination and CT scan, and in four of nine patients imaged metastatic foci were confirmed by operative results.f" The value of monoclonal antibodies in localization of occult MTC remains to be proved. Anticalcitonin monoclonal antibodies have also been evaluated in a small number of cases but have never gained broad attention."
Medullary Thyroid Carcinoma - -
In addition, studies have examined the imaging of cholecystokinin B receptors, which have been demonstrated in a high percentage of MTCs in vitro in patients with MTC. 90,91 Radioimmunoguided surgery is a technique designed to facilitate the intraoperative detection of metastases. After systemic administration of tumor-specific radiolabeled monoclonal antibodies, a hand-held gamma counter is used to scan the operative field. Areas of increased activity are explored, and soft tissue and nodes from these areas are resected. In five patients in whom immunoscintigraphy using an anti-CEA monoclonal antibody was applied, all previously identified metastases could be visualized. According to the authors, the technique detected tumor foci missed by intraoperative inspection and palpation in three of five patients. Radioimmunoguided surgery did not identify two small (10 mm x 10 rom) lesions that were resected and found to contain microscopic cancer." In a case report, intraoperative scanning after III In pentetreotide administration was used to localize metastatic sites. Plasma calcitonin levels fell remarkably after surgery but were not reduced to normal values.f Although these results are promising, surgical cures were not noted, and a compartment-oriented resection or observation may also be considered in asymptomatic patients." Fluorodeoxyglucose (FDG) positron emission tomography (PET) has been evaluated by our group in the staging of MTC. From January to December 1996, 10 consecutively treated patients (7 men and 3 women) with elevated serum calcitonin levels after primary operative treatment for MTC were included in the study. FDG-PET images were compared with CT and MRI images, and suspected metastatic foci were assessed by correlation with intraoperative and histopathologic findings.?" FDG-PET imaging proved to be more sensitive but less specific in detecting cervicomediastinal metastatic lesions compared with CT or MRI, respectively. Two patients with liver metastases detected by laparoscopy only, however, had no evidence of abnormal liver FDG uptake on PET imaging."
Diagnostic Laparoscopy MTC metastatic to the liver often has a miliary appearance, with multiple small (1 to 3 mm), white, raised nodules on the liver surface, which are easy to see with the laparoscope but may not be detected by CT scan, MRI, or other imaging techniques. We have routinely used diagnostic laparoscopy to look for liver metastases in patients with elevated calcitonin levels after primary surgery for MTC (Fig. 15-5).77 In a series of 41 patients, liver metastases were demonstrated in 8 patients, 7 of whom had negative CT imaging. In an update of this series, 136 patients had direct inspection of the liver by laparoscopy (126) or open procedure (10). Liver metastases were identified in 29 patients (21.3%).77
Surgical Treatment of Recurrent or Persistent Medullary Thyroid Cancer Because of the lack of success reported for other modalities in the treatment of persistent or recurrent MTC, surgical
137
B FIGURE 15-5. A, Computed tomography (CT) of liver from patient with multiple endocrine neoplasia type 2A, recurrent medullary thyroid carcinoma (MTC), and elevated calcitonin levels. There is no evidence of liver metastases on the scan. B, Laparoscopic view of liver from the same patient showing multiple small raised whitish lesions on andjust beneath the surface of the liver, confirmed to be metastatic MTC by biopsy. These small, multiple metastases are often not seen with routine CT scanning or other imaging modalities, including nuclear scanning. (From Tung WS, Veseley TM, Moley IF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995;118:1024.)
reintervention has been used by several groups to attempt to control the disease. MTC is often indolent and remains in the neck for long periods of time. It is possible that removal of residual or recurrent disease in the neck will result in cure in some cases and arrest the course of the disease in others. Several groups have reported their experience with reoperation for persistent or recurrent MTC in the neck.29.73.95.96 A significant reduction in stimulated calcitonin levels after reoperation was reported in many patients, and normalization of calcitonin levels was noted in some. In 1986, Tisell and colleagues reported a series of 11 MTC patients with persistent hypercalcitoninemia after previous apparently adequate surgery.97 Tisell performed what he called a "microdissection." This involves a meticulous dissection of all lymph node and fatty tissue of the central and lateral zones of the neck, including the thyroid bed, both recurrent nerves, and nodes in the lateral neck, extending from the level of the mastoid process down to the innominate vein and subclavian arteries and out laterally to the level of the
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Thyroid Gland
spinal accessory nerve. In several cases, a median sternotomy and resection of upper mediastinal nodes were also performed. In this series, the calcitonin levels were normalized in four patients and significantly lowered in three. We reported two series of cervical reoperations for MTC: from 1990 to 1993 98 and from 1993 to 1996. 99 In the first series, 37 operations were done in 32 patients. The patients had previously undergone total thyroidectomy and most of the patients also had previous lymph node dissections. All patients had elevated stimulated calcitonin levels. Localization studies, including selected venous catheterization, CT scanning, and physical examination, were successful in localizing tumor in half the cases. Operative morbidity was low and there were no deaths. In 28 of the 35 operations, discharge from the hospital occurred 2 to 5 days postoperatively. In nine cases (group 1), calcitonin was reduced to undetectable levels following reoperation. In 13 cases (group 2), postoperative calcitonin levels were decreased by 40% or more. In 10 cases (group 3), postoperative calcitonin levels were not improved. Patients' sex, disease, number of nodes previously resected, preoperative calcitonin levels, and preoperative localization study results were not significantly different among the three groups and therefore unlikely to predict outcome for reoperation. Previously resected tumors from patients in group 3, however, were more likely to have demonstrated invasive features (invasion of adjacent structures, extranodal or extracapsular spread) than tumors from patients in groups 1 and 2 (P < .05, Fisher's exact test)." In this series, reoperation resulted in normalization of calcitonin levels in 28% of patients and a decrease in calcitonin levels by 40% or more in another 42% of patients. The results also suggested that determination of the degree of invasiveness of the primary tumor may help in selecting patients likely to benefit from reoperative surgery for recurrent medullary thyroid cancer. In the second series, we sought to improve our results through better selection of patients likely to benefit from
reoperation.?? This was achieved by obtaining a systematic metastatic work-up including routine staging laparoscopy, described earlier. One hundred and fifteen patients with persistent elevation of calcitonin after primary surgery for MTC were evaluated. After metastatic work-up, which revealed distant disease in 25% of these patients, and discussion of the options (including observation in patients without gross cervical disease), 52 patients elected to undergo cervical reoperation. Seven patients had paIliative procedures and 45 patients had cervical re-exploration with curative intent. In the seven patients who had paIliative cervical operations, one patient had persistent postoperative hypocalcemia. There were no other complications in that group. In the 45 patients who underwent reoperation with curative intent, there were no postoperative deaths and no transfusions were required. Complications included thoracic duct leak in four patients (8.9%) and hypocalcemia (2 patients [4%] at follow-up of 3 months and 2 years). Careful identification and exposure of the recurrent laryngeal nerves (RLNs) were done through a previously undissected area by the lateral, backdoor, or anterior approach. There were no permanent recurrent nerve injures."? In the 45 patients who had reoperation with curative intent, the mean decrease in postoperative stimulated calcitonin level was 73.1% (see Fig. 15-4). In 22 of 45 patients (48%), the postoperative stimulated calcitonin level dropped more than 90% compared with the preoperative value (Fig. 15-6). Seventeen (38%) had postoperative stimulated calcitonin levels that were within the normal range (group 1), and six (13%) had no significant decrease in stimulated calcitonin levels (group 3). The remaining patients had a greater than 35% reduction in stimulated calcitonin levels (group 2). As in our earlier series, tumor invasiveness was the only parameter correlated with failure to reduce postoperative calcitonin levels to the normal range (P < .05, Fisher's exact test)." These results indicate an improvement in outcome after reoperation for persistent or recurrent MTC. In the second
100 90 -+-11• • •- - - - - - - - - - · · - - - - - - - - - - 80 c: 70
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30 20 10 0 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45
Patients
FIGURE 15-6. Postoperative change in peak stimulated calcitonin levels. The shaded bars indicate the postoperative stimulated calcitonin levels of the 45 patients who underwent curative cervical reexploration and dissection. The postoperative calcitonin level is expressed as a percentage of the preoperative calcitonin level. One hundred percent indicates no change in calcitonin level, and 10% indicates that the stimulated calcitonin level fell by 90%. 'Postoperative levels were higher than preoperative levels. (From Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: Recommendations for extent of node dissection. Ann Surg 1999;229:880.)
Medullary Thyroid Carcinoma - -
series (1992 to 1996),38% (17 of 45) of patients had normal postoperative stimulated calcitonin levels, compared with 28% (9 0["32) in the first series. Only 13% (6 of 45) of patients had no decrease in calcitonin levels following reoperation, compared with 31% (10 of 32) in the first series (P = .07, Fisher's exact test). This improvement occurred through better preoperative selection of patients and the institution of routine laparoscopic liver examination preoperatively, which identified metastases in 10 patients, 9 of whom had normal CT or MR imaging of the liver and who would otherwise have undergone neck reoperation with curative intent. In this series of 115 patients, 24 decided not to have surgical intervention."? If a patient with elevated calcitonin levels has had an adequate previous operation and results of imaging studies are negative, an expectant approach with routine yearly screening is appropriate in many cases.P We do, however, believe that it is important to observe these patients closely with routine CT or MRI of the neck and chest. If central recurrence develops, resection prevents death from airway or great vessel invasion in some patients. Tumor debulking may afford some patients relief from symptoms caused by local disease in the neck or from tumor-induced flushing and diarrhea. We treated six patients with severe, disabling diarrhea who had preoperative stimulated calcitonin levels greater than 25 ng/mL, in whom surgery reduced calcitonin levels and abolished the diarrhea (author, unpublished results). These reports support the use of reoperation in patients with persistently elevated calcitonin levels after surgery for MTC. Although patients with highly invasive tumors are not as likely to benefit from this approach, these operations can be done safely in the majority of cases and may result in long-term survival benefit and prevention of recurrence complications in the neck. Long-term follow-up of these patients is needed to confirm the presumed benefit derived from these operations.
Summary and Conclusions MTC is a tumor of the thyroid C cells that occurs in sporadic and hereditary clinical settings. Measurement of plasma calcitonin is a sensitive marker for the presence of this tumor. Hereditary forms of MTC, including MEN 2A, MEN 2B, and FMTC, are associated with mutations in the RET protooncogene. Genetic testing can identify mutant gene carriers, and preventive thyroidectomy should be done in patients found to have inherited a mutant gene. Surgical treatment for palpable MTC is total thyroidectomy with central and lateral functional neck dissection. Recurrent or residual MTC may be localized by ultrasonography, CT scanning, MRI, nuclear scanning, or SVc. Reoperation with systematic node dissection in patients with localized or occult MTC and no evidence of distant metastases has resulted in normalization of calcitonin levels in a significant number of patients. Radiation and chemotherapy have not been shown to be consistently effective in the treatment of MTC, and the treatment of patients with widely metastatic disease is unsatisfactory. Clinical trials of newer chemotherapeutic agents may identify more effective regimens.
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140 - - Thyroid Gland 27. Busnardo B, Girelli ME, Simioni N, et aJ. Nonparallel patterns of calcitonin and carcinoembryonic antigen levels in the follow-up of medullary thyroid carcinoma. Cancer 1984;53:278. 28. Lippman S, Mendelsohn G, Trump DL, et aJ. The prognostic and biological significance of cellular heterogeneity in medullary thyroid carcinoma: A study of calcitonin, L-dopa, decarboxylase and histaminase. 1 Clin Endocrinol Metab 1982;54:233. 29. Dralle H. Lymph node dissection and medullary thyroid carcinoma. Br 1 Surg 2002;89: 1073. 30. Moley IF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: Recommendations for extent of node dissection. Ann Surg 1999;229:880; discussion 887. 31. Dralle H, Damm I, Scheumann GF, et aJ. Compartment-oriented microdissectionof regional lymph nodes in medullary thyroid carcinoma. Surg Today 1994;24:112. 32. Decker RA, Geiger ID, Cox CE, et aJ. Prophylactic surgery for multiple endocrine neoplasia type Ila after genetic diagnosis: Is parathyroid transplantation indicated? World 1 Surg 1996;20:814; discussion, 820. 33. Dralle H, Gimm 0, Simon D, et aJ. Prophylactic thyroidectomy in 75 children with hereditary medullary thyroid carcinoma: German and Austrian experience. World 1 Surg 1998;22:744. 34. Frilling A, Dralle H, Eng C, et aJ. Presymptomatic DNA screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Surgery 1995;118:1099; discussion. 1103. 35. O'Riordain DS, O'Brien T, Weaver AL, et aJ. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery 1994;116:1017. 36. Russell CF, Van Heerden lA, Sizemore GW, et aJ. The surgical management of medullary thyroid carcinoma. Ann Surg 1983;197:42. 37. Olson lA lr, DeBenedetti MK, Baumann DS, Wells SA lr. Parathyroid autotransplantation during thyroidectomy: Results of long-term follow-up. Ann Surg 1996;223:472. 38. Wells SA Jr, Ross Al 3rd, Dale lK, Gray RS. Transplantation of the parathyroid glands: Current status. Surg Clin North Am 1979;59:167. 39. Fleming IB, Lee JE, Bouvet M, et aJ. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg 1999;230:697. 40. Moley IF, DeBenedetti M. Patterns of nodal metastases in palpable medullary thyroid carcinoma. Ann Surg 1999;229:880. 41. Mulligan L, Kwok 1, Healy C. Germ-line mutations of the RET protooncogene in multiple endocrine neoplasia type 2A (MEN 2A). Nature 1993;363:458. 42. Donis-Keller H, Dou S, Chi D, et aJ. Mutations in the RET protooncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993;2:851. 43. Eng C. RET proto-oncogene in the development of human cancer. 1 Clin OncoI1999;17:380. 44. Santoro M, Carlomagno F, Romano A, et aJ. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995;267:381. 45. Pacini F, Romei C, Miccoli P, et aJ. Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for RET gene mutations. Surgery 1995;118:1031. 46. Learoyd D, Marsh Dl, Richardson AL, et aJ. Genetic testing for familial cancer: Consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2. Arch Surg 1997;132:1022. 47. Frank-Raue K, Hoppner W, Buhr H, et aJ. Application of genetic screening in families with hereditary medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes 1996;104(suppI4):108. 48. Skinner MA, DeBenedetti MK, Moley IF, et aJ. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. 1 Pediatr Surg 1996;31:177; discussion, 181. 49. Wells SA Jr, Skinner MA. Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 1998;106:29. 50. Block M, lackson CE, Greenawald KA, et aJ. Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma. Arch Surg 1980;115:142. 51. Stepanas A, Samaan NA, Hill CS Jr, Hickey RC. Medullary thyroid carcinoma: Importance of serial serum calcitonin measurement. Cancer 1979;43:825. 52. Block M, lackson C, Tashjian A. Management of occult medullary thyroid carcinoma: Evidenced only by serum calcitonin elevations after apparently adequate neck operations. Arch Surg 1978;113:368.
53. Van Heerden 1, Grant CS, Gharib H, et aJ. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 1990;212:395. 54. Saad M, Guido 1, Samaan N. Radioactive iodine in the treatment of medullary carcinoma of the thyroid. 1 Clin Endocrinol Metab 1983;57:124. 55. Halnan K. The non-surgical treatment of thyroid cancer. Br 1 Surg 1975;62:769. 56. Brierley ID, Tsang RW. External radiation therapy in the treatment of thyroid malignancy. Endocrinol Metab Clin North Am 1996;25: 141. 57. Simpson W. Radiotherapy in thyroid cancer. Can Med Assoc 1 1975;113:115. 58. Steinfeld A. The role of radiation therapy in medullary carcinoma of the thyroid. Radiology 1977;123:745. 59. Williams E, Brown C, Doniach 1. Pathological and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid. 1 Clin Pathol 1966;19:103. 60. Nguyen T, Chassard lL, Lagarde P, et al. Results of postoperative radiation therapy in medullary carcinoma of the thyroid: A retrospective study by the French Federation of Cancer Institutes-The Radiotherapy Cooperative Group. Radiother Oncol 1992;23:1. 61. Husain M, Alsever RN, Lock IP, et aJ. Failure of medullary carcinoma of the thyroid to respond to doxorubicin therapy. Horm Res 1978;9:22. 62. Scherubl H, Raue F, Ziegler R. Combination chemotherapy of advanced medullary and differentiated thyroid cancer. Phase II study. 1 Cancer Res Clin Oncol 1990;116:21. 63. Orlandi F, Caraci P, Berruti A, et aJ. Chemotherapy with dacarbazine and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol 1994;5:763. 64. Schlumberger M, Abdelmoumene M, Delisle Ml, Couette IF. Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FU-streptozocin and 5 FU-dacarbazine. Br 1 Cancer 1995;71:363. 65. Grohn P, Kumpulainen E, lakobsson M. Response of medullary thyroid cancer to low-dose alpha-interferon therapy. Acta Oncol 1990;29:950. 66. luweid ME, Hajjar G, Stein R, et aJ. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using tJII-MN-14F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. 1 Nucl Med 2000;41 :93. 67. Schott M, Feldkamp 1, Klucken M, et aJ. Calcitonin-specific antitumor immunity in medullary thyroid carcinoma following dendritic cell vaccination. Cancer Immunolimmunother 2002;51 :663. 68. Cohen MS, Hussain HB, Moley IF. Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 2002; 132:960. 69. Carlomagno F, Vitagliano D, Guida T, et aJ. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002;62:7284. 70. Carlomagno F, Vitagliano D, Guida T, et aJ. The kinase inhibitor PPlblocks tumorigenesis induced by RET oncogenes. Cancer Res 2002;62: 1077. 71. Raue F, Winter 1, Frank-Raue K, et aJ. Diagnostic procedure before reoperation in patients with medullary thyroid carcinoma. Horm Metab Res Suppl 1989;21:31. 72. Frank-Raue K, Raue F, Buhr HI, et aJ. Localization of occult persisting medullary thyroid carcinoma before microsurgical reoperation: High sensitivity of selective venous catheterization. Thyroid 1992;2: 113. 73. Norton 1, Doppman 1, Brennan M. Localization and resection of clinically inapparent medullary carcinoma of the thyroid. Surgery 1980;87:616. 74. Mrad M, Gardet P, Roche A, et aJ. Value of venous catheterization and calcitonin studies in the treatment and management of clinically inapparent medullary thyroid cancer. Cancer 1989;63: 133. 75. Abdelmoumene N, Schlumberger M, Gardet P, et aJ. Selective venous sampling catheterisation for localisation of persisting medullary thyroid carcinoma. Br 1 Cancer 1994;69: 1141. 76. Gautvik KM, Talle K, Hager B, et aJ. Early liver metastases in patients with medullary carcinoma of the thyroid gland. Cancer 1989;63: 175. 77. Tung WS, Veseley TM, Moley IF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995;118: 1024.
Medullary Thyroid Carcinoma - - 141 78. Bigsby RJ, Lepp EK, Litwin DE, et al. Technetium 99m pentavalent dimercaptosuccinic acid and thallium 20 I in detecting recurrent medullary carcinoma of the thyroid. Can J Surg 1992;35:388. 79. Ohnishi T, Noguchi S, Murakami N, et al. Detection of recurrent thyroid cancer: MR versus thallium-201 scintigraphy. AJNR Am J Neuroradiol 1993;14:105!. 80. Udelsman R, Ball D, Baylin SB, et al. Preoperative localization of occult medullary carcinoma of the thyroid gland with single-photon emission tomography dimercaptosuccinic acid. Surgery 1993;114:1083. 81. !toh H, Sugie K, Toyooka S, et al. Detection of metastatic medullary thyroid cancer with 1311-MIBG scans in Sipple's syndrome. Eur J Nucl Med 1986;11:502. 82. Skowsky WR, Wilf LH. Iodine 131 metaiodobenzylguanidine scintigraphy of medullary carcinoma of the thyroid (erratum in South Med J 1991;84:816, 937). South Med J 1991;84:636. 83. Kwekkeboom DJ, Reubi JC, Lamberts SW, et al. In vivo somatostatin receptor imaging in medullary thyroid carcinoma. J Clin Endocrinol Metab 1993;76:1413. 84. Krausz Y, Ish-Shalom S, Dejong RB, et al. Somatostatin-receptor imaging of medullary thyroid carcinoma. Clin Nucl Med 1994;19:416. 85. O'Byrne KJ, Hamilton D, Robinson I, et al. Imaging of medullary carcinoma of the thyroid using IIIIn-labeled anti-CEA monoclonal antibody fragments. Nucl Med Commun 1992;13:142. 86. Peltier P,Curtet C, Chatal JF, et al. Radioimmunodetection of medullary thyroid cancer using a bispecific anti-CEAlanti-indium-DTPA antibody and an indium-l l I-labeled DTPA dimer, J Nucl Med 1993;43:1267. 87. Juweid ME, Sharkey RM, Behr T, et al. Targeting and initial radioimmunotherapy of medullary thyroid carcinoma with 13lI-labeled monoclonal antibodies to carcinoembryonic antigen. Cancer Res 1995;55(Suppl):5946s. 88. Juweid M, Sharkey RM, Behr T, et al. Improved detection of medullary thyroid cancer with radio-labeled antibodies to carcinoembryonic antigen. J Clinical OncoI1996;14:1209.
89. Manil L, Boudet F, Motte P. Positive anticalcitonin immunoscintigraphy in patients with medullary thyroid carcinoma. Cancer Res 1989;49:5480. 90. Kwekkeboom DJ, Bakker WH, Kooij PP, et al. Cholecystokinin receptor imaging using octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma. Eur J Nucl Med 2000;27:1312. 9!. Behr TM, Jenner N, Behe M, et al. Radiolabeled peptides for targeting cholecystokinin-B/gastrin receptor-expressing tumors. J Nucl Med 1999;40: 1029. 92. Waddington WA, Kettle AG, Heddle RM, Coakley AJ. Intraoperative localization of recurrent medullary carcinoma of the thyroid using indium-III pentetreotide and a nuclear surgical probe. Eur J Nuc1 Med 1994;21:363. 93. Musholt TJ, Moley JF. Management of persistent or recurrent medullary thyroid carcinoma. Prob Gen Surg 1997;14:89. 94. Musholt TJ, Musholt PB, Dehdashti F, Moley JF. Evaluation of tluorodeoxyglucose-positron emission tomographic scanning and its association with glucose transporter expression in medullary thyroid carcinoma and pheochromocytoma: A clinical and molecular study. Surgery 1997;122: 1049; discussion, 1060. 95. Block M, Jackson C, Tashjian A. Management of occult medullary thyroid carcinoma: Evidenced only by serum calcitonin level elevations after apparently adequate neck operations. Arch Surg 1992;113:368. 96. Buhr H, Kallinowski F, Raue F, et al. Microsurgical neck dissection for occultly metastasizing medullary thyroid carcinoma: Three year results. Cancer 1993;72:3685. 97. Tisell L, Hansson G, Jansson S, Salander H. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986;99:60. 98. Moley JF, Wells SA, Dilley WG, Tisell LE. Reoperation for recurrent or persistent medullary thyroid cancer. Surgery 1993;114:1090. 99. Moley J, Dilley W, DeBenedetti M. Improved results of cervical reoperation for medullary thyroid carcinoma. Ann Surg 1997;225:734.
Localization Tests in Patients with Thyroid Cancer Shiro Noguchi, MD, PhD, FJCS, FACE
Differentiated Thyroid Cancer of Follicular Cell Origin The minimal test for determining the diagnosis of a thyroid nodule is fine-needle aspiration cytology with or without ultrasonography. Use of these two tests enables one to discriminate benign from malignant thyroid tumors in about 85% of patients. The remaining 15% of thyroid malignancies are follicular cancer, Htirthle cell cancer, and some follicular variants of papillary thyroid cancer. Various imaging techniques are used for detecting regional and/or distant metastasis and identifying local invasion of adjacent structures.
Ultrasonography for Papillary Cancer Since the advent of high-resolution ultrasonography, it is sometimes possible to establish the diagnosis of papillary cancer with only ultrasonography, and fine-needle aspiration cytology is used to confirm the diagnosis.!:" Papillary cancer is most frequently thyroid cancer (""80%). The presence of calcification, irregular shape, absence of a halo and hypoechogenicity, and local invasion suggest it is a malignant nodule. Calcification is identified as multiple, small hyperecho genic spots in a hypoechogenic area (Figs. 16-1 and 16-2). They are usually due to superimposed psammoma bodies. Larger papillary thyroid cancers often degenerate, and complex cyst formation is common. These partially cystic areas are usually located at the peripheral part of the tumor (Fig. 16-3). A protrusion of solid tumor into the cyst can frequently be seen. Lymph node metastases or recurrence in lymph nodes is also identified with ultrasonography. Lymph nodes greater than 9 mm in diameter, those with a longitudinal-transverse diameter ratio of less than 2.0, and those with a round configuration are likely to contain metastatic cancer (Fig. 16-4).5.7 When one or more suspicious nodes are identified by ultrasonography, fine-needle aspiration cytology is usually recommended for confirmation of diagnosis. Ultrasonography is an accurate and sensitive localization test for diagnosing cervical metastases, but unfortunately it is
142
not useful for identifying metastases in the retroclavicular area and mediastinum. Thus, when serum thyroglobulin levels are increased, other localization tests are necessary, such as magnetic resonance imaging (MRI) or radioiodine whole-body scanning (WBS), the latter for the patient who has previously had a total or near-total thyroidectomy. The search for enlarged lymph node metastases in the neck has become easier because of ultrasonography; however, microscopic metastases are also present in about 80% of patients with papillary thyroid cancer who have no evident cervical metastases on clinical examination.f-? These small metastases mayor may not be visualized with ultrasonography." In patients with papillary thyroid cancer, the importance of nodal metastasis on survival is controversial. Some studies suggest that the presence of clinically evident lymph node metastases in patients with papillary and follicular cancer has an adverse effect on survival. 11·16 Extracapsular invasion of nodal metastases of thyroid cancer is associated with a poorer survival rate in patients with papillary microcarcinoma." Other studies suggest that lymph node metastases are associated with increased recurrence rate, but survival is not affected.":" Since cervical lymph node is the most frequent site for recurrent tumor, ultrasonography of the neck is helpful for the management of patients with papillary thyroid cancer.
Radioiodine Scintigraphy Iodine 131 ( 1311) is a favored scanning agent for following patients after total or near-total thyroidectomy for thyroid cancer of follicular cell origin because 1311 can be used therapeutically. Many studies have examined the sensitivity and specificity of a low dose (370 MBq, or lower) and high dose of 131 1 (2.9 GBq, 80 mCi, or more) for the detection of disease. 22. 34 The sensitivity ranges from 40% to 84% depending on the dose of 1311, the age of the patient, tumor differentiation, and tumor location. The specificity is high and the range is narrow, from 90% to 100% (Fig. 16-5). The sensitivity for detecting lung metastases is reported to vary from 42% to 60%, and for bone metastasis it varies from
Localization Tests in Patients with Thyroid Cancer - -
143
ultrasonography, 18F-2-fluoro-2-deoxY-D-glucose positronemission tomography (FDG-PET), or Tc 99m sestamibi are often used alone or in combination to document the presence and site of persistent or recurrent disease. 1231 is a pure lower energy (l59-keV) gamma emitter, whereas 131 1 is a high-energy (364-keV) gamma and beta emitter. 1231has better resolution imaging properties than 131 I because 1231 does not emit beta particles; therefore, a larger dose of 1231 can be administered with a lower risk of stunning, which reduces subsequent therapeutic efficacy." Image quality after radioiodine administration is good in terms of resolution and low background at 24 hours. The recommended dose of 1231 is 56 MBq; there is little incremental advantage of sensitivity after scanning using larger doses. The concordance with 131 1 is almost identical with post-therapy scan.37.38 The overall sensitivity of 1231 is 93% when compared with 1311.
Scintigraphy with Alternative Nucleotides THALLIUM 201 CHLORIDE
B FIGURE 16-1. Papillary cancer. A and B, Many small hyperechoic spots are seen in the hypoechoic region.
54% to 60%.26,35 The sensitivity for detecting lymph node metastasis is only about 22%26; luckily, ultrasonography, computed tomography (CT), MRI, Tc 99m sestamibi, and thallium can usually detect cervical lymph node metastases. The sensitivity may change depending on the definition of tumor presence. Serum thyroglobulin levels, 20lTI scan, neck
Thallium 201 eOIT!) was first used in the early 1980s for detecting metastases from both well-differentiated thyroid cancer and recurrent medullary cancer in 1980s.39. 44 It accumulates in the tumor and gives a positive image by contrasting with the negative image by radioiodine and remains in the tumor longer than it does in normal thyroid (Fig. 16-6). Tc 99m sestamibi became available around 1987, and many investigators compared the results of 20lTI scintigraphy to Tc 99m sestamibi. Although these two imaging isotopes gave comparable results, Tc 99m sestamibi results were slightly better and clearer than those with 20lTI in patients with differentiated thyroid cancer.45,46 For patients with medullary cancer 99mTc(V)-dimercaptosuccinic acid (Tc 99m DMSA) appeared to be somewhat more accurate than 20lTI for routine clinical use." 20lTI imaging is most useful after total or near-total thyroidectomy and 131 1 ablative therapy in patients with rising or elevated serum thyroglobulin levels. In addition, about 10% of hypothyroid patients with verified thyroid cancer and positive 20lTI scan have a low serum thyroglobulin leve1. 48,49 20lTI imaging has an additional advantage in that it can be done in the patients who are
FIGURE 16-2. Papillary cancer. Arrow I, right carotid artery; arrow 2, primary tumor; arrow 3, trachea; arrow 4, esophagus; and arrow 5, left carotid artery.
1
2
3
4
5
144 - -
Thyroid Gland
negative 131 1 scan in a patient with an elevated serum thyroglobulin level. 28,49 20lTI scanning is helpful for detecting cervicomediastinal nodal metastases but is not accurate for detecting a normal thyroid remnant or pulmonary metastasis. Overall, 20lTI is the most commonly used radioactive pharmaceuticals for patients with thyroid cancer, other than 1311. TECHNETIUM 99M SESTAMIBI
FIGURE 16-3. Papillary thyroid cancer with cystic degeneration.
receivmg thyroid hormone. Discontinuation of thyroid hormone medication stimulates increased thyroid-stimulating hormone (TSH) secretion, which can stimulate thyroid tumor uptake of radioiodine and tumor growth. Imaging with 20lTI also requires only one visit, in contrast with scanning with 131 1 using human recombinant TSH, which requires several visits. The sensitivities reported for 20lTI vary depending on the dose of 20lTI and the timing of imaging after injection of the isotope. When imaging is done 15 to 20 minutes after injection, sensitivities ranging from 74% to 94% have been reported.23.27.50 Reported specificities range from 84% to 97%.27,49 In a large retrospective series including 326 patients, 20lTI scintigraphy demonstrated abnormal findings in 39 patients who had negative 131 1 studies." Among these patients, 26 were confirmed histologically and 5 radiologically, and 8 had no definite confirmation. The sensitivity was 94% and the specificity was 98%. There is a large discordance between 20lTI and 131 1 studies in patients with remaining normal thyroid tissue, because the sensitivity oeolTI is poor when normal thyroid remains, whereas 131 1 uptake is high in this tissue.t' After ablation with 1311, 20lTI has a sensitivity of 94% and a specificity of 96%.23 The sensitivity of 20lTI is equivalent or superior to low-dose 131 1 but less sensitive than high-dose 1311. 20lTI is particularly useful in the setting of a
Scanning with Tc 99m sestamibi in thyroid cancer patients has been compared to radioiodine." with 201TI,45 with Tc 99m terrofosmin, and with MRI.52 Tc 99m sestamibi, like 20ITI, does not require discontinuing thyroid hormone and requires only one visit. This is an advantage of Tc 99m sestamibi over 1311. Imaging with non iodine radiopharmaceuticals is independent of TSH stimulation, but TSH stimulation improve the quality of images. Contemporary gamma cameras are optimized for imaging at the emission energy of 99mTc (140 keY) rather than much higher emission energies of 1311 (364 keY) or the lower emission energy of 20lTI (69 to 81 keY). Tc 99m sestamibi has the advantage of the availability of a kit-based radiopharmaceutical with same-day imaging. The other advantage ofTc 99m sestamibi over 20lTI is a short physical half-life of 6 hours, whereas 20lTI has a physical half-life of 73 hours. Therefore, Tc 99m sestamibi can be administered in a larger dose (20 to 25 mCi), resulting in better images and lower radiation exposure to the patient.
Invasion of Papillary Cancer to Adjacent Organs Involvement of the recurrent laryngeal nerve by tumor cannot be determined preoperatively unless vocal cord palsy is evident on direct laryngoscopy. However, the size and position of the primary tumor provide some information. Among our 3148 patients with papillary thyroid cancer larger than 10 mm in maximum dimension, there was a direct correlation between adhesion/invasion of the recurrent laryngeal nerve. Thus, involvement occurred in 9.2% of tumors 10 to 14 mm, 17.3% of tumors 15 to 24 mm, and 33.0% of tumor more than 25 mm in maximum diameter. Using the same size criteria, as determined by frozen section, invasion/adhesion occurred within the esophagus in 2.7%,9.2%, and 21.4%. respectively. CT, MR!, conventional esophagography, and esophagoscopy may help predict the
FIGURE 16-4. Lymph node metastasis
with calcification (A) and with cystic degeneration (B).
A
B
Localization Tests in Patients with Thyroid Cancer - - 145
A
c
FIGURE 16-5. Lung metastases. A, With conventional chest radiograph, no metastases were seen. B, With high-dose 1311
scintigraphy, extensive metastases were shown. C, With helical CT,multiple small shadows of metastases wereseen in one patient.
B
presence of invasion of thyroid cancer into the esophagus; however, these modalities are insufficient for a precise diagnosis and determination of exact depth of invasion. Recently, endoscopic ultrasonography was reported to be superior to MRI and esophogography in terms of accuracy and specificity regarding esophageal invasion." Invasion of the trachea is also difficult to determine preoperatively. Using the same size criteria, adhesion/invasion to the trachea was observed in 17%, 29%, and 40%, respectively; however, when the tumor was close to Berry's ligament, it
was hard to differentiate. These figures therefore could be an overestimation. Tumor size is a well-known predictor of tumor behavior. 54•55 MRI helps determine extent of tracheal invasion. Characteristic findings include a soft tissue signal in the tracheal cartilage, intraluminal mass, and degree of tumor circumference around the trachea abutting 180 degrees or more.>' An anterior part of the trachea is most likely to be invaded by thyroid cancer in primary cases; however, in cases of recurrence, invasion can occur in any part of the trachea. Endoscopic documentation of
146 - - Thyroid Gland
A
B
FIGURE 16-6. Thallium scan, showing early image (A) and delayed image (B). The arrow in B indicates tumor localization.
laryngotracheal invasion was recently reported. The major findings included mucous membrane swelling, dilated capillaries, localized reddening, localized swelling, edema, and erosion (Fig. 16-7). Intraluminal tumor is rare." When these findings are present, resection of a part of the trachea followed by end-to-end anastomosis or partial resection with preservation of the recurrent laryngeal nerve is recommended rather than shaving the tumor off the surface of the trachea.T"
A
B
c
D
Follow-Up of Patients Who Lost Differentiation Markers Although the serum thyroglobulin level is the most sensitive and useful marker for follow-up of patients with differentiated thyroid cancer, especially in patients after total thyroidectomy, in some patients serum basal thyroglobulin levels are not increased and fail to increase when TSH levels are increased. Thyroglobulin in this small group does not
FIGURE 16-7. A, Stage I thyroid cancer that extended through the capsule of the thyroid gland and abutted the external perichondrium. B, Stage 2 thyroid cancer that invaded between the rings of cartilage or destroyed the cartilage. C, Stage 3 thyroid cancer that extended through the cartilage or between the cartilaginous plates into the lamina propria of the tracheal mucosa. D, Stage 4 thyroid cancer that extended through the entire thickness of and expanded the tracheal mucosa.
Localization Tests in Patients with Thyroid Cancer - - 147 serve as a useful marker for recurrence. Some thyroid cancers also dedifferentiate, particularly with advanced disease and age. 131 1 ablation is less effective in these patients. 7,45,48,52,59-61 Since the most common site of recurrence is in the neck lymph nodes, ultrasonography would be selected first for local disease and 20lTI or Tc 99m sestamibi for WBS. For lung metastases with small miliary foci, helical CT is better than WBS. External-beam radiation can be helpful for treatment of high-risk patients with persistent or recurrent disease. Redifferentiation with retinoic acid and other agents may be helpful.F
Image Diagnosis of Medullary Cancer All patients with a preoperative diagnosis of medullary cancer of the thyroid should be tested for a ret protooncogene germline point mutation and also be screened for pheochromocytoma and hyperparathyroidism (see other chapters regarding medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism). Medullary cancer secretes calcitonin and carcinoembryonic antigen (CEA) and occasionally neuron-specific enolase, serotonin, chromogranin, gastrin-releasing peptide, substance P, pro-opiomelanocortin-derived products, and somatostatin. Among them, calcitonin and CEA are used as tumor markers for following patients for persistent disease or recurrent disease. Calcitonin is the most sensitive biochemical marker for predicting the presence of tumor. A steep slope with rapidly rising CEA levels indicates that the patients have rapidly progressive tumor. A normal CEA level or a flat slope indicates that patients may be cured or they have only slowly progressive disease.63,64 Decrease of the calcitonin/CEA ratio indicates dedifferentiation of medullary thyroid cancer.
Ultrasonography Medullary cancer is a considerably rare disease, constituting only 4% to 9% of all thyroid cancers. Ultrasonography is the most recommended helpful modality for detecting primary tumor as well as localizing cervical metastases in the central or lateral neck nodes, particularly those associated with multiple endocrine neoplasia (MEN) type 2A. Ultrasonography is superior to radionucleotide scanning for detecting
cancer foci within the thyroid or in the cervical lymph nodes. One can identify primary tumors as small as 3 mm by high-resolution ultrasonography. Lymph node metastases are common in patients with MEN 2A and familial medullary cancer. Pathologic examinations of the lymph nodes during primary staging revealed cervical lymph node involvement in 31% to 33% of the p'I'I cases,65.66 in 53% of the pT2 cases." and in 100% of the pT3 and pT4 patients. Ultrasonographic features include hypoechoic nodules with disseminated or focal echogenic calcifications that may cast an acoustic shadow and smooth or irregular delimited nodules with pseudopod-like projections (Fig. 16-8). These features are found both in primary tumors as well as in lymph node metastases. Since these ultrasonographic findings are nonspecific and may be present in adenomatous nodular goiters, one should interpret the ultrasonographic findings with the serum calcitonin levels.67,68 Serum calcitonin levels are highly specific for medullary thyroid cancer and are helpful for both preoperative planning and postoperative evaluation. Most patients with mild increases in calcitonin have metastatic tumors only in the cervical lymph nodes. Some of these metastatic nodes are too small to detect by palpation but may be detected by ultrasound scanning. Ultrasonography therefore is the first choice as a localization test. It is inexpensive and there is no radiation hazard. An experienced ultrasonographer, however, is essential for good results.
MmG Three years after the advent of 1321-metaiodobenzylguanidine (MIBG) as an imaging agent for pheochromocytomata.v? it was noted that some medullary thyroid cancers also could be identified by MIBG scanning. This is also true for metastases.?? From these observations it was expected that MIBG might be a helpful therapeutic agent." Unfortunately, due to the poor sensitivity of MIBG scintigraphy in medullary thyroid cancer, this agent is not suitable for initial diagnosis but can be used when internal radiation therapy with 1311-MIBG is planned. 1311-MIBG has been used for treatment of pheochromocytoma, paraganglioma, and medullary cancer when MIBG scanning is positive. Symptomatic control was achieved in all patients treated with 1311-MIBG alone, including hormonal improvement and tumor regression or stabilization in patients with
FIGURE 16-8. Calcification of medullary thyroid cancer (A) and of part of a multinodular goiter (B).
A
B
148 - -
Thyroid Gland
metastatic tumors with minimal adverse effects." Also, in many other articles, no important adverse effect is mentioned.Y" However, in one article, a patient with metastatic pheochromocytoma to the lung, liver, and paraaortic lymph node was treated with 3.7 GBq (100 mCi) of 1311_MIBG. The metastatic nodes in the lung and liver disappeared, and the secretion of catecholamine levels decreased to normal. Major but temporary untoward responses were hypertension and hyperglycemia."
Anti-CEA Monoclonal Antibody Medullary cancer contains and secretes CEA as well as calcitonin. 1311-labeled or 1llln-labeled CEA unfortunately detects only relatively large metastases (> 10 mrn'') as occurred in 5 of II patients with medullary thyroid cancer.s" Initially, radiolabeled CEA monoclonal antibodies were reported to be specific but not very sensitive. Subsequent investigation demonstrated nonspecific uptake of radiolabeled CEA in the spleen, kidneys, bone marrow, and liver, presumably due to the poor specificity of the antibody that was used." Hoefnagel," Zanin.t' and their associates suggested that 1311-labeled monoclonal antibody might be used therapeutically in patients with medullary thyroid cancer. In 1997, Juweid and colleagues'" reported that anti-CEA monoclonal antibodies were excellent agents for imaging recurrent, residual, or metastatic medullary thyroid cancer. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease preoperatively or postoperatively, and especially for evaluating patients with recurrent or persistent elevated calcitonin or CEA levels after primary surgery." Sensitivity of anti-CEA radiolabeled antibody technique seems to be dependent on the quality of monoclonal antibody.P Combined therapy using 1311-labeled CEA with conventional chemotherapy of medullary thyroid cancer has been reported in animals.f" Behr and coworkers reported that 30 patients with smallvolume metastatic colorectal cancers have been treated with 13 'Llabeled anti-CEA as an adjuvant setting."
99mTc(V)-Dimercaptosuccinic Acid and Somatostatin Analog Ohta and associates first reported the use of DMSA for imaging medullary cancer of the thyroid in 1984. 88 Four patients with medullary cancer showed clear and specific tumor uptake in primary and/or metastatic foci. DMSA uptake was subsequently noted in the nasopharynx, axial skeleton, breast, liver, spleen, heart, kidney, urinary bladder, great vessels, and skeletal muscles." There was no DMSA uptake in the male breast. Positive uptake was seen in only one of three subjects younger than 15 years of age, in 16 of 23 patients (70%) between 15 and 50, and in 7 of 25 (28%) older than 50. 90 The overall sensitivity of DMSA ranged from 57% to 95%.91-96 The differences in sensitivity may depend on the method of preparing pentavalent DMSA since the pH of the mixture has to be high (7.5) for highest activity. When the pH is low, trivalent DMSA is synthesized, which makes DMSA sensitivity low.?? Unfortunately, most subsequent studies have not found DMSA to be sensitive
enough to recommend it for routine use in patients with medullary thyroid cancer. Kwekkeboom and colleagues'" have reported tumor localization in 11 of 17 patients (65%) with 1llln-octreotide with medullary thyroid cancer. They reported that neither serum calcitonin nor CEA levels differed significantly between patients whose tumor accumulated labeled octreotide in vivo and those tumors that did not. Numerous authors have subsequently presented their experience using octreotide scintigraphy for the localization of recurrent medullary cancer.99-107 When somatostatin scintigraphy was compared with MRI scanning in nine patients, the same 17 lesions were seen by both methods; however, 13 additional suspicious lesions were seen with somatostatin scintigraphy. Histologic confirmation was available from 19 metastases; MRI was positive in 13 (68%) and somatostatin receptor scintigraphy was positive in 18 (95%).99.100 Comparison of 1llln-octreotide and DMSA has also been done. Three papers concluded that octreotide is superior; however, the sensitivity of DMSA is relatively IOW. 91,1 02.108 Another investigation suggests that both 1111n and DMSA are relatively that insensitive. 103
Imaging of Metastases of Thyroid Cancer with Fluorine 18 Fluorodeoxyglucose FDG is a o-glucose analog, which is converted in cells to FDG-6-phosphate by hexokinase. FDG-6-phosphate is metabolically trapped and accumulates in tissue where glucose-6-phosphatase is lacking. Metabolic trapping is the key factor responsible for the biodistribution of 18F-2-deoxyglucose.109 Because other enzymes that act on glucose-6-phosphate have only a negligible affinity for FDG-6-phosphate and membrane permeability is low, the rate of accumulation of FDG-6-phosphate is proportional to the phosphorylation rate of exogenous glucose and o-glucose utilization of the tissue. 18F has a half-life of about 109 minutes, so that the patient is exposed to a tolerable amount of radiation. 110 FDG-PET is primarily used to localize recurrent differentiated and poorly differentiated thyroid cancers, especially in patients who are serum thyroglobulin positive and 131 1 WBS negative. Serum thyroglobulin determination and diagnostic 131 1 WBS provide the diagnosis of recurrent disease. Recurrent differentiated thyroid cancer mayor may not take up radioiodine. III A patient whose recurrent tumor is detected by radioiodine scanning has a significantly better prognosis than does a patient whose tumor does not take up 131I.ll2 FDG-PET can be positive in the same site as a WBS-positive site or WBS-negative site, or both can be present in the same patient. Grunwald and associates 113 reported that FDG-PET was particularly useful in WBSnegative patients, showing a high sensitivity of 85%. Patients with poorly differentiated thyroid cancers were more likely to be WBS negative and FDG-PET positive. Those patients also have a worse prognosis-FDG-PET helps stage the disease and guide treatment strategy. Possible therapeutic strategies include surgery, external-beam radiation, and redifferentiation therapy.Uv'!? Patients who
Localization Tests in Patients with Thyroid Cancer - - 149 are WBS positive and FDG-PET negative usually respond better to treatment with 1311. The result obtained from FDG-PET scanning may influence therapy; for example, the removal of mediastinum lymph node metastases usually should be omitted when additional distant metastases are detected by FDG-PET scan in 131 1 scan-negative patients. The benefit of further radioiodine therapy in thyroglobulin-positive 1311 scan-negative patients is controversial. Correlation between the grade of differentiation and the rate of detectability with FDG-PET and MIBI or WBS exists. Since glucose metabolism is increased particularly in poorly differentiated tumors, a higher sensitivity of FDGPET can be expected in these tumors, in association with a low sensitivity ofWBS.118-123 Metastases showing high FDG uptake but low 131 1 uptake often grow more rapidly and are generally more aggressive.l" A higher mortality rate in patients who have a negative WBS (with or without elevated thyroglobulin levels) in spite of proven metastases has also been reported.l" Grunwald and coworkersl-" reported a higher rate of positive FDG-PET scans in patients with highrisk patients by TNM staging. Thus, positive FDG-PET scans were observed in 2 of 14 patients (14%) with pTl/pT2 tumor stage versus 8 of 17 patients (47%) with pT3/pT4 tumors. Higher tumor stage correlates with a poorer prognosis. Positive FDG-PET scans also occur in patients with sarcoidosis.l" granulomas.I" parathyroid tumors.!" Hiirthle cell adenomas.F' follicular adenomas, and adenomatous goiters.F" FDG-PET scanning can detect metastases in lymph nodes less than 1 em in diameter. 123 Small pulmonary metastases «I em), with or without radioiodine uptake, were not detected by FDG-PET but were detected by spiral CT scanning.123.124
Conclusion Localization tests are helpful for documenting metastases in patients with thyroid cancer. Ultrasonography is recommended for cervical nodal metastases, spiral CT for pulmonary metastases, and FDG-PET scans for patients with poorly differentiated thyroid cancers and for thyroglobulin-positive, WBS-negative patients. Radioiodine scans are positive in about 75% of patients with metastases. Radioiodine scans require a previous total or near-total thyroidectomy. 131} can be used for ablative therapy. Sestamibi, thallium, DSMA, and octreotide scans are occasionally helpful but are not sensitive enough to be recommended for routine use in the follow-up of most patients.
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Localization Tests in Patients with Thyroid Cancer - - 151 80. Lumbroso J, Berche C, Mach JP, et al. [Use of tomographic scintigraphy with radiolabeled monoelonal antibodies for detecting human digestive cancers and medullary cancers of the thyroid]. Bull Cancer 1983;70:96. 81. O'Byrne KJ, Hamilton D, Robinson I, et al. Imaging of medullary carcinoma of the thyroid using 1IlIn-labelled anti-CEA monoelonal antibody fragments. Nuel Med Commun 1992;13: 142. 82. Hoefnagel CA, Delprat CC, Zanin D, van der Schoot JB. New radionuclide tracers for the diagnosis and therapy of medullary thyroid carcinoma. Clin Nuel Med 1988;13:159. 83. Zanin DE, van Dongen A, Hoefnagel CA, Bruning PE Radioimmunoscintigraphy using iodine-I 3 I-anti-CEA monoelonal antibodies and thallium-201 scintigraphy in medullary thyroid carcinoma: A case report. J Nuel Med 1990;31:1854. 84. Juweid M, Sharkey RM, Swayne LC, Goldenberg DM. Improved selection of patients for reoperation for medullary thyroid cancer by imaging with radiolabeled anticarcinoembryonic antigen antibodies. Surgery 1997;122:1156. 85. Juweid M, Sharkey RM, Behr T, et al. Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen. J Clin OncoI1996;14:1209. 86. Stein R, Chen S, Reed L, et al. Combining radioimmunotherapy and chemotherapy for treatment of medullary thyroid carcinoma: Effectiveness of dacarbazine. Cancer 2002;94:5 I. 87. Behr TM, Liersch T, Greiner-Bechert L, et al. Radioimmunotherapy of small-volume disease of metastatic colorectal cancer. Cancer 2002;94: 1373. 88. Ohta H, Yamamoto K, Endo K, et aJ. A new imaging agent for medullary carcinoma of the thyroid. J Nuel Med 1984;25:323. 89. Udelsman R, Ball D, Baylin SB, et al. Preoperative localization of occult medullary carcinoma of the thyroid gland with single-photon emission tomography dimercaptosuccinic acid. Surgery 1993;114:1083. 90. Nakamoto Y, Sakahara H, Kobayashi H, et aJ. Technetium-99m (V)-dimercaptosuccinic acid: Normal accumulation in the breasts. Eur J Nuel Med 1997;24: 1146. 91. Arslan N, Ilgan S, Yuksel D, et al. Comparison of In-Ill octreotide and Tc-99m(V)DMSA scintigraphy in the detection of medullary thyroid tumor foci in patients with elevated levels of tumor markers after surgery. Clin Nuel Med 2001 ;26:683. 92. Adams S, Baum RP, Hertel A, et aJ. Comparison of metabolic and receptor imaging in recurrent medullary thyroid carcinoma with histopathological findings. Eur J Nuel Med 1998;25:1277. 93. Kujat C, Neidl K, Muller-Leisse C. [Medullary carcinoma of the thyroid and 99mTc(V)-DMSAscintigraphy: Clinical results with a new radiopharmaceutical]. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1990;153:495. 94. Clarke SE, Lazarus C, Mistry R, Maisey MN, The role of technetium99m pentavalent DMSA in the management of patients with medullary carcinoma of the thyroid. Br J Radiol 1987;60: 1089. 95. Clarke S, Lazarus C, Maisey M. Experience in imaging medullary thyroid carcinoma using 99mTc(V)dimercaptosuccinic acid (DMSA). Henry Ford Hosp Med J 1989;37:167. 96. Guerra UP, Pizzocaro C, Terzi A, et al. New tracers for the imaging of the medullary thyroid carcinoma. Nuel Med Commun 1989;10:285. 97. Hirano T, Tomiyoshi K, Zhang YJ, et aJ. Preparation and elinical evaluation of technetium-99m dimercaptosuccinic acid for tumour scintigraphy. EurJ Nuel Med 1994;21:82. 98. Kwekkeboom DJ, Reubi JC, Lamberts SW, et al. In vivo somatostatin receptor imaging in medullary thyroid carcinoma. J Clin Endocrinol Metab 1993;76:1413. 99. Dorr U, Frank-Raue K, Raue F, et al. The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma. Nuel Med Commun 1993;14:439. 100. Dorr U, Wurstlin S, Frank-Raue K, et al. Somatostatin receptor scintigraphy and magnetic resonance imaging in recurrent medullary thyroid carcinoma: A comparative study. Horm Metab Res SuppI1993;27:48. 101. Frank-Raue K, Bihl H, Dorr U, et al. Somatostatin receptor imaging in persistent medullary thyroid carcinoma. Clin Endocrinol (Oxf) 1995;42:31. 102. Eising EG, Farahati J, Bier D, et al. [Somatostatin receptor scintigraphy in medullary thyroid carcinomas, GEP and carcinoid tumors]. Nuklearmedizin 1995;34:1. 103. Bema L, Cabezas R, Mora J, et al. 11IIn-octreotide and 99mTc(V)_ dimercaptosuccinic acid studies in the imaging of recurrent medullary thyroid carcinoma. J Endocrinol 1995;144:339.
104. Baudin E, Lumbroso J, Schlumberger M, et al. Comparison of octreotide scintigraphy and conventional imaging in medullary thyroid carcinoma. J Nuel Med 1996;37:912. 105. O'Byrne KJ, O'Hare N, Sweeney E, et al. Somatostatin and somatostatin analogues in medullary thyroid carcinoma. Nuel Med Commun 1996;17:810. 106. Behr TM, Gratz S, Markus PM, et al. Anti-carcinoembryonic antigen antibodies versus somatostatin analogs in the detection of metastatic medullary thyroid carcinoma: Are carcinoembryonic antigen and somatostatin receptor expression prognostic factors? Cancer 1997;80:2436. 107. Tisell LE, Ahlman H, Wangberg B, et al. Somatostatin receptor scintigraphy in medullary thyroid carcinoma. Br J Surg 1997;84:543. 108. Celentano L, Sullo P, Klain M, et al. II I In-pentetreotide scintigraphy in the post-thyroidectomy follow-up of patients with medullary thyroid carcinoma. Q J Nuel Med 1995;39: 13 I. 109. Gallagher BM, Fowler JS, Gutterson NI, et al. Metabolic trapping as a principle of radiopharmaceutical design: Some factors responsible for the biodistribution of [1 8F]2-deoxy-2-fluoro-o-glucose. J Nuel Med 1978;19:1154. 110. Jones SC, Alavi A, Christman D, et al. The radiation dosimetry of 2 [F-18]fluoro-2-deoxy-o-glucose in man. J Nuel Med 1982;23:613. III. Schlumberger MJ, Incerti C, Pacini F, Reiners C. The role of recombinant thyroid-stimulating hormone (rhTSH) in the detection and management of well-differentiated thyroid carcinoma: A roundtable discussion. J Endocrinol Invest 1999;22:35. 112. Coburn M, Teates D, Wanebo HI. Recurrent thyroid cancer: Role of surgery versus radioactive iodine (' 311). Ann Surg 1994;219:587. 113. Grunwald F, Briele B, Biersack HJ. Non-P'Lscintigraphy in the treatment and follow-up of thyroid cancer: Single-photon-emitters or FDG-PET? Q J Nuel Med 1999;43:195. 114. Lerch H, Schober 0, Kuwert T, Saur HB. Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol 1997;15:2067. 115. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer: Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer 1996;77: 172. 116. Grunwald F, Menzel C, Bender H, et al. Redifferentiation therapyinduced radioiodine uptake in thyroid cancer. J Nuel Med 1998;39:1903. 117. Grunwald F, Pakos E, Bender H, et al. Redifferentiation therapy with retinoic acid in follicular thyroid cancer. J Nuel Med 1998;39: 1555. 118. Joensuu H, Ahonen A. Imaging of metastases of thyroid carcinoma with fluorine-18 fluorodeoxyglucose. J Nuel Med 1987;28:910. 119. Sisson JC, Ackermann RJ, Meyer MA, Wahl RL. Uptake of 18-fluoro-2-deoxy-o-glucose by thyroid cancer: Implications for diagnosis and therapy. J Clin Endocrinol Metab 1993;77:1090. 120. Fridrich L, Messa C, Landoni C, et al. Whole-body scintigraphy with 99Tcm-MIBI, 18F-FDG and 131 1 in patients with metastatic thyroid carcinoma. Nuel Med Commun 1997;18:3. 121. Feine U, Lietzenmayer R, Hanke JP, et al. [18FDG whole-body PET in differentiated thyroid carcinoma: Flipflop in uptake patterns of 18FDGand 131 1]. Nuklearmedizin 1995;34:127. 122. Gasparoni P, Rubello D, Ferlin G. Potential role of fluorine18-deoxyglucose (FDG) positron emission tomography (PET) in the staging of primitive and recurrent medullary thyroid carcinoma. J Endocrinol Invest 1997;20:527. 123. Dietlein M, Scheidhauer K, Voth E, et aJ. Fluorine-18 fluorodeoxyglucose positron-emission tomography and iodine-131 whole-body scintigraphy in the follow-up of differentiated thyroid cancer. Eur J Nucl Med 1997;24:1342. 124. Grunwald F, Schomburg A, Bender H, et al. Fluorine-18 fluorodeoxyglucose positron-emission tomography in the follow-up of differentiated thyroid cancer. Eur J Nuel Med 1996;23:312. 125. Platz D, Lubeck M, Beyer W. Einsatz der [18F]-deoxyglukose-PET in der Nachsorge von Patienten mit differenziertem und medullaren Schilddruesenkarzinom. Nuklearmedizin 1995;34: 152A. 126. Arslan N, Rydzewski B. Detection of a recurrent parathyroid carcinoma with FDG positron-emission tomography. Clin Nuel Med 2002;27:221. 127. Wiesner W, Engel H, von Schulthess GK, et al. FDG-PET-negative liver metastases of a malignant melanoma and FDG-PET-positive Hiirthle cell tumor of the thyroid. Eur Radiol 1999;9:975. 128. Adler LP, Bloom AD. Positron-emission tomography of thyroid masses. Thyroid 1993;3:195.
Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases Paolo Miccoli, MD • Furia Pacini, MD
Patients with distant metastases from differentiated thyroid carcinoma present an important therapeutic challenge. Among our nearly 3000 patients with thyroid cancer, 12.4% had distant metastases. J Similar percentages have been reported in other large series.>? Distant metastases, particularly in the bone, may be the presenting symptom of the disease, but about two thirds of distant metastases are found at the time of diagnosis or are identified by the postthyroidectomy iodine 131 scan. 1 Distant metastases may also develop as long as 15 years after initial treatment.t" Long-term follow-up of patients with differentiated thyroid cancer is certainly recommended.
Location of Distant Metastases The lungs are the most common site of distant metastases in differentiated thyroid cancer, followed by the skeleton. Both lung and bone metastases also occur in about one third of patients with distant metastases. Other less common sites of metastases are the brain, the liver, the skin, and, rarely, the omentum and adrenal glands." These rare sites of metastatic disease are found more frequently in patients with lung and bone metastases. The pattern of metastatic lung involvement may vary from one or more macronodular (> 1 em in diameter) nodules to a diffuse micronodular spread.l-v' The latter is usually not detected by chest x-ray films and sometimes not even by computed tomography (CT) scan but can be easily diagnosed by an 131 1 whole-body scan (WBS). Enlarged mediastinal lymph node metastases are relatively common in patients with papillary thyroid cancer.s'? Only 3.8% of our patients with differentiated thyroid cancer had bone metastases. They usually occur in patients with follicular cancer and in older patients. The vertebrae, pelvis, and ribs are the most frequently affected sites, but any bone may be involved. Single bone metastases are
152
present in one third of the patients. As shown in Table 17-1, most metastases are detectable by both WBS and x-ray film, but a significant proportion (25% in our series) were visible only by WBS.2,11 The latter group is more likely to respond to 131 1 therapy.
Diagnostic Procedures The identification of distant metastases from differentiated thyroid cancer requires a complete evaluation because many of the distant metastases are initially asymptomatic. Patients with pulmonary metastases are usually asymptomatic unless the metastases involve the pleura (21% in the series by Schlumberger and colleagues-). Bone metastases are more likely to cause pain or neurologic symptoms because of the tumor itself or because of the associated pathologic fractures. As mentioned, some patients with bone metastases are completely asymptomatic. After total thyroidectomy, postoperative 131 1 ablation of any thyroid remnant tissue, serum thyroglobulin (Tg) measurement, and 131 1WBS are valuable for detecting distant metastases.
Serum Thyroglobulin Measurement Most patients (about 95%) with distant metastases have an elevated serum Tg concentration when measured after withdrawal of thyroid-stimulating hormone (TSH) suppressive therapy. While patients are receiving i.-thyroxine (L-T4), their serum Tg concentrations are often relatively low, but these levels are usually higher than in patients with nodal metastases (Fig. 17_1).2,12 The best time to determine the serum Tg level is when the patient is hypothyroid in preparation for a radioscan. There is usually a good correlation between the serum Tg levels and 131 1WBS uptake.13,14 Detectable serum Tg levels are usually associated with a positive WBS, and undetectable
Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases - -
serum Tg levels are found in patients with a negative scan, indicating that the patient is in complete remission. However, serum Tg measurement results are more sensitive than WBS in predicting the presence of metastases. About 95% of patients with persistent thyroid cancer after total thyroidectomy have serum Tg levels above 3 mg/mL, whereas only about 75% of patients with metastatic thyroid cancer have uptake in the tumor. IS
Iodine 131 Whole-Body Scan Because most primary and metastatic well-differentiated thyroid cancers retain their ability to concentrate iodine, 131 1 is usually used to scan for and treat metastases.
105
NODES
METASTASES BONE "c,'}d LUNG
~
:J
a::
w
en
10
nd
ON
OFF
ON THERAPY
OFF
FIGURE 17-1. Behavior of serum thyroglobulin (Tg) levels in
patients with node metastases or distant metastases (bone and/or lung) studied with and without levothyroxine (L-T4 ) therapy. Note that when not receiving L-T4 , all patientshave elevatedserum Tg levels;when patientsare receivingL-T4, the serumTg levelsare still elevated, or at least detectable, in those with distant metastases (with one exception) and are suppressed to undetectable values in many of those with node metastases.
153
Radioiodine uptake by metastatic tumor increases as TSH stimulation increases. To increase serum TSH levels, total or near-total thyroidectomy is required before it is possible to detect or ablate local or distant metastases. It is important to withdraw thyroid hormone therapy for a long enough period of time to induce a state of hypothyroidism sufficient to elicit high endogenous serum levels of TSH.16.I7 The minimum level of serum TSH required for adequate incorporation of 131 1 in neoplastic tissues is about 30 ul.l/ml., a level that is usually achieved after 30 to 45 days without L-T4 and after 2 weeks without t-triiodothyronine (L-T 3). For effective 131 1 uptake, and thus treatment, the patient must also avoid any iodine intake, such as with intravenous contrast material during a CT scan. We also recommend a low-iodine diet for at least 2 weeks before scanning. The most frequent causes of a false-negative 131 1 WBS result are an insufficiently increased TSH and an increased iodine intake. Several centers, therefore, advocate checking the serum TSH concentration and urinary iodine concentration before performing 131 1 WBS and 131 1 therapy. WBS is performed 48 to 72 hours after the administration of 131 1, with the use of either a rectilinear scanner or a gamma camera. l3I1 doses of 2 to 5 mCi are usually used for scanning; higher doses are not indicated because of the possibility of producing a sublethal radiation effect in the metastatic cells, thus preventing uptake of the subsequent therapeutic dose of 1311. 18 When there is no abnormal 131 1 uptake despite elevation of serum Tg with the patient not receiving T 4, the search for metastases should include chest x-ray film, CT scan (without contrast), bone scintigraphy, and liver and neck echography. If no localization is found, a WBS performed 5 to 7 days after the administration of 100 mCi of 131 1 often allows the localization of small neoplastic foci not found by the conventional WBS and has a therapeutic effect in most patients. 19.20 The need to render the patient hypothyroid has been avoided by using exogenous TSH stimulation by the injection of recombinant human TSH (rhTSH, Thyrogen, Genzyme Therapeutics). Several large studies have shown that preparation of the patient by hypothyroidism or rhTSH is equally effective in eliciting sufficient uptake of radioiodine and Tg secretion by the tumor. 21· 24 Whenever a metastasis has been identified by WBS, a complete radiologic work-up should also be done. When a single bone metastasis is identified, we recommend surgical removal followed by 131 1 ablative treatment because such treatment is occasionally curative. 11.2S When pulmonary metastases are present, it is also extremely important to establish whether there is one or more macronodular lesions or multiple micronodules, not visible on the chest x-ray film but identified by the 131 1 scanning. Diffuse lung metastases, not detectable by x-ray film but identifiable by radioiodine scanning, such as those frequently encountered in children, are highly responsive to treatment with 13IJ.26.28 About two thirds of patients who are radioiodine scan positive and chest x-ray or CT scan negative can be rendered tumor free, whereas only about 8% of those with metastases seen on x-ray film or CT scan can be rendered tumor free. 16.26
154 - - Thyroid Gland
Therapeutic Procedures Surgery The decision to treat distant metastases surgically in patients with differentiated thyroid cancer depends on the overall health of the patient, the extent and number of distant metastases, the ability of the metastases to concentrate radioiodine, and the radiologic pattern. Pulmonary micrometastases are frequently completely ablated by radioiodine therapy. Surgical therapy is, therefore, useful in a minority of patients with a single or several macronodular metastases with or without mediastinal lymph node involvement, especially when these metastases do not take up radioiodine. The presence of mediastinal lymph node metastases supports a surgical approach.? These patients must be carefully selected because often more pulmonary metastases are present than expected. Operation generally consists of enucleation of the metastases or lobectomy; a pneumonectomy is rarely performed. Isolated metastases can often be removed thoracoscopically. Too few patients have been operated on for pulmonary metastases to know whether this treatment improves survival; however, in some of our patients, a long-term remission has been achieved, and in patients with isolated metastases, even definitive cure has been described." For patients with bone metastases, a surgical approach is gaining in popularity because of the relative insensitivity of these tumors to radioiodine therapy.9,11.25 The resection of bone metastases may be palliative or curative. Palliation is required in case of pathologic fractures or to ameliorate neurologic symptoms resulting from spinal cord compression by vertebral metastases. In these cases, the operation generally consists of laminectomy and sometimes must be performed emergently. Curative surgery is possible when the metastasis is single and localized, but this situation is uncommon. Large metastases are difficult to ablate with 131 1, and the pelvis is a more favorable site of bone metastases (Fig. 17-2). When the bones are large or are not totally resectable, surgery may help reduce the tumor mass, making subsequent treatment with radioiodine therapy more effective (Fig. 17-3). Among our patients with bone metastases, surgery was performed in 14 patients: 3 patients underwent laminectomy to ameliorate neurologic manifestations, 5 were operated on for palliation of pathologic fractures, and 6 patients, with a single bone metastasis, underwent radical resection; complete cure was achieved in 3 of these patients. Brain metastases are rare, ranging from 0.15% to 1.3% in different series. 30-33 When these metastases are present, the prognosis is poor. Although these metastases usually take up 131 1, the therapy of choice, whenever feasible, is surgical resection because of severe neurologic symptoms. External radiation is also sometimes required to treat pain and prevent fracture. It, unfortunately, is usually palliative rather than curative.
Radioiodine The role of and indications for 131 1 therapy in the management of distant metastases from differentiated thyroid
FIGURE 17-2. Surgical specimen of a single bone metastasis (rib) from follicular thyroid carcinoma treated with surgery. The patient had no recurrence in the subsequent follow-up.
carcinoma are well established. The results are reproducible in large series of patients and indicate complete responses in 35% and 45% of patients. 1,2,4,5,28 As mentioned, pulmonary metastases have a better response than bone metastases. In adult patients, the treatment dosage is usually 100 to 150 mCi, repeated every 8 to 12 months. Lower doses (empirically 1 mCi/kg body weight) should be used in children with lung metastases, particularly of the diffuse type, to avoid the risk of acute pulmonary insufficiency or more chronic radiation-induced pulmonary fibrosis. 25,34 In a review of 118 of our patients with distant metastases treated with 131 1, 43 patients (36.4%) were cured (defined as negative WBS and undetectable serum Tg in the absence of L-T 4), 28 (23.7%) died of their disease, and the others have persistent disease (Figs. 17-4 and 17-5).1 Of those who died, 10 had lung metastases, 8 had bone metastases, 9 had both, and 1 had skin metastases. Interestingly, patients with metastatic papillary cancers did better than patients with follicular tumors. The risk of dying was higher if lung metastases were macronodular and detectable by chest x-ray films, if bone metastases were multiple, and if both lung and bone metastases were present. The mean cumulative dosage of 131 1 used in cured patients was 233 mCi, delivered in 2.2 treatment courses during 3.4 years. Loss of radioiodine uptake was seen in four (5.2%) patients after a mean cumulative dose of 161 mCi 2.7 years from the beginning of treatment. Six patients with single bone metastases and one with
Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases - -
155
FIGURE 17-3. X-ray film and corresponding iodine 131 (1 311) whole-body scan (WBS) in a patient who had a partial response to
1311 therapy and a complete response after surgical resection of the iliac metastasis. Upper row, At the first diagnosis. Middle row, X-ray film and WBS after 700 mCi of 1311. It is possible to note the reduction of 1311 uptake in the left iliac bone and the disappearance of uptake in the middle area corresponding to L-3 (x-ray negative). Lower row, After resection of the left iliac lesion, no 1311 uptake was detected in this area; serum Tg at this stage was undetectable. (From Marcocci C, Pacini F, Elisei R, et al. Clinical and biologic behavior of bone metastases from differentiated thyroid carcinoma. Surgery 1989;106:960.)
156 - -
Thyroid Gland
80
[J papillary (n=77) .follicular(n=41)
70
71
l:iIaU (n=118)
60
FIGURE 17-4. Effect of radioiodine therapy in patients with distant metastases. Mean millicuries delivered, mean number of doses, and mean years over which iodine 131 was administered are shown at the bottom. (From Pacini F, Cetani F, Miccoli P, er al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg 1994;18:600.)
50
40
30 20 10 O~=
meen
cured
mel
233 2.2 3.4
n.do... y_",
nouptake
continued disease
161 1.5 2.7
a macronodular lung metastasis were treated surgically. In these patients, histology revealed that the metastatic tumor was less well differentiated than the corresponding primary tumor. Among patients with elevated serum Tg levels but no appreciable uptake, 13,14 the site of the metastatic deposits was usually the lung or mediastinal lymph nodes.13·14.19.26 About 20% of our patients with distant metastases were included in this group. The administration of high doses of 131 1 has a therapeutic effect on metastatic deposits in patients with low radioiodine uptake. Our data demonstrate that, within a few days after the administration of 131 1 therapy, there is a transient increase in serum Tg concentrations, which, in our opinion, can be explained only by the release of Tg into the circulation by radiation-damaged malignant cells. A progressive decrease of serum Tg levels and normalization of the abnormal chest CT scan in patients with radiographic evidence of micronodular lung metastases" have been observed in some patients. 19.26 Overall, about one third of these patients appeared to receive appreciable clinical benefits.f
A
536 4.7 4.3
Side Effects and Complications of Radioiodine Therapy Side effects after the administration oftherapeutic 131 1 doses are frequent but usually transient and mild. The symptoms usually include gastrointestinal symptoms, nausea, vomiting, and acute sialoadenitis. The last side effect, which is potentially serious if it becomes chronic (after several doses), may be reduced, in our experience, by hydration and by giving low doses of corticosteroids for 2 to 3 days after treatment. More serious complications are those involving blood and bone marrow. An increased risk of leukemia, on the order of five cases per 1000 treated patients, has been reported." The risk is increased by increasing cumulative doses, by reducing the intervals between treatments, and by giving total blood doses per treatment higher than 2 Gy.35 Pancytopenia has been reported in 4.4% of patients treated with mean 1311 doses of 536 mCi by Schober and colleagues." In the same study, anemia was found in about 25% of the patients and thrombocytopenia in 33%.
B
FIGURE 17-5. Representative example of negative diagnostic whole-body scan (WBS) with 5-mCi tracer dose (A) and of post-therapy (l00 mCi) WBS (B) showing diffuse uptake in the lung in the same patient.
Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases - -
Another complication of radioiodine therapy is radiationinduced pulmonary fibrosis, which may develop in patients treated repeatedly for lung metastases, particularly of the extensive diffuse type. Children seem to be particularly susceptible to this complication. We observed a 22-year-old woman who had been treated in another institution with high doses of 131 1 since she was 10 years old for lung metastases, who died, apparently free from disease, from pulmonary fibrosis.'? The occurrence of a second solid cancer after radioiodine treatment has also been reported. Three extra cases of bladder carcinoma and three extra cases of breast carcinoma among 258 patients treated for differentiated thyroid cancer have been documented." All these patients were treated with more than 900 mCi of 1311. The development of second malignancies is controversial, but there may be a very slight increased risk of developing other tumors. Whether radioiodine treatment can promote the transformation of a well-differentiated thyroid cancer to an anaplastic cancer is also controversial. Although a varying degree of "dedifferentiation" is observed in almost all series of thyroid cancer, the question is whether this is due to radioiodine or whether it is an independent biologic event. Studies of molecular biology38,39 have shown that anaplastic thyroid carcinoma is strictly associated with the loss of expression or function of the oncosuppressor gene p53, whereas p53 mutations are rare in differentiated thyroid tumors. It is possible, but not proved, that differentiated thyroid cancers, through a radiation-induced second mutation in the p53 gene or for other reasons, shift toward the poorly differentiated or undifferentiated histotype. Mutations of the p53 gene have not been detected in differentiated thyroid cancer of Belarussian children exposed to radiation after the Chernobyl accident.'" We have also reported the presence of reversible and nonreversible testicular damage, limited to the germinal epithelium, in men treated with high levels of administered activity of 131 1, particularly when they were treated for bone metastases close to the testis."
Prognostic Factors Successful treatment of patients with distant metastases depends largely on the size, location, and number of metastatic lesions and their ability to take up radioiodine. Patients with micronodular diffuse lung metastases and, to a lesser extent, small metastases in bone revealed by WBS in the absence of radiographic abnormalities have the greatest chance of cure. This is particularly true in children, who often have this pattern of metastatic pulmonary spread and yet do exceptionally well after treatment with radioiodine therapy.27,42 Patients with macronodules in the lung and large or multiple bone metastases have a poor prognosis, but long-term palliation and occasional cure can be accomplished by resection of these tumors in selected patients. Loss of radioiodine uptake by the metastatic tumor is also a prognostic indicator of a poor outcome. These findings emphasize the importance of early recognition and early treatment of distant metastases. This is best accomplished by total thyroidectomy or near-total thyroidectomy with
157
postoperative ablation of the remnant, and then serum Tg determination and radioiodine scanning to detect micrometastases that can be successfully ablated with 1311.
Importance of L- Thyroxine Suppressive Therapy Both the function and the growth of some metastatic thyroid tumors are under TSH control. It is a common observation that bone or lung metastases increase in size and take up radioiodine during periods of T, withdrawal, whereas a reduction in size and lack of uptake are observed during periods of T4 therapy. Serum Tg, a marker of cell function, increases dramatically during hypothyroidism (see Fig. 17-1), whereas Tg levels return to low values during treatment with T4 • In the classic article by Mazzaferri.P thyroid hormone therapy significantly influenced both recurrence rate and survival as an independent variable. In this regard, suppression of endogenous TSH to undetectable levels is to be regarded as a true antineoplastic therapy and should never be omitted in patients with active disease. The drug of choice is T4 , and the effective dosage is between 2.2 and 2.8 ug/kg body weight. Higher dosages are usually required in children. In any patient, attempts should be made to use the lowest dose necessary to suppress TSH secretion. The adequacy of the therapy is monitored by measurement of serum TSH, which should be undetectable with an ultrasensitive assay, and serum free T 3, which should be in the normal range to avoid iatrogenic thyrotoxicosis. When these guidelines are followed, T4 suppressive therapy is safe and is devoid of long-term side effects on the heart or bone."
Summary Distant metastases were present in 12.4% of nearly 1000 patients with differentiated thyroid cancer. Pulmonary metastases were most common, and bone metastases occurred in 3.8% of patients. Patients with distant metastases, in general, have a poor prognosis, but when these metastases are small and take up radioiodine, curative treatment or complete remission with 1311 ablative therapy is still possible in about 35% of patients. Children and young adults with pulmonary micrometastases identified by radiographic scanning, but not seen on chest x-ray film, have the best prognosis. These and other micrometastases are best detected when patients are treated by total thyroidectomy. Serum Tg levels and radioiodine scanning are the sensitive indicators of persistent disease. Our data and those in the literature support the use of total thyroidectomy and postoperative serum Tg and radioiodine scanning to detect and treat metastatic disease.
REFERENCES 1. Pacini F, Cetani F, Miccoli P, et al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg 1994;18:600. 2. Sch1umberger M, Tubiana M, De Vathaire F, et al. Long-term results of treatment of 238 patients with lung and bone metastases from differentiated thyroid carcinoma. J C1inEndocrinol Metab 1986;63:960.
158 - - Thyroid Gland 3. Hoie J, Stenwig AE, Kullmann G, et aJ. Distant metastases in papillary thyroid cancer: A review of91 patients. Cancer 1988;61:1. 4. Brown AP, Greening WP, McCready VR, et aJ. Radioiodine treatment of metastatic thyroid carcinoma: The Royal Marsden Hospital experience. BrJ Radiol 1984;57:323. 5. Samaan NA, Schultz PN, Haynie TP, et aJ. Pulmonary metastasis of differentiated thyroid carcinoma: Treatment results in 10I patients. J Clin Endocrinol Metab 1985;60:376. 6. Massin JP, Savoie JC, Gamier H, et aJ. Pulmonary metastases in differentiated thyroid carcinoma: Study of 58 cases with implications for the primary tumor treatment. Cancer 1984;53:982. 7. Ruegemer JJ, Hay ID, Bergstralh EJ, et aJ. Distant metastases in differentiated thyroid carcinoma: A multivariate analysis of prognostic variables. J Clin Endocrinol Metab 1988;67:501. 8. Tubiana M, Haddad E, Schlumberger M, et aJ. External radiotherapy in thyroid cancers. Cancer 1985;55:2062. 9. Niederle B, Roka R, Schemper M, et aJ. Surgical treatment of distant metastases in differentiated thyroid cancer: Indication and results. Surgery 1986;100: 1088. 10. Beierwaltes WH, Nishiyama RH, Thompson NW, et aJ. Survival time and "cure" in papillary and follicular thyroid carcinoma with distant metastases: Statistics following University of Michigan therapy. J Nucl Med 1982;23:561. II. Marcocci C, Pacini F, Elisei R, et aJ. Clinical and biological behaviour of bone metastases from differentiated thyroid carcinoma. Surgery 1989;106:960. 12. Pacini F, Lari R, Mazzeo S, et aJ. Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol 1985;23:405. 13. Pacini F, Pinchera A, Giani C, et aJ. Serum thyroglobulin concentrations and 1311 whole body scans in the diagnosis of metastases from differentiated thyroid carcinoma (after thyroidectomy). Clin Endocrinol 1980;13:107. 14. Ashcraft MW, Van Herle AJ. The comparative value of serum thyroglobulin measurements and iodine-131 total body scans in the follow-up study of patients with treated differentiated thyroid cancer. AmJMed 1981;71:806. 15. Pacini F, Ceccarelli C, Elisei R, et al, Serum thyroglobulin determination in thyroid cancer: A ten year experience. In: Nagataki S, Torizuka K (eds), The Thyroid. New York, Elsevier Science, 1988, p 685. 16. Schlumberger M, Charbord P, Fragu P, et aJ. Circulating thyroglobulin and thyroid hormones in patients with metastases of differentiated thyroid carcinoma: Relationship to serum thyrotropin levels. J Clin Endocrinol Metab 1980;51:513. 17. Schneider AB, Line BR, Goldman JM, et aJ. Sequential serum thyroglobulin determination 1311 scan and 1311 uptakes after triiodothyronine withdrawal in patients with thyroid cancer. J Clin Endocrinol Metab 1981;53:1199. 18. Jeevanram RK, Shah DH, Sharma SM, et aJ. Influence of initial large dose on subsequent uptake of therapeutic radioiodine in thyroid cancer patients. Nucl Med Bioi 1986;13:277. 19. Pacini F, Lippi F, Formica N, et aJ. Therapeutic doses of iodine-131 reveal undiagnosed metastases in thyroid cancer patients with detectable serum thyroglobulin levels. J Nucl Med 1987;28:1988. 20. Clark OH, Hoeltins T. Management of patients with differentiated thyroid cancer who have positive serum thyroglobulin levels and negative radioiodine scans. Thyroid 1994;4:501. 21. Haugen BR, Pacini F, Reiners C, et aJ. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877. 22. Pacini F, Molinaro E, Lippi F, et aJ. Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical
23.
24.
25. 26. 27. 28.
29. 30. 31. 32. 33. 34.
35. 36. 37. 38. 39.
40. 41. 42. 43.
follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 200 I ;86:5686. Robbins RJ, Tuttle RM, Sharaf RN, et aJ. Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:619. Pacini F, Molinaro E, Castagna MG, et aJ. Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 2003;88:3668. Roy-Camille R, Leger FA, Merland JJ, et aJ. Perspectives actuelles dans le traitement des metastases osseuses des cancers thyroidiens. Chirurgie 1980; I06:32. Schlumberger M, Arcangioli 0, Piekarski JD, et aJ. Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest x-ray. J Nucl Med 1988;29: 1790. Ceccareli C, Pacini F, Lippi F, et aJ. Thyroid cancer in children and adolescents. Surgery 1988; I04: 1143. Maxon HR, Smith HS. Radioiodine-I 3 I in the diagnosis and treatment of metastatic well-differentiated thyroid cancer. Endocrinol Metab Clin NorthAm 1990;19:685. Proye CAG, Dromer DHR, Carnaille BM, et aJ. Is it still worthwhile to treat bone metastases from differentiated thyroid carcinoma with radioactive iodine? World J Surg 1992;16:640. Mazzaferri EL. Papillary and follicular thyroid cancer: A selective approach to diagnosis and treatment. Annu Rev Med 1981;32:73. Parker LN, Wu SY, Kim DD, et aJ. Recurrence of papillary thyroid carcinoma presenting as a focal neurological deficit. Arch Intern Med 1986; 146: 1985. Hay ID. Brain metastases from papillary thyroid carcinoma. Arch Intern Med 1987;147:607. Venkatesh A, Leavens ME, Samaan NA. Brain metastases in patients with well-differentiated thyroid carcinoma: Study of II cases. Eur J Surg Oncol 1990; 16:448. Rail JE, Alpers JB, Lewallen CG, et aJ. Radiation pneumonitis and fibrosis: A complication of radioiodine treatment of pulmonary metastases from cancer of the thyroid. J Clin Endocrinol Metab 1957;17:1263. Leeper R. Controversies in the treatment of thyroid cancer: The New York Memorial Hospital approach. Thyroid Today 1982;5: 1. Schober 0, Gunter HH, Schwarzrock R, et aJ. Hamatologische Langzeitveranderungen bei der Schilddrusenkarzinoms. Strahlenther OnkoI1987;163:464. Edmonds CJ, Smith T. The long-term hazard of the treatment of thyroid cancer with radioiodine. Br J RadioI1986;59:45. Herrmann MA, Hay ID, Bartelt DH Jr, et aJ. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest. 1991 Nov;88(5):1596-604. Pacini F, Pinchera A, Mancusi F, et aJ. Anaplastic thyroid carcinoma: A retrospective clinical and immunohistochemical study. Oncol Rep 1994; I :921. Fugazzola L, Pilotti S, Pinchera A, et aJ. Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res 1995;55:5617. Pacini F, Gasperi M, Fugazzola L, et aJ. Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine. J Nucl Med 1994;35: 1418. Schlumberger M, De Vathaire F, Travagli JP, et aJ. Differentiated thyroid carcinoma in childhood: Long-term follow-up of 72 patients. J Clin Endocrinol Metab 1987;65: 1088. Marcocci C, Golia F, Bruno-Bossio G, et aJ. Carefully monitored levothyroxine suppressive therapy is not associated with bone loss in premenopausal women. J Clin Endocrinol Metab 1994;78:818.
Anaplastic Carcinoma of the Thyroid Gland Irving B. Rosen, MD • Sylvia L. Asa, MD, PhD • James D. Brierley, BSc, MB
It is ironic that the thyroid gland harbors two polar variants of cancer in regard to aggressiveness in behavior. At the one pole is the common, unaggressive, infrequently lethal, well-differentiated carcinoma, usually papillary, sometimes follicular, which makes up 80% of all thyroid cancers. At the other pole is anaplastic thyroid cancer (ATC), which is invariably lethal and has until recently constituted 4% to 18% of thyroid cancer. Currently, ATC is showing a marked decline throughout the world, but in the United States it still constitutes 1.6% of thyroid cancers and accounts for more than half of the deaths from thyroid cancer. The survival of ATC cases is usually measured in months. Although there is a paucity of cases, leading institutions throughout the world nevertheless have reported their results of treatment in up to 160 patients, usually after several decades of experience. Authors agree that ATC is an infrequent cancer that is highly lethal and is usually unresponsive to currently available treatment such as surgery, radiation, and chemotherapy. New treatments are therefore necessary and are being developed in the hope that they will lead to improved survival in ATC patients."!"
Clinical Presentation Anaplastic cancer, unlike its well-differentiated counterpart, presents a clinical picture that unarguably indicates the presence of an underlying cancer. Patients can be categorized into four different groups': (1) patients whose previous well-differentiated carcinoma had undergone treatment, has been stable over a long period of time, and then changes character; (2) patients who have been viewed and treated for presumptive benign goiter over a long period of time who then demonstrate a rapid growth and change in character of goiter; (3) patients who present de novo and acutely with an extensive thyroid mass; and (4) patients whose widespread
metastatic cancer may demonstrate evidence of anaplastic change. The process of transformation, poorly understood, should be appreciated. Two of our patients had undergone incisional biopsies for adenoma elsewhere as a basis for conservative nonsurgical management with the eventual emergence of fatal anaplastic cancer years to a decade later. Such patients demonstrate not only anaplastic transformation but also the fallibility of incisional biopsy results in long-term prognostication. In consideration of anaplastic transformation.P'P one should recognize that there is a high incidence of p53 mutations in ATC,15 which is not the case for differentiated cancer, even when the two are coexistent. Inactivating mutations of the tumor suppressor gene p53 are of importance in the progression of differentiated to undifferentiated or anaplastic cancer." The N-ras oncogene shows an inverse correlation with thyroglobulin expression that is absent in ATe. No N-ras mutations were seen in well-differentiated thyroid cancer in some reports, whereas gene mutations were present in ATC that usually did not secrete thyroglobulin." Other oncogenes have been identified in some ATC cases, including c-myc and NM23,1O as well as other alterations in tumor suppressor genes. 15 RET/PTC rearrangements are common in papillary thyroid cancer but uncommon in poorly differentiated malignancy so that progression from a well-differentiated to poorly differentiated malignancy is questioned. 16 Mutations in ~-catenin. a widely expressed cytoplasmic protein that has a crucial role both in E-cadherinmediated cell-cell adhesion and as a downstream signal molecule, are common in ATC.I? ~-Catenins activate transcription factors, supporting the idea that they act as an oncogene that contributes to the highly aggressive behavior of ATe. Investigations have shown that both adenomas and follicular carcinomas have N-ras mutations but that p53 mutation is unique in occurring in poorly and undifferentiated thyroid cancer, supporting a multistep transformation
159
160 - -
Thyroid Gland
in such tumors." Studies have further demonstrated that ATC frequently involves a loss of l6P as documented by comparative genomic hybridization studies and associated with transformation from well-differentiated thyroid cancer to anaplastic tumor.'? ATC also often overexpresses the protooncogene HGF (hepatocyte growth factor) and its receptor HGF-R.
Clinical Features Anaplastic cancer affects women and men in a ratio of 1.0:1.5.2 The peak incidence of this disease occurs in the seventh decade of life (mean, 64 yearsj.l-' It is unusual for patients younger than 40 years to be affected by this disease, and when it occurs one should question the reliability of the diagnosis. Radiation exposure has been documented but does not seem to have a critical role in pathogenesis. Patients usually present with a rapidly enlarging, bulky, thyroid mass1,2·5 that is firm to hard and frequently fixed. There may be a variation in the extent of anaplasia because some thyroid tumors may show small areas of dedifferentiation, which would still qualify them in the consideration of anaplastic cancer. However, such cases usually do not pose the same problem or have the dire outlook of the diffusely involved gland. Anaplastic cancer may compress the trachea and infiltrate the skin, causing overlying necrosis. Lymph node enlargement is frequent (84%) and early.l-' The tumor extends to and becomes fixed to the larynx, esophagus, and carotid vessels. Vocal cord paralysis can occur because of tumor infiltration of the recurrent laryngeal nerve or vocal cord, and glottic obstruction is of concern. Obstruction of the superior vena cava can be seen in more extensive cancer, particularly when there is a retrosternal component. Symptoms such as dysphagia, dysphonia, and dyspnea are common.P> Systemic metastases occur in 75% of patients and usually involve lung (more than 80%) as well as bone and brain (15%), adrenal glands (33%), and intra-abdominal nodes (17%).1,2 Investigation can vary and depends on the circumstances of the individual patient. Thyroid function tests are usually normal, but with a rapidly growing tumor, evidence of at least incipient compensated hypothyroidism can be seen by virtue of an elevated thyroid-stimulating hormone serum level by sensitive assay. Scintiscan of the thyroid gland shows a classic cold area at the site of the tumor. Chest x-ray film and computed tomography scan can demonstrate extrathyroidal extension and invasion. Diagnosis can be established by fine-needle aspiration biopsy (FNAB).4.7 Scandinavian authors adamantly prefer FNAB for tissue diagnosis because they view incisional biopsy as associated with poor healing, delay of treatment, and acceleration of tumor growth.t? The diagnosis of anaplastic cancer must be differentiated from that of lymphoma and poorly differentiated medullary carcinoma, and appropriate immunophenotyping and other marker examinations may be required. DNA cytometry of anaplastic cancer usually shows an aneuploid picture indicative of a poor outlook. Other thyroid investigational imaging procedures such as ultrasonography,
computed tomography scan, and magnetic resonance imaging document the limits of the imaging of a mass and sometimes extensive invasion but cannot establish the tumor histology. Somatostatin scans are occasionally positive in ATC and in other thyroid cancers. Positron emission tomography scans are unreliable in ATCs but appear to be positive in patients with poorly differentiated thyroid cancer that does not take up radioiodine."
Pathology Microscopically, three general patterns can be recognized. The most common type is the giant cell variant, which is composed mainly of large cells with marked cytologic pleomorphism.P The plump tumor cells harbor bizarre, often multiple hyperchromatic nuclei (Fig. 18-1) with abundant amphophilic or eosinophilic granular cytoplasm and densely acidophilic, intracytoplasmic, hyaline globules. These tumors grow in solid sheets; artifactual tissue fragmentation may create the appearance of an alveolar pattern. The squamoid variant is composed of nests of large, moderately pleomorphic epithelial cells resembling squamous carcinoma, which may form keratin pearls. Spindle cell anaplastic carcinomas resemble sarcomas (Fig. 18-2); the fascicular architecture and dense stromal collagen may resemble fibrosarcoma, markedly atypical cells and inflammatory infiltrates may suggest malignant fibrous histiocytoma, and prominent vascularization may mimic hemangioendotheliorna.P>' In all three variants, mitotic figures, including atypical forms, are frequent. Vascularization is prominent, and extensive areas of necrosis surrounded by inflammation may occur so that the only viable tumor is seen around blood vessels. Reactive osteoclast-like giant cells of monocytic-histiocytic lineage may be seen. 25,26 Malignant cells usually grow between residual thyroid follicles, invading skeletal muscle, adipose tissue, and other peri thyroidal structures. Blood vessel invasion and thrombosis with or without tumor cell involvement are frequent.
FIGURE 18-1. A giant cell anaplastic thyroid carcinoma is composed of large pleomorphic cells with abundant cytoplasm and hyperchromatic, often multiple, nuclei. Mitoses are conspicuous (arrows).
Anaplastic Carcinoma of the Thyroid Gland - -
FIGURE 18-2. A spindle cell anaplastic thyroid carcinoma h~s
fascicular architecture resembling that of a sarcoma. (Hematoxylin and eosin stain.)
Anaplastic carcinomas do not usually show reactivity for thyroglobulin, and the few that are positive show a weak or focal reaction 26-3o that may be due to trapped nontumorous follicles or isolated follicular cells and the known phenomenon of thyroglobulin diffusion into tumor cel.ls.23 T~e epithelial nature of the malignant cells ca~ be ven~ed w~th stains for low-molecular-weight cytokeratms and vimentm, and in squamoid areas there may be reactivity for highmolecular-weight cytokeratins and epithelial membrane antigen as well. 26-28 Carcinoembryonic antigen (CEA) may be localized in the center of squamoid nests. 26-28 Occasional tumors have been reported to exhibit reactivity for calcitonin, but this finding should alter the diagnosis to that of anaplastic medullary carcinoma.v-" It has been shown that . anap Iast'IC carcmom . as 24-28., p53 mutations are frequent m mutated forms of this putative tumor suppressor gene have prolonged half-lives, permitting immunolocalization.P and the application of this technique has yielded positive results in ATCs (Fig. 18-3).34
161
By electron microscopy,25.27,29,35.36 ther~ may ?e evidence of epithelial differentiation with the formation of mtercellular junctions of the zona adherens type an~ the presence ~f microvilli. The cells may form basal lammae focally. Their large nuclei have clumped chromatin and prominent nucleoli; the abundant cytoplasm usually contains poorly developed endoplasmic reticulum, numerous free ribosomes, lipid droplets, lysosomes, and mitochondria. Scattere~, dense bodies may be seen, but the cells do not contam secretory granules. Occasional intermediate filaments probably represent keratin or vimentin; these may form filamentous whorls that correspond to the acidophilic hyaline globules seen by light microscopy. . Small cell carcinomas and lymphomas constItute a source of diagnostic error, often being misclassified as anaplastic carcinornas.P:" The former are now well r~cognized as neuroendocrine carcinomas, usually poorly differentiated medullary carcinomas that can mimic giant cell or spindle cell anaplastic carcinomas. They can be recogni~ed by immunohistochemical positivity for neuron-specific enolase, chromogranin, calcitonin, calcitonin gene-related peptide, and CEA and by the ultrastructural detection of membrane-bound secretory granules. Lymphoma is usually composed of relatively uniform, small, round cells that do not exhibit the marked pleomorphism of anaplastic carcinoma but do stain for leukocyte common antigen and other immunohistochemical markers of lymphoid cells, and have features of lymphocytes by electron microscopy. Rarely, primary intrathyroidal thymoma may be mistaken for anaplastic carcinoma." Even in tumors without immunohistochemical or ultrastructural markers of epithelial differentiation, the diagnosis of anaplastic carcinoma should be favored for any thyroid pleomorphic lesion occurring in an older patient. Poorly differentiated or insular carcinoma is a tumor of follicular cell differentiation with morphologic and biologic attributes between those of differentiated and anaplastic carcinomas of the thyroid 38.39 and is composed of large, well-defined clusters or nests of neoplastic cells reminiscent of neuroendocrine tumors (Fig. 18-4). The neoplastic cells are moderate to small and uniform in size and shape, with
FIGURE 18-3. Many tumor cells in an anaplastic thyroid carci-
noma show nuclear reactivity for p53, indicating accumulation of protein as a result of mutation. (Streptavidin-biotin peroxidase method with hematoxylin counterstain.)
FIGURE 18-4. An insular thyroid carcinoma is composed of solid
nests of small, polygonal, follicular epithelial cells with individual cell necrosis (arrows). (Hematoxylin and eosin stain.)
162 - -
Thyroid Gland
FIGURE 18-5. A focus of anaplastic thyroid carcinoma characterized by giant epithelial cells (arrow) is seen in a tumor that is predominantly well-differentiated papillary carcinoma (top left) but also exhibits insular architecture (bottom right). (Hematoxylin and eosin stain.)
little pleomorphism and no bizarre, giant, or multinucleated cells. There is a variable degree of mitotic activity, and single-cell necrosis is prominent. Tumor cells stain for lowmolecular-weight cytokeratins and are focally positive for thyroglobulin. Insular carcinoma appears to be intermediate in the spectrum from well-differentiated to anaplastic carcinoma and may represent a transition of the former into the latter 39 .40 (Fig. 18-5) because of factors still to be defined. Accumulation of genetic mutations underlying oncogene activation or the loss of tumor suppressor gene activity correlates with the stepwise progression from adenoma to carcinoma in tissues," and a similar pattern of molecular events has been suggested for thyroid." The expression of various ras mutations in benign thyroid tumors and welldifferentiated carcinomas suggests that activation of this oncogene is an early event.t'" The expression of p53 in anaplastic carcinomas is consistent with a late event that may account for the aggressive behavior of such tumors.
Treatment The standard form of treatment of thyroid cancer has been surgical ablation, but in anaplastic cancer this maneuver is usually not feasible. In our experience, in only 2 of 20 patients labeled initially as having anaplastic cancer could total thyroidectomy be carried out; subsequently, it was demonstrated that these cases represented respectively lymphoma and secondary thyroid cancer from a pancreatic primary tumor. Nonetheless, there appears to be well-documented, ongoing experiences with thyroidectomy. Venkatesh and colleagues I reported that 47% of 100 patients underwent total thyroidectomy, 8% underwent subtotal thyroidectomy, and 30% had lobectomy. Only 25% underwent biopsy only. Tann and colleagues also reported that 7 of 21 (33%) patients had undergone a thyroidectomy.- Famebo and coworkers" also viewed thyroid resection as a possibility after induction chemotherapy.
Postoperative external radiation has been historically used. Of 91 patients, in 30 of whom curative surgery had been attempted, 86 underwent postoperative external beam radiation, 18 with chemotherapy.f Overall survival reported by Junor and associates" was 11% at 3 years (median survival, 21 months). Local recurrence occurred in 50 patients, distant only in 20, demonstrating the inability of external beam radiation to guarantee local control, which is highly desirable to avoid an unpleasant death of the patient. Attempting to improve on the historic radiation approach, Simpson" gave hyperfractionated radiation to 32 patients with unresectable disease (age range, 31 to 87 years). This was done with a single 5-Gy fraction followed by hyperfractionated radiation, 1 Gy four times daily, with an interfraction period of 3 hours, for a total dose of 35 to 45 Gy. Fourteen patients received doxorubicin every 3 weeks. This gave a local control rate of 22% with a median survival of 6 months and 3-year survival of 18%. There were three treatment deaths resulting from radiation-myelopathy (two) and neutropenic sepsis (one)-and this protocol was discontinued (Fig. 18-6). Multimodality therapy was further pursued. Kim and Leiper" reported a complete remission rate of 84% and local control of 68% in 19 patients treated with hyperfractionated radiation and weekly doxorubicin (median survival, 6 months; 3-year survival, 20%). Schlumberger and coworkers," using low-dose hyperfractionated radiation with doxorubicin, cisplatin, or mitomycin C, reported a complete response rate in 5 of 20 patients, although only 3 patients survived more than 20 months. Tennvall and colleagues" gave combined radiation and chemotherapy preoperatively and postoperatively by hyperfractionation using doxorubicin as a single agent replacing
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0.0 +-----,--,-------,----,---r-----\ 12 o 24 36 Months FIGURE 18-6. Survival graph of 32 patients wirh anaplastic thyroid cancer treated by hyperfractionated radiotherapy (Princess Margaret Hospital experience'"),
Anaplastic Carcinoma of the Thyroid Gland - -
bleomycin, 5-fluorouracil (5-FU), and cyclophosphamide because of reduced toxicity. In 33 such patients, debulking surgery was possible in 23 (70%), achieving local control in 48% with death from local disease in 8 of 33 patients. Only four patients lived for more than 2 years. Chemotherapeutic agents such as doxorubicin, cisplatin, and 5-FU have radiation-sensitizing activity and have been given beyond termination of radiation in an attempt to improve survival. Hoskin and Harmer f studied the use of single and combination agents and found only partial responses in three patients, or 17% of the series. Williams and coworkers'? reported on a phase II study from the Southeastern Cancer Study Group using combined doxorubicin and cisplatin in seven patients, with only one partial response and considerable toxicity. Shimaoka and colleagues," in a randomized, controlled study through the Eastern Cooperative Oncology Group, compared doxorubicin with doxorubicin and cisplatin in 39 patients with anaplastic cancer. There was a 5% partial response rate to doxorubicin but an 18% response to the combined regimen, suggesting that combined drug therapy was superior to single-agent therapy but bore the cost of increased toxicity. Schlumberger and associates," who gave doxorubicin every 4 weeks for up to nine courses in addition to radiation, achieved 15% survival at 20 months. Radioiodine and external thyroid feeding appeared to have no inhibiting influence on anaplastic thyroid carcinoma. The role of chemotherapy alone in anaplastic cancer is limited. At one of the University of Toronto's radiation centersthe Princess Margaret Hospital-hyperfractionated radiotherapy'" without chemotherapy (60 Gy in 40 fractions, 1.5-Gy fractions twice a day over 4 weeks) was prescribed for the rare patient who had had a resection and for other patients who had no evidence of metastatic disease and had good performance status. Otherwise, palliative radiation was given at 20 Gy in five 4-Gy fractions over 1 week. This was repeated 4 weeks later if a good response had been achieved. An expectant policy was pursued in elderly patients with poor performance status or patients with distant metastatic disease and relatively little in the way of local symptoms (Fig. 18-7). Although anaplastic cancer is a rare tumor, an increasing number of patients have been reported in series in the literature. The role of surgery in management has been significantly supported with l-year survival rates of 73%, 60%, and 21%, respectively, for patients with incidental and ordinary ATC who underwent surgery and those with ordinary ATC who underwent no surgery.P These figures seem inordinately high and appear to be based on selection bias. They document, however, that thyroidectomy, when feasible, should be performed. The Mayo Clinic reported the results of treatment in 134 patients. In 30%, complete resection was possible with 9.7% I-year survival. Thirty patients were treated with multimodal treatment consisting of debulking procedures, postoperative radiation, and chemotherapy, and only 23% survived more than 1 year. Overall survival did not vary among these groups. They concluded that "ATC is a lethal malignancy" that has "seen no improvement in outcome during 50 years." The Thyroid Center at Padua General Hospital reported on 39 consecutive ATC patients and noted that a combination
163
FIGURE 18-7. A 75-year-old patient with anaplastic thyroid
cancer 10 years after incisional biopsy of "benign adenoma" who died within 2 months of diagnosis.
of therapy with radiation, total thyroidectomy, and chemotherapy provided apparent benefits and that preoperative chemotherapy and radiotherapy may enhance surgical resectability.P The Institute of Oncology in Ljubljana, Slovenia, reported on 79 patients; their best results were obtained in those who had the tumor surgically removed and had primary chemotherapy and radiotherapy. 14 The Swedish group has had a long-standing repeated program for the management of patients with ATC that they have reported. Their experience indicates that multimodality treatment consisting of radiation, chemotherapy, and then surgery and further radiation and chemotherapy provides the best results.t-"!' Their current standardized strategy includes radiation of 46 Gy in 29 fractions, namely 1.6 Gy twice a day, with simultaneous doxorubicin at 20 mg intravenously once weekly for 4 weeks and surgery between the fourth and fifth weeks, consisting of total thyroidectomy when possible as well as nodal resection. Currently, no patient has failed to complete the protocol because of toxicity, and in only 25% of cases was death attributed to local failure. Five patients or 9% of the group survived more than 2 years. 11 There have been ongoing attempts at accelerating radiation treatment aiming to improve local response. One such program treated patients twice daily 5 days a week to a total dose of 60.8 Gy in 32 fractions over 20 to 24 days. Although the response rate was encouraging, the program was modified because toxicity was unacceptable.>' Chemotherapy has also received attention. In a phase 2 trial, the collaborativeAnaplastic Thyroid Health InterventionTrials Group assessed paclitaxel." This agent failed to improve survival in patients with ATC, suggesting other new agents or combined agents are necessary. 55 Adding manumycin to paclitaxel resulted in an enhanced cytotoxic effect and increased apoptotic cell death in ATC cells in vitro and in vivo.56 Activity of this combination was also deemed effective, without significant toxicity. The combination of gemcitabine and cisplatin in anaplastic thyroid cell lines appeared to show promising cytostatic activity in an in vitro study.57
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Thyroid Gland
Survival Figures Survival figures vary and are based on a small number of cases. They have been reported at 2 years as near 0%,5 14%,2 and 17%1; at more than 3 years as 12%7; and at 5 years as 10%.2 Assiduous attempts have been made to define prognostic factors. I Factors favoring prolonged survival included younger age «45 years), disease confined to the neck, treatment characterized by total or subtotal thyroidectomy, and treatment by radiotherapy or chemotherapy or both. There appeared to be no significant survival advantage in the transformed group over the de novo anaplastic group. Analysis of long-term survivors (>24 months) indicated that they were significantly younger at diagnosis, had less disease, and received more extensive surgery, although this had not reached statistical significance. Ten of 12 long-term surviving patients received combined radiotherapy and chemotherapy postoperatively.' In the Roswell Park Memorial series," patients who were female, who had tumors smaller than 6 em and who had undergone complete resection survived significantly longer. One study from Latin America reported significantly longer survival in (l) patients with differentiated carcinoma with areas of anaplastic lesions limited to one lobe, (2) patients receiving a complete chemotherapy regimen, (3) patients with tumors smaller than 10 em, and (4) those with a symptom duration of less than 4 months-" A Japanese study reported a I-year survival rate in 44 patients with ATC to be 16%. The presence of acute symptoms, large tumors (>5 em), distant metastasis, and leukocytosis correlated with a poor outcome. A prognostic index (PI) based on these four factors was devised; patients with a PI less than or equal to 1 had 62% survival at 6 months, whereas no patients with a PI greater than 3 survived longer than 6 months.59
Investigation The dismal outcome of patients after treatment in ATC has stimulated research investigation to improve outcome results. Exogenous interleukin 6 has been used but unfortunately was ineffective/" After gene transfection with wild-type p53,
three ATC cell lines became more sensitive to doxorubicin (Adriamycin), suggesting that combining wild-type p53 and chemotherapy might improve the results of therapy?' The transfection of a human thyroperoxidase gene to restore iodine trapping in non-iodide-concentrating tumor cells seen in anaplastic cancer was not effective.f Bone morphogenetic protein (BMP-7) resulted in growth inhibition in ATC cells by inhibiting cyclin-dependent kinase activity, shifting the Rb protein to the hypophosphorylated state. 63 The compound 1,25-dihydroxyvitamin D 3 and several of its non-calciomimetic analogs show dose-dependent inhibition of cell growth in ATC cells in vitro'" and in vivo. 65 Growth inhibition of anaplastic cancer cells was also demonstrated by histone deacetylase inhibitors as a result of increased apoptosis, with activation of the caspase cascade and the induction of a cell cycle arrest through reduction of cyclindependent kinase activity/" Bovine seminal ribonuclease has been reported to have beneficial effects for treatment of aggressive thyroid cancer/" An ElB 55-kDa gene-defective adenovirus (ONYX-015) worked synergistically with two antineoplastic drugs (doxorubicin and paclitaxel) to increase cell death in ATC.68 Apigenin, a flavonoid, showed promise by inhibiting the signal transduction pathways regulating growth and survival in human ATC cells.s? It has also been documented that levels of (k)alpha 1 tubulin relative to thyroglobulin were greatly increased in anaplastic cancer so that chemotherapy targeted at microtubulin might prove to be useful for ATC treatment."? Restoration of p53 expression in ATC inhibited proliferation and restored differentiation in human ATC cells as well as responsiveness to physiologic stimuli." It has also been reported that CA4P, a tubulin-binding agent derived from the African bush willow, may have antitumor effects in ATC, thought to be due to a combination of primary antineoplastic effects and impairment of tumor vascularity." Although investigation into the biologic character of ATC continues, therapeutic innovations are still relatively scanty. Even as prospective trials continue to be limited, it has been noted that ATC arising from papillary or follicular thyroid malignancies have different genetic backgrounds and retain some of the cytogenetic characteristics of the parent problem.F BRAF mutations have been demonstrated to be
Anaplastic Carcinoma of the Thyroid Gland - -
restricted to papillary cancer and poorly differentiated and anaplastic cancer arrising from papillary malignancy, with distinct properties that enable them to develop poorly differentiated and anaplastic cancer." Also, a panel of tumor suppressor genes has been studied that is associated with thyroid neoplasia. The results demonstrate a pattern of alloleic loss, so that the majority of cases showed mutations in two distinct areas and substantial increases in mutation rates in the anaplastic components of the transformed ATC from preexisting well-differentiated malignancy?" PlO7 is thought to play a constitutive role in the progression of papillary cancer to anaplasia, showing a marked decrease in the anaplastic component." Efforts have also been made to investigate the expression of cytokeratin 20 (ck20) in differentiated and anaplastic cancer, and the resultant investigation has demonstrated that ck20-positive tumors have a poor prognosis, reinforcing the need for adjuvant treatment in such a selected group." Cytogenetic work has also shown that different gene dosage copy sequence and balances are important to pathways of transformation of follicular into anaplastic cancers." The transcriptional factor E2Fl controls the RB-E2F signaling pathway, and there is enough regulation of E2Fl in papillary cancer as compared with ATC that may demonstrate a role in carcinogenesis." Gene therapy of ATC has been investigated using the interleukin-l Z gene in BALB/C (nulnu) mice, and initial results suggest a clinical application may be considered." Other investigation has demonstrated that the radiosensitivity of transformed thyroid cells is due in part to the elevated basal activity in the induction of the active form of nuclear transcription factor kappa B, prompting investigators to theorize that inhibition of NF-kappa B could enhance radiation therapy of ATC.8o Workers have also looked at imatineb mesylate monotherapy in treatment of ATC only to find that future clinical studies are futile and not to be encouraged." It has also been demonstrated that experimental in vitro incorporation of gemcitabine into liposomes enhances the drug's cytotoxic effect, indicating a more effective drug intake inside the cell, which may permit lower dosage of this drug in the treatment of ATC.82 Etiology and more complex treatment programs may be investigated, but surgical investigators are still left with the rather simplistic feeling that, although there is no successful treatment for ATC, patients who have undergone liberal surgery for thyroid neoplasia or early surgery with complete resection of ATC have the best chance of response and survival. 83
Conclusion ATC is rare and lethal; fortunately, it appears to be decreasing in frequency" but is nevertheless still a persistent occurrence. The decrease in frequency appears to be associated with improvement in socioeconomic status, more accurate diagnosis, histologic definition and exclusion of medullary cancer and lymphoma, and the elimination of iodine deficiency. It is apparent that the traditional approaches of surgery and postoperative radiation are inadequate in ATC treatment if one is to expect a curative outcome. Currently, the most effective treatment, at least for the control of local disease, is a multimodality treatment consisting of a combination of
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initial simultaneous radiotherapy and chemotherapy, followed by surgical resection of as much tumor as safely possible, followed by combined chemoradiotherapy, u Obviously, more research is required and deserves support so that a new therapeutic regimen may evolve to produce improved and more successful results. 55-83
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55. Ain K, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with paclitaxel: Phase 2 trial using ninety-six-hour infusion. Thyroid 2000;10:587. 56. Yeung SC, Xu G, Pan J, et al. Manumycin enhances the cytotoxic effect of paclitaxel on anaplastic thyroid carcinoma cells. Cancer Res 2000;60:650. 57. Voigt W, Bulankin A, Muller T, et al. Schedule dependent antagonism of gerncitabine and cisplatin in human anaplastic thyroid cancer cell lines. Clin Cancer Res 2000;6:2087. 58. Pacheco-Ojeda LA, Martinez AL, Alvarez M. Anaplastic thyroid carcinoma in Ecuador: Analysis of prognostic factors. Int Surg 2001;86:117. 59. Sugitani I, Nobukatsu K, Fujimoto Y, Akio Y. Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid. World J Surg 2001;25:617. 60. Fiore L, Pollina L, Fontanini G, et al. Cytokine production by new undifferentiated human thyroid carcinoma cell line FB-I. J Clin Endocrinol Metab 1997;82:4094. 61. B1agosklonny MV, Giannakakou P, Wojtowicz M, et al. Effects of P53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 1998; 83:2516. 62. Haberkorn U, Altmann A, Jiang S. Iodine uptake in human anaplastic thyroid carcinoma cells after transfer of human thyroid peroxidase gene. Eur J Nucl Med 2001;28:633. 63. Franzen A, Heldin NE. BMP-7-induced cell cycle arrest of anaplastic thyroid carcinoma cells via p21 (CIP\) and p27 (KIP\). Biochem Biophys Res Commun 2001 ;285:773. 64. Liu W, Asa SL, Fantus IG, et al. Vitamin D arrests thyroid carcinoma cell growth and induces p27 dephosphorylation and accumulation through PTEN/akt-dependent and -independent pathways. Am J Pathol 2002;160:511. 65. Dackiw AP, Ezzat S, Haung P, et al. Vitamin D3 administration induces nuclear p27 accumulation, restores differentiation, and reduces tumor burden in a mouse model of metastatic follicular thyroid cancer. Endocrinology 2004; 145:5840. 66. Krainberg VL, Williams JM, Cogswell JP, et al. Histone deacetylase inhibitors promote apoptosis in differential cell cycle arrest in anaplastic thyroid cells. Thyroid 2001; II: 315. 67. Kotchetkov R, Cinatl J, Krivtchik AA, et al. Selective activity of BS-RNase against anaplastic thyroid cancer. Anticancer Res 200 I; 21:1035. 68. Portell a G, Scala S, Vitagliano D, et al. Onyx-015. an EIB gene-defective adenovirus, induces cell death in human anaplastic thyroid carcinoma cell lines. J Clin Endocrinol Metab 2002;87:2525. 69. Yin F, Giuliano AE, VanHerle AJ. Signal pathways involved in apigenin inhibition of growth in induction of apoptosis of human anaplastic thyroid cancer cells (ARO). Anticancer Res 1999; 19:4297. 70. Takano T, Hasegawa Y, Miyauchi A, et al. Overexpression of kalpha I tubulin mRNA in thyroid anaplastic carcinoma. Cancer Lett 200 I; 168:51. 71. Dziba J, Marcinek R, Venkataraman G. et al. Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors. Thyroid 2002; 12:1063. 72. Miura D, Wada N, Chin K, et al. Anaplastic thyroid cancer. Thyroid 2003; 13:283. 73. Nikiforova M, Kimura E, Gandhi M, et al. BRAF mutation in thyroid tumors. J Clin Endocrinol Metab 2003:88:5399. 74. Hunt J, Tometsko N, Livolsi V, et al. Molecular evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the thyroid. Am J Surg Pathol 2003: 12: 1559. 75. Ito Y, Yoshida H, Tomoda C, et al. Decreased expression of pl07 as correlated with anaplastic transformation in papillary carcinoma of the thyroid. Anticancer Res 2003:23:3819. 76. Schmidt-Winnenthal F. Weckauf H, Haufe S, et al. Detection and prognosis relevance of cytokeratin 20 in differentiated and anaplastic thyroid carcinoma by RT-PCR. Surgery 2003;134:964. 77. Rodrigues R, Roque L, Rosa-Santos J, et al. Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinoma. Br J Cancer 2004;90:492. 78. Onda M, Nagai H, Yoshida H. Up-regulation of transcriptional factor B2FI in papillary and anaplastic thyroid cancer, J Hum Genet 2004; 49:312.
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ineffective in suppressing human anaplastic thyroid carcinoma cell growth in vitro. J Clin Endocrinol Metab 2004;89:2127. 82. Ciano M, Calvagno M, Bulotta S, et al. Cytotoxic effects of gemcitabine loaded liposomes in human anaplastic thyroid carcinoma cells. BMC Cancer 2004;4:63. 83. Kihara M, Miyauchi A, Yamauchi A, Yokomise A. Prognostic factors of anaplastic thyroid carcinoma. Surg Today 2004:34:394.
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid Janice L. Pasieka, MD, FRCSC, FACS • Lloyd A. Mack, MD, FRCSC
Unusual Thyroid Cancers Unusual thyroid cancers, including the intermediately differentiated carcinomas, account for only 10% to 15% of all primary thyroid neoplasms (Table 19-1). This unique group of neoplasms behaves differently than the more common type-the well-differentiated thyroid cancers (WDTCs). They therefore present a challenge to both the surgeon and the endocrinologist-oncologist. Most of these cancers behave in an aggressive fashion and, at times, present as a medical emergency. Multimodality therapy is the mainstay of treatment for these tumors. As a result, it is important for the endocrine surgeon to have a clear understanding of the nature of these tumors and recognize when surgery is indicated.
Plasmacytoma Primary extramedullary plasmacytomas are rare forms of plasma cell tumors. Solitary extramedullary plasmacytomas may develop in any organ, but they occur predominantly in the upper respiratory tract. 1·4 The thyroid gland is one of the rarer sites; approximately 50 cases of solitary lesions have been reported in the literature.l It is not uncommon, however, for multiple myeloma to involve the thyroid gland.r" The diagnosis of solitary extramedullary plasmacytoma can be made only after the exclusion of skeletal multiple myeloma on long-term follow-up.v'? Clinical Features. Extramedullary plasmacytoma of the thyroid usually presents with a painless diffuse or nodular goiter. In several cases, it was a rapidly enlarged goiter that brought the patient to seek medical advice.5.8.9.11 Typically, the patient is euthyroid and presents in the sixth decade of life. Extramedullary plasmacytoma predominantly affects females. II On physical examination, the thyroid is a firm, nontender, mobile, multilobulated goiter. There is usually no associated
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cervical lymphadenopathy. Biochemically, antithyroid antibodies may be elevated. Some authors have suggested an association with autoimmune thyroiditis." However, the thyroiditis may represent a nonspecific inflammatory reaction to the presence of the tumor and may not be linked to the cause of the tumor. Pathology. Grossly, the lesions have a fleshy, red-brown neoplastic appearance. Histologically, the tumor demonstrates a dense infiltration of mature plasma cell arranged in sheets or clusters replacing the normal thyroid architecture. Cellular atypia may be seen and mitotic figures can be numerous (Fig. 19-1). 8 Immunohistochemical staining can demonstrate monoclonal plasma cells for both kappa or lambda immunoglobulin chains." Diagnosis and Treatment. The diagnosis of a solitary extramedullary plasmacytoma of the thyroid is suspected on the clinical presentation and the pathologic appearance of the tumor. Fine-needle aspiration (FNA) cytology results may be misinterpreted as medullary thyroid carcinoma.'? Because of the rarity of these tumors, there are no reported cases of the diagnosis being made on the basis of FNA. As stated earlier, it is important to rule out disseminated multiple myeloma by performing a bone marrow aspiration. Up to 25% of patients with solitary plasmacytoma have elevated levels of M proteins in their blood or urine. 13 The optimal treatment for this tumor consists of a total thyroidectomy plus high-dose external-beam radiation to the neck. Surgery or low-dose radiation therapy alone has been associated with a high local recurrence rate. 13 Some institutions have treated these rare tumors with only high-dose radiation (5000 to 6000 rad) and have had relative success.t'" Local recurrence does not appear to alter survival, and most reported cases have been controlled with further radiation therapy. I I The overall 5-year survival using combined treatment is 85%.9 However, long-term follow-up of these patients is necessary because progression to multiple myeloma has been reported.t
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - - 169
Paraganglioma Paragangliomas are rare tumors derived from the extra-adrenal paraganglia cells of the autonomic nervous system. Most paragangliomas occur in the retroperitoneum or the head and neck region (carotid body tumor). Over the last few decades, several authors have reported unique thyroid lesions that have been categorized as paraganglioma of the thyroid.'>" The presence of a primary paraganglioma in the thyroid is difficult to explain embryologically. Some authors have suggested that these lesions may be a form of medullary thyroid cancer. However, amyloid has not been identified in these lesions, and none of the lesions have stained for calcitonin.l'v" Several authors have described lesions that appear to have a histologic appearance similar to paragangliomas on light microscopy but demonstrated positive thyroglobulin immunoreactivity and negative immunoreactivity for calcitonin and neurofilament.t-P These investigators concluded that true paraganglioma of the thyroid has not been proven to exist and that these lesions represent a variant of follicular adenomas, describing these lesions as "hyalinizing trabecular adenoma"23.24 or "paraganglioma-like adenoma.r'P
FIGURE 19-1. Plasmacytoma of the thyroid: two thyroid follicles entrapped in a sea of plasma cells (hematoxylin-eosin stain).
Clinical Features. The patients usually present with a solitary, nontender thyroid nodule. Patients' ages range from 27 to 67 years (mean age, 46 years). Paragangliomas occur predominantly in women.P:'? Some of these lesions are "hot" on thyroid scintigraphy. Pathology. The cytologic features on FNA can resemble those of medullary thyroid cancer. Negative staining for calcitonin of these cells can aid in the differential diagnosis preoperatively (Fig. 19-2A). Grossly, the lesions are solid and well encapsulated. They are described as tan to pink-gray in appearance and granular in texture. Histologically, the tumors are composed of oval, elongated spindle cells arranged in a trabecular fashion. The cytoplasm is eosinophilic and finely granular (Fig. 19-2B). Immunohistochemically, the lesions stain positive for thyroglobulin, neuron-specific enolase, and S-IOO but negative for calcitonin and neurofilament.20-23 LaGuette and associates" suggest that an immunohistochemical panel is essential for making the correct diagnosis of this rare tumor. Diagnosis and Treatment. Whether these lesions represent a variant of follicular adenomas or are truly paragangliomas of the thyroid is debatable. However, these rare lesions exhibit several microscopic characteristics that are similar to those of medullary thyroid cancer and can be potentially misinterpreted if not initially recognized as such. Most patients reported to date have been successfully treated with surgical excision alone. 22.23 External-beam radiation was used unsuccessfully in one report.'? The literature suggests that most of these lesions can be treated in a similar fashion to a follicular adenoma, that of an unilateral thyroid lobectomy, and these patients have the same excellent prognosis. It is unclear whether lesions demonstrating local invasion are arising from the thyroid or are extrathyroidal in origin, invading into the thyroid.l'v'? Therefore, when local invasion is found, complete en bloc excision of the paraganglioma is necessary.
Sarcoma Throughout the medical literature there are many case reports of sarcoma arising in the thyroid gland. This is to be distinguished from anaplastic thyroid carcinoma that has been shown to demonstrate a variety of growth patterns, including those resembling sarcomas.P:" In the case reports of primary thyroid sarcoma presented in the literature, patients usually present with large, ill-defined masses of the thyroid associated with rapid growth.P?' Gender predilection appears to be equal. The question as to whether primary mesenchymal thyroid neoplasms exist continues to be debated in the literature. There are, however, reports of hemangioendotheliomas of the thyroid that have confirmed the endothelial nature of the tumor with electron microscopy, immunohistochemical staining, and lack of thyroglobulin messenger RNA expression. 29,31-3S Liposarcomas, carcinosarcomas, dendritic cell sarcomas, and leiomyosarcomas of the thyroid gland have also been reported. 26.30,36-39 Immunoreactivity of these tumors for actin, desmin, and vimentin with negativity for thyroglobulin, cytokeratin, and S-IOO protein supports the distinct identity of these rare tumors. 30.38 All subgroups of these tumors generally have a poor prognosis despite treatment attempts with surgery, external-beam radiation, and/or chemotherapy.29,31,34,3S,38,39
170 - - Thyroid Gland squamous cell carcinoma of the thyroid is rare, having been estimated to make up only 0.2% to 0.3% of all thyroid cancers.v A unique group of spindle cell squamous carcinomas associated with tall cell papillary thyroid cancer (PTC) has also been described.">? The patients tend to be women in their seventh decade of life.53.55.56.58 Most patients have advanced disease at presentation, with invasion into adjacent structures and distant metastases being common. Few patients survive more than 12 months. 53.55.57.58 Diagnosis is usually made after pathologic examination of the surgical specimen, although Mai and colleagues described diagnosis based on FNA,59 Total excision of gross disease, when possible, may be curative when followed by external-beam radiation. 53,6o The clinical usefulness of chemotherapy is uncertain, with no proven responses.w'" Useful palliation may be achieved with combined surgical debulking and radiation in selected patients. 53,6o
Intermediately Differentiated Carcinomas
B FIGURE 19-2. A, Cytology of a thyroid paraganglioma. B, Paraganglioma of the thyroid. Shown are oval, elongated spindle cells arranged in a trabecular fashion (hematoxylin-eosin stain).
Teratoma Teratomas are believed to arise from totipotential cells and, therefore, commonly arise in the reproductive organs. The exact site of origin in the thyroid is unclear. Teratomas of the thyroid can be either benign or malignant.f? The benign teratomas are usually cystic and occur in children. 41,42 Teratomas that develop in adults are more common in women, present with progressively enlarging thyroid masses, and are usually malignant.Pr'? In the adult, thyroid teratomas are characteristically large tumors with areas of hemorrhage and necrosis. Microscopically, the tumors demonstrate an admixture of immature tissues with features of the three germ cell layers. These tumors are highly aggressive. To date, treatment consists of total thyroidectomy and neck dissection for diagnosis and potential locoregional control. External-beam radiation has been used; however, in general, these tumors tend to be resistant to chemotherapy and radiation therapy.43,47,49 There have been a few long-term survivors with aggressive combination chemotherapy.s'-"
Squamous Cell Carcinoma Primary squamous cell carcinoma of the thyroid has been extensively described in the literature.v" The frequency of
A recent classification of thyroid cancer based on tumor prognosis has been suggested by Fadda and LiVolsi. 61 This classification includes a group of intermediate variants of thyroid cancer, including insular, columnar, mucoepidermoid, and diffuse sclerosing PTC; tall cell carcinoma; and the solid/trabecular variant of PTC.61.63 These tumors have a biologic aggressiveness that is intermediate between that seen in WDTC and that of lethal anaplastic thyroid cancer. Although the intermediate variants make up only 10% to 15% of all thyroid cancers, they are important variants for the endocrine surgeon to be aware of because in many cases they require a multimodality therapy that differs from that of WDTC. INSULAR CARCINOMA
Insular carcinoma of the thyroid was first described by Langhans in 1907,64 and several decades later, Carcangiu and coworkers established diagnostic criteria for this tumor.s' There are now more than 200 cases reported in the literature, accounting for 2% to 6% of all thyroid cancers. 66,67 Clinical Features. Insular carcinoma is a highly aggressive form of thyroid cancer.f Most of the tumors are relatively large, with a mean size of 5.5 em (ranging from 5 to 10 cm).68 There is a 2: 1 female predominance; age of onset ranges from 37 to 76 years, with the mean age of presentation being 56 years. Most patients are euthyroid and present with a cold thyroid nodule. There is usually no history of low-dose radiation to the head and neck region in these patients." Most patients have cervical and mediastinallymphadenopathy on presentation. Locoregional and/or distant metastases have been reported in up to 70% of patients." Pathology. Macroscopically, insular carcinoma is a solid pale or gray color, often with areas of necrosis or hemorrhage. Microscopically, the tumor is characterized by the formation of a large, well-defined nest of monotonous round and oval tumor cells with occasional small follicles. These nest of tumor cells resembles the pattern seen with carcinoid tumors-hence, the name insular. 65 ,69 The tumor cells are uniform and lack prominent nucleoli. Many of the nuclei are optically clear, resembling the ground-glass nuclei of PTC. Mitotic figures are present in all tumors (Fig. 19-3).65
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - -
FIGURE 19-3. Insular carcinoma: well-defined nests (insulae) of
round oval cells.
There is increasing evidence to support the concept that insular carcinoma represents an intermediate step in the dedifferentiation of WDTC to anaplastic thyroid cancer. First, the presence of WDTC in combination with insular cancer is seen in up to 59% of reported cases.F" Second, similar to WDTC, insular carcinomas stain positive for thyroglobulin and negative for calcitonin, chromogranin, and carcinoembryonic antigen. 65. 72 Finally, up to 38% of insular cancers stain positive for p53 mutations, which is a higher rate than reported in WDTC and significantly lower than that seen in anaplastic carcinoma." Diagnosis and Treatment. The rarity of these tumors has not allowed for a uniform approach to treatment. In the series of 25 patients by Carcangiu and associates, most of the patients with insular carcinoma underwent total or neartotal thyroidectomy. Some patients had neck dissections, and others received external-beam radiation. The extent of surgical excision did not seem to influence the local or distant recurrence rates. More than 85% of patients developed local, regional, or distant metastases in the 8-year follow-up. The mortality rate during this same period of follow-up was 56%.65 In a recent review of the literature, the mean rate of local and/or distant metastasis for insular carcinoma was calculated to be 64%.68 In one series, 75% of metastatic insular tumors concentrated radioiodine." Therefore, the current treatment for insular thyroid cancer remains aggressive surgical intervention, with or without lymph node dissection, adjuvant radioiodine treatment (although not prospectively evaluated), plus the possibility of external-beam radiation for incompletely excised tumors.
171
an aggressive behavior and an unfavorable prognosis. However, in two small series, when the tumor was circumscribed and encapsulated, the prognosis was similar to that of WDTC,79.82 Mean age at presentation is 44 years. 79.8l The tumors tend to be large, with a mean tumor size of 5.3 cm. 68 Patients typically present with a cold thyroid nodule and may have regional lymph node metastases. The overall rate of distant metastases is 32%, although no cases of distant metastases have been reported when the tumor was encapsulated. Distant metastases when present are found predominantly in lung, bone, and regional lymph nodes.68.79.81 Pathology. FNA cytology has been described for these lesions." The cytologic features can be confused with PTC, medullary carcinoma of the thyroid, and metastatic adenocarcinoma. Grossly, the thyroid tumor tends to be an irregular, multinodular, tanned mass (Fig. 19-4A). Histologically, the tumors may be encapsulated or diffusely invasive. 79,82 In contrast to well-differentiated PTC, the epithelium consists of tall, columnar tumor cells displaying a pronounced nuclear stratification. Columnar cell carcinoma has scant cytoplasm with no oxyphilic changes. Most tumors display a papillary growth pattern with mitotic figures and immunohistochemically stain positive for thyroglobulin (Fig. 19-4B).
COLUMNAR CELL CARCINOMA
Evans 74 in 1986 described two cases of thyroid cancer with a distinct histologic pattern that he termed columnar cell carcinoma. Others have since reported similar cases, all displaying aggressive clinical behavior and a universally poor prognosis.25.75.78 Columnar cell carcinoma is rare, accounting for only 0.15% of all PTCS.79.81 Clinical Features. Earlier reports suggested a higher incidence in males; however, in a recent review of the reported cases in the literature, there was a female predominance.f Most of these columnar cell tumors are associated with
B FIGURE 19-4. A, Columnar cell carcinoma of the thyroid: Gross picture of a resected liver metastasis. The multilobulated, tanned color of this tumor is characteristic of these tumors. B, Columnar cell carcinoma of the thyroid. The tall columnar tumor cells display pronounced nuclear stratification (hematoxylin-eosin stain).
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Thyroid Gland
Columnar cell carcinoma differs histologically from the tall cell variant of PTC51,52,83 in that the degree of nuclear stratification and height of the columnar cell are much more excessive in columnar cell tumors.r'-" The exact proportion of columnar cells displaying nuclear stratification required to make the diagnosis of columnar cell variant has not been defined. In the largest reported series, the diagnosis of columnar cell variant required more than 70% of the tumor demonstrating nuclear stratification." Diagnosis and Treatment. Most patients have been treated with total or near-total thyroidectomy, with or without lymph node dissection. Until recently the prog~osis of columnar cell carcinoma was thought to be universally poor.74.76 Encapsulated or minimally infiltrative lesions h~ve a relatively good prognosis, with all reported cases remaming disease free at 5 years. In contrast, tumors with extrathyroidal spread have a high incidence of distant metastases, and 67% of the patients have died of the disease, with a mean mortality of only 40 months. 68,79,81,82 Radioactive iodine has been used in about 60% of cases without evidence of demonstrated improvement.Y" External-beam radiation should be considered when residual disease is present or for palliation. MUCOEPIDERMOID CARCINOMA
In 1977, Rhatigan and colleagues's first described primary mucoepidermoid carcinoma of the thyroid. Fourteen years later, Chan and coworkers described sclerosing mucoepidermoid thyroid carcinoma arising from a metaplastic follicle in Hashimoto's thyroiditis.f" There have been several case reports of this rare tumor, with significant debate in the literature regarding its histogenesis.t"?' It is believed that mucoepidermoid tumors of the thyroid arise from either metaplasia of the follicular epithelium89,92,93 or as vestiges of the ultimobranchial body.94-98 Clinical Features. Although these tumors were original described as indolent or low-grade tumors,63,84 many case series suggest a more aggressive behavior, with a high incidence of local invasion,85,86.9I,93 ability to metastasize distantly,87.88 and mortality.P?' The tumor presents as a painless neck mass that is "cold" on thyroid scintigraphy. There is a female predominance occurring most commonly in the fifth to eighth decades of life.84,85,89
Pathology. Microscopically, neoplastic proliferation is composed of squamous or epidermoid areas with intermingling mucous cells. The epidermoid cells have round or oval nuclei, prominent nucleoli, and eosinophilic cytoplasm. Mucocytes with abundant clear to foamy-appearing cytoplasm and peripheral hyperchromatic nuclei are present. Sclerosing mucoepidermoid carcinoma with the eosinophilia variant often has a background of thyroiditis and prominent sclerohyaline stroma infiltrated with eosinophils.Pv" Immunohistochemistry on these tumor is positive for mucin '.c . 63 '85 ,89 . stains . but negative and cytokeratin lor ca lei citorun. Diagnosis and Treatment. FNA cytology has diagnosed these tumors; however, more commonly the diagnosis is only made after surgical excision."? An en bloc thyroidectomy is the treatment of choice with potential for cure even in locally invasive disease.84,91,100 External-beam radiation and chemotherapy have been used with minimal success at controlling locoregional disease.87,88,92,93 Information regarding this tumor's usual clinical course is lacking because of its rare occurrence.
DIFFUSE SCLEROSING VARIANT OF PAPILLARY THYROID CANCER
The simultaneous occurrence of thyroiditis and PTC was first described in 1985 by Vickery and associates. 101 This variant, termed diffuse sclerosing variant of PTe, was later incorporated into the World Health Organization (WHO) classification of thyroid tumors and today accounts for 2% to 6% of all thyroid tumors. 102-105 To date, there have been 72 cases of diffuse sclerosing PTC reported in the adult literature.P Diffuse sclerosing PTC has also been described in the children affected by the Chernobyl disaster. 106,107 Clinical Features. Diffuse sclerosing PTC occurs predominantly in females, with the age of presentation being in the third decade of life. Patients present with either localized or diffuse thyroid enlargement that may be painfu1.68,108 Fifty to 70% of patients have measurable titers of antimicrosomal and antithyroglobulin antibodies, leading to the mistaken diagnosis at presentation of subacute or chronic thyroiditis in 28% to 40% of patients. 102,108 Cervical lymph node metastases are found in 70% of patients, and distant metastases can be found in up to 60%.68,102-104 Pathology. The FNA cytology of diffuse sclerosing PTC demonstrates the usual nuclear features of PTC: nuclear grooves, pseudoinclusions, and overlapping nuclei. !he presence of relative nuclear enlargement and pleomorphism may help distinguish this variant from the usual PTC.109 These tumors usually demonstrate a diffuse involvement of the thyroid lobe, with a pale, fibrous appearance macroscopically. Histologically, diffuse sclerosing PTC is made up of numerous papillae with squamous metaplasia. The tumors tend to have interstitial fibrosis, psammoma bodies in a background of lymphocytic inflammatory infiltrate (Fig. 19-5). Extrathyroidal extension is seen in 40% of patients. I 10 Diagnosis and Treatment. Diffuse sclerosing PTC tends to have a higher propensity for locoregional metatatic compared with that found in WDTC. Local recurrence rates are reported to be as high as 50%, and distant metastatic rates of 60% have been described. 102,103,108,110 In a recent review of 65 reported adult cases of diffuse sclerosing PTC,
FIGURE 19-5. Diffuse sclerosing papillary thyroid cancer, This
low-power view demonstrates interstitial fibrosis, psammoma bodies, and lymphocytic infiltrate.
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - -
173
the mean weighted local recurrence rate was only 13%, and the mean weighted distant metastatic rate was calculated to be only 19%.68 Tumor-related mortality for this variant is excellent, with only one reported death in the literature. 103 The treatment of diffuse sclerosing PTC begins with the awareness of this tumor's ability to mimic subacute thyroiditis at the time of presentation. The treatment of this tumor should involve an en bloc excision of the thyroid gland and any of the infiltrated structures within the neck. Given the high rate of lymph node metastases, a modified neck dissection should also be included. Following surgery, adjuvant radioactive iodine therapy should be used. TALL CELL VARIANT OF PAPILLARY THYROID CANCER
The tall cell variant of thyroid cancer accounts for 3% to 12% of all PTCs of the thyroid, although this is believed to be an underestimate of the disease because of the difficulty the pathologist may have at making the diagnosis.!" Tall cell cancer of the thyroid was first described by Hawk and Hazard in 1976. 52 These tumors are characterized by having a significant proportion of the tumor composed of cells in which the cell height is at least twice its width. There is variation in the literature regarding the percentage of tall cells within the tumor required to make the diagnosis. Most series have used a minimum of 30% of the tumor composed of tall cells to classify the tumor as a tall cell variant, whereas others have used percentages as high as 50% to 70%.111-114
Clinical Features. There have been more than 200 reported cases in the English literature of tall cell variant thyroid cancer." Although some authors have described a male predominance, 115. 11664% of the patients reported in the literature were women, with the average age of presentation being 51 years (range, 43% to 65%).68 The tumor tends to be larger than WDTC, averaging a diameter greater than 3 cm. 117 Extrathyroid extension is common and is found on average in 67% of the patients, in contrast with WDTC that demonstrates extrathyroid invasion in less than 20% of patients. Regional lymph node metastases occur on average in 57% of the patients (range, 40% to 83%). Distant metastases typically appear in the lung and bone and are found on average in 22% of the patients.v" Pathology. The cytologic features of tall cell cancer are similar to those seen in PTC, including nuclear pseudoinclusions, nuclear enlargement, and nuclear grooves. ll8,119 Feature that help the cytopathologist to differentiate this variant from PTC include larger cell size, eccentric nucleus, and increased nuclear pleomorphism. Macroscopically, these tumors appear as pale, firm neoplasms. Multifocality is commonly seen in 36% to 58%.116 The characteristic tall cells have a height that is at least twice their width, with abundant cytoplasm and basal positioning of the nucleus (Fig. 19-6). These features are distinct from the columnar cell variant of PTC, which has stratification of its nuclei and less cellular cytoplasm (see Fig. 19-4B). Most tall cell tumors stain positive for thyroglobulin, vimentin, and kertin.'!" Tall cell tumors have been shown to have a significantly higher incidence of p53 mutations compared to welldifferentiated PTC (61% vs. 11%); however, p53 mutations
FIGURE 19-6. Tall cell variant of papillary thyroid cancer. The height of the cells is greater than twice their width.
have not been demonstrated to be a predictor of worse outcome. I12 Diagnosis and Treatment. Regardless of the patient's age or the tumor size, the histologic diagnosis of tall cell carcinoma has been demonstrated to be an independently poor prognostic factor. 113,120 With the exception of Ozaki and coworkers.!" who found no recurrence or mortality in 13 patients with tall cell cancer, most authors have reported tumor-related mortality rates up to as high as 74%.lI1,I15.117 Locoregional recurrence rates are greater than those seen in PTC, with the risk of recurrence being greater in patients older than 50 years of age and in tumors larger than 4 cm. 11 I,117 In the study of 18 patients by Taylor and associates, the use of radioiodine therapy in 131I-avid tumors was shown to reduce the progression of the tumor signiflcantly.V' However, in another study, Ain found that only 13% of tall cell tumors were 131I-avid, and half of these patients eventually lost radioiodine uptake in the metastases over time.P" The aggressive nature of this tumor warrants aggressive surgical intervention. Total thyroidectomy combined with lymphadenectomy of cervical nodes and an en bloc resection of adjacent tissues should be done when there is evidence of local invasion. Since radioiodine therapy has been shown to be of benefit in some patients, it should be used in all P'f-avid tumors. External-beam radiation should be considered in all cases of tall cell carcinoma that have demonstrated extrathyroidal extension, incomplete resection, or positive lymph node involvement. SOLIDITRABECULAR VARIANT OF PAPILLARY THYROID CANCER
The presence of focal areas of solid or trabecular growth patterns in WDTC is common. When the tumor demonstrates exclusively or predominantly a solid or trabecular pattern, the diagnosis of a solid/trabecular variant of PTC is made. Between 12% and 16% of PTCs are the solid/trabecular variants. 123.124 More recently, this variant has been identified in 37% of the radiation-induced thyroid cancers seen in children exposed to the Chernobyl nuclear disaster.l'" This is a
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Thyroid Gland
significantly higher rate of occurrence than that seen in agematched nonradiation-induced PTC, in which the solid/ trabecular variant made up only 4% of the tumors. 125 Clinical Features. The solid/trabecular variant is seen in both the adult and pediatric population. In adults, the mean age of presentation is in the fifth decade of life, with a strong female predominance.P' In contrast, the radiationinduced tumors in the pediatric population exposed in the Chernobyl disaster affected both males and females equally.I'" Most of these children presented with a thyroid nodule averaging 2 em in size, with clinical lymphadenopathy found in 85%. In adults, cervical nodal disease occurs in between 57% and 83% of cases, and distant metastases are found in up to 21% of patients at presentation. 123,124 Pathology. Macroscopically, these tumors appear as nonencapsulated, firm, whitish nodules with evidence of local invasion present in 84% of the patients. 106 Microscopically, these tumors are made up of solid nests or a cordiike trabecular arrangement of epithelial cells, as shown in Figure 19-7. The solid variant has typical nuclear features of PTC, including nuclear inclusions and nuclear grooves. Most tumors stain positive for thyroglobulin, and a high prevalence of ret/PTC3 rearrangement has been demonstrated. 125 Diagnosis and Treatment. It is unclear in the literature as to whether the solid/trabecular variant has a worse prognosis than that of WDTC. Mizukarni and colleagues reported a lO-year survival rate of the only 72% in a series of 30 patients.!" In contrast, Carcangui and coworkers reported no tumor mortality in their series of 28 patients followed longer than 6 years.123 The follow-up of solid/trabecular variant tumors from the Chernobyl disaster is too brief to draw any conclusions on the long-term prognosis of these children. Total thyroidectomy and cervical lymph node dissection should be the treatment of choice because of the high propensity of the solid/trabecular variant to extend beyond the thyroid and to metastasize to lymph nodes. The use of radioactive iodine in these tumors has not been studied. Given that the histologic features of these tumors resemble those of PTC, it seems reasonable to use radioiodine therapy following surgical intervention.
Lymphoma of the Thyroid Primary lymphomas of the thyroid are rare, accounting for only 1% to 2% of thyroid malignancies and less than 2% of extranodal Iymphomas.P'P''!" Most thyroid lymphomas are non-Hodgkin's lymphomas of B-cell origin, although Hodgkin's disease of the thyroid has been described. 126.129 I~ a large proportion of cases, thyroid lymphomas are associated with Hashimoto's thyroiditis and histologically may be difficult to distinguish from this chronic lymphocytic disease.25,130 Follow-up studies have estimated the relative risk of thyroid lymphoma in patients with chronic lymphocytic thyroiditis to be 70 to 80 times higher than in controls. 131 The actual relationship between Hashimoto's thyroiditis and thyroid lymphomas remains obscure. Whether the presence of lymphocytes in the thyroid provides the tissue in which the lymphoma can develop or whether the chronic stimulation of the lymphocytes predisposes the cells to develop malignant clones has not been defined. Clinically, primary lymphoma poses a diagnostic and therapeutic challenge because it can present in a fashion similar to that of small cell anaplastic carcinoma of the thyroid. 132-135 As a result, it is essential to be able to distinguish these two diseases, because there are different therapeutic and prognostic implications for each.
Clinical Features Most patients present with a several-week history of a rapidly enlarging goiter. 134,135 Thyroid lymphomas tend to present in women in their seventh decade of life who may have had a long-standing history of Hashimoto's thyroiditis. It is usually painless and often associated with hoarseness and dysphagia. 26,130.135 Less frequently, the patients may present with tracheal compression, dyspnea, and respiratory obstruction.!" Most patients are euthyroid. On palpation, the thyroid is firm, with either unilateral or bilateral involvement. The gland may be fixed to adjacent structures, and enlarged regional lymph nodes are not unusual. Computed tomography usually demonstrates a diffusely enlarged thyroid gland with evidence of invasion into adjacent structures and lymphadenopathy (Fig. 19-8A). PATHOLOGY
FIGURE 19-7. Solid/trabecular variant of papillary thyroid cancer. This high-power view demonstrates a cordlike trabecular arrangement of the cells.
Thyroid lymphomas grossly appear as pale gray or light tan fleshy tumors (Fig. 19-8B). Most thyroid lymphomas are the non-Hodgkin's type. 134,135 Aozasa and colleagues!" reported that most thyroid lymphomas appear to be exclusively B-cell-derived tumors. Histologically, primary thyroid lymphomas can be of several subtypes, classified by the Revised European-American Lymphoma study group (REAL) and the WHO classifications.Pv'F Deringer and coworkers'> described four main subtypes in their large series: 38% diffuse large B-celilymphoma without marginal zone lymphoma, 33% diffuse large B-cell lymphoma with marginal zone B-celilymphoma, 28% marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), and fewer than I % follicle-center lymphoma. The percentage of MALT lymphoma varies in the literature from 23% to 77%.134.135,138.140 Many authors suggest that large cell
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - -
c
175
D
FIGURE 19-8. A, CT scan of a thyroid lymphoma, showing diffuse enlargement with tracheal compression. B, Thyroid lymphoma: left resected lobe of the thyroid, with fleshy appearance on the cut surface. C, Thyroid lymphoma demonstrating diffuse replacement of the thyroid parenchyma by lymphoma. D, Thyroid lymphoma extending beyond the thyroid capsule to invade surrounding strap muscles (C and D, hematoxylin-eosin stain).
lymphomas may also evolve from low-grade lymphomas of MALT.140-143 In general, the tumor cells are noncohesive and have a lymphoid monomorphoric appearance.i" Thyroid lymphoma may form nodules or may present with a diffuse infiltrative pattern. Mitotic figures can be numerous (Fig. 19-8C). Extrathyroid extension of the neoplastic cells helps the pathologist distinguish this as a neoplastic process versus chronic inflammation. DNA flow cytology and immunohistochemical staining for CD 19 and CD20 are helpful for demonstrating the B-cell nature of the lymphocytes, and the restricted expression of immunoglobulin light chains allows for the distinction from chronic lymphocytic thyroiditis.25.128.134.144
Diagnosis and Treatment Thyroid lymphoma can be confused clinically with an anaplastic thyroid carcinoma. FNA has helped distinguish these two conditions preoperatively and has decreased the need for open biopsy.126.130.145 Up to 88% of thyroid
lymphomas in some series are diagnosed on FNA alone without further invasive testing.145.146 The use of flow cytometry, immunohistochemistry, and polymerase chain reaction has improved diagnostic results. 138.147.148 However, FNA is experience dependent, and there are difficulties in distinguishing thyroid lymphoma from Hashimoto's thyroiditis. This difficulty can lead to the need for open surgical biopsy to make the diagnosis. 149.150 Once the diagnosis has been established or is suspected, the patient's disease must be staged, as follows: • Stage IE involves localized disease within the thyroid. • Stage lIE is disease confined to the thyroid and regional lymph nodes. • Stage IIIE involves disease on both sides of the diaphragm. • Stage IVE is disseminated disease. The treatment of thyroid lymphoma remains controversial. Initially, surgery was used extensively for the treatment of this disease. More recently, however, surgical removal has been shown to have a limited benefit. 150.151 Not all investigators
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Thyroid Gland
have agreed with this; some have suggested that the addition of surgical debulking is necessary because the amount of residual disease in the neck correlated to the relapse rate for stages IE and lIE disease. Rosen and associates'V demonstrated a longer overall and relapse-free survival with complete or near-complete resection. However, most of the literature reports have failed to demonstrate the benefit of aggressive surgical intervention compared with combined radiation and chemotherapy. The Mayo Clinic achieved a complete response with predominantly radiation therapy in stages IE and lIE lymphomas in 88% of its patients. 151 Since most patients present with disease beyond the thyroid, the surgical role in advanced tumors is limited to open biopsy when needed.135.150.15I Thyroid lymphomas have been shown to be both radiosensitive and chemosensitive; therefore, most current recommendations are to treat these tumors with a combinedmodality therapy.127.150.153 Doria and colleagues, in their large 1994 review, demonstrated that nearly 30% of patients with localized stage IE or lIE disease have systemic relapse when treated with local radiation alone or in combination with surgical debulking.F' They suggested that combined radiation and chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without the addition of methotrexate, doxorubicin, or both may decrease the chance of distant relapse. Radiation alone, however, has been successfully used in localized thyroid lymphoma of the MALT variety. Similar to MALT lymphomas of other sites, radiation alone has resulted in a 96% complete response, with only a 30% relapse rate. I39,154 Many centers treat all thyroid lymphomas (localized or disseminated) with multimodality therapy, including radiation and chemotherapy. 134,150 Advanced stage of the tumor, a size greater than 10 em, mediastinal involvement, and the presence of dysphagia have been shown to be poor prognostic factors in primary thyroid lymphoma.P'T" Most recurrences develop within the first 4 years. The overall survival of patients with thyroid lymphoma ranges from 50% to 70%.150,151 The 5-year survival is 80% for stage IE, 50% for stage lIE, and less than 36% for stages IIIE and IVE. 151
renal cancer patients, 10% of lung cancer patients, and 10% of patients with primary head and neck tumors.P" Case reports and studies of metastases to the thyroid gland from less common primary tumor sites have been published, including colon, soft tissue, neuroendocrine, stomach, bladder, and gynecologic tumors.160-165 The incidence of clinically apparent metastases appears to be lower than the incidence found in autopsy material. According to Shimaoka and colleagues.P" the thyroid metastases were clinically apparent in only 5% to 10% of patients in their study. Renal cell carcinoma is the most common secondary to the thyroid when defined by clinical detection. ' 64,166-168 Usually, there is a latency period lasting years between the diagnosis of the primary cancer and the appearance of a thyroid mass. 159,166-171 This finding is especially true for breast and renal primary tumors. Less commonly, patients may present with metastatic disease in the thyroid before a primary diagnosis of cancer. l7u n
Diagnosis and Treatment The presentation of a cold thyroid nodule years after the treatment of a primary cancer often poses a diagnostic dilemma. FNA has allowed for the preoperative diagnosis of a secondary tumor, thus changing the preoperative work-up of such a patient (Fig. 19_9).168,172.173 Once the diagnosis of metastatic disease has been confirmed on FNA, the patient should undergo a metastatic work-up to rule out other distant metastases. Several authors have demonstrated that for isolated thyroid metastasis, thyroidectomy has prolonged survival. l 64,166.167,169-171 This is especially true for tumors that
Metastases to the Thyroid The true incidence of metastases to the thyroid gland has not been clearly established. Autopsy studies have reported an incidence ranging from 2% to 25%.156-159 In the study by Mortensen and colleagues, 4% of patients with metastatic neoplasms had secondary tumors of the thyroid gland.P? Silverberg and Vidone-? found the incidence to be much higher. In their study, they meticulously examined the thyroid and found the incidence of metastatic disease to the thyroid to be 24% in patients dying from metastatic cancer. This study suggested that the incidence of microscopic disease in the thyroid is greater the more diligently it is looked for. Shimaoka and coworkersl'" studied the occurrence of thyroid metastases for a given primary neoplasm. In their autopsy study of patients who died of metastatic cancer, they found that metastases to the thyroid occurred in 39% of melanoma patients, 21% of breast cancer patients, 12% of
FIGURE 19-9. Algorithm outlining the approach to a thyroid nodule in the face of a history of primary cancer. FNA = fine-needle aspiration.
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - - 177
present years after the treatment of the primary cancer and for breast and renal carcinomas. 164.166.167.170.171
Summary Unusual thyroid neoplasms, intermediate variants, primary lymphomas, and metastases to the thyroid gland make up a rare group of tumors. Although they are uncommon, it is important for the endocrine surgeon and endocrine oncologist to be able to recognize and differentiate them from the more common thyroid neoplasms. These tumors, on the whole, tend to behave more aggressively and, in most cases, the use of multimodality therapy is recommended.
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Recurrent Thyroid Cancer Erol Diiren, MD • Mete Diiren, MD
The clinical course of patients with thyroid cancer is unpredictable. Numerous studies, however,have documented that patients can be classified into groups at low or high risk for recurrence or death on the basis of age, gender, tumor size, histology, and extent of local invasion as well as the presence or absence of distant metastases. 1 Resectability and extent of resection, with the adjuvant use of iodine 131 and thyroid-stimulating hormone (TSH) suppression therapy, also influence outcome. The various scoring systems such as AGES (age, grade, extent, and size), AMES (ages, metastases, extent, and size), and TNM (tumor, node, metastasis) attempt to identify prognostic factors of tumor behavior for recurrence and survival.I Goiter, or thyroid nodules, occur in 4% to 6% of women and in 2% of men in North America; clinical thyroid cancer, however, occurs only in about 40 persons per million.' A selective approach, therefore, must be used to determine who will benefit from thyroidectomy and who can be safely observed or treated with thyroid hormone. If this selection process is not judicious, there will be delays in diagnosis and an adverse outcome. Earlier diagnosis of thyroid cancer, in the much larger number of patients with goiter, has a considerable impact on both the recurrence and the survival rate of patients with thyroid cancer. Recurrent thyroid cancer after treatment may be local, regional, or distant. Local recurrence is related both to the invasiveness of the cancer at presentation and to the surgical procedure used for the eradication of the malignant tissue. Extracapsular invasion and multicentricity of the tumor are determinant factors that also need to be considered. Unfortunately, these factors usually cannot be ascertained preoperatively to determine the extent of the resection. In high-risk patients, recurrence is common (-30%), and treatment of recurrence is less successful.v' Because one cannot precisely predict tumor behavior, we favor total thyroidectomy for most patients with thyroid cancer when this operation can be safely performed. Just as the expression "no acid, no ulcer" is generally accepted in patients with peptic ulcer disease, the notion that "no tissue left, no local recurrence" may also be valid. In patients with clinical thyroid cancer, local recurrence may occur in the residual thyroid tissue, in the thyroid bed, or in the immediately adjacent area, excluding lymph nodes. An insufficient thyroidectomy, failure to remove all the thyroid, and the cancer may be
responsible for some recurrences; microscopic extension into the adjacent tissue accounts for the remainder. The results of thyroidectomy are well documented in the study of 963 papillary thyroid cancer patients at the Mayo Clinic by Grant and associates.' The risk of cancer death with a local recurrence located outside the thyroid remnant was much greater than with a remnant recurrence alone. Practically, however, the exact type of this kind of recurrence, whether in residual tissue or in thyroid bed and adjacent tissues, is often difficult to determine when the recurrent tumor has reached appreciable size. Of concern also is that even patients judged to be at low risk have about a 15% recurrence rate, and at least 33% of these patients die from their thyroid cancer. 1,3
Efforts to Prevent Recurrence Preoperative Recognition of the Malignancy Efforts to prevent local recurrence should start with the preoperative, or at least perioperative, recognition of the malignancy. Once it is revealed, a total or near-total thyroidectomy is the procedure of choice. It is common practice for our surgical group to perform a meticulous, complete lobectomy on the tumor side, and, while preparing the other lobe, confirm the diagnosis histologically by frozen section examination, if it is not already known to be a cancer by fine-needle aspiration (FNA) biopsy cytology. The contralateral lobe is then removed unless there is concern about the viability of the parathyroid glands. In the latter patients, a small amount ('"1 em) of thyroid tissue may be left to protect the contralateral upper parathyroid gland or recurrent laryngeal nerve at the level of the cricoid cartilage at the posteromedial limit of the thyroid. For patients who have thyroid cancer diagnosed by FNA, we remove the entire thyroid gland as one piece because we do not wish to violate the thyroid capsule. Extra care must be taken when performing a total thyroidectomy, because permanent hypoparathyroidism and recurrent laryngeal nerve injuries are serious complications. 3,6 Thyroid cancers should also not be fractured during the thyroidectomy because of possible implantation in the thyroid bed.
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182 - - Thyroid Gland Total thyroidectomy is usually not necessary for patients with occult papillary thyroid cancer or minimally invasive follicular thyroid cancer (capsular invasion only). Reoperation for minimally invasive follicular cancer or occult papillary carcinomas is also usually unnecessary.' The prognosis in such patients is usually excellent. The outcome of such patients, when compared with similar patients with papillary thyroid cancer who underwent total thyroidectomy during the same period, was similar, suggesting that reoperation is usually not necessary for patients with occult or minimally invasive tumors who have undergone lobectomy. This compromise is mainly due to the increasing morbidity of reintervention and because the prognosis is good without reoperation. Reoperative thyroidectomy is often associated with increased complications, including recurrent laryngeal nerve injury and hypoparathyroidism. Bearhs" reported that vocal cord paralysis occurred in 12.1% and hypoparathyroidism in 11.2% of the patients having thyroid reoperations for malignant disease. A low incidence of vocal cord paralysis (2%) and permanent hypoparathyroidism (4%) at reoperation has been reported by Reeve," Levin,'? Attie, 1I and their colleagues. Reeve and coworkers' experience with 408 secondary thyroidectomies during a 20-year period appears to be associated with an improved outcome." Levin and associates'? reported that there should be no higher complication rate if patients were initially treated by a thyroid lobectomy, because the remaining parathyroid glands and recurrent nerve are in unviolated territory. Nevertheless, preoperative or intraoperative recognition of the malignancy is important in limiting the number of patients requiring reoperation, and the easiest time to perform a total thyroidectomy is at the initial operation.
Total Thyroidectomy Despite possible increased risks of complications, we recommend a completion total thyroidectomy in most patients with thyroid cancer when a significant amount of normal or neoplastic thyroid tissue remains. Most papillary thyroid cancers are multifocal. Even though multifocality has only a minor detrimental effect on outcome, the likelihood of malignancy in the contralateral thyroid lobe is great." Clark reviewed his personal experience with 82 consecutive patients who underwent total thyroidectomy.P Evaluation of the resected thyroid showed that if less than a total, or "near-total," thyroidectomy were performed, 31 (61%) of the 51 patients with thyroid cancer would have had malignancy remaining in the contralateral thyroid lobe.'? Despite this observation, in most patients residual microscopic thyroid cancer in the remaining thyroid lobe does not recur. Tollefsen and colleagues 13 examined the thyroid glands of the patients who had been treated by total thyroidectomy despite clinical involvement of one lobe and found that 5 of the 17 patients (29%) had occult thyroid carcinoma in the other lobe. Despite this observation, only 4.6% of the patients who initially underwent one-sided total lobectomy proceeded to develop clinical recurrence in the opposite lobe within 15 years. This striking difference between the local recurrence rate in the opposite lobe in the group of patients undergoing lobectomy (4.6%) and the six times higher frequency of minute cancer found in the contralateral lobe
of total thyroidectomized patients has been reported by other groups.I? Obviously, most occult thyroid cancers do not grow, but no one as yet has been able to predict the course of a particular patient with residual disease. Similar observations have also been made in patients with metastatic cervical lymph nodes. Ozaki and coworkers!" studied the extent of regional lymph node involvement in 586 patients. Among the 78 patients judged as stage NO during the operation, histologic examination of the prophylactically removed lymphatic tissue revealed micrometastases in 34 cases (43.6%). Noguchi and associates'S reported that more than 80% of patients with papillary thyroid cancer who underwent prophylactic neck dissections had occult nodal metastases. Despite this observation, clinically evident nodal metastases develop in only about 8% of similar patients who do not have prophylactic neck dissections.' It also appears that papillary thyroid cancer in lymph nodes rarely metastasize to distant sites. Follicular thyroid cancers account for about 10% of thyroid cancers, are somewhat more aggressive than papillary thyroid cancers, and usually metastasize by the hematogenous route rather than the lymphogenous route." Simpson and colleagues'? analyzed 1074 patients with papillary cancer and 504 with follicular cancer treated in Canada. They demonstrated that, from a recurrence point of view, prognostic factors of papillary and follicular cancers differed. They recommended total thyroidectomy for patients with follicular thyroid cancer to facilitate postoperative uptake of radioactive iodine by possible subclinical metastases. It is also important to emphasize, however that microscopic distant pulmonary metastases in patients with papillary thyroid cancer can also be ablated with radioiodine." For this reason, we recommend total thyroidectomy and postoperative l3 l I scanning and ablative therapy for patients with papillary thyroid cancers larger than 1.5 em in diameter or extending through the thyroid capsule and in high-risk patients with thyroid cancer of follicular cell origin. Tisell and coworkers'? reported that, in 32 patients with medullary thyroid carcinoma (MTC) who had elevated stimulated plasma calcitonin (CT) levels after thyroidectomy, completion total thyroidectomy and meticulous nodal dissection resulted in normalization of CT levels in 28% of these patients and a decrease in CT levels by 40% or more in another 42%. For patients whose primary MTC invaded beyond the thyroid gland or into lymph nodes and for patients with markedly elevated CT levels, repeat operations are unlikely to be curative and CT levels usually remain elevated.P Van Heerden and associates'? reported satisfactory long-term results with a "wait-and-see" policy in the management of patients with persistently elevated CT levels but no patients were cured. These authors recommended reintervention only in those patients with radiologically or clinically demonstrable disease. We would agree that a wait-and-see policy is indicated when patients have had definitive surgery-that is, total thyroidectomy, bilateral central, and lateral neck dissections.
Thyroid-Stimulating Hormone Suppression Ozaki and colleagues" identified 19 patients with thyroid cancer among 743 patients with Graves' disease. These patients had markedly invasive tumors with lymph node
Recurrent Thyroid Cancer - - 183 metastases, even though the primary tumor was small. The clinical course in these patients suggested that thyroidstimulating antibodies playa part in the progression of these neoplasms and that these antibodies may promote thyroid cancer growth and invasion in a manner similar to TSH. Pellegriti-' and Belfiore-' and their coworkers made similar observations, but many other groups have not drawn this conclusion." Considerable clinical and biologic data suggest that welldifferentiated thyroid cancer cells of follicular cell origin often respond to TSH stimulation; TSH suppression with oral thyroxine (T4) has been a standard practice in the management of patients with thyroid cancer. To benefit, patients should receive enough thyroid hormone to suppress TSH secretion. Clark stated that dosage of thyroid hormone is critical to obtain adequate reduction of TSH.2.25 Mazzaferri and Young" studied the impact of medical (TSH suppression), surgical, and radioiodine treatment in 576 patients with papillary thyroid carcinoma. They documented a significantly lower recurrence rate in patients who received enough thyroid hormone to suppress TSH secretion. There was recurrence in 40% of patients who did not receive thyroid hormone but in only 13.1% of patients who received thyroid hormone. Unfortunately, some patients eventually escape from the suppressive effects of this treatment." Pujol et aF7 more recently reported a longer tumor-free period and improved survival among 141 patients whose TSH levels were suppressed less than 0.1 IlU/mL. Cady and colleagues" studied 761 patients who had operable, well-differentiated thyroid cancer. Contrary to these and most other reports, they did not find statistically significant improvement in survival among patients receiving thyroid hormone.i" These authors volunteered, however, that they did not know whether their patients were compliant in taking their thyroid medication and that their observation should not alter current recommendations for postoperative treatment with thyroid hormone to suppress serum TSH levels. Overall, it appears from clinical observations and laboratory studies that TSH suppression has a positive impact, at least on prolongation of the disease-free interval between surgery and recurrence, if not on survival rate, as mentioned earlier.3.27,29.}0 Therefore, all patients with differentiated thyroid cancer of follicular cell origin should be treated postoperatively with suppressive doses of thyroid hormone whether or not endogenous thyroid gland secretion is sufficient to prevent hypothyroidism. Patients with MTC and anaplastic thyroid cancer should receive enough thyroid hormone to keep them euthyroid, but suppressive doses are unnecessary because these tumors do not have TSH receptors.
Adjuvant Use of Iodine 131 A long follow-up period is required to determine the effectiveness of any treatment modality in patients with welldifferentiated thyroid cancer. Many, but certainly not all, clinicians reserve the adjuvant use of 131 1 after total or neartotal thyroidectomy for moderate- to high-risk patients with well-differentiated thyroid cancer (i.e., for those with invasive disease and less well-differentiated cancer, for tumors> 1.5 em, and for patients> 45 years of age)." Mazzaferri and Young" noted that the recurrence rate in patients who
were judged to be free of disease after surgical treatment was lower when the patients were treated with radioiodine and TSH suppression when compared with patients receiving only thyroid hormone (6.4% vs. 13.1%, respectively). In the subgroup of these patients with small primary tumors «1 em), the results of treatment with thyroid hormone only were similar to those after treatment with both 131 1 and TSH suppression. A few well-differentiated thyroid carcinomas have been documented to concentrate radioiodine in the presence of functional normal thyroid tissue. However, in most patients, removal or ablation of all normal thyroid tissue is necessary before 131 1 is effective in ablating metastatic disease. Normal thyroid tissue generally has a 100-fold greater avidity for radioactive iodine than does differentiated thyroid cancer.' Before scanning, TSH values should be greater than 30 mU/mL. This degree of hypothyroidism is usually reached 6 weeks after discontinuing T4 , 2 weeks after discontinuing triiodothyronine (T3) , or after treatment with two doses of recombinant TSH. We recommend waiting at least 6 weeks after thyroidectomy and treatment with T 3 to avoid the unpleasant symptoms of hypothyroidism and to allow the operative wound to recover from the operative edema and tissue ischemia that may influence the uptake of 131 1 by the tumor. T 3 treatment is then discontinued for 2 weeks, during which time the patient is given a low-iodine diet before scanning to increase the endogenous serum TSH level. A scanning dose of 131 1 or a treatment dose of 131 1 is then given. Several days prior to scanning and treatment, a blood test is obtained for thyroglobulin (Tg) and TSH and a pregnancy test for patients who could become pregnant. Since TSH is the best provocative test for increasing the Tg level in patients with residual thyroid cancer of follicular cell origin, documenting the Tg level is most important. A longer period of hypothyroidism prior to radioiodine treatment may influence the amount of radioactive iodine taken up by the tumor, but patients are uncomfortable." Recombinant human TSH is an alternative method used for scanning and avoids hypothyroidism.Y'" It is used for patients with brain metastases when hypothyroidism might stimulate tumor growth.
External Radiation Therapy External irradiation offers effective treatment for some patients with locally invasive, inoperable, or recurrent differentiated or poorly differentiated thyroid cancers, as well as for patients with undifferentiated thyroid cancer. External irradiation is used when there is no appreciable uptake of radioiodine in patients with known microscopic or macroscopic unresectable cancer after thyroidectomy. Such treatment is thus used in patients when other treatments have failed. These patients obviously have the least favorable prognosis. Tubiana" reported that in 15 patients with MTC who received postoperative prophylactic radiation therapy, the elevated CT levels decreased slowly. In many patients with MTC, serum CT levels remain elevated for years despite the absence of clinically recurrent tumor. Virtually all these patients have micrometastases, usually in the liver. Currently, most studies do not support the use of external radiation for occult disease.P One must be sure that patients with MTC
184 - -
Thyroid Gland
Measurement of Serum Thyroglobulin
FIGURE 20-1. MRl of a 65-year-old woman with anaplastic thyroid cancer that invades the surrounding tissues.
have received definitive treatment, which includes total thyroidectomy and bilateral central neck and ipsilateral (unilateral disease) or bilateral modified neck dissection. Several studies document that meticulous surgery can return serum CT levels to normal and presumably cure patients, especially when the CT values are slightly elevated.'? Anaplastic carcinomas of the thyroid are locally invasive and often metastatic (Fig. 20-1). Although some tumors can be completely resected, most cannot. Treatment therefore usually includes radiation and chemotherapy. Thyroidectomy is recommended as the initial treatment when complete resection is possible, whereas radiation and chemotherapy are recommended when it is not. Unfortunately, the long-term outlook is dismal, even in patients with respectable tumors. When resection is done first, the neck and mediastinum should be subsequently irradiated as soon as wound healing permits. Unfortunately, in patients with undifferentiated thyroid cancer, recurrence occurs commonly, even after surgery and radiation therapy. Some clinicians recommend the combined use of chemotherapy and radiation therapy first for 4 weeks, followed 2 weeks later with removal of as much as is safely possible, and then after 2 weeks completion of the course of radiation and chemotherapy." This is the mode of treatment we generally recommend.
Diagnosis of Recurrence After thyroid resection in patients with thyroid cancer some patients develop (l) local recurrence in the thyroid bed, (2) recurrence in the regional lymph nodes, usually ipsilateral, or (3) distant metastases. Tumor markers, Tg for papillary, follicular, and their Hurthle cell variations and calcitonin for MTC, are sensitive methods for detecting tumor persistence and recurrence.
Because normal and abnormal thyroid tissue are the only sources of Tg in the peripheral blood, patients who have undergone total thyroidectomy should have no circulating Tg except that produced by residual normal thyroid tissue or local or metastatic thyroid cancer. Measuring serum Tg levels is most useful and sensitive after total ablation of the thyroid gland, either surgically or after thyroidectomy and 1311 ablation. Tg is normally present in serum in low concentrations «60 ng/mL). Most (",95%) thyroid cancers of follicular cell origin are sufficiently differentiated to produce Tg. Even poorly differentiated thyroid cancers usually retain the ability to make Tg, even though the ability for these cancers to take up iodine has been lost. LoGerfo and associates'? reported that Tg levels in 46 members of a healthy control group ranged from 0 to 60 ng/mL, whereas all 10 patients with recurrent thyroid cancer had increased Tg levels of more than 90 ng/mL. Seven of 10 patients with known active metastatic disease had Tg levels higher than 450 ng/ml., whereas the other 3 patients with known residual but clinically inactive disease had moderately raised levels of 100 to 260 ng/mL. Duren." Schlurnberger.'? and their colleagues suggested that Tg levels higher than 40 to 50 ng/mL after total thyroidectomy suggest distant metastases. Tg levels are currently the most sensitive indicator of persistent or recurrent disease after total thyroidectomy, but Tg levels can also be helpful for following patients after treatment with less extensive procedures such as lobectomy, especially when preoperative Tg values are available.'? Measurement of Tg levels in patients receiving suppressive doses of T4 provides useful information about the presence of thyroid cancer but is not as sensitive as Tg levels after recombinant TSH or after thyroid hormone withdrawal, resulting in hypothyroidism." Tg levels in patients with residual thyroid cancer usually increase when serum TSH levels increase (e.g., when the patient is not receiving thyroid hormone in preparation for a radioiodine scan). Elevated antithyroglobulin antibody levels can produce inaccurate Tg levels in 8% to 22% of patients.f However, measuring messenger RNA transcripts of Tg in peripheral blood may solve this problem.f Tumor-associated glycoprotein antigen CA 50 has also been used as a marker for patients with persistent thyroid cancer." For patients with MTC, determining serum CT and carcinoembryonic antigen levels helps determine tumor persistence or recurrence.
Radioactive Iodine Scintigraphy Radioiodine can be given as soon as 6 weeks after total or near-total thyroidectomy. The delay following total or near-total thyroidectomy allows endogenous blood thyroid hormone levels to decrease and subsequently blood TSH levels to increase. Patients can receive T3 during the first 4 weeks to avoid hypothyroidism. T 3 is used rather than T4 because it has a much shorter half-life than T 4 (T 3 half-life '" 1 day vs. T4 haf-life '" 7 days). As previously mentioned, all thyroid hormone is then discontinued for 2 weeks and a lowiodine diet is given before scanning and or ablation. Also, as previously mentioned, thyroid cancer rarely concentrates enough 1311 to be seen in the presence of remaining normal
Recurrent Thyroid Cancer - -
thyroid tissue. Therefore, when the thyroid operation is less than near- total thyroidectomy, postoperative scanning with 131 1 identifies only the remnant normal thyroid tissue. This tissue can be ablated with about 30 mCi of 1311, but completion thyroidectomy is generally recommended. A repeat scan can be done again after at least 6 months to document possible metastatic disease. Such treatment wastes 1311, which might subsequently be necessary to ablate residual cancer. 1311 whole-body scanning is more sensitive than radiography or computed tomography scanning for detecting pulmonary or osseous metastases. However, some poorly differentiated thyroid cancers may produce Tg but not take up 1311. This is especially true in patients with poorly differentiated tumors. In such patients, Tg levels may be high (>60 ng/mL), but there is no uptake of 1311. 45 Serum Tg determination and radioiodine scanning should be considered to be complementary.tv" Kodama and coworkers" used immunohistochemical staining for T 4, T 3, and Tg. Tumors that were positive for T 4, T 3, and Tg were most likely to "take up" radioiodine. In the absence of T4 and T 3 staining, however, no prediction could be made. We recommend scanning after total thyroidectomy in hypothyroid patients and a follow-up scan 1 year after 1311 ablation in patients who had evidence of radioiodine uptake outside the thyroid bed. Subsequent scanning is probably unnecessary in low-risk patients, unless they experience clinical abnormalities or an increase in serum Tg level or, as mentioned, unless the previous radioiodine scan was positive. Ablative therapy with 1311 should rarely be used more frequently than at 6-month intervals, and for most patients at I-year intervals, because leukemia is reported to be more likely with shorter periods. Thallium 201 scintigraphy, computed tomography, magnetic resonance imaging (MRI), and positron emission tomography (PET) are also used for the detection of recurrent or metastatic thyroid carcinoma." Ohnishi and associates'? compared MRI with thallium 201 scintigraphy in the followup of 39 patients who had undergone thyroidectomy and modified radical neck dissection for differentiated thyroid carcinoma. Among 51 tumor sites, 39 sites of recurrence were detected by MRI and 24 were detected by thallium 201 scintigraphy. According to the results obtained, MRI was more sensitive than thallium 201 scintigraphy for the detection of recurrent tumors (especially for small metastatic nodes). In Japan, most surgeons treat patients with papillary thyroid cancer with lobectomy and ipsilateral neck dissection so that postoperative radioiodine scanning is usually not useful. We recommend computed tomography (without contrast material) or MRI scanning, and sometimes sestamibi or thallium scanning, for patients who are at high risk for recurrence and have residual thyroid tissue or who have no uptake on radioiodine scanning and for patients who have elevated serum Tg levels and negative radioiodine scans.
Incidence of Various Kinds of Recurrence and Management Despite the satisfying results of treatment modalities and favorable clinical course of most patients with differentiated
185
thyroid carcinomas, approximately one third of the patients who develop recurrent thyroid cancer, including low-risk patients, eventually die from the disease.v'? Among 74 patients with recurrent differentiated thyroid cancer studied retrospectively by Coburn and colleagues.l" 53% of recurrences were regional, 28% were local, 13% were in the form of distant metastases, and 6% were combined locoregional metastases. This anatomic distribution is consistent with other investigations.v-? The site of recurrence appears to influence the prognosis. Thus, Rossi and coworkers" reported that treatment was successful in 73% of patients with nodal recurrence but in only 53% of patients with local recurrence and 25% of patients with distant metastases. Coburn and associates'? reported similar findings. All of their patients with recurrent disease and distant metastases died, regardless of treatment. Kukkonen and colleagues-' reported that 11 of 20 patients (55%) with recurrent papillary thyroid cancer in the neck died and 8 of 11 patients (73%) with distant metastases died. However, other studies reported long-term survival in patients with recurrent metastatic well-differentiated thyroid cancer, especially when the metastatic foci concentrated 1311. 6,54 Different survival rates have also been reported in patients whose recurrence was detected scintigraphically versus those diagnosed clinically. The mortality or persistence of the recurrence after treatment was significantly higher in clinically diagnosed cases in contrast with scintigraphically detected cases." Obviously, when larger tumors are present, they are more difficult to remove and probably are more likely to have metastasized. Also, tumors that take up radioiodine are better differentiated and, therefore, are more likely to be less aggressive; most of these patients can be successfully treated with radioiodine. The site and predisposition for recurrence vary in different types of thyroid cancer. For example, of 168 of our patients with differentiated thyroid cancer, 8 patients with papillary cancer and 3 with follicular thyroid cancer experienced recurrent cancer in the neck. In contrast, only 2 patients with papillary cancer and 5 patients with follicular cancer experienced distant metastases." Wu and coworkers'" also reported that patients with papillary thyroid cancer are more likely to die of recurrent central neck disease and those with follicular cancer from distant metastases. Patients who develop recurrent cancer in lateral cervical lymph nodes are easier to treat successfully than those who develop recurrent cancer in the central neck, because the operative field is in unviolated tissues. Reoperative central dissections are often tedious and place the parathyroid glands and recurrent laryngeal nerve at risk." Lung metastases from differentiated thyroid cancers have been shown to accumulate more radioactive iodine than bone metastases, so that patients with lung metastases respond better to radioiodine therapy than those with bone metastases. This is especially true for micrometastases in the lung. For patients with isolated (Fig. 20-2) or only several bone metastases, surgical resection followed by radioiodine treatment is recommended. If no uptake of 1311 occurs, external radiation therapy usually relieves pain, decreases the risk of fracture, and is occasionally curative.V-? Schlumberger and associates.V as mentioned, also documented that 1311 is more effective for treatment of pulmonary micrometastases than for palliation of macronodules.
186 - - Thyroid Gland micrometastases can frequently be ablated after total thyroidectomy with postoperative 1311 therapy, especially in young patients. Resection of recurrent disease is most successful for nodal metastases, but cure and long-term palliation can also be obtained by resection of central neck recurrence as well as isolated distant metastases followed by 1311 ablation. Palliative resection is also indicated to avoid progression of central neck and mediastinal disease. In patients who have no 1311uptake in their tumors and who are Tg negative, a redifferentiation trial with retinoids has been proposed as a treatment option by Simon and colleagues, but overall the effects have unfortunately not proven to be very helpful.60
Summary
FIGURE 20-2. Radiograph of the right femur of a 60-year-old woman with follicular cancer metastasis.
This finding supports the concept of detecting and treating recurrent or persistent thyroid cancers before they become clinicallyevident. Such tumors can only be detected in patients who have been treated by total thyroidectomy and receive radioiodine scans. Recurrent cancer in regional lymph nodes is best detected by ultrasound examination and treated by modified radical neck dissection. Local recurrence in the central neck should be treated surgically and with postoperative 1311 ablation and TSH suppression therapy. External radiation treatment is helpful when tumors cannot be completely removed. As mentioned, however, local recurrence carries a poorer prognosis compared with regional lymph node metastases. Reoperations in the form of total thyroidectomy for patients who have already had bilateral procedures or debulking of the tumor masses are also associated with a higher morbidity rate and subsequent recurrent disease. For this reason, it is essential to perform a meticulous, complete hemithyroidectomy for all unilateral nodules that might be cancerous, with removal of any possible involved nodes in the central neck. Close follow-up for recurrent disease is also indicated because it is easier to cure patients and resect small rather than large metastases. Thus, initial treatment with total or near-total thyroidectomy, radioiodine scanning, and postoperative ablation with 131 1 and TSH suppressive treatment appear to decrease the incidence of recurrent thyroid cancer. 18,54 Distant
Despite the favorable clinical course of most patients with differentiated thyroid carcinoma, nearly one third of the patients who experience recurrent thyroid cancer eventually die from this disease. Therefore, every effort should be made to prevent recurrence, including (1) early diagnosis and treatment of the disease; (2) complete removal of the tumor at the initial operation; (3) total thyroidectomy, ipsilateral central neck dissection, and ipsilateral therapeutic modified radical neck dissection when indicated and when this can be done safely; (4) adjuvant use of 1311 therapy, particularly in high-risk patients postoperatively; (5) TSH suppression therapy; and (6) selective use of external radiation therapy in patients with unresectable cancer. For patients with MTC, bilateral central and lateral neck dissection are necessary. Blood Tg and calcitonin level determinations are sensitive techniques for detecting recurrent or persistent subclinical disease in patients with tumors of follicular and parafollicular cell origin, respectively. 1311 scintigraphy, ultrasonography, computed tomography, MRI, and PET are helpful, as are regular and long-term follow-up physical examinations. Early diagnosis and treatment of recurrent or persistent disease appear to improve survival; recurrence with definitive surgery or other surgery improves survival.
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bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102:1088. Clark OH. Thyroid nodules and thyroid cancer. In: Clark, OH (ed), Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985, P 56. Cady B. Surgery of thyroid cancer. World J Surg 1981;5:3. Harness JK, McLeod MK, Thompson NW. et aJ. Deaths due to differentiated thyroid cancer: A 46-year perspective. World J Surg 1988;12:623. Grant CS, Hay !D, Gough IR, et aJ. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988;104:954. Rossi RL, Cady B. Silverman ML, et aJ. Current results of conservative surgery for differentiated thyroid carcinoma. World J Surg 1986; 10:612. Sugino K, Ita K, Mimura T, et aJ. The enucleation of thyroid tumors indeterminate before surgery as a papillary thyroid carcinoma: Should immediate reoperation be performed? Jpn J Surg 1994;24:305. Beahrs OH. Surgical treatment for thyroid cancer. Br J Surg 1984; 71:976.
Recurrent Thyroid Cancer - - 187 9. Reeve TS, Delbridge L, Brady P, et al. Secondary thyroidectomy: A twenty-year experience. World J Surg 1988;12:449. 10. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;III :604. II. Attie IN, Moskowitz GW, Margouleff D, et al. Feasibility of total thyroidectomy in the treatment of thyroid cancer. Am J Surg 1979;38:555. 12. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361. 13. Tollefsen HR, Shah JP, Huvos AG. Papillary carcinoma of the thyroid: Recurrence in the thyroid gland after initial surgical treatment. Am J Surg 1972;124:468. 14. Ozaki 0, Ito K, Kobayashi K, et al. Modified neck dissection for patients with nonadvanced, differentiated carcinoma of the thyroid. World J Surg 1988;12:825. 15. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid: Developing pattern of metastases. Cancer 1970;26: 1053. 16. Donohue JH, Goldfein SD, Miller TR, et al. Do the prognoses of papillary and follicular thyroid carcinomas differ? Am J Surg 1984;148:168. 17. Simpson WJ, McKinney SE, Carruthers JS, et al. Papillary and follicular thyroid cancer: Prognostic factors in 1578 patients. Am J Med 1987;83:479. 18. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: A IO-year follow-up report of the impact of therapy in 576 patients. Am J Med 1981;70:511. 19. Tisell LE, Moley JF, Wells SA, et al. Reoperation for recurrent or persistent medullary thyroid cancer. Surgery 1993;114:1090. 20. Van Heerden JA, Grant CS, Gharib H, et al. Long-term course of patients with persistent hypercaicitoninemia after apparent curative primary surgery for medullary thyroid cancer. Ann Surg 1990;212:395. 21. Ozaki 0, Ito K, Kobayashi K, et al. Thyroid carcinoma in Graves' disease. World J Surg 1990;14:437. 22. Pellegriti G, Belfiore A, Giuffrida D, et al. Outcome of differentiated thyroid cancer in Graves' patients. J Clin Endocrinol Metab 1998; 83:2805. 23. Belfiore A, Russo D, Vigneri R, et al. Graves' disease, thyroid nodules and thyroid cancer. Clin Endocrinol (Oxf) 2001;55:711. 24. Burman KD, Baker JR Jr. Immune mechanisms in Graves' disease. Endocr Rev 1985;6:183. 25. Clark OH. TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 1981;5:39. 26. Block MA. Management of the carcinoma of the thyroid. Ann Surg 1977;185:133. 27. Pujol P, Daures JP, Nskala N, et al. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 1996;81:4318. 28. Cady B, Cohn K, Rossi RL, et al. The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma. Surgery 1983;94:978. 29. Crile G Jr. Changing end results in patients with papillary carcinoma of the thyroid. Surg Gynecol Obstet 1971;132:460. 30. DeGroot MJ, Stanbury lB. The Thyroid and Its Diseases, 4th ed. New York, John Wiley, 1975, p 666. 31. Hamburger Jl, Serum TSH levels in therapy of thyroid carcinoma. J Nucl Med 1980;21:492. 32. Haber RS. Recombinant human TSH testing for recurrent thyroid cancer: A re-appraisal. Thyroid 2002; 12:599. 33. Ladenson PW. Recombinant thyrotropin for detection of recurrent thyroid cancer. Trans Am Clin Climatol Assoc 2002;113:21. 34. Tubiana M. External radiotherapy and radioiodine in the treatment of thyroid cancer. World J Surg 1981;5:75. 35. Sizemore GW, van Heerden JA, Carney JA. Medullary carcinoma of the thyroid gland and the multiple endocrine neoplasia type 2 syndrome. In: Kaplan EL (ed), Surgery of the Thyroid and Parathyroid Glands. Edinburgh, Churchill Livingstone, 1983, p 75. 36. Kim JH, Leeper RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987;60:2372. 37. LoGerfo P, Stillman T, Colacchio D, et al. Serum thyroglobulin and recurrent thyroid cancer. Lancet 1977;23:881.
38. Duren M, Siperstein A, Shen W, et al. Value of stimulated thyroglobulin levels for detecting persistent or recurrent differentiated thyroid cancer in high- and low-risk patients. Surgery 1999;126:13. 39. Schlumberger M, Charbord P, Fragu P, et al. Circulating thyroglobulin and thyroid hormones in patient with metastases of differentiated thyroid carcinoma: Relationship to serum thyrotropin levels. J Clin Endocrinol Metab 1980;51:513. 40. Harvey RD, Matheson NA, Grabowski PS, et al. Measurement of serum thyroglobulin is of value in detecting tumor recurrence following treatment of differentiated carcinoma by lobectomy. Br J Surg 1990;77:324. 41. Black EG, Gimlette TMD, Maisey MN, et al. Serum thyroglobulin in thyroid cancer. Lancet 1981;2:443. 42. Sisson Je. Thyroid. In: Early PJ, Sodee DB (eds), Principles and Practice of Nuclear Medicine, 2nd ed. St. Louis, Mosby-Year Book, 1995, p 617. 43. Biscolla RP, Cerutti JM, Maciel RM. Detection of recurrent thyroid cancer by sensitive nested reverse transcription-polymerase chain reaction of thyroglobulin and sodium/iodide symporter messenger ribonucleic acid transcripts in peripheral blood. J Clin Endocrinol Metab. 2000;85:3623. 44. Skrzypek J, Jarzab B, Podwinski A. Tumor-associated glycoprotein antigens in thyroid cancer. Br J Surg 1994;81(Suppl):46. 45. Clark OH, Hoelting T. Management of patients with differentiated thyroid cancer who have positive serum thyroglobulin levels and negative radioiodine scans. Thyroid 1994;4:50 I. 46. Robbins J. Thyroid cancer. In: van Middleswort L (ed), The Thyroid Gland. Chicago, Year Book, 1986, p 405. 47. Kodama T, Fujimoto Y, Obara T, et al. Histochemical demonstration of thyroxine, triiodothyronine, and thyroglobulin in the primary lesion of thyroid carcinoma, and its predictability for radioiodine uptake by metastatic lesions. World J Surg 1988;12:439. 48. Lips P, Comans EF, Hoekstra OS, et al. Positron emission tomography for the detection of metastases of differentiated thyroid carcinoma. Neth J Med 2000;57: 150. 49. Ohnishi T, Noguchi S, Murakami N, et al. Detection of recurrent thyroid cancer: MR versus thallium-201 scintigraphy. Am J Neuroradiol 1993; 14:1051. 50. Coburn M, Teates D, Wanebo HJ. Recurrent thyroid cancer: Role of surgery versus radioactive iodine (1-131). Ann Surg 1994;219:587. 51. Davies C. Surgery of thyroid cancer. In: Lynn J, Bloom SR (eds), Surgical Endocrinology. Oxford, England, Butterworth/Heinemann, 1993, p 254. 52. Young RL, Mazzaferri EL, Rahe AJ, et al. Pure follicular thyroid carcinoma: Impact of therapy in 214 patients. J Nucl Med 1980;21:733. 53. Kukkonen ST, Reijo KH, Kaarle OF, et al. Papillary thyroid carcinoma: The new, age-related TNM classification system in a retrospective analysis of 199 patients. World J Surg 1990;14:837. 54. Grant MD, Hay MB, Gough IR, et al. Local recurrence in papillary thyroid carcinoma: Is extent of surgical resection important? Surgery 1988;104:954. 55. Diiren M, Ertem M, Biikey Y, et al. [Thyroid carcinoma: An analysis of a personal series.] Ulusal Cerrahi Dergisi 1996;12:43. 56. Wu HS, Young MT, Ituarte PH, et al. Death from thyroid cancer of follicular cell origin. J Am Coli Surg 2000; 191:600. 57. Hamming JF, van de Velde CJH, Fleuren GJ, et al. Differentiated thyroid cancer: A stage-adapted approach to the treatment of regional lymph node metastases. In: Hamming JF (ed), Differentiated Thyroid Cancer: Current Considerations on Diagnosis and Surgical Treatment. Leiden, Netherlands, Drukkerij Groen BV, 1988, P 65. 58. Schlumberger M, Tubiana M, de Vathaire F, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960. 59. Marocci C, Pacini F, Elisei R, et al. Clinical and biological behaviour of bone metastases from differentiated thyroid carcinoma. Surgery 1989;106:960. 60. Simon D, Koehrle J, Reiners C, et al. Redifferentiation therapy with retinoids: Therapeutic option for advanced follicular and papillary thyroid carcinoma. World J Surg 1998;22:569.
Thyroidectomy Sten Lennquist, MD, PhD
The Accurately Performed Thyroidectomy: A Challenge with a Bad Response Thyroid surgery has been and always will be the most common endocrine surgical operation. Some subspecialists in endocrine surgery are performing only thyroid and parathyroid operations. Even in specialized centers in which the rarer endocrine tumors (adrenal and gastrointestinal) constitute an appreciable part of the workload, thyroid gland operations are still the most common procedures. An accurately performed operation on the thyroid gland requires both experience and technical ability. In my experience, including more than 20 years of highly specialized endocrine surgery in a large university hospital, a good thyroid operation presents a greater challenge and requires more technical precision and skill than an adrenalectomy or removal of any gastrointestinal endocrine tumor. Many other experienced endocrine surgeons are of the same opinion. The thyroid operation is considered by many to be at the zenith of endocrine surgery; the surgeon who can perform a good thyroidectomy can, with little additional training, handle most of the other operations within this field, because the technique required is much the same. With this background it is astonishing that relatively little effort is put into teaching the art of thyroid surgery. The main reason for this may be that it is more glamorous to teach and talk about rare endocrine tumors (that most general surgeons will never see) than to teach "everyday routine work." Teaching about proper surgical technique is essential if we, as surgeons, are to avoid complications. When thyroid operations are performed without sufficient interest, training, or experience, the incidence of preventable complications increases. In many reported series, the incidence of complications is high: figures such as 5% for persistent recurrent laryngeal nerve injuries after operations for benign thyroid lesions have been reported, I whereas it has been documented repeatedly that the incidence of such complications can be close to 0% or at least less than 1%.2-5 Figures for
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persistent hypoparathyroidism of 20% or more after bilateral operations have been reported," whereas it has also been shown that with careful technique this figure should be less than 1%.2-5,7 Of concern is that the figures in unreported series are even higher," Both hypoparathyroidism and recurrent laryngeal nerve injury cause disability and suffering for patients. One of the greatest responsibilities for endocrine surgeons today is to make these poor results a thing of the past by designing appropriate training programs that establish uniform protocols for accurate reporting of results and uniform guidelines and standards for performing these operations.
General Principles The following principles apply to all thyroid operations: 1. Good exposure of the thyroid gland is essential for good results. 2. No operation should be performed on the thyroid gland without proper identification of the anatomic structures. 3. Bleeding can and should be kept to a minimum. 4. Diathermy (even bipolar) should be avoided in the area around the laryngeal nerves.
Optimal Access As in all operations, optimal access to the entire operative field is one of the keys to success. It is a misconception, however, that good exposure means a long incision. Good exposure can be achieved by a number of simple procedures, which are described later. Time and effort spent learning these techniques are repaid many times during the operation.
Identification of the Anatomic Structures Another misconception is that operations in this area could or even should be done without proper identification of the anatomic structures. It is hoped that this way of operating
Thyroidectomy - - 189 has been abandoned today. As late as 1976, however, published recommendations could be found that advocated that "the dissection at no time should be directed at identification and uncovering of the recurrent laryngeal nerve," I and identification of the parathyroid glands was described as "an erroneous guesswork implying a risk of inducing hypoparathyroidism."} It is still possible to find surgeons who continue to follow these principles; this is difficult to understand because the general principle in surgery is that it is "always better to see what you are doing." It is generally considered to be impossible to perform a safe, complete lobectomy without identification of the anatomic structures. The argument that time is saved by not identifying the anatomic structures is also based on a false premise: a surgeon who can see what he or she is doing operates not only more safely but also faster than a surgeon who does not know precisely where the parathyroid glands or recurrent nerves are positioned."
Minimal Bleeding My recommendation is that suction should not be used routinely during thyroid surgery. First, the surgeon who does not use suction dissects gently and precisely, with meticulous ligation of vessels. Second, frequent suctioning may injure the parathyroid glands and the nerves.
Restricted Use of Diathermy The true state of the art of thyroid surgery can best be judged by the way in which the recurrent laryngeal nerves are handled. This is where the truly skilled thyroid surgeon can be separated from the others. The process of meticulous dissection and ligation of the vessels in Berry's ligament requires absolute precision. It is a good technical exercise for the whole field of endocrine surgery and should be done properly. This is the only safe way to avoid injuries to the recurrent laryngeal nerve.
description of the additional maneuvers needed for a resection or total thyroidectomy.
Access to the Gland Dressing of the operation field, lines of incision, and the technique of freeing and mobilizing the thyroid gland are shown in Figures 21-1, 21-2, and 21-3. After these first steps, it is a matter of personal preference whether to start the free dissection of the lobe by the lateral (starting at the recurrent laryngeal nerve and inferior thyroid artery) or the cranial (starting with the superior thyroid artery) approach. Both are used by experienced thyroid surgeons, but I prefer to start with the lateral approach, which I also use when teaching. This approach provides good mobilization of the thyroid lobe at an early stage of the operation and, therefore, facilitates dissection of the superior pole vessels. It also provides better exposure of the external branch of the superior laryngeal nerve. When the goiter or tumor is large, however, it can be difficult to identify the inferior thyroid artery and recurrent laryngeal nerve without first mobilizing and dividing the superior pole vessels, so in these cases I start superiorly.
The Recurrent Laryngeal Nerve and the Inferior Thyroid Artery The best way to identify the recurrent laryngeal nerve is to stand on the opposite side of the patient, with the patient rotated toward you, and apply firm traction to the thyroid lobe, pulling it upward and toward the midline, putting the tissues lateral to the thyroid under tension. This traction is best applied with a gauze sponge held in the surgeon's hand. Passing grasping instruments or sutures through the thyroid
Resection or Complete Lobectomy? A complete thyroid lobectomy and isthmectomy should be performed for all unilateral nodules, for several reasons. First, if additional surgery is required, the field of a previous operation should be avoided because it makes reoperation more difficult and considerably increases the risk of complications. This can easily happen because neither fine-needle aspiration cytology nor frozen section will always give the correct histopathologic diagnosis. Second, if one accepts the concept that operations on the thyroid gland should be performed only with proper identification of the anatomic structures, complete hemithyroidectomy is no more difficult than resection and may be even simpler and more straightforward." In fact, it can be accomplished with less bleeding and more precision. In most training programs in endocrine surgery, the first step should be to learn how to perform a complete lobectomy followed at a later stage by a resection. The technique of hemithyroidectomy is described in the following text in detail, step by step, followed by a short
FIGURE 21-1. The incision is made two fingerbreadths above the clavicles and 3 to 3.5 cm on each side of the midline, which is
sufficient for full access to the thyroidgland. If there are metastatic lymph nodes in the lateral compartment of the neck, the line of incision should be somewhat extended, but vertical incisions should be avoided. (From LennquistS. Surgical strategyin thyroid carcinoma. Acta Chir Scand 1986; 152:321.)
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A
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c
B
FIGURE 21-2. A, The subcutaneous fat and platysma muscle are divided in the line of incision and dissected free from the underlying investing fascia of the neck and the anterior jugular veins. To facilitate the later dissection in the midline, it is important that the free dissection of the platysma is extended in a cephalad direction to well above the thyroid cartilage (B) and in a caudal direction to the substernal notch (C). (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand 1986;152:321.)
gland is less effective and may cause bleeding from the thyroid capsule or possible spreading of malignant cells. During this traction, the fascia between the thyroid gland and the common carotid artery can be opened by a combination of sharp and gentle blunt dissection with a hemostatic forceps, starting laterally. The dissection should always be parallel, rather than perpendicular, to the anticipated course of the nerve. The neurovascular intersection (where the inferior thyroid artery crosses the recurrent laryngeal nerve) should be identified (Fig. 21-4), and a loop placed around the trunk of the inferior thyroid artery. Slight tension applied to this loop facilitates further gentle dissection around the recurrent laryngeal nerve. This loop should be removed when the dissection has been completed. The inferior thyroid artery should be ligated not truncally but peripherally on the
A
capsule of the thyroid gland to preserve the vascular supply to the parathyroid glands (see Fig. 21-4).
The Superior Laryngeal Nerve and the Superior Thyroid Artery As mentioned, the dissection around the superior thyroid artery is made considerably easier by the procedure just described: incision of the fascia in the midline as far as the sternal border and previous lateral mobilization of the thyroid lobe. After these procedures are completed, one can place a finger behind the superior pole and rotate it upward. Transverse division of the muscles is rarely necessary. The most critical structure to keep in mind when dividing the vessels of the superior pole is the external branch of the
B
FIGURE 21-3. A, After division of the investing fascia in the midline, the fascia covering the thyroid gland is carefully incised so that the surface of the gland is clearly seen. It is most important to obtain the correct plane of cleavage. The thyroid lobe in most cases can easily be mobilized and rotated medially and upward with a sweeping finger movement. B, During this mobilization, care must be taken not to tear the medial thyroid vein, which is ligated and divided. (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand 1986;152:321.)
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FIGURE 21-4. The first step after mobilization of the thyroid lobe is to identify the recurrent laryngeal nerve (1) and the inferior thyroid artery. As soon as the nerve is identified, a thread is pulled around the trunk of the inferior thyroid artery (2). Slight tension on this thread facilitates further dissection to free the nerve. After free dissection of the nerve, this thread should be removed and the artery ligated, not truncally but peripherally. Otherwise, the vascular supply of the parathyroid glands (3) will be compromised. (From Lennquist S. The thyroid nodule: Diagnosis and surgical treatment. Surg Clin NorthAm 1987;67:221.)
superior laryngeal nerve. This nerve branch has been referred to as the "neglected" nerve in thyroid surgery. Injuries to it may easily be overlooked because they are difficult to diagnose at laryngoscopy and because the initial symptoms are often minimal and regarded as "natural postoperative voice disturbance without injury to the recurrent laryngeal nerve." Jansson and Tisell lo performed electromyographic studies in an unselected series of patients after thyroid surgery and reported that more than 20% had persistent symptoms (e.g., voice exhaustion and impaired ability to sing) that were confirmed by electromyography as being caused by injury to the external branch of the superior laryngeal nerve. These symptoms can be especially troublesome to singers and professional speakers. Preservation of this nerve deserves proper attention. In anatomic and clinical studies of the superior laryngeal nerve, with special reference to its anatomic relations to the pharyngeal constrictor muscle, we found that in 20% of cases the distal part of the nerve was entirely covered by fibers of that muscle. I I In these cases, the nerve could not be identified without intramuscular dissection, which probably does more harm than good. On the other hand, 20% of the nerves that passed lateral to the pharyngeal constrictor muscle took a perilous course, partly lateral to the superior thyroid artery and its branches. I recommend that the tracheothyroid space always be carefully dissected and that the superior thyroid artery and its branches be skeletonized before division. When the superior laryngeal nerve is not identified during this procedure, identification by dissection into the pharyngeal constrictor muscle is not recommended. Our technique is shown in Figure 21-5. This does not take long, and it lessens the risk of injuring the external branch of the superior laryngeal nerve. In this way, many patients can be spared the unnecessary
C
FIGURE 21-5. Technique for preservation of the external branch of the superior laryngeal nerve. A, A hemostatic forceps is placed on the thyroid part of the superior thyroid artery (4). B, During traction on this forceps caudally and laterally, the cricothyroid space is opened up with another forceps so that the external branch of the superior laryngeal nerve (5) can be identified and dissected free. C, The superior pole vessels can now be ligated easily without risk of injury to the nerve. (From Lennquist S. The thyroid nodule: Diagnosis and surgical treatment. Surg Clin North Am 1987;67:222.)
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inconvenience and discomfort of vocal disturbance and loss of singing ability. When the vessels of the superior pole have been ligated and divided, the pole is mobilized, and the lobe can be retracted medially and downward and inspected in its entirety from the lateral side.
The Parathyroid Glands Even though hypoparathyroidism does not occur after unilateral thyroid operations, one should treat every parathyroid as if it were the last, because one never knows whether the patient may require a thyroid operation on the other side. This means that one should always attempt to identify both parathyroid glands on both sides. Some parathyroid glands are present in ectopic locations so that all parathyroid glands will not be identified in all patients (see Chap. 38). The lower gland, for example, is frequently situated in the thymus. Routine exploration of the thymus to find such a gland is not recommended because it might devascularize the parathyroid glands. When neither parathyroid gland can be identified during thyroid lobectomy, the thyroid capsule must be scrupulously examined to ensure that the missing gland is not removed accidentally. It has long been thought that the vascular supply of the parathyroids comes only from the inferior or superior thyroid artery, or both. This is not true. We used laser Doppler flowmetry to study the parathyroid circulation during thyroid surgery" and found that an appreciable part of the vascular supply to the parathyroid glands comes from the small vessels in the thyroid capsule, without apparent communication with the superior or inferior thyroid arteries. Using meticulous technique, most of these vessels can be preserved by dissecting them downward, even during complete removal of the thyroid gland. Truncal ligation of the inferior thyroid artery should be avoided and should be done only when technical problems arise; otherwise, it should be divided peripherally to the neucovascular intersection on the thyroid capsule (see Fig. 21-7 A). The procedure for preservation of the parathyroid glands is shown in Figure 21-6. In some patients, it is impossible to dissect the parathyroid gland free from the thyroid capsule with an adequate vascular supply. Such glands should be removed, cut into small pieces with a microsurgical knife, confirmed histologically, implanted into an adjacent muscle, and marked by a nonabsorbable suture. In the case of an aggressive tumor with the potential for recurrence, the parathyroid gland should be autotransplanted outside the operation field.
Final Dissection of the Recurrent Laryngeal Nerve As the thyroid lobe is rotated further medially, the recurrent laryngeal nerve should be systematically and carefully dissected free from the thyroid gland (Fig. 21-7A to C). There are many variations in the anatomic relationship among the recurrent laryngeal nerve, the inferior thyroid artery and its branches, and the thyroid gland. The nerve may run in front of or behind the inferior thyroid artery and its branches, and more than 30 variations have been described, sometimes differing on the two sides. In 40% to 80% of cases, the nerve
A
B FIGURE 21-6. Technique for preservation of the parathyroid gland. A, The upper parathyroid gland (3) is gently loosened from
the thyroid capsule and dissected downward, with preservation of its vascularsupply. B, The figurealso illustrates the rather common branching of the recurrent laryngeal nerve (I) immediately after the neurovascular intersection where the nerve passes the inferior thyroid artery (2). (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand 1986;152:321.)
may branch into two or more parts before it enters the larynx (see Fig. 21-6). This branching may be below the level of the thyroid, which further increases the number of possible variations. In about 1% of patients, the recurrent laryngeal nerve on the right side is nonrecurrent and runs directly from the cervical vagus to the larynx. It may also be transposed among branches of the inferior thyroid artery, resulting in its transposition to a level anterior to the wall of the trachea. Consequently, there is no "safe" level at which the surgeon can maneuver without first identifying the recurrent nerve. It is clear that the recurrent laryngeal nerve must be identified and dissected precisely (see Figs. 21-6 and Fig. 21-7). After the thyroid lobe has been separated from the tracheal wall, the isthmus is divided at the point where it enters the opposite lobe, and the remaining thyroid tissue is continuously sutured.
Thyroidectomy - - 193 Using intraoperative scintigraphy, we have shown that one of the most common areas in which there is residual uptake of iodine is the site of the pyramidal lobe. 13 This indicates that this structure is difficult to identify and remove completely. Good access to the pyramidal lobe by extension of the midline incision between the strap muscles is, therefore, important. The pretracheal fascia (anterior superior suspensory ligament) and all thyroid tissue associated with it should be excised, together with the thyroid gland.' Care should be taken to stay medial when mobilizing the pyramidal lobe and to stay caudal to the cricothyroid muscle when dividing the anterior superior suspensory ligament to avoid injury to the external branch of the superior laryngeal nerve.
A
B
Closing the Wound Using drains after thyroidectomy cannot replace good hemostasis and are of little or no use if severe postoperative bleeding occurs. To reduce or remove a small hematoma, however, a drain can sometimes be useful. If a drain is used, it should be a small silicone drain with a closed, passive evacuation system. Active suction fails to increase the evacuation capacity and may injure the recurrent laryngeal nerve. The strap muscles are reapproximated, as is the platysma, with interrupted or continuous absorbable sutures. The skin may be closed by subcuticular suture, or with the use of special broad clips removed after the first or second day, and Steri-Strips placed. Whichever technique is used, it should be done carefully; scars in this area can and should be almost invisible.
Resection of the Opposite Side The only difference between thyroid lobectomy and thyroid resection, if or when this is indicated, should be that the final separation of the thyroid lobe from the wall of the trachea is not done. Identification of the anatomic structures and the thorough mobilization of the thyroid lobe are the same.' Mobilization of the thyroid lobe by the technique just mentioned enables adjustment of the remnant to the optimal size and makes a safe resection possible, with minimal risk or complications.!':'"
C FIGURE 21-7. Technique for final free dissection of the inferior laryngeal nerve (I). A, The branches of the inferior thyroid artery (2) are individually ligated with absorbable sutures and divided;
in this way, the lobe can be successively separatedfrom the nerve. Before entering the laryngeal cartilage, the superior laryngeal nerve temporarily diverges in a ventral direction and then turns back toward its entrance. This "knee" of the nerve is one of the most critical points of the dissection. In the final separation of the thyroid lobe from the tracheal wall,the fine paratracheal vessels (6) in the ligament of Berry have to be ligated before division. At this closerangeto the nerve, diathermy shouldnotbe used. C, Afterdivision of the ligament of Berry, the thyroid gland can be separated from the tracheal wall with a sharp knife. The thyroidcapsulenow can be removed intact, and no residual tissue is left on the tracheal wall (8) or at the nerve entrance (7). 9 = carotid artery; 10 = vagal nerve; II = internal jugularvein. (FromLennquist S. Surgical strategy in thyroid carcinoma. ActaChir Scand 1986;152:321.) B,
Total Thyroidectomy Total thyroidectomy in reality is two hernithyroidectomies.P'" Because every surgeon who deals with the thyroid gland should be able to perform a safe, complete lobectomy, he or she should also be able to perform a safe complete bilateral hemithyroidectomy or total thyroidectomy.' When performing a total thyroidectomy, I recommend an en bloc procedure, which means that the hemithyroidectomy is continued on the opposite side without dividing the isthmus, and the whole thyroid is removed as one piece (together with the lymph nodes in the central compartment of the neck if there are any lymph node metastases). This technique has been described in detail elsewhere.t->!? Dissection of the lymph nodes in the lateral compartment of the neck and the management of invasive tumors are described in Chapter 22.
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Goiters or Thyroid Tumors in the Mediastinum It is possible to remove most intrathoracic goiters and thyroid tumors through a cervical incision. If it is difficult to mobilize the thyroid lobe from the mediastinum, several procedures, discussed next, may help. TRANSVERSE DMSION OF THE STRAP MUSCLES
When it is necessary to divide the sternohyoid or sternothyroid muscles, or both, this should be done in the top of the wound to avoid scar fixation and to denervate less muscle, because the ansa hypoglossal nerve innervates these muscles inferiorly. DMSION OF THE SUPERIOR THYROID ARTERY
One should divide the superior thyroid artery and veins because this makes it easier to pull the lobe upward. DMSION OF THE ISTHMUS
Division of the isthmus further facilitates the pulling of the goiter upward from the mediastinum. T INCISION
Although making an inferior T in the Kocher transverse collar incision is rarely necessary, in some patients it avoids a mediastinotomy and also increases the preparedness for a sternal split if excessive bleeding were to occur when mobilizing the substernal mass. If these procedures, done by an experienced surgeon, are insufficient to mobilize the thyroid from the mediastinum, I do not recommend dividing or morselizing the tissue to get it up, as has been advocated by others. This is not good surgery, and in these patients a median sternotomy should be done. The risks and discomforts of median sternotomy have been exaggerated. The procedure is performed daily in thousands of patients worldwide for cardiac operations and can be done with minimal morbidity. 18 Some patients have pain after sternotomy because it is not done properly. Some surgeons believe that performing a partial split is less dangerous and causes less pain. This is wrong. Partial sternotomy means breaking the sternocostal cartilage when opening the chest. This causes considerable postoperative pain. The technique for mediastinal exploration is described elsewhere."
Summary Thyroid surgery requires experience and recogrution of the anatomy, especially the parathyroid glands and recurrent, and external laryngeal nerves. The risk of complications
during thyroid operations should not exceed 1% to 2%. Complication rates higher than 5% suggest that the surgeon does not have sufficient training or interest in thyroid surgery and should improve his or her training or refer the patients elsewhere.
REFERENCES I. Perzik SL. The place of total thyroidectomy in the management of patients with thyroid disease. Am J Surg 1976;132:480. 2. Clark OH. Total thyroidectomy: The treatment of choice for patients with differential thyroid cancer. Ann Surg 1982;196:361. 3. Smeds S, Madsen M, Lennquist S, et al. Evaluation of preoperative diagnosis and surgical management of thyroid tumors Acta Chir Scand 1984;150:513. 4. Total thyroidectomy in the treatment of thyroid carcinoma. In: Thompson NW, Vinik AU (eds), Endocrine Surgery Update. New York, Grone & Stratton, 1983. 5. Thompson NW. The resection therapy of carcinoma of the thyroid. Surg Rounds 1984;100. 6. Crile G Jr. Changing trends and results in patients with papillary carcinoma of the thyroid. Surg Gynecol Obstet 1971;131:460. 7. Andaker L, Johansson K, Lennquist S, Smeds S. Surgery for hyperthyroidism: Hemithytoidectomy plus contralateral resection or bilatera resection? A prospective randomized study with regard to postoperative complications and long-term results. World J Surg 1992;16:765. 8. Scandinavian Surgical Society. Multicenter study on thyroid carcinoma. Proceedings of the Scandinavian Surgical Society, Division of Endocrine Surgery, Stockholm, 1991. 9. Lennquist S. Total Thyroidectomy with Safe Preservation of the Laryngeal Nerves and Parathyroid Glands. Chicago, American College of Surgeons Film Library, 1991. 10. Jansson S, Tisell LE. Partial superior laryngeal nerve (SLN) lesions before and after thyroid surgery. World J Surg 1988;12:526. II. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in thyroid surgery. Surgery 1987;102:999. 12. Ander S, Johansson K, Lennquist S, Smeds S. Human parathyroid blood supply determined by laser Doppler flowmetry. World J Surg 1994;18:417. 13. Lennquist S, Persliden J, Smeds S. The value of intraoperative scintigraphy as a routine procedure in thyroid carcinoma. World J Surg 1988;12:586. 14. Lennquist S, Smeds S. The hypermetabolic syndrome hyperthyroidism. Surg EndocrinoI1991;9:127. 15. Lennquist S. Surgical strategy in thyroid carcinoma: A clinical review. Acta Chir Scand 1986;152:321. 16. Lennquist S. The thyroid nodule: Diagnosis and surgical treatment. Surg Clin North Am 1987;67:213. 17. Lennquist S. The laryngeal nerves in thyroid surgery. In: van Heerden J (ed), Common Problems in Endocrine Surgery. Chicago, Year Book, 1988, p 123. 18. Lennquist S, Andaker L, Lindvall B, Smeds S. Combined cervicothoracic approach in thymectomy. Acta Chir Scand 1990;156:53.
Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer J. F. Hamming, MD, PhD. J. A. Roukema, MD, PhD
The surgical management of patients with thyroid cancer continues to be a challenge. Over the last 3 decades surgeons have debated about the "best" management of patients with this disease. Randomized trials concerning the surgical treatment are nonexistent, because execution of such studies is hampered by the low incidence of thyroid carcinoma and the relatively indolent behavior. Treatment results are based on retrospective analysis of mostly heterogeneous groups of patients. The discussion section in publications almost invariably leads to the statement that the proposed and presented treatment modalities are to be preferred, but in fact only tentative conclusions can be drawn. Proponents of more extensive surgery can find theoretical arguments, and proponents of more conservative management refer to the lack of proven benefit of the aggressive approach. This is applicable to the extent of thyroidectomy as well as the approach toward the management of regional lymph nodes.' Nevertheless, progress has been made, and there is a tendency toward more selected management for the different types of thyroid cancer. Differences in opinion toward the management of regional lymph node metastases of thyroid cancer concern mainly papillary, follicular, and medullary thyroid cancer. The treatment of lymph node metastases of other less frequently occurring types of thyroid cancer is not discussed in this chapter. Well-differentiated, papillary, and follicular adenocarcinomas arise from follicular cells and are the most common types of thyroid cancer. Medullary carcinoma represents about 7% of all thyroid cancers, but 15% of deaths due to thyroid cancer. It is also considered to be a differentiated form of thyroid carcinoma, but it originates from parafollicular, or C, cells. Its biologic behavior is somewhat more aggressive than papillary or follicular thyroid cancer. The prognosis of patients with thyroid cancer correlates with histologic type, extrathyroidal growth of the primary tumor, and the presence of distant metastases at the time of
diagnosis. The prognosis of patients with intrathyroid papillary cancer differs only slightly from the average life expectancy. On the other hand, patients with distant metastases of medullary carcinoma have a short life expectancy. Patient-related factors such as age and-to a lesser extentgender are also important in assessing prognosis in an individual patient with thyroid cancer. The natural history of the three types of differentiated thyroid carcinoma differs from each other. Papillary cancer spreads predominantly to the regional lymph nodes. The influence of regional lymph node metastases on prognosis in patients with papillary cancer is questionable. Distant metastases occur in about 10% of patients and predict an unfavorable prognosis. Follicular cancer mostly spreads to distant sites; lymph node metastases are far less common than in papillary carcinoma and, when present, indicate a worse outcome. Medullary cancer frequently metastasizes to the regional lymph nodes and the presence of nodal involvement predicts a worse prognosis. Distant metastases, especially to the liver, are common. Although total thyroidectomy in patients with medullary cancer is widely accepted, the necessity of total thyroidectomy in all cases of papillary and follicular cancer remains controversial. Radical neck dissection for lymph node metastases in patients with differentiated thyroid cancer is no longer considered necessary. Modified radical neck dissection, also referred to as modified neck dissection, is usually recommended for patients with regional lymph node metastases due to papillary, follicular, and medullary cancer. For most patients with medullary cancer, standard modified neck dissection is advocated. Since the influence of regional lymph node metastases on the prognosis of patients with papillary cancer is debated, the benefit of prophylactic or elective neck dissection in these patients has not been established. The "best" management of lymph node metastases
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Thyroid Gland
is based on retrospective series and tradition. In this chapter we describe the rationale and technique of modified neck dissection for papillary, follicular, and medullary thyroid cancer. Although there are no major disagreements about the technique of modified neck dissection, the rationale and indications for prophylactic neck dissection remain controversial. To formulate a sensible approach for the treatment of patients with thyroid cancer metastatic to cervical and mediastinal lymph nodes, the lymphatic drainage and the incidence and localization of nodal metastases at the time of diagnosis must also be considered.
Lymphatic Drainage of the Thyroid The thyroid has an extensive lymphatic drainage, which may flow in a variety of directions.P Thyroid follicles are enveloped with lymphatic vessels. The intraglandular lymphatic connections are extensive and enable lymphatic drainage from one lobe to the other through a complex of intrathyroidal and pericapsular nodes." The major lymph vessels running efferently follow the branches of the thyroid arteries and veins in three main directions: superiorly, laterally, and inferiorly. The upper region of the thyroid is drained along the superior thyroid vessels to the upper jugular lymph nodes. From the isthmus, the lymph vessels run to the prelaryngeal, or Delphian, nodes, which are connected to the upper jugular nodes. Lateral lymph vessels follow the medial thyroid vein to the mid- and lower jugular nodes. The lower lymphatic drainage is to the pretracheal and paratracheal nodes and the lower jugular chain. Connections to the anterior mediastinal nodes and retropharyngeal nodes are common, but drainage to the submandibular and suprahyoid nodes is less common. Through the pericapsular, pretracheal, and prelaryngeal nodes, contralateral nodal involvement occurs.' The extensive intrathyroid and extrathyroid lymphatic connections probably contribute to the high incidence of multifocal intraglandular thyroid carcinoma." Initial lymph node metastases are most commonly observed in the central neck compartment (medially to the carotid sheet) in the pretracheal and paratracheal nodes and subsequently spread to the lateral compartment in the deep inferior and lateral cervical nodes.' In general, patients with larger primary thyroid tumors and multifocal intraglandular tumors have more extensive lymph node metastases," but patients may also present with nodal metastases and an occult thyroid cancer.
Applied Surgical Anatomy Anatomic subdivisions of the neck define its borders and are important to recognize." Recently, the Committee for Head and Neck Surgery and Oncology of the American Academy of Otolaryngology-Head and Neck Surgery has proposed an update of the neck dissection classification." The new guidelines present some minor revisions but do not differ substantially from the previous guideline. The sternocleidomastoid muscle is the most prominent landmark and covers the major vessels of the neck: the carotid artery and the internal jugular vein.
Six major nodal regions can be distinguished and are expressed as levels in the classification. A superior or submandibular and submental triangle (level l) is bounded by the mandible, the hyoid bone, and the posterior belly of the digastric muscle. The anterior belly of the digastric muscle divides the superior triangle in a submental part anteriorly and a submandibular part posteriorly. The submandibular gland is part of this region. Three jugular regions are anteriorly bound by the lateral margin of the sternohyoid muscle and the posterior edge of the sternocleidomastoid muscle. The upper jugular nodes (level 2) run down from the skull base to the level of the horizontal border of the hyoid bone, which forms the cranial limit of the midjugular region (level 3). The inferior border of the cricoid cartilage bounds the rnidjugular (level 3) from the lower jugular region (level 4); the lower jugular nodes are located between the inferior border of the cricoid cartilage and the clavicle. The superior boundary of the posterior triangle of the neck (level 5) is the apex formed by the convergence of the sternocleidomastoid and trapezius muscle. It is bounded anteriorly by the posterior border of the sternocleidomastoid muscle, posteriorly by the anterior margin of the trapezius muscle, and inferiorly by the clavicle. The anterior neck compartment (level 6) runs from the suprasternal notch to the hyoid bone and from the trachea to the carotid sheath. This compartment harbors the lymph nodes, which are most frequently involved in patients with thyroid cancer, and includes the lymph nodes around the thyroid, along the recurrent laryngeal nerve, the precricoid (Delphian) nodes, and the pretracheal and paratracheallymph nodes. The region from the lower neck, from the suprasternal notch to the innominate vein, is considered the superior mediastinum (level 7) and is considered separately from the six levels" but is also frequently involved in patients with thyroid cancer with metastatic nodes in the tracheoesophageal groove. Level 6 and the superior mediastinum together form the central neck compartment. Starting dorsally in the neck at the anterior border of the trapezius muscle, the deep layer or "floor" of the operating field consists of the splenius muscle of the head and the levator muscle of the scapula with the spinal accessory nerve. Then the scalenus muscles follow with the brachial plexus running between the anterior and middle scalenus muscles. The phrenic nerve runs across the anterior scalenus muscle. Anteriorly, one comes to the vagal nerve, the internal jugular vein, and the carotid sheath. The hypoglossal nerve passes under the digastric muscle. Ventrally, the laryngeal muscles, esophagus, trachea, and thyroid are located and in this area special attention has to be drawn to the superior laryngeal nerve, recurrent laryngeal nerve, and parathyroid glands. The surgical anatomy of the superior and recurrent laryngeal nerve as well as the parathyroids are discussed elsewhere (see Chapter 2). Lymph nodes can usually be removed from the superior mediastinum via the Kocher collar incision. The removal of lymph nodes caudal to the innominate vein in the mediastinum usually requires a median sternotomy. For lymph node dissections in patients with thyroid cancer, the neck should be divided into a central and a lateral neck compartment divided by the carotid sheath.' The fatty tissue encompassing the lymph nodes in the neck is situated between the first and third layers of deep
Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -
cervical fascia. The first layer of fascia is formed by the back side fascia of the sternocleidomastoid muscle; it runs posteriorly to the trapezius muscle and anteriorly to the digastric muscle and covers the strap muscles. The deep, or third, layer of cervical fascia covers the trachea and esophagus and runs laterally over the scalenus muscles, the levator muscle of the scapula, and the splenius muscle of the head to join the superficial cervical fascia at the trapezius muscle. The second layer of deep cervical fascia is also called the prethyroidalfascia. An aponeurotic sheet, which originates from the carotid sheet, runs sagitally to the fascia covering the strap muscles superficially and to the deep cervical fascia covering the scalenus muscles posteriorly. This aponeurotic sheet with the carotid artery as its predominant structure divides the fascia-covered tissue in a central and a lateral compartment. Because separate visceral compartments can be distinguished, the laterally located nodes cannot be truly resected en bloc with the thyroid."Consequently,the neck dissection is to be subdivided into a central neck dissection and a lateral neck dissection. In the central neck compartment, the thyroid is situated along with the trachea, esophagus, thyroid, parathyroids, and recurrent laryngeal nerves in one visceral space, which also contains the strap muscles. Superiorly it extends as far as the hyoid bone and inferiorly it runs into the superior mediastinum to the innominate vein. Laterally lies the carotid sheath, which serves as a medial border for the separate lateral compartment containing the lateral cervical lymph nodes. A modified neck dissection usually includes resection of the three jugular regions (levels 2 to 4) and the posterior triangle (level 5) as described earlier. The superior triangle or suprahyoid area harbors the submandibular and submental lymph nodes. It is usually not included in the modified neck dissection for thyroid cancer, because lymphatic spread to this region is rare.
Incidence and Localization of Lymph Node Metastases As mentioned before, papillary and medullary thyroid carcinomas frequently spread to the regional lymph nodes. Nodal involvement in follicular cancer is uncommon and when present one should consider that the tumor is a follicular variant of a papillary thyroid cancer. Although the presence and extent of initial lymph node metastases in patients with papillary thyroid cancer is correlated with tumor size,5.6,ID lymph node metastases often occur at an early stage of the disease.P'!' Even in patients with papillary carcinoma smaller than I em, metastases to the regional lymph nodes are not uncommon. I 1-13 Thus, lymphatic spread of papillary thyroid cancer is not always a sign of advanced primary disease. Lymph node metastases are sometimes the presenting symptom in patients without a palpable lesion in the thyroid.!"!? When prophylactic neck dissections are done in patients without clinical evidence of nodal involvement, 30% to 80% of patients are found to have lymph node metastases. 5,18-21 With more thorough examination, up to 90% of patients with papillary thyroid cancer have nodal involvement.5,18,19 Thus, most patients with papillary thyroid cancer have either clinical or occult regional lymph node metastases at the time of their primary treatment. Another interesting
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phenomenon is the fact that the incidence of cervical lymph node metastases is higher in young patients. 12.16, 17,22 In patients with intrathyroidal follicular cancer without distant metastases, lymph node metastases occur in about 5% of patients. Nodal involvement in patients with follicular carcinoma is associated with extrathyroidal extension of the primary tumor and is therefore a sign of advanced disease.F The presence of clinically enlarged lymph nodes in medullary thyroid cancer varies between 25% and more than 60%.23-27 More than half of the patients with medullary thyroid tumors have nodal involvement, but surprisingly about half the patients whose medullary thyroid cancers were detected by family screening also had lymph node metastases.24.26-28 Patients with hereditary medullary thyroid carcinoma may have more nodal involvement than patients with sporadic cancer.23,29 In familial disease the primary tumor is located bilaterally and lymph node metastases are also bilateral. Nodal involvement in patients with multiple endocrine neoplasia (MEN) 2B familial medullary thyroid carcinoma is more frequent than in the MEN 2A patients.'? Calcitonin is a sensitive and highly specific marker in persistent disease in patients with medullary thyroid cancer, especially after pentagastrin and/or calcium provocative testing. 31-34 Most patients with papillary and medullary thyroid cancer have unilateral lymph node metastases, but bilateral or contralateral spread occurs, especially in hereditary medullary thyroid cancer.5,6,16.19,23,35-37 Central neck nodes adjacent to the thyroid nodule are usually first involved.5,10,37-42 Metastases are found in the fatty tissue along the trachea, along the recurrent laryngeal nerves, and in the tracheoesophageal groove reaching laterally to the carotid artery (level 6). Metastatic nodes also occur in the pretracheal region and along the superior thyroid vessels. The lateral compartment along the jugular chain is usually not involved, until at least occult lymph node metastases exist adjacent to the thyroid gland.5.9,16,34,35 In the lateral compartment, the nodes along the mid and lower parts of the internal jugular vein (levels 3 and 4) are more frequently involved than those along the upper third of the vein (level 2) and those in the posterior triangle and supraclavicular region (level 5). Of all patients with nodal involvement, 80% of the metastases are found in the central neck compartment in level 6 and along the mid and lower internal jugular vein (levels 3 and 4). Unless there is extensive lymph node involvement, the submandibular and submental nodes (level I) in thyroid cancer are seldom affected. 5,16.19,43 Although lymphatic pathways to the retropharyngeal nodes are usually present.? lymph node metastases are rare in this area. The superior mediastinum is less frequently involved in patients with papillary than in patients with medullary carcinoma, although mediastinal nodal involvement is relatively common in both conditions. 6,22,24,43.44 Bilateral metastases are often found concomitantly with mediastinal nodes in patients with medullary carcinoma. 27,29,45 Metastases to the superior mediastinal lymph nodes occur most frequently when there is involvement along the internal jugular vein contralaterally to the primary tumor. 17,44,46 More distant mediastinal nodal metastases are rare, except in patients with advanced locoregional disease."
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Prognostic Significance of Regional Lymph Node Metastases In epidermoid cancers of the head and neck, the presence of regional lymph node metastases is associated with an unfavorable prognosis. In papillary thyroid cancer, nodal metastases appear to be a minor rather than a major risk factor. The prognostic significance of lymph node metastases is different for the three types of thyroid cancer. In general, nodal involvement at the time of diagnosis in papillary cancer increases the risk of recurrent cancer but has only a minor influence on overall survival. Regional lymph nodes are not commonly involved in patients with follicular thyroid cancer, but in these patients the tumor tends to behave more aggressively. Lymph node metastases in patients with medullary thyroid cancer adversely influence survival. The most important determinants for survival in thyroid cancer of follicular cell origin are tumor stage, age, histologic type, local invasiveness, and to a lesser extent gender. 12,15,22,26,47-57 Some studies suggest that the presence of clinically evident lymph node metastases in patients with papillary and follicular carcinoma has an adverse effect on survival.6,49,53,58-60 Other authors have reported that patients with nodal metastases have an increased recurrence rate, but survival is not adversely affected,15,48,51,56,61-63 Only patients with stage tumor growth beyond the lymph node capsule (pN3) have an impaired survival.>' Other studies suggest that lymph node metastases in patients with papillary carcinoma have no adverse effect on survival or recurrence rate in their patients. 12,17,47,50,55 In one study, even a slightly better prognosis in these patients was suggested.P However, these authors did not account for the fact that young patients are more likely to have nodal metastases and that the prognosis is more favorable in younger than older patients with papillary thyroid cancer. 22.58,59 In one study, which contained a relatively high proportion of node-positive patients with papillary thyroid cancer older than 45 years of age, nodal involvement was a strong independent risk factor for survival. 6 The difference in frequency of lymph node metastases in younger versus older patients with papillary thyroid cancer could explain the varying influence of lymph node metastases on prognosis. Other authors noticed that, when patients were matched by age, the presence of positive lymph nodes did have an adverse effect on the survival and recurrence rate." However, in this study 12% of the patients with nodal involvement had a follicular carcinoma and the lymph node metastases in patients with this type of thyroid cancer are known to have a more ominous effect on prognosis than in patients with papillary carcinoma. 13,56,60,64 The prognostic significance of lymph node metastases from papillary and follicular carcinoma should therefore be considered separately. Also, other authors do not discriminate between lymph node metastases from papillary or follicular carcinoma,14,36.53,59.65,66 which hampers comparative evaluation of survival analyses and does not justify selecting one type of neck dissection over another. Although most patients with papillary thyroid carcinoma have at least microscopic lymph node metastases, the recurrence rate in patients without macroscopic nodal involvement,
who are not treated with a prophylactic neck dissection, is low and usually does not exceed 20%,10,13,15.21.36,48,51,67-70 Moreover, the presence of metastatic nodes in the central neck makes nodal metastases in the lateral neck more likely, but subsequent development of recurrent disease in the lymph nodes in the jugular chain or lateral neck is relatively uncommon." Apparently, most of these occult metastases fail to grow and some may regress, The development of lymph node recurrence after primary treatment of papillary carcinoma seems to have an independent significant effect on survival in older patients, whereas the effect in younger patients is less evident. 71 As already mentioned, the presence of lymph node metastases in patients with medullary carcinoma is associated with a poorer prognosis,23,24,26,27,72 especially when metastases are found in the mediastinum.Pv' In fact, the presence of more than three nodes and nodes larger than 1 em correlate with a worse prognosis." Measurement of plasma calcitonin levels after administration of calcium and/or pentagastrin is a sensitive method of documenting when persistent disease is present. 31-33 Elevated calcitonin and carcinoembryonic antigen (CEA) levels are associated with residual or recurrent disease.
Choice of Neck Dissection Operations used to remove cervical lymph nodes vary from removing only grossly affected lymph nodes ("node picking") to the classic radical neck dissection. Crile in 1906 developed the classic radical neck dissection for local control of head and neck cancers.P Although this operation became the standard operation for most head and neck cancers, it is not used today for patients with thyroid cancer. Radical .neck dissection is associated with disfiguring cosmetic and functional results, and equally good local control and cure can be obtained with less extensive operations. 9.14,15,18.26,35.38,55,74,75 The modified neck dissection, which is called "functional" neck dissection by other surgeons." allows for an en bloc dissection ofthe lymphatic network of the neck, while preserving the functionally important structures (muscles, vessels, and nerves). The technique of modified neck dissection for thyroid carcinoma has been described,9,18,74 and the operation can be performed with minimal morbidity and favorable cosmetic results. 9,I0,36 During dissection of the central neck, it is essential to preserve the recurrent laryngeal nerve and the blood supply to the parathyroid glands. The dissection of the superior mediastinum is part of the central neck compartment dissection, including removing nodes from around the thymus gland. In patients with extensive invasive papillary and follicular thyroid cancers and more commonly with medullary cancer, it is sometimes necessary to perform a median sternotomy and remove all fatty tissue, thymus, and lymph nodes from the anterosuperior mediastinum." A modified neck dissection can be done, because most nodal metastases from thyroid carcinoma do not invade adjacent anatomic structures. Lymph node metastases are rarely found within the substance of the sternocleidomastoid muscle, even when there is extensive nodal involvement.P-" It is therefore unnecessary to sacrifice this muscle. In most
Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -
cases, it is possible to dissect the spinal accessory nerve free from surrounding tissue. Deformity of the neck, shoulder, and subsequently the back is reduced by the preserving the spinal accessory nerve. The internal jugular vein can also usually be preserved, but it is essential to dissect all nodes along the vein, especially behind the lower end." During bilateral modified neck dissection it is important to preserve at least one internal jugular vein to avoid possible severe facial swelling and edema. A modified or functional neck dissection is the treatment of choice for patients with metastatic thyroid cancer in the cervical nodes. It benefits especially young women, which form the largest group of patients with papillary, follicular, and medullary thyroid cancer. Sentinel lymph node dissection is now used to assess the status of lymph nodes in patients with breast cancer and melanoma and has changed the surgical management. Intraoperative lymphatic mapping has also been investigated in thyroid cancer.76-78 The technique has been carried out with a vital dye technique and/or a radiotracer technique. The sentinel node dissection seems feasible, although the false-negative rate is difficult to establish since not all patients undergo a central and modified neck dissection. As mentioned previously, the influence of occult lymph node metastases on prognosis of papillary cancer is the most questionable. Therefore, the usefulness in papillary cancer is limited because most surgeons would agree that systematic surgical resection of lymph nodes should be limited to therapeutic dissection in patients with enlarged lymph nodes. Sentinel lymph node studies might be helpful in patients with medullary cancer and small primary tumors since surgeons advocate a standard lateral neck dissection in these patients. The identification of a sentinel node in the lateral neck compartment in patients without central neck involvement might provide arguments to perform a lateral neck dissection. Further information should be obtained to clarify this issue.
Papillary and Follicular Thyroid Carcinoma A prophylactic modified neck dissection is not generally advocated. Only a few authors advocated prophylactic neck dissections, 18.62 and most recommend a more disease-related strategy. Systematic neck dissection in patients with nodal involvement and papillary or follicular thyroid cancer reduces regional tumor recurrence compared to limited nodal excision ("node picking"), but the extent of neck dissection has no proven influence on overall surviva1. 55,66,68,75 Although in one study nodal involvement of papillary carcinoma adversely influenced survival as well as the recurrence rate, more aggressive treatment did not appear to have any influence on prognosis."? Therefore, an attempt to eradicate all lymph node tissue to eliminate tumor in patients with papillary and follicular thyroid cancer seems unjustified, and it increases the risk of morbidity. However, evident metastatic disease should be resected when this can be done with minimal increased morbidity. Some surgeons6,18,62,80,8! have recommended routine removal of cervical lymph nodes from the central neck compartment concomitant with the total thyroidectomy, Other surgeons 38,49,69,82 mention careful inspection of the central neck with removal of suspicious nodes for frozen
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section; if positive, the lymph nodes in the central neck compartment are removed. Most surgeons 1,9,14,39,41,48,52,58,62,69,82-84 use the latter strategy in patients with papillary and follicular carcinoma and reserve modified neck dissection for patients with clinically evident lymph node metastases in the lateral neck. In patients without nodal involvement in the lateral neck, a therapeutic modified neck dissection can be performed later, if recurrence occurs in the lateral neck, A subsequent neck dissection is not difficult because this area has not previously been explored. Some authorities on thyroid cancer advocate mid- and lower jugular sampling in patients without clinically evident nodal involvement to decide whether a modified neck dissection is necessary.36,65,66,70,80 When these nodes are positive, a modified neck dissection is performed. They argue that lymph node metastases are associated with more aggressive differentiated thyroid cancer even though most studies using multivariate analysis fail to show an adverse effect on prognosis. A few surgeons reserve the modified neck dissection for patients with more extensive nodal involvement rather than for all patients with nodal metastases and use a limited resection or node picking for patients with limited nodal involvement. 39,47,73,81
MedUllary Thyroid Carcinoma Medullary thyroid carcinoma is biologically more aggressive than papillary or follicular thyroid carcinoma, and the presence of lymph node metastases correlates with a poorer prognosis. Medullary thyroid cancer in contrast with papillary and follicular cancer usually does not concentrate radioactive iodine,26,57,85 so this form of adjuvant therapy is usually ineffective to treat persistent or recurrent disease. Most medullary thyroid cancers are also resistant to chemotherapy or external irradiation. For these reasons, a more extensive surgical approach is warranted than in patients with papillary or follicular thyroid cancer. In patients with medullary thyroid cancer, a bilateral central neck dissection concomitantly with the total thyroidectomy is essential and uniformly advocated by experts in the field. 25,28,29,34,35,45,57,63,65,86-92 There is a potential risk of recurrent disease in the central neck in these patients, because micrometastases are frequently present in clinically node-negative patients and secondary surgery in the central neck area is associated with a high complication rate." Standard modified neck dissectionin patients with medullary thyroid cancer is controversial. Some authors45,57,65 advocate modified neck dissection directed by sampling of the lymph nodes along the ipsilateral lower and middle parts of the internal jugular vein during primary surgery in all patients. Other surgeons88,89 do not advocate jugular sampling and recommend an ipsilateral modified neck dissection when the primary thyroid cancer is 1.5 em or larger. Most surgeons29,37,90 would recommend at least ipsilateral modified neck dissection in all patients with any nodal involvement in the central neck compartment. In addition, standard ipsilateral or bilateral lateral neck dissection is advocated by some authors in all patients with medullary thyroid cancer.91,92 More evidence is necessary to determine whether extensive cervical lymphadenectomy improves overall survival. However, a normal basal and stimulated calcitonin level after completion of the neck dissection suggests a better long-term outcome.
200 - - Thyroid Gland A common problem arises when the serum calcitonin level remains elevated despite adequate surgery including total thyroidectomy, and bilateral central and lateral neck dissection including the upper mediastinum. Noninvasive and invasive imaging studies as well as venous sampling of calcitonin have been used to try and identify site or sites of persistent disease. When the localization studies are negative and the patient has had definitive surgery (total thyroidectomy, central neck dissection and a modified neck dissection), there is no consensus about how to best manage these patients. Prophylactic re-explorations have only infrequently resulted in normalization of calcitonin levels in patients who have already had appropriate dissections.W" Nevertheless long-term survival is relatively good in this group of patients without reoperations.t-P-" In medullary thyroid carcinoma, a systematic microdissection of the neck has been recommended. A thorough neck dissection using microdissection techniques with the help of magnifying glasses is performed to remove all identifiable metastatic tissue from the neck. 28,29.34 Meticulous dissection of regional lymph nodes in the central neck compartment including the superior mediastinum as well as a bilateral modified neck dissection has been shown to be superior compared to less systematic procedures with regard to the normalization of calcitonin levels and survival. 28,29,34 Some surgeons have extended the operation with a dissection of the mediastinum using median sternotomy when positive nodes were found in the superior mediastinum, but this extension has not improved their results." A longer follow-up period is necessary to confirm the merit of these procedures, but the results are promising, with serum calcitonin levels becoming undetectable in about 25% of these patients. Microdissection of the neck is time consuming, and meticulous dissection is best performed at the primary procedure before adhesions make dissections more difficult.P Medullary thyroid cancer is a relatively rare tumor, and patients with these tumors require the most experienced thyroid surgeons for the best results.
Operative Technique The lymph nodes in the central neck compartment are usually resected in continuity with the thyroid itself. The strap muscles are retracted laterally during the dissection. When the strap muscles inhibit exposure, they can be divided superiorly, since they are innervated from below. The technique of the total thyroidectomy has been described in previous chapters. As mentioned earlier, the central neck dissection puts the recurrent laryngeal nerve and the blood supply to the parathyroids at risk. The parathyroid glands are delicately dissected away from the thyroid, preserving their vascular pedicles during thyroidectomy. When they cannot be kept on a vascular pedicle, they should be removed, biopsied with frozen section, and autotransplanted.All fatty tissue and lymph nodes between the carotid sheath and the esophagus can be removed from the recurrent laryngeal nerve along the trachea and from the tracheoesophageal groove (Fig. 22-1). The recurrent laryngeal nerves must be identified to minimize the risk of injury and consequent paralysis of the vocal cords. When lymph nodes are extensively involved,
the position of the recurrent laryngeal nerve can be displaced and identification can be more difficult. In most patients removal of nodes from the recurrent nerve can be done safely. When there is extensive nodal involvement, it may be difficult to preserve the lower parathyroid gland on this side. The upper parathyroid gland is usually easier to preserve because it is situated more dorsally. Positive identification and preservation of the contralateral parathyroid glands are essential. The central neck dissection is continued into the superior mediastinum while dissecting along the recurrent laryngeal nerves bilaterally. The superior mediastinum can be dissected by removing the upper thymus with the fatty tissue after determining its relation with the inferior parathyroid glands. When the inferior parathyroid glands have not been found during thyroidectomy, they are probably embedded in the cranial portion of the thymus. Opening of the capsule of the cranial part of the thymus usually uncovers the intrathymic parathyroid gland. When another parathyroid gland has not been positively identified, it is best to leave the thymus in situ or to autotransplant the identified intrathymic parathyroid gland. The dissection is extended toward the innominate vein. Occasionally it is necessary to split the sternum (median sternotomy) for invasive or extensive tumors. When a modified neck dissection is planned, the Kocher transverse collar incision is extended laterally (MacFee extension), which provides adequate exposure in most cases. The cosmetic results of this extension are favorable. Good exposure can also be achieved by a vertical extension toward the angle of the jaw, but this extension is cosmetically less favorable. A second horizontal incision high in the neck and parallel to the initial incision is preferable cosmetically. The dissection plane of the skin flaps continues just deep to the platysma muscle and anterior to the external jugular vein. Special attention must be given to the retraction of the cranial skin flap: the mandibular marginal branch of the facial nerve runs just below the mandibula and can be compressed by retractors. This must be avoided because it results in drooling from the comer of the mouth. It is usually not necessary to transect the sternocleidomastoid muscle. The neck dissection can be performed adequately by retracting the muscle medially and laterally and working beneath it. This can be done with retractors or a rubber cord. Alternatively,the muscle can temporarily be disconnected just caudal to its insertion to the clavicle and sternum. In this situation the muscle is dissected and elevated toward the mastoid region. The superficial cervical fascia covering the sternocleidomastoid muscle is incised longitudinally over the whole length of the muscle and dissected away. When possible the external jugular vein and greater auricular nerve are preserved and retracted posteriorly by a separate vessel loop. The anterior part of the superficial fascia is dissected from the muscle and is left in continuity with the fascia, which covers the internal jugular vein and its contiguous chain of lymph nodes. The dissection either commences medially at the junction of the lower part of the internal jugular vein and the clavicle or laterally at the junction of the anterior border of the trapezius muscle and the clavicle. We prefer the medial approach where the fatty tissue and embedded lymph nodes are dissected from the internal jugular vein starting just above the sternoclavicular joint. On the left side, one should identify the thoracic duct just above the junction of the
Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -
201
FIGURE 22-1. Total thyroidectomy with dissection of central neck compartment and midjugular sampling.
innominate vein and the internal jugular and subclavian veins. The duct can be distended by compression of the areolar tissue near the bifurcation, which facilitates its identification. The thoracic duct must be divided and ligated when injured or the patient may develop a chyle fistula. The internaljugular vein is dissected free from its surrounding lymph node-bearing tissue, which contains the beginning of the modified neck dissection. Special attention must be drawn to the lower jugular nodes, which are located behind the vein. The vein should be retracted either medially or laterally to obtain a good view of this area. This retraction should be done gently to avoid tearing the vein, which might cause air embolism. The dissection is continued by exposing the
carotid artery, sympathetic chain, and vagus nerve. The lymph node containing fatty tissue is mobilized laterally and superiorly along the clavicle, creating the inferior border of the lateral compartment dissection specimen. Care is taken to avoid injury to the pleura. The specimen is gradually dissected upward from the floor of the lateral compartment. The phrenic nerve is identified running obliquely on the scalenus anticus muscle, and the brachial plexus is identified between the scalenus anticus and medius muscles (Fig. 22-2). The anterior border of the trapezius muscle is dissected and the spinal accessory nerve is identified approximately 1 em anteriorly from the margin of the muscle. The trapezius muscle represents the lateral border of the lateral
202 - - Thyroid Gland
FIGURE 22-2. Modified dissection of central neckcompartment.
neck compartment. The spinal accessory nerve runs parallel to the trapezius muscle over the levator muscle of the scapula. The nerve itself is rarely invaded by tumor but is often surrounded by lymph nodes. It should be carefully dissected from the adjacent tissues upward to the cranial part of the sternocleidomastoid muscle. The spinal accessory nerve is in a superficial position in the posterior triangle of the neck. A plexus of branches from the cervical sensory nerves is located caudal and parallel to the spinal accessory nerve and the phrenic nerve, and these nerves should be preserved when possible. The greater auricular nerve turns toward the sternocleidomastoid muscle near this point. In this area, too, care must be taken to preserve the branch of the occipital artery, which vascularizes partly the sternocleidomastoid muscle. The occipital artery represents the upper posterior limit of
the dissection of the lateral compartment. The dissection continues to the prevertebral fascia. The tissue behind and above the spinal accessory nerve is mobilized from the nerve itself and is dissected upward from the levator muscle of the scapula and splenius muscle of the head. The inferior, lateral, and upper posterior parts of the dissection are completed, and the specimen is passed underneath the sternocleidomastoid muscle, which is now retracted laterally. The anterior part of the specimen is freed from the carotid sheet and jugular vein, and the dissection continues superiorly along the jugular vein, mobilizing the mid- and upper jugular lymph nodes. The hypoglossal nerve, which runs behind the facial vein, is identified. Sometimes the facial vein has to be ligated and transected to obtain an adequate exposure to the hypoglossal nerve while removing the upper jugular lymph nodes.
Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -
203
Macroscopic lymphadenopathy
FIGURE 22-3. Proposed strategy for management of regional lymph nodes in papillary and follicular thyroid carcinoma. Modified neck dissection includes a central neck dissection. Central neck dissection includes a dissection of the superior mediastinum. Middle and lower jugular sampling is optional. See additional considerations in the section "Therapeutic Strategy."
Modified neck dissection
Central neck dissection
(Positive jugular sampling)
The dissection is terminated at the posterior belly of the digastric muscle. The lymph nodes in the submandibular region are rarely involved in patients with thyroid cancer and are therefore not removed unless there is extensive lymphadenopathy adjacent to this area. The digastric muscle marks the upper border of the dissection. The specimen can now be removed. Careful hemostasis is performed, and suction drains are often used. The heads of the sternocleidomastoid muscle, when previously divided, are reapproximated. The platysma muscle is approximated and the skin is closed.
Complications of Neck Dissection More extensive neck dissections, especially in the central neck compartment, are associated with a higher risk of hypoparathyroidism and other complications.tv" With complete resection of all fatty and lymph node tissue from the central neck, the recurrent laryngeal nerves and the vascular supply to the parathyroid glands are at risk, especially when combined with total thyroidectomy.14,47,62,69,94-96 Awareness of these potential problems emphasizes the importance of meticulous dissection and positive identification of the recurrent laryngeal nerves and parathyroid glands. Magnifying glasses (x2.5) and bipolar coagulation are helpful. The patient should not receive muscle relaxants. The recurrent laryngeal nerve should be dissected over its complete length with special care for the part caudal to the thyroid. Unilateral paralysis causes hoarseness, which is inconvenient to the patient. Bilateral injury is a life-threatening complication that may make an emergency tracheostomy necessary. Resection of the trachea and esophagus muscle wall is occasionally necessary in patients with extensive extracapsular tumor growth. The modified neck dissection is designed to remove all of the metastatic lymph nodes in the lateral neck yet minimize morbidity. In experienced surgical hands, modified neck dissection is a safe procedure with minimal morbidity. 10.36.94 Resection of the spinal accessory nerve results in paralysis of the trapezius muscle with a shoulder drop and decreased abduction of the arm. Besides loss of function, paralysis of the trapezius muscle is disfiguring. The choice of the incision as well as the preservation of the sternocleidomastoid
muscle and the spinal accessory nerve is an important aspect for a favorable cosmetic result of a modified neck dissection. Injury to the phrenic nerve can result in paralysis of the diaphragm, whereas injury to the sympathic ganglion leads to Homer's syndrome. Resection of branches of the cervical sensory nerves can cause sensory loss of the shoulder. As previously stated, the identification of the thoracic duct on the left side can be difficult. When the duct is injured, chylous fluid collection or cyst occurs. The duct should therefore be ligated to prevent postoperative chylous fistula or chylothorax. When such a complication occurs, reoperation and ligation of the duct are often necessary. Both modified neck dissection and dissection of the superior mediastinum can cause a pneumothorax. A postoperative chest radiograph is recommended. When a pneumothorax is present, a chest catheter is placed under water seal. Bilateral neck dissection can cause significant postoperative edema, and a temporary tracheostomy is rarely necessary. When one internal jugular vein is resected, the contralateral neck dissection should be delayed for at least 6 weeks to avoid this problem. Wound infections are uncommon (Figs. 22-3 and 22-4).
Bilateral central neck dissection
FIGURE 22-4. Proposed strategy for management of regional lymph nodes in medullary thyroid carcinoma. Ipsilateral neck dissection is advocated if central neck nodes are involved with tumor. All patients with tumors larger than 2 cm should undergo standard ipsilateral neck dissection. Central neck dissection includes dissection of the superior mediastinum. See additional considerations in the section "Therapeutic Strategy."
204 - - Thyroid Gland
Therapeutic Strategy Papillary and Follicular Thyroid Carcinoma Figure 22-3 shows our strategy for the management of the regional lymph nodes in patients with papillary or follicular thyroid carcinoma. The object is to remove fatty and lymphatic tissue with minimal risk of complications. As mentioned previously, prophylactic neck dissections for probable microscopic nodal involvement do not appear to be indicated, except possibly in older male patients with central node involvement. While performing total thyroidectomy, the central neck compartment is carefully examined. Enlarged nodes are removed and sent for frozen section analysis. When positive, a central neck dissection is performed, including removing nodal tissue from the superior mediastinum. When there are numerous lymph node metastases in the central neck, the lateral lymph nodes are palpated, and, if present, they are removed (levels 2 to 5). Modified neck dissection can usually be performed with minimal associated morbidity. When there is nodal involvement in the lateral neck compartment without evident involvement in the central neck, a modified neck dissection as well as a central neck dissection, including removing the lymph nodes from the superior mediastinum, is performed. En bloc or compartment dissections are preferable to limited dissections or node picking to decrease the likelihood of recurrent disease. Repeat operations in previously explored areas are associated with increased morbidity but can offer significant palliation.
Medullary Thyroid Carcinoma Figure 22-4 shows the strategy for the management of the regional lymph nodes in patients with medullary carcinoma. Total thyroidectomy with bilateral central neck dissection, including the dissection of the superior mediastinum, is recommended. Microdissection is helpful for identifying all lymph node-bearing tissue so that it can be removed from the central neck compartment bilaterally. When nodes contain medullary thyroid cancer in the central neck, a modified neck dissection is performed on the involved side. Although we formerly advocated jugular node sampling, we now recommend either leaving the lateral compartment alone or proceeding with a systematic modified neck dissection. Formation of scar tissue after jugular sampling make a subsequent dissection of levels 3 and 4 more difficult. Patients with large tumors (> 1.5 ern) should have standard prophylactic ipsilateral modified neck dissection, and this should be done bilaterally in patients with familial disease or with bilateral tumor involvement. When at the initial operation the central neck nodes are not involved, the operation can be limited to the central neck dissection. If a subsequent modified neck dissection is required, adhesions will not be a problem. Nevertheless, elective modified neck dissection should be performed in a secondary session, when central neck nodes are involved with medullary thyroid cancer at final histology and the basal or stimulated serum calcitonin level is elevated. Postoperatively, patients should be followed cautiously by monitoring the serum calcitonin and CEA levels. In patients with persistent elevated basal or stimulated calcitonin levels, noninvasive studies such as magnetic resonance imaging of the neck and
mediastinum should be performed. Selective venous sampling for calcitonin'? or microdissection of nonpreviously explored compartments of the neck is useful in selected patients.28.29.34 Microdissection by experienced surgeons has reduced serum calcitonin levels to normal in about one third of the patients. In patients with distant metastases, local control is important and therapeutic but not prophylactic nodal resections are recommended.
Treatment of Regional Recurrences in the Neck Recurrent thyroid cancer most commonly occurs in the cervical lymph nodes.47.66.69 Recurrent disease in the lateral neck should be treated by modified neck dissection. When a recurrence occurs after neck dissection, a repeat neck dissection or local excision should be performed. Central neck re-explorations are hazardous, and although excellent results have been reported." the recurrent laryngeal nerve and the parathyroid glands are at increased risk of injury in secondary explorations. Recurrences in the central neck in patients with papillary and follicular cancer can be treated with surgical excision and/or radioactive iodine. If the recurrence is small « I em) and located in the thyroid bed, the tumor is often best controlled by radioactive iodine or external irradiation. Larger tumor deposits should be resected. Follicular cancers appear to be more amenable to radioactive iodine treatment than papillary cancers.l.85.99 Medullary cancer is usually insensitive to radioactive iodine therapy, and patients with nonresectable cancer should be treated with external radiation.v" Median sternotomy should be done for patients with elevated serum calcitonin levels and a mediastinal mass. Prophylactic median sternotomy is more controversial.34 Esophageal or tracheal resection is indicated in selected patients and can usually be accomplished with minimal morbidity.
Summary and Conclusions The extent of lymph node dissection must be based on individual tumor type and stage, extent of nodal involvement at the time of operation, and patient-related factors such as age and general condition. The surgeon's experience should also be taken into account. As mentioned previously, more aggressive surgical procedures do not always influence overall survival in patients with papillary and follicular thyroid cancer. Most patients with well-differentiated thyroid cancer of follicular cell origin benefit from therapeutic nodal dissection, but prophylactic node dissection is not necessary. An extensive search for micrometastases also does not seem warranted. Although most patients with papillary carcinoma have at least microscopic nodal involvement, the recurrence is low even in patients not treated with prophylactic neck dissection. Compartment-related dissections appear to be preferable to local excision of lymph nodes to minimize local recurrence: central neck dissection in case of lymph node metastases in the central neck medially to the carotid arteries (level 6 and the superior mediastinum) and modified
Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -
neck dissection of levels 2 to 5 for nodal involvement of the lateral neck. In patients with medullary thyroid carcinoma, a more extensive surgical approach is warranted. Medullary carcinoma is more aggressive than papillary and follicular thyroid cancer and ablative treatment with 1311 is generally not effective. A total thyroidectomy and bilateral central neck dissection are therefore recommended for most patients with medullary thyroid cancer. Ipsilateral modified neck dissection of levels 2 to 5 is indicated in all patients with primary tumors larger than 1.5 em and bilateral neck dissection in patients with bilateral thyroid tumors and hereditary medullary thyroid cancer. Postoperatively, patients should be followed cautiously by monitoring the serum calcitonin and CEA levels. Some patients without demonstrable tumor but with elevated calcitonin levels benefit from repeat central and bilateral modified neck dissection of renewed surgery in the neck using microsurgical techniques if this has not already been done.
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73. Crile G. Excision of cancer of the head and neck with special reference to the plan of dissection based on one hundred and thirty-two operations. JAMA 1906;47:1780. 74. Bocca E, Pignataro 0, Oldini C, Cappa C. Functional neck dissection: An evaluation of review of 843 cases. Laryngoscope 1984;94:942. 75. McGregor or, Luoma A, Jackson SM. Lymph node metastases from well-differentiated thyroid cancer: A clinical review. Am J Surg 1985;149:610. 76. Kelemen PR, Van Herle AJ, Giuliano AB. Sentinel lymphadenectomy in thyroid malignant neoplasms. Arch Surg 1998;133:288. 77. Arch-Ferrer J, Velazquez D, Fajardo R, et al. Accuracy of sentinel lymph node in papillary thyroid carcinoma. Surgery 2001;130:907. 78. Wiseman S, Hicks W, Chu Q, Rigual N. Sentinel lymph node biopsy in staging of differentiated thyroid cancer: A critical review. Surg Oncol 2002;11:137. 79. Noguchi M, Earashi M, Kitagawa H, et al. Papillary thyroid cancer and its surgical management. J Surg OncoI1992;49:140. 80. Boom RPA. Problemen bij de chirurgische behandeling van het gedifferentieerde schildkliercarcinoom, in het bijzonder bij remterventie, [Dissertation]. Amsterdam, University of Amsterdam, 1982. 81. Gemsenjager E. Zur chirurgischen therapie der differenzierten schilddrusenkarzinome. Dtsch Med Wochenschr 1978;103:749. 82. Sisson GA, Feldman DE. The management of thyroid carcinoma metastatic to the neck and mediastinum. Otolaryngol Clin North Am 1980;13:119. 83. Lennquist S. Surgical strategy in thyroid carcinoma: A clinical review. Acta Chir Scand 1986;152:321. 84. Ballantyne AJ. Neck dissection for thyroid cancer. Semin Surg Oncol 1991;7:100. 85. Tubiana M. External radiotherapy and radioiodine in the treatment of thyroid cancer. World J Surg 1981;5:75. 86. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361. 87. Block MA. Surgical treatment of medullary carcinoma of the thyroid. Otolaryngol Clin North Am 1990;23:453. 88. Duh QY, Sancho JJ, Greenspan FS. Medullary thyroid carcinoma: The need for early diagnosis and total thyroidectomy. Arch Surg 1989;124:1206. 89. Moley JF. Medullary thyroid cancer. Surg Clin NorthAm 1995;75:405. 90. Kebebew E, Clark OH. Curr Treat Options Oncol 2000; I:359. 91. Fleming JB, Lee, JE, Bouvet M, et al. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg 1999;230:697. 92. Dralle H. Lymph node dissection and medullary thyroid carcinoma. Br J Surg 2002;89: 1073. 93. Norton JA, Doppman JL, Brennan MD. Localization and resection of clinical inapparent medullary carcinoma of the thyroid. Surgery 1980;87:616. 94. Cheah WK, Arici C, Ituarte PHG, et al. Complications of neck dissection for thyroid cancer. World J Surg 2002;26: 1013. 95. Scanlon EF, Kellogg JE, Winchester DP, et al. The morbidity of total thyroidectomy. Arch Surg 1981;116:568. 96. Harness JK, Fung L, Thompson NW, et al. Total thyroidectomy: Complications and technique. World J Surg 1986;10:781. 97. Wells SA Jr, Baylin SB, Johnsrude IS, et al. Thyroid venous catheterization in early diagnosis of familial medullary thyroid carcinoma. Ann Surg 1982;196:505. 98. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992; III :604. 99. Schlumberger M, Tubiana M, DeVathaire F, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinomas. J Clin Endocrinol Metab 1986;63:960.
Occurrence and Prevention of Complications in Thyroid Surgery Job Kievit, MD, PhD • Bert A. Bonsing, MD, PhD • Ilfet Songun, MD, PhD • Comelis J.H. van de Velde, MD, PhD
The first surgeon to receive the Nobel Prize in medicine was Theodor Kocher (1841-1917) in 1909, a pioneer in thyroid surgery. One of his accomplishments was to reduce the frequency of thyroid surgery complications. The refinements of his surgical methods from his first important article on thyroidectomy (1878) led to a reduction in mortality from high initial figures (50%) to less than 4.5%. Currently, the mortality rate of thyroidectomy, as reported in several large series, approaches zero. The morbidity of thyroidectomy, however, continues to be a matter of concern. Meticulous attention to operative technique is required, as is a flexible approach that balances the requirements of resection to avoid recurrences against the risk of complications. In 1989, in the United Kingdom, surgical claims for thyroidectomy complications accounted for 4% of general surgical claims, all of which involved recurrent laryngeal nerve injury.' Claims underrepresent complications, and complications in routine care may occur more frequently than in published series. Most complications of thyroidectomy can be avoided by detailed knowledge of the anatomy and careful surgical technique. Although it is a surgical truism that volume generally improves quality, recent research suggests that surgeons may differ in their ability to perform this refined surgery with sufficient care.' Regardless of the background of the surgeon (general surgeon, head and neck surgeon, or endocrine surgeon), the collaboration with an endocrinologist and broad experience in thyroid surgery not only will improve quality but will give confidence in any legal challenge and will help educate future surgeons in proper surgical decision making and technique.
Surgery for Thyroid Disease In the foregoing chapters, the indications for thyroid surgery for different pathologic entities have been discussed. Naturally, benefits of surgical therapy must outweigh the
risks involved. About 1 in 10 solitary thyroid nodules is malignant.' Therefore, a selective approach must be used to determine who will benefit from thyroidectomy and who can be safely observed. The same applies to the extent of thyroid surgery (e.g., total vs. subtotal thyroidectomy) or of surgery for lymph node metastases (node picking or radical neck dissection).
Complications in Patients Undergoing Thyroid Surgery In this chapter, we discuss "complications," being defined as unfavorable and unintended outcomes of care-in short, adverse outcomes. Complications of thyroid surgery can be divided into general or specific complications, the latter being directly related to surgical technique, and the former being more or less independent of the surgical technical procedure itself. Examples of general complications are circulatory and respiratory problems and urinary tract infections. Specific complications include vocal cord dysfunction resulting from injury to the recurrent or external laryngeal nerves, hypoparathyroidism, bleeding, serous or lymphatic leakage, and hypoparathyroidism (origination from damage or ischemia to the parathyroid glands). The nerves at risk during thyroid operations are the external branch of the superior laryngeal nerve (EBSLN), the recurrent laryngeal nerve, and, depending on the surgical approach chosen, the various branches of the hypoglossal ansa. Other complications, such as lesions of the esophagus, thoracic duct, jugular vein, and carotid artery, are extremely rare and are likely to occur only in patients with large, invasive tumors requiring more extensive surgery. In the next sections, we deal with most general and specific complications, drawing both from literature data and from a series of 752 patients undergoing thyroid surgery at the Leiden University Medical Center (27% of them being reoperations). Attention is paid especially to the local anatomy,
207
208 - - Thyroid Gland surgical techniques that can prevent damage to the structures at risk, and handling of complications.
General Complications The most frequent general complications involve the heart and the lungs. In our series, benign cardiac arrhythmias occurred in 0.4% of patients; however, one patient (0.1 %) died because of a cardiac arrest. Pulmonary complications involved bronchitis or pneumonia (0.5%); none of these caused severe morbidity or mortality. Other general complications were cystitis (0.2%) and fever (0.2%).
Specific Complications Edema Facial, neck, or tracheal edema may be caused by decreased venous or lymphatic drainage from the operating field. It may interfere with inspiration and occurs especially if thyroidectomy is combined with bilateral lymphadenectomy, such as may be required in patients with medullary cancer.t-' Severe edema in the case of isolated thyroid surgery is rare; none of our patients needed treatment for this complication. It is more common in patients with neck dissections, and it can be prevented or reduced by keeping the head elevated and applying cortisone preparations.
Bleeding Bleeding in the operating field may occur from superficial arteries and veins in the neck, lying on the superficial cervical fascia and from vessels around the thyroid. Such bleeding occurred in nine patients (1.2%) in our series, half of them requiring reoperation. Ligatures tied around the superficial neck veins may come loose and cause subcutaneous bleeding or hematoma. The rich vascular supply of the thyroid gland contributes to its bleeding tendency and stresses the need for meticulous hemostasis. Perioperative bleeding may be decreased by having the patient in a reverse Trendelenburg position, with the head elevated 20 degrees. To test for possible bleeding at the conclusion of the thyroidectomy, the head can be tilted down and the lungs hyperinflated by the anesthetist to increase intrathoracic pressure as well as blood pressure in the neck veins. After thyroid surgery, patients should be kept in a low Fowler position with the head and shoulders elevated 10 to 20 degrees to keep a negative pressure in the veins; they should be observed in the postanesthesia care unit for several hours because most significant hemorrhages with evident tracheal compression occur within hours after operation. In accordance with recent research, we do not routinely use drains, but only if bleeding during or at the end of surgery causes concem.v!" If used at all, drains should be at least be 14 gauge. Drains are certainly not a reason to decrease concern: clots may form and prevent adequate drain function of the placed drains. Extensive dressings may hide the complication and prevent inspection of the contour of the neck and are, therefore, not advised. In the case of symptomatic postoperative hematomas, a liberal attitude toward re-exploration is justified. Hematoma or seroma
occurring after several days is uncommon and generally can be managed expectantly.
Wound Healing Disorders and Infection A well-positioned collar incision, approximately 2 em above the jugulum or 1 em below the cricoid cartilage, extended laterally and closed by intracutaneous running suture, gives the best cosmetic result. A lower incision is more prone to keloid development. If this occurs, excision of the scar after I year may reduce the size of the deformity. Infections occur rarely in thyroid surgery, most often when combined with lymph node dissection (3 patients [0.4%1 in our series, one of whom also had a tracheostomy). Apart from normal surgical hygiene and disinfection and the avoidance of operations in patients with acute sore throats, no additional preventive measures are required. Infections should be treated by opening the wound and evacuating the pus. After adequate drainage, when granulation starts, the wound can be excised and closed secondarily by intracutaneous suture, which gives the same excellent aesthetic result as in uncomplicated primary closure. Seroma can be treated by aspiration.
Vascular and Lymphatic Lesions Other specific surgical complications, typical for thyroid surgery, involve the thyroid vessels and the thoracic duct. The vessels most easily damaged during thyroidectomy are the middle and inferior thyroid veins, which may be severed between their origin from the internal jugular vein and their entrance into the lateral margin of the thyroid lobe. This is especially the case when very large goiters obscure the trajectory of these vessels. Bleeding is easily controlled by ligation and has no adverse effects. Damage to the thyroid arteries rarely occurs accidentally but generally occurs on purpose to devascularize the thyroid lobe. Ligation of both arteries, but more so of the inferior than of the superior thyroid artery, may cause parathyroid ischemia. Some authors contend that ligation of the inferior thyroid artery causes ischemia to both the inferior and the superior parathyroid glands, especially if the artery is ligated far away from the thyroid gland. Lesions to the thoracic duct may occur when thyroid surgery is combined with lymph node dissection (Fig. 23-1). The duct is most frequently damaged at its craniolateral aspect, where lymphatic vessels from the neck enter into the duct, resulting in leakage of clear or milky chylous fluid. If the thoracic duct, or one of its branches, is injured intraoperatively, it should be ligated. Ligation is sometimes difficult because it may be hard to identify the duct. In such cases, suturing the surrounding middle or deep cervical fascia over the duct leak is often possible. Alternatively, the investing fascia of the anterior scalenus muscle may be mobilized in a craniocaudal direction and used to cover the site of leakage. In that case, extreme care should be paid to the phrenic nerve, and its prescalenal trajectory may obviate usage of the anterior scalenus fascia. After successful suture ligation treatment of leakage, any coverage achieved should be reinforced with the use of fibrin sealant in combination with collagen (e.g., Tissuecol).
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FIGURE 23-1. Extensive lymphatic branching of the thoracic duct in a patient undergoing neck dissection for thyroid cancer.
If leakage of the thoracic duct is recognized postoperatively (because of the production of clear or milky fluid from the wound drain), it may be treated conservatively (by total parenteral nutrition for several weeks) or surgically. Surgery is the most effective treatment and involves reopening the neck, identifying the lesion, and treating it as described previously. In our series, we were able to obtain surgical control of the duct in all cases in which leakage occurred both intraoperatively (1.2% of our patient series) and postoperatively (0.4% of patients in our series).
Nerve Damage to the Recurrent Laryngeal Nerve The recurrent laryngeal nerve is involved in most claims concerning complications of thyroid surgery.' Morbidity related to this injury ranges from minimal changes in voice quality to recurrent tracheal aspiration and/or severe dyspnea requiring tracheostomy. The incidence of injury to the recurrent laryngeal nerve(s) during thyroid surgery is influenced by many factors. The risk is higher in more extended thyroid resections, in patients with malignant thyroid disease, in patients in whom the recurrent laryngeal nerves could not be identified, and in re-operations due to recurrent thyroid disease.'!"? Although it is recognized that experience reduces complication rates in surgery in general and reoperations on thyroid disease specifically, reports concerning this topic in primary thyroid surgery are conflicting and emphasize the importance of individual surgical skill and performance. I 1.12.14,16.18,19 Use of a harmonic scalpel reduces operating time but was not shown in small studies to be safer in avoiding recurrent laryngeal nerve injury than bipolar coagulation and ligatures. 20 -22 The same is true for use of minimally invasive video-assisted procedures.P:" At present, there are mainly three strategies that can reduce the risk of recurrent laryngeal nerve injury. The first and most frequently used method is visual control by complete dissection of the full extralaryngeal trajectory of the recurrent laryngeal nerve. I I Second, intraoperative electrical nerve stimulation of the surgical field in addition to visual control can be used to delineate the presence, function, and
FIGURE 23-2. Right-sided non-recurrent recurrent laryngeal nerve in a woman with tertiary hyperparathyroidism.
possibly the course of the recurrent laryngeal nerves by observing contractions of the cricopharyngeus muscle. 27- 32 Third, uninterrupted monitoring of laryngeal electromyographic activity through electrodes placed against the posterior cricoarytenoid muscles can be used. It reveals changes in mechanical activation by manipulation of the recurrent laryngeal nerves during dissection. 27,33-36 Either way, detailed knowledge of the anatomy is of paramount importance to avoid damage to the recurrent laryngeal nerve. The anatomy of the recurrent laryngeal nerves can be quite variable, especially in patients with large goiters, and in cases of "redo" surgery for recurrent thyroid outgrowth. Normally, the right laryngeal nerve arises anterior to the right subclavian artery or brachiocephalic trunk, ascends in the neck behind the common carotid artery, and then curves medially and ventrally, running obliquely and superiorly toward the cricoid cartilage and inferior constrictor. In less than I % of patients, the right recurrent nerve is nonrecurrent and may enter the thyroid from a superior or lateral direction. I I ,37-39 Combinations of recurrent and nonrecurrent branches do also occur (Figs. 23-2 to 23-4).11
FIGURE 23-3. Right-sided partially non-recurrent recurrent laryngeal nerve in young woman with multiple endocrine neoplasia type I hyperparathyroidism.
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FIGURE 23-4. Right-sided partially non-recurrent recurrent laryngeal nerve in a young woman with severe Hashimoto's thyroiditis.
The left recurrent nerve arises from the nervus vagus on the left side of the aortic arch and winds around the arch behind the attachment of the ligamentum arteriosum. It then ascends in the anterior mediastinum and neck in a more medial position, running in the left tracheoesophageal groove. Both nerves subsequently ascend in the neck and cross the lower lateral border of the thyroid at the level of the inferior thyroid artery. They then pass behind the thyroid lobe and laterodorsally to Berry's ligament before they penetrate the cricothyroid muscle to enter the larynx.4o•42 Inside the larynx, the nerve divides into two or three branches-a lateral and a medial branch-that innervate different laryngeal muscles. In addition to this normal rarnification pattern within the larynx, the recurrent nerve may also give off branches in its extralaryngeal ascent in the neck in 60% to 75% of the patients." In the first place, the nerve may divide at any level between its origin and its entry in the larynx, resulting in a full or partial duplication of the nerve within the neck. These branches then ascend in the neck in a parallel course until their entry in the larynx. Besides duplication of the recurrent laryngeal nerve itself, the nerve may give off branches that do not enter the larynx but connect the nerve to other structures within the neck. In the lower part of the neck, small branches may divert from the lateral aspect of the nerve to reach the sympathetic chain, where they connect to the cranial and medial cardiac nerves. Other small branches separate from the nerve medially to innervate the trachea, esophagus, and larynx. Finally, the recurrent nerve may infrequently give off a large lateral branch that runs in a cranial and lateral direction and connects with the superior laryngeal nerve: the communicating branch of the recurrent laryngeal nerve. In conclusion, the recurrent nerve is not always a single strand that ascends in the neck to enter the larynx. It may exhibit a relatively complicated pattern of branches. The easiest site at which to identify the recurrent nerve is near where the inferior thyroid artery (which can easily be seen or palpated between the carotid artery and the lateral aspect of the lower pole of the thyroid) crosses the lateral border of the lower pole of the thyroid gland. The recurrent nerve or one of its branches may pass behind, between, or before the branches of the artery, with at least one nerve branch passing before the artery in about 40% of cases. An advantage of this approach is its relative ease; a slight disadvantage is the risk that the nerve has already given off
one or more branches at a more caudal level that are missed. A result of such variation may be that if only one of two or more branches of the recurrent nerve is identified, it may be falsely assumed that "the" recurrent nerve has been found, and the other branches may inadvertently be severed. Fortunately, this situation is quite uncommon. There are four other ways of identifying the recurrent nerve. 1. The nerve can be located most caudally where it crosses behind the cranial and medial curves of the common carotid artery. At this level, the nerve lies further dorsally than at more cranial levels, but it can always be identified if dissection is performed along the mediocranial surface of the artery, exploring from a lateral to a medial and dorsal direction toward the trachea and esophagus. An advantage of this approach is that the nerve is larger because it has not given off branches. A second advantage is that, in case of reoperation, the neck at this level may be unviolated, facilitating identification of the recurrent nerve with a lower risk of injury. A minor disadvantage of this procedure is its slightly more cumbersome nature, necessitating dissection of the loose connective, fatty, and lymphoid tissues caudally in the neck. 2. The recurrent nerve can be identified at the level of Berry's ligament, just caudal to its level of entry through the cricothyroid muscle into the larynx. The advantage of this approach is that the location of the nerve at this level is fairly fixed. An important disadvantage is that it is located behind the thyroid, which makes access difficult. In addition, this area is hypervascular, and annoying bleeding may easily occur, especially from a small branch of the inferior laryngeal artery, which runs on the cranial border of Berry's ligament and bleeds in close approximation to the entry of the recurrent laryngeal nerve. Bleeding from this artery should be treated with fine (5-0 or 6-0 Prolene) sutures or a hemoclip, a technique that is preferable in all cases of bleeding close to the recurrent laryngeal nerve. Coagulation with bipolar diathermy is acceptable at distances of at least 5 mm from the nerve and is therefore not the preferred method of hemostasis in this area. 3. The recurrent laryngeal nerve can be identified with the use of palpation instead of visually guided dissection. By gently pressing the loose connective, fatty, and lymphoid tissues below the lower thyroid pole against the trachea and moving the finger slowly ventrally and dorsally and back and forth, the nerve can often be felt as a string that moves on the surface of the trachea and tends to "snap" from underneath the palpating finger. Once this sensation has been felt, the connective tissue can be separated carefully in the direction of the nerve. Careful alternation between palpation and dissection prevents injury to the nerve. 4. Finally, neuromonitoring such as described earlier can be used to identify the recurrent laryngeal nerve and its course. 27. 37,46 Especially in reoperations, this can be helpful, as are alternative surgical approaches to the thyroid using previously undissected surgical planes (i.e., an approach around the lateral border of the sternohyoid and sternothyroid muscles)."
Occurrence and Prevention of Complications in Thyroid Surgery - - 211
Complications concerning the laryngeal nerve cause considerable morbidity and occur in 0% to 5% of the patients. 11,27.44-48 In our series involving 755 nerves at risk, the overall risk of permanent injury was 0.5%. Postoperative hoarseness may be caused by several mechanisms. If it occurs in the first 2 to 5 days postoperatively, it is most likely caused by edema in the operating field as a selflimited, innocent process. Long-term hoarseness (~6 months) may occur if the recurrent nerve has been kept intact, whereas stretching it too forcefully has damaged its axons. This can be avoided by handling the nerve gently in all stages of the operation. The nerve should be separated carefully from the thyroid gland before the gland is retracted medially or otherwise manipulated. Vessel loops, put around the nerve for better anatomic identification, should never be kept in hemostats or otherwise fixated, because traction on the loop may cause nerve damage. In the case of nerve stretching, new axon ends need to grow into the axon sheath, a process that takes 1 day to grow 1 mm. Inadvertent cutting or clamping the recurrent laryngeal nerve may cause permanent hoarseness. If this is observed perioperatively, reanastomosis can be performed using the operating microscope and 10-0 Prolene sutures, but the outcome is often unsatisfactory.f'?' When lesions of both recurrent laryngeal nerves occur, patients have dyspnea and difficulty in breathing. These patients should be reintubated or should have a tracheostomy. Most recover some function, but if dysfunction is permanent, a lateralization or laser treatment of the vocal cords is mandatory. Preoperative direct or indirect laryngoscopy should be performed in all patients with a voice change, with proven malignancy, or with a history of neck exploration. In our opinion, postoperative laryngoscopy does not need to be performed routinely but instead may be reserved for patients with vocal cord dysfunction seen at laryngoscopy during extubation and for patients with voice change after thyroid surgery. When vocal cord dysfunction continues for 1 year, it is most likely permanent. However, in cases of nerve reanastomosis, improvement is still possible, even after 1 to 2 years, in our own experience.
artery, and divides into terminal branches. Some of these branches may communicate with branches of the recurrent laryngeal nerve, either within the larynx, or externally. The internal branch provides sensory innervation of the pharyngeal and laryngeal mucosa, extending from the base of the tongue to the glottis and subglottic region. Lesion of the nerve causes loss of sensation of the ipsilateral mucosa. This loss is manifested clinically by aspiration of food and drink on swallowing, caused by the defective sensori motor coordination of the glottis. Treatment consists of specialized physiotherapy, in which the patient is trained to exhale while swallowing. The EBSLN takes a more caudal course, running in close proximity to the medial aspect of the superior thyroid artery. Cranial to the superior pole of the thyroid lobe, it curves medially to innervate the cricothyroid muscle, which regulates the tension in the ipsilateral vocal cord. Two aspects of its anatomy are important determinants of the risk of it being injured during surgery at the upper pole of the thyroid: (1) the level at which it crosses the (vessels of) the upper pole of the thyroid and (2) whether it runs superficial to, or is covered by, the inferior constrictor of the pharynx. Cernea and associates have provided a classification system for the course of the EBSLN that is widely accepted.52-54 Cernea type 1 means that the nerve crosses medially into the cricothyroid muscle more than 1 em cranially to the upper pole of the thyroid lobe; it occurs in about two thirds of cases. Cernea type 2 means that the EBSLN runs within a distance less than 1 em from the upper pole of the thyroid gland, or passes even more caudally, thereby being at risk during surgery at or near the upper pole; it occurs in the remaining one third of cases. Depending on how far caudally the nerve extends, Cernea type 2 is subdivided into types 2a and 2b. In Cernea type 2a, the nerve remains cranial to the upper pole of the thyroid lobe. A nerve that in its most caudal position comes to lie below the upper pole of the thyroid lobe is considered Cernea type 2b (Figs. 23-5 and 23-6). This location has clear surgical importance
Nerve Damage to the External Branch of the Superior Laryngeal Nerve Damage to the EBSLN causes less severe symptoms than damage of the recurrent laryngeal nerve and is therefore less easily recognized and documented. Because the course of this nerve varies even more than that of the recurrent nerve, knowledge of its anatomy is vital. The superior laryngeal nerve, like the recurrent laryngeal nerve, originates from the vagus nerve, in this case close to the caudal end of the nodose ganglion above the hyoid bone. The nerve subsequently descends in the neck in a caudal, medial, and ventral direction, crossing behind the external carotid artery or the carotid bifurcation, where it gives off branches to the carotid body. At the level of the hyoid bone, it divides into an internal (sensory) branch and an external (motor) branch. The common trajectory of the superior laryngeal nerve and its internal branch is positioned cephalad to the dissection area used during thyroidectomy and is therefore not encountered in standard thyroid surgery. The internal branch of the superior laryngeal nerve curves medially, perforates the thyrohyoid membrane above the superior laryngeal
FIGURE 23-5. External branch of superior laryngeal nerve (EBSLN) passing below the left upper pole in a case of enlarged dysplastic thyroid (Cernea type 2b).
212 - - Thyroid Gland
FIGURE 23-6. External branch of superior laryngeal nerve
(EBSLN) running on the mediodorsal surface of the left upperpole in a patient operated on acutely for asphyxia caused by a grossly enlarged thyroid (Cernea type 2b).
because of an increased risk of injury during the dissection and ligation of the superior thyroid pedicle during thyroidectomy (so-called high-risk nervesj." It goes without saying that, especially in cases of type 2 crossing, the nerve is at risk for inadvertent damage if the superior thyroid vessels are clamped en masse and divided before the nerve is freed. The technique of identification of the EBSLN has been described by several authors. 55-62 Of course, one should first of all have adequate cranial exposure of the upper pole of the thyroid by an adequate skin incision and by a sufficiently high division of the linea alba cervicalis. Subsequently, the sternohyoid and sternothyroid muscles are carefully dissected free from the underlying thyroid and are retracted laterally. An excellent procedure for identifying the EBSLN is Lennquists's stepwise method, using (1) a midline incision between the strap muscles, (2) opening of the space between the upper pole and the cricothyroid muscle by laterocaudal traction of the thyroid, (3) careful dissection of the thyroid vascular pedicle, and (4) careful inspection of the inferior pharyngeal constrictor." Most essential is step 2, in which the upper part of the sternothyroid muscle is retracted laterally and cranially to free the upper pole of the thyroid. While this traction is continued, the loose connective tissue located medial to the superior thyroid vessels is opened, and the entire medial border of the thyroid lobe is carefully inspected from the thyroid isthmus to the upper pole. One should keep in mind that, if there are no nerve branches crossing from the thyroid surface medially to enter the cricothyroid muscle, one should not fear an EBSLN entering the thyroid vascular pedicle more cranially. For that reason, we prefer freeing the cricothyroid space in a mediocaudal to laterocranial direction. Dissection is continued up to 1 em cranially from the end of the upper pole, until the EBSLN is either identified and freed, or the superior thyroid vessels are freed over a sufficiently long course to make certain that an unidentified nerve is not included in the vascular pedicle. In cases in which sparing of the EBSLN is crucial (e.g., in professional singers), use of the nerve stimulator should be considered, especially in those cases where
anatomic identification of the nerve fails. Effective prevention of iatrogenic lesions during thyroidectomy by intraoperative identification of the external branch with a nerve stimulator is described by Cernea and colleagues'? and Eisele. 63 However, identifying the nerve is not sufficient as long as other important principles are forgotten. Lennquist and coworkers reported that inappropriate use of diathermy close to the external branch can cause damage, which also occurs to the recurrent laryngeal nerves, and should therefore be avoided, in favor of ligatures." In all cases in which sparing the EBSLN is considered relevant, the vessels of the upper pole should be dissected individually and be ligated as caudally as possible on the surface of the thyroid. The use of clamps should be avoided in favor of suture ligation between thin (4-0 or 5-0) absorbable ligatures. The variations just described must be kept in mind when one performs this procedure. Another important finding is considerable asymmetry of the left and right EBSLNs. Iatrogenic lesions of the external branch during thyroidectomy are not infrequent because of the anatomic variations in relation to the superior thyroid vessels. The importance of preserving the external branch during thyroidectomy was dramatically demonstrated in 1935, when the famous opera soprano Amelita Galli-Curci sustained injury to a superior laryngeal nerve during thyroidectomy for an enlarged toxic goiter, which ended her career. In singers, injury to this nerve is a serious problem, although for some patients symptoms are minimal and are often overlooked. Some patients complain of mild hoarseness, voice weakness or fatigue, loss of voice range (especially upper singing registers), and lower voice volume. When both left and right superior laryngeal nerves are injured, patients experience swallowing disorders, which make them vulnerable to pneumonias. The most accurate test for postoperative assessment of superior laryngeal nerve paralysis is laryngeal electromyography; evaluation by laryngoscopy can be quite difficult. The vocal cord on the involved side is usually bowed and at a lower level than the contralateral vocal cord. In addition, the anterior larynx is slightly rotated to the contralateral side because of the action of the intact contralateral cricothyroid muscle.
Hypoparathyroidism Most individuals have four parathyroid glands situated on the posterolateral capsule of the thyroid. Anatomic studies have demonstrated that 80% to 86% of upper parathyroid arteries and 90% to 95% of lower parathyroid arteries originate from the inferior thyroid artery. Truncal ligation of the inferior thyroid arteries during thyroidectomy, however, does not cause more hypoparathyroidism compared with ligation of the branches of these arteries at the resection margin of the thyroid capsule.v' Becuase superior thyroid arteries may contribute significantly to the parathyroid blood supply, and sufficient parathyroid blood supply may be ensured by collaterals between thyroid vessels and neighboring esophageal and tracheal arteries. The upper parathyroid glands are usually located lateral to the recurrent laryngeal nerve at the level of Berry's ligament and are the glands that are usually the easiest to preserve
Occurrence and Prevention of Complications in Thyroid Surgery - - 213
during thyroidectomy because of their more lateral and posterior position. The lower parathyroid glands are almost always situated anterior to the recurrent laryngeal nerves and caudal to where the recurrent laryngeal nerve crosses the inferior thyroid artery. Permanent hypoparathyroidism occurs in less than 3% ~f the patients, whereas transient postoperative hypocalcemia is much more common. 65-69 Ischemia or removal of the parathyroid glands results in temporary or per~anent hypoparathyroidism and may be caused ~y ?ccIdental coagulation by heat induction, by devascularization, or by accidental removal of the parathyroid glands. For better identification of the vascularization of the gland, magnifying glasses (x2.5) are helpful. The parathyroid glands should not be mobilized extensively, or they may be devascularized during the dissection. When a parathyroid gland cannot be safely dissected from the thyroid gland on a good vascular pedicle, it should be removed and then autotransplanted into the sternocleidomastoid muscle or into t~e brachioradial muscle of the nondominant arm. Parathyroid glands should be inspected carefully with m~gnifying glasses both during and at the end of the operatron. Any gland that appears ischemic should be removed and aut.otransplanted because there is no reason to assume that Its vascular supply will recover. Not doing so means unnecessarily running the risk of hypoparathyroidism. On the other hand, there is no reason to perform biopsy of normalappearing parathyroid glands durin~. thyroid. su.rgery because this obviously subjects them to injury. Earlier III our patient series, when parathyroid biopsy was regularly used, symptomatic hypocalcemia requiring supplementation occurred in about 10% of patients, and permanent hypocalcemia (6 weeks to 6 months after thyroid surgery) was seen in 3.5%. In later years, we have more and more come to rely on surgical identification of the parathyroids. The criteria ~e use are (1) position; (2) mobility independent of the thyroid gland; (3) brownish color; (4) smooth, finely granular surface; (5) presence of vascular pedicle; (6) easy bleeding on manipulation, in particular the rapid spread of a subcapsular hematoma in case of manipulation with forceps; and (7) the presence of a small "fatty hood." With these seven criteria, we rarely need frozen section biopsy to identify parathyroids. Permanent hypoparathyroidism has thereby decreased to below 2%. Preoperative serum calcium levels should be checked routinely in each patient undergoing bilateral thyroid procedures. Postoperative hypocalcemia resulting from hypoparathyroidism is seen after bilateral thyroidectomy but almost never after unilateral thyroidectomy unless the patient has had previous thyroid surgery. If there are clinical symptoms, oral calcium should be given. Permanent hypoparathyroidism is evident when, after 1 year: serum calcium levels are below 2.25 mmol/L and the patIent has symptoms and requires treatment with vitamin D and calcium. Such patients also have high phosphate levels. Permanent hypoparathyroidism results in lifetime disability. Despite frequent testing and adjustments in therapy, fatigue, paresthesias, and irritability are common. Cata~acts h~ve been reported in as many as 70% to 80% of patients WIth permanent hypoparathyroidism, despite laboratory evidence of normocalcemia.s?
Hypothyroidism Hypothyroidism occurs after total or near-total thyroidectomy and increases in frequency after subtotal procedur~s as the size of the remnant decreases. Menegaux and associates compared the outcome of surgical treatment for Graves' disease from 1966 to 1980 and from 1981 to 1988. 70 During the second period, in which bilateral subtotal thyroidectomy was abandoned for unilateral total lobectomy and a subtotal lobectomy on the other side (Dunhill procedure), the rate of permanent recurrent laryngeal nerve and recurrent hyperthyroidism decreased (from 1% to 0% and from 11% to 3.7%, respectively), whereas the rate of permanent hypoparathyroidism and hypothyroidism increased (from 1% to 1.9% and 13% to 48.7%, respectively).
Summary During thyroid operations, it is important to achieve a balance between the benefits of extensive resection for cure and the increased potential for complications. More extensive thyroid resections, especially when combined with bilateral and central neck and modified radical neck dissections, are associated with more postoperative complications, as are reoperations.":" However, the literature contains numerous reports of total thyroidectomy and reintervention by experienced surgeons in which the prevalence of recurrent laryngeal nerve injury and permanent hypoparathyroidism is 2% or less, demonstrating that these operations can be done with minimal morbidity." Total thyroidectomy has been proposed for multinodular goiters involving the entire g~a.nd, Graves' disease, and malignancies by a few authorities, because total thyroidectomy eliminates the possibility of recurrence. However, complications may occur, even in experienced hands, and in the same surgeon's hands more extensive thyroid operations are associated with more complications. To keep morbidity to a minimum, thyroid operations for patients with cancer or large goiters should be performed by surgeons trained in endocrine surgery, with extensive knowledge of the topographic anatomy and its variations. To maintain surgical skills, we believe that individual surgeons bearing responsibility for surgical outcomes should perform no fewer than 10 thyroidectomies annually. If these principles are followed, thyroid surgery can be performed in teaching hospitals such as ours with minimal morbidity and almost zero mortality.18,74-76
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214 - - Thyroid Gland 6. Joudinaud T, Corre FL, Pages JC, et al. [Drainage after thyroid surgery: 264 patients.] Ann Otolaryngol Chir Cervicofac 2002;119:146. 7. Tugergen D, Moning E, Richter A, Lorenz D. [Assessment of drain insertion in thyroid surgery?] Zentralbl Chir 2001;126:960. 8. Hurtado-Lopez LM, Lopez-Romero S, Rizzo-Fuentes C, et al. Selective use of drains in thyroid surgery. Head Neck 2001;23:189. 9. Tabaqchali MA, Hanson 1M, Proud G. Drains for thyroidectomy/ parathyroidectomy: Fact or fiction? Ann R Coli Surg Engl 1999;81:302. 10. Karayacin K, Besim H, Ercan F, et aI. Thyroidectomy with and without drains. EastAfr Med J 1997;74:431. 11. Hermann M, Alk G, Roka R, et al. Laryngeal recurrent nerve injury in surgery for benign thyroid diseases: Effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk. Ann Surg 2002;235:261. 12. Hermann M, Keminger K, Kober F, Nekahm D. [Risk factors in recurrent nerve paralysis: A statistical analysis of 7566 cases of struma surgery.] Chirurg 1991;62:182. 13. Lo CY, Kwok KF, Yuen pw. A prospective evaluation of recurrent laryngeal nerve paralysis during thyroidectomy. Arch Surg 2000;135:204. 14. Menegaux F, Turpin G, Dahman M, et al. Secondary thyroidectomy in patients with prior thyroid surgery for benign disease: A study of 203 cases. Surgery 1999;126:479. 15. Misiolek M, Waler J, Namyslowski G, et al. Recurrent laryngeal nerve palsy after thyroid cancer surgery: A laryngological and surgical problem. Eur Arch Otorhinolaryngol 2001;258:460. 16. Moley JF, Lairmore TC, Doherty GM, et al. Preservation of the recurrent laryngeal nerves in thyroid and parathyroid reoperations. Surgery 1999;126:673. 17. Steurer M, PassIer C, Denk DM, et al. Advantages of recurrent laryngeal nerve identification in thyroidectomy and parathyroidectomy and the importance of preoperative and postoperative laryngoscopic examination in more that 1000 nerves at risk. Laryngoscope 2002;112:124. 18. Lamade W, Renz K, Willeke F, et al. Effect of training on the incidence of nerve damage in thyroid surgery. Br J Surg 1999;86:388. 19. Thomusch 0, Machens A, Sekulla C, et al. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: A multivariate analysis of 5846 consecutive patients. Surgery 2003;133:180. 20. Siperstein AE, Berber E, Morkoyun E. The use of the harmonic scalpel versus conventional knot tying for vessel ligation in thyroid surgery. Arch Surg 2002;137:137. 21. Vach B, Fanta J, Velenska Z. [The harmonic scalpel and surgery of the thyroid gland.] Rozhl Chir 2oo2;81(Suppll):S3-S7. 22. Voutilainen PE, Haglund CH. Ultrasonically activated shears in thyroidectomies: A randomized trial. Ann Surg 2000;231:322. 23. Bellantone R, Lombardi CP, Bossola M, et al. Video-assisted versus conventional thyroid lobectomy: A randomized trial. Arch Surg 2002;137:301. 24. Bellantone R, Lombardi CP, Raffaelli M, et al. Minimally invasive, totally gasless video-assisted thyroid lobectomy. Am J Surg 1999; 177:342. 25. Miccoli P, Bellantone R, Mourad M, et al. Minimally invasive videoassisted thyroidectomy: Multi-institutional experience. World J Surg 2002;26:972. 26. Yeh TS, Jan YY, Hsu BR, et aI. Video-assisted endoscopic thyroidectomy. Am J Surg 2000;180:82. 27. Marcus B, Edwards B, Yoo S, et al. Recurrent laryngeal nerve monitoring in thyroid and parathyroid surgery: The University of Michigan experience. Laryngoscope 2003;113:356. 28. Hillermann CL, Tarpey J, Phillips DE. Laryngeal nerve identification during thyroid surgery: Feasibility of a novel approach. Can J Anaesth 2003;50: 189. 29. Scheuller MC, Ellison D. Laryngeal mask anesthesia with intraoperative laryngoscopy for identification of the recurrent laryngeal nerve during thyroidectomy. Laryngoscope 2002; 112:1594. 30. Eltzschig HK, Posner M, Moore FD Jr. The use of readily available equipment in a simple method for intraoperative monitoring of recurrent laryngeal nerve function during thyroid surgery: Initial experience with more than 300 cases. Arch Surg 2002;137:452. 31. Dimov RS, Mitov FS, Deenichin GP, et al. Stimulation electromyography as a method of intraoperative identification of the recurrent laryngeal nerve in thyroid surgery. Folia Med (Plovdiv) 2001;43:17.
32. Jonas J, Bahr R. [Intraoperative electromyographic identification of the recurrent laryngeal nerve.] Chirurg 2000;71 :534. 33. Lambert AW, Cosgrove C, Barwell J, et al. Vagus nerve stimulation: Quality control in thyroid and parathyroid surgery. J Laryngol Otol 2000;114:125. 34. Otto RA, Cochran CS. Sensitivity and specificity of intraoperative recurrent laryngeal nerve stimulation in predicting postoperative nerve paralysis. Ann Otol Rhinol Laryngol 2002;111:1005. 35. Timon Cl, Rafferty M. Nerve monitoring in thyroid surgery: Is it worthwhile? Clin Otolaryngol 1999;24:487. 36. Thomusch 0, Sekulla C, Walls G, et al. Intraoperative neuromonitoring of surgery for benign goiter. Am J Surg 2002;183:673. 37. Vuillard P, Bouchet A, Gouillat C, Armand D. [Non-recurrent inferior laryngeal nerve: 15 operative cases.] Bull Assoc Anat (Nancy) 1978;62:497. 38. Wijetilaka SE. Non-recurrent laryngeal nerve. Br J Surg 1978;65:179. 39. Ardito G, Manni R, Vincenzoni D, et aI. [The non-recurrent inferior laryngeal nerve: Surgical experience.] Ann Ital Chir 1998;69:21. 40. Lekacos NL, Tzardis PJ, Sfikakis PG, et al. Course of the recurrent laryngeal nerve relative to the inferior thyroid artery and the suspensory ligament of Berry. Int Surg 1992;77:287. 41. Leow CK, Webb AJ. The lateral thyroid ligament of Berry. Int Surg 1998;83:75. 42. Sasou S, Nakamura S, Kurihara H. Suspensory ligament of Berry: Its relationship to recurrent laryngeal nerve and anatomic examination of 24 autopsies. Head Neck 1998;20:695. 43. Katz AD, Nemiroff P. Anastomoses and bifurcations of the recurrent laryngeal nerve: Report of 1177 nerves visualized. Am Surg 1993;59:188. 44. Calrk OH, Levin K, Zeng QH, et al. Thyroid cancer: The case for total thyroidectomy. Eur J Cancer Clin Oncol 1988;24:305. 45. de Roy van Zuidewijn DB, Songun I, Kievit J, van de Velde CJ. Complications of thyroid surgery. Ann Surg Oncol 1995;2:56. 46. Dralle H. [Intraoperative neuromonitoring in thyroid surgery and surgery of the parathyroid gland.] Zentralbl Chir 2002;127:393. 47. Martensson H, Terins J. Recurrent laryngeal nerve palsy in thyroid gland surgery related to operations and nerves at risk. Arch Surg 1985;120:475. 48. Shindo ML, Sinha UK, Rice DH. Safety of thyroidectomy in residency: A review of 186 consecutive cases. Laryngoscopy 1995;105:1173. 49. Chou FF, Su CY, Jeng SF, et al. Neurorrhaphy of the recurrent laryngeal nerve. J Am Coli Surg 2003;197:52. 50. Damrose EJ, Huang RY,Ye M, et al. Surgical anatomy of the recurrent laryngeal nerve: Implications for laryngeal reinnervation. Ann Otol Rhinol Laryngol 2003;112:434. 51. Maronian N, Waugh P, Robinson L, Hillel A. Electromyographic findings in recurrent laryngeal nerve reinnervation. Ann Otol Rhinol LaryngoI2003:112:314. 52. Cernea CR, Ferraz AR, Furlani J, et al. Identification of the external branch of the superior laryngeal nerve during thyroidectomy. Am J Surg 1992;164:634. 53. Cernea CR, Ferraz AR, Nishio S, et al. Surgical anatomy of the external branch of the superior laryngeal nerve. Head Neck 1992;14:380. 54. Cernea CR, Nishio S, Hojaij FC. Identification of the external branch of the superior laryngeal nerve (EBSLN) in large goiters. Am J OtolaryngoI1995;16:307. 55. Durham CF, Harrison TS. The surgical anatomy of the superior laryngeal nerve. Surg Gynecol Obstet 1964;118;38. 56. Friedman M, LoSavio P, Ibrahim H. Superior laryngeal nerve identification and preservation in thyroidectomy. Arch Otolaryngol Head Neck Surg 2002;128:296. 57. Kambic V, Kargi M, Radsel Z. Topographic anatomy of the external branch of the superior laryngeal nerve: Its importance in head and neck surgery. J Laryngol Otol 1984;98: 1121. 58. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in thyroid surgery. Surgery 1987;102:999. 59. Lore JM Jr, Kokocharov SI, Kaufman S, et al. Thirty-eight-year evaluation of a surgical technique to protect the external branch of the superior laryngeal nerve during thyroidectomy. Ann Otol Rhinol LaryngoI1998;107:1015. 60. Monfared A, Kim D, Jaikumar S, et al. Microsurgical anatomy of the superior and recurrent laryngeal nerves. Neurosurgery 2001;49:925. 61. Lore JM Jr. Practical anatomical considerations in thyroid tumor surgery. Arch Otolaryngol 1983;109:568.
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69. Schwartz AE, Friedman EW. Preservation of the parathyroid glands in total thyroidectomy. Surg Gynecol Obstet 1987;165:327. 70. Menegaux F, Ruprecht T, Chigot IP. The surgical treatment of Graves' disease. Surg Gynecol Obstet 1993;176:277. 71. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;111:604. 72. Shaha AR, Jaffe BM. Completion thyroidectomy: A critical appraisal. Surgery 1992;112:1148. 73. Chao TC, Jeng LB, Lin rn, Chen ME Reoperative thyroid surgery. World I Surg 1997;21:644. 74. Lynnerup TH, Wamberg PA, Axelsson CK. [Thyroid gland surgery in a teaching department of parenchymal surgery: Quality control and perspectives based on a IO-year material.] Ugeskr Laeger 1995;157:5971. 75. Martin L, Delbridge L, Martin I, et al. Trainee surgery in teaching hospitals: Is there a cost? Aust N Z I Surg 1989;59:257. 76. Friedrich T, Steinert M, Keitel R, et al. [Incidence of damage to the recurrent laryngeal nerve in surgical therapy of various thyroid gland diseases: A retrospective study.) Zentralbl Chir 1998;123:25.
Thyroid Emergencies: Thyroid Storm and Myxedema Coma Chen-Hsen Lee, MD • Hong-Da Lin, MD
Thyroid storm and myxedema coma are life-threatening medical emergencies resulting from extreme hyperthyroidism or hypothyroidism with multiorgan dysfunction. Although they are rare conditions, when they are not recognized and treated quickly, the outcome may be fatal. Today, these conditions rarely occur after thyroid operations. Nevertheless, it is important that surgeons understand the clinical manifestations, pathophysiology, and effective treatment of these conditions because they may be precipitated by trauma, and patients with untreated or inadequately treated preexisting hyperthyroidism or hypothyroidism may require urgent operations.
Thyroid Storm Thyroid storm is a poorly defined clinical syndrome. The synonyms include thyroid crisis, thyrotoxic storm, and thyrotoxic crisis. Thyroid surgery, once the most common pathogenesis of thyroid storm, has become a rare cause of this disorder. Even senior surgeons have seen only a few such patients. This is attributable to recognition of these patients, to administration of appropriate antithyroid drugs, and to the popularity of radioactive iodine therapy for treating patients with thyrotoxicosis. Nonthyroid surgery, major trauma, infection, and image studies with iodinated contrast medium in patients with unrecognized thyrotoxicosis may act as precipitating factors of thyroid storm. For unequivocal cases of thyroid storm at our medical center, pneumonia, perforation of a peptic ulcer, iodinated contrast medium, and coexistent hyperparathyroidism with extreme hypercalcemia (serum calcium> 15 mg/dL) were considered precipitants. Known precipitants of thyroid storm are listed in Table 24-1.1. 3 Without early clinical recognition and initiation of therapy, thyroid storm carries a 10% to 75% mortality in hospitalized populations."
Clinical Manifestations Thyroid storm is usually abrupt in onset, with clinical features of thyrotoxicosis. Hypermetabolism contributes to the
216
development of fever, with temperatures occasionally exceeding 40° C, and is usually considered a major factor in differentiating thyroid storm from nonstorm thyrotoxicosis.> Without treatment, the fever may progressively increase to lethal levels within 24 to 48 hours. Patients with thyroid storm have warm skin and are flushed, with profuse diaphoresis. A goiter as well as exophthalmos mayor may not be evident. Tachycardia-s-often greater than 140 beats/minand atrial fibrillation are common, and tachypnea is frequently seen. Ventricular dysfunction and acute pulmonary edema or congestive heart failure may develop. Tremor and severe agitation are characteristic. Emotional lability, restlessness, confusion, and delirium are common and may progress to frank psychosis, stupor, and coma. Severe diarrhea is the most common gastrointestinal symptom, but nausea, vomiting, and abdominal pain also occur and may suggest an acute abdominal emergency. Hepatomegaly is often present, and mild jaundice and abnormal liver function tests suggestive of hepatocellular dysfunction are sometimes present. Leukocytosis is present occasionally, especially in patients with coexistent infections.
Diagnosis Early diagnosis and treatment remain the most important determinants in the successful management of patients with thyroid storm. Any delay in establishing this diagnosis and instituting treatment may increase the risk of a fatal outcome. Laboratory examinations for serum triiodothyronine (T 3), thyroxine (T4 ) , and free T 4 are usually nondiagnostic, because these tests are similar in patients with storm and nonstorm thyrotoxicosis." It is important to recognize that this condition is a clinical diagnosis. Characteristic features such as Bayley's symptom complex? of insomnia, anorexia, vomiting, diarrhea, marked sweating, and great emotional instability are reliable in predicting impending storm. A temperature greater than 38° C, marked tachycardia, accentuated symptoms and signs of thyrotoxicosis, and central nervous system (CNS), cardiovascular, or gastrointestinal system dysfunction indicate storm.v" A score of 25 to 44 using the scale of Burch and Wartofsky" is suggestive of
Thyroid Emergencies: Thyroid Storm and Myxedema Coma - - 217
impending storm, and a score of 45 or higher is highly suggestive of storm (Table 24-2). One should be aware that patients rarely have thyroid storm and apathetic thyrotoxicosis, coma, cerebral infarction, status epilepticus, rhabdomyolysis, and acute renal failure."
Pathophysiology The mechanism underlying the pathogenesis of thyroid storm is not completely known. A dramatic increase in serum free T4 level is commonly observed and may precipitate the onset of thyroid storm. Additional factors such as poor nutrition and complicating medical, surgical, and emotional effects on thyroid hormone binding, metabolic clearance, general physiologic reserve, and increased catecholamines are other important contributors." Besides, in our unique experience with thyroid storm combined with primary hyperparathyroidism, a markedly elevated serum calcium level may augment the action of T4 via its role as a second messenger. 10
Treatment It is crucial that treatment be instituted promptly. One should not wait for the results of measurements of serum total and free T4 or T 3 concentrations to begin treatment.' Therapy is directed at blocking thyroid hormone synthesis, secretion, and action on peripheral tissues. Supporting treatment to reverse the ongoing or incipient decompensation of normal homeostatic mechanisms, with elimination of any known precipitating factor or concurrent illness, is imperative. Continuous monitoring and minute to minute titration of therapy in an intensive care unit are mandatory. ANTITHYROID THERAPY
The antithyroid drug propylthiouracil (PTU) is administered by mouth to block new hormone synthesis and to decrease the extrathyroidal conversion of T4 to T3 • The effect of this
treatment begins within an hour of administration. Burch and Wartofsky" advised a loading dose of 600 to 1000 mg PTU followed by 200 to 250 mg every 4 hours. In our experience, a loading dose of 200 mg followed by 200 mg of PTU every 4 hours can be equally effective. Methimazole (20 mg every 4 hours) is not recommended because, even though it decreases thyroid hormone synthesis, unlike PTU it does not affect extrathyroidal conversion of T4 or T3. In patients with severe vomiting or in those who cannot take anything orally, rectal administration can be an alternative. 1I In the stuporous, comatose, or uncooperative patient, gavage is advised via a nasogastric tube. Inorganic iodide is given to inhibit iodine pump, colloid proteolysis, and release of T4 and T3 from the thyroid gland.
218 - -
Thyroid Gland
Oral dosages from 0.2 to 2 g/day are recommended. It can be given as Lugol's solution, 8 drops every 6 hours, or a saturated solution of potassium iodide,S drops every 6 hours. Sodium iodide for intravenous use, such as the radiographic contrast medium sodium ipodate, if available, should be infused slowly in a dosage of 0.5 to 1 g every 12 hours.F It is advised that iodine therapy not be started until an effective blockade of new hormone synthesis has been established with antithyroid therapy ('"1 hour), because iodine alone will lead to a further fortification of the thyrotoxic state and increase surgical risk owing to an enrichment of glandular hormone store." Treatment with iodide blocks thyroid gland secretion and, therefore, has a faster onset of effective therapy than PTU, which blocks synthesis in a thyroid gland that has a large store of already formed hormone. ADRENERGIC DEPLETION
The fact that the manifestations of thyrotoxicosis closely resemble those of sympathetic, especially p-adrenergic, overactivity provides the rationale for adrenergic depletion. Reserpine and guanethidine, either alone or in combination with other modes of therapy, have been successful in the treatment of thyroid storm. However, owing to hypotension and other untoward side effects, their use has been replaced by a p-adrenergic receptor blocker as the agent of choice. Propranolol is the most frequently used p blocker, which also inhibits peripheral conversion of T, to T 3 . It is, however, contraindicated in patients with bronchial asthma because of precipitating bronchospasm. Propranolol also blocks the symptoms of hypoglycemia so that patients with insulinrequiring diabetes mellitus may not experience warning signs of this dangerous situation. It should also be used with caution in patients with heart failure unless one is sure that the cardiac embarrassment is not due to intrinsic heart disease. On the other hand, severe bradycardia in response to propranolol may be treated with atropine, and bronchospasm or left ventricular compromise may be treated with isoproterenol. The recommended dosage of propranolol varies from 20 to 80 mg orally, every, 4 to 6 hours. For a more rapid effect, propranolol may be given intravenously by slow push at an initial dose of 0.5 to 1 mg, along with continuous electrocardiographic monitoring. Subsequent intravenous doses of 1 to 2 mg at IS-minute intervals are used to titrate the patient's heart rate. The ultrashort p blocker esmolol has been reported successful in the perioperative management of thyroid storm. 13,14 A loading dose of 250 to 500 ug/kg followed by a continuous infusion rate of 50 to 100 ug/kg/min has been demonstrated. TREATMENT OF SYSTEMIC DECOMPENSATION
Treatment of systemic decompensation includes reversal of hyperthermia, dehydration, congestive heart failure, and dysrhythmia and prevention of adrenal crisis. Hyperthermia should be aggressively treated with antipyretics and peripheral cooling. Acetaminophen is preferred to salicylates for this purpose because aspirin increases free hormone levels by decreasing the binding to T4-binding globulin and potentially could aggravate the thyroid storm." Alcohol sponges, ice packs, and cooling blankets are frequently used for peripheral cooling. It is important to prevent or decrease shivering during the rapid reduction in elevated body temperature with
small doses of chlorpromazine and meperidine; the latter is used so as not to depress the state of mentation.? To replace fluid loss, either gastrointestinal or insensible, a volume of 3 to 5 L/day may be required. A central venous pressure catheter, pulmonary wedge pressure monitoring, or both, is necessary to evaluate fluid replacement carefully. Electrolytes, glucose, and vitamins, especially thiamine, are essential to replace possible deficiency. Cardiovascular complications, including atrial fibrillation and congestive heart failure, are treated conventionally. Larger loading and maintenance doses of digoxin may be required because of the more rapid clearance in patients with marked hyperthyroidism. Serum digoxin levels should be closely monitored, particularly as thyroid storm improves and metabolic rate is lowered, to prevent digitalis intoxication. Intravenous hydrocortisone, 300 mg initially followed by 100 mg every 8 hours, is administered to prevent adrenal crisis because of relative adrenal insufficiency. Steroids also decrease the extrathyroidal conversion of T4 to T 3' TREATMENT OF COEXISTENT ILLNESS AND DEFINITIVE TREATMENT
Because most patients in thyroid storm are febrile, with leukocytosis, an inflammatory or infectious focus should be sought and bacterial cultures obtained. Prophylactic antibiotic treatment is not recommended." Any coexistent hypoglycemia, hypercalcemia, or diabetic ketoacidosis should be corrected, and standard treatment for stroke or pulmonary embolism should be instituted simultaneously with the treatment of thyroid storm. In the stuporous, comatose patient or one with poor communication abilities, a history may be unavailable or inaccurate. As many as 25% to 43% of patients with thyroid storm present with no known precipitating event.4.7 •8 In most patients, clinical improvement is observed within 24 hours, and complete recovery from storm occurs within a few days to a week. These treatment modalities should be withdrawn gradually to prevent recurrent crisis, because the half-life of T, is approximately 1 week. For patients requiring emergency operation and those who have sustained significant trauma, surgical intervention should be performed as soon as the patient is stabilized with such measures as hydration, p blockade, intravenous sodium ipodate, hydrocortisone, PTU, and cooling. For definitive treatment of thyrotoxicosis, a subtotal thyroidectomy or other therapy is performed when the patient is euthyroid and the crisis situation has resolved. Unless contraindicated, p blockade should be continued during the postoperative period. Our patient with thyroid storm and hypercalcemic crisis was successfully treated by urgent removal of a 3-g parathyroid adenoma and simultaneous subtotal thyroidectomy after rapid preoperative treatment of the hypercalcemia and storm were instituted (Fig. 24-1). The mortality rate has fallen from nearly 100% to about 20% with a better understanding of appropriate management of patients with thyroid storm, although the improvement may also be partly attributable to the relaxation of diagnostic criteria.I-?
Prevention Given the significant mortality associated with thyroid storm, it would be beneficial to prevent episodes completely
Thyroid Emergencies: Thyroid Storm and Myxedema Coma - -
219
Hydration, diuretics, and ATD
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' A cohort of more than 100,000 residents of these cities with a variable exposure dose on the basis of proximity to the sites of explosion has been identified and monitored. Relative risk of thyroid cancer clearly increased in this population on the basis of age at exposure and dose of radiation received. Younger people and, in particular, females younger than 30 years at the time of the blasts had the most increased relative risk. The dose response is particularly well documented in Nagasaki, and the estimated relative risks are 1.28, 1.61,2.36, and 3.82 for estimated exposure doses of 25, 50, 100, and 200 rad, respectively.-' This increased risk is pertinent only to gamma ray exposure but does not correlate with neutron radiation exposure. Within this population, studied after the atomic bomb explosions, there have been 112 total cases of thyroid cancer: 62 from Hiroshima and 50 from Nagasaki." Histologically, the vast majority of this radiation-associated thyroid cancer has been papillary. The long-term survival for radiation-associated papillary thyroid cancer in Hiroshima is 82% compared with 85% for comparable cases not associated with radiation exposure from that area." These equivalent survival data suggest that radiation-induced thyroid cancer does not have an altered or more aggressive natural history.
244 - - Thyroid Gland
Although, on the basis of the Japanese studies, acute gamma radiation exposure from a single event such as an atomic explosion clearly increases the risk of thyroid cancer, chronic gamma radiation exposure does not have the same effect. 25 A long-term study of subjects in southern China, where a high level of background radiation is present as a result of radioactive sand, showed an increase in chromosome abnormalities of the thyroid gland but no increased incidence of thyroid neoplasia. The estimated exposure over 40 years in this population was a total of 14 rad, which as an acute exposure would increase the risk of thyroid cancer, and the relative risk was 1.02 compared with control subjects after this chronic exposure.P Nuclear weapon explosions also produce radioisotopes of iodine in fallout that can contaminate water and food supplies, leading to ingestion by patients. Like medically administered iodine, these isotopes concentrate in the thyroid gland and can deliver focal radiation to the gland. Whereas 1311 is used medically, nuclear fallout contains a mixture of 1311 with short-lived radioisotopes such as 1291, 1321, 1331, 1341, and l351.26.27 The best data concerning nuclear weapon fallout exposure come from testing sites in the Marshall Islands and Nevada. On March I, 1954, a 15-megaton bomb was detonated in the atmosphere over a test site on the uninhabited Bikini atoll in the northern Marshall Islands." Unfortunately, high-activity radiation fallout from this blast exposed 253 residents of the neighboring two islands, causing acute radiation sickness. Among the 86 subjects most exposed on the closest atoll, thyroid nodules developed in 32% of the total population and in 63% of children younger than 10 years at exposure." One report demonstrated that 12 other Marshall Island atolls thought initially to be unexposed to fallout had an increased incidence of thyroid nodules inversely proportional to the distance from the test site. The estimated doseresponse relationship defined in this study is II excess cases per rad per year per I million population." A second study of nuclear fallout involved Nevada test sites. The U.S. Atomic Energy Commission conducted more than 100 aboveground nuclear detonations between 1951 and 1958 at these sites.F This exposure was not as precisely defined in time and amount as the Marshall Islands incident, but dosimetry of surrounding areas including soil, vegetation, and milk from cattle showed that areas of Utah, Nevada, and Arizona were exposed. A cohort was identified including 4818 children who ranged in age from 0 to 7 years in 1953, the estimated time of peak exposure from fallout. An increased relative risk of 3.4 for the development of thyroid nodules was shown in the group of children with an estimated thyroid exposure greater than 40 rad? Again, the short-lived radioisotopes of iodine were believed to be a major factor in this exposure. All of the environmental exposures described previously occurred more than 40 years ago and have in large part been studied retrospectively to provide a long-term database for acute gamma radiation and nuclear fallout exposure. In April 1986, the Chernobyl nuclear power plant explosion released an estimated 50 million Ci of radioactive materials into the atmosphere and exposed an estimated 1.5 million people in southern Belarus and the northern Ukraine." The fallout early in the disaster consisted of a large amount of 1311 together with short-lived isotopes 1291, 1321, l331, 1341, and 1351. 29
An early study completed 4.5 years after the event using clinical examination and ultrasonographic studies showed no significant increased incidence of thyroid nodules in exposed populations versus control subjects." However, this study was completed just as the latent period after this exposure was ending. Cases of pediatric thyroid cancer in Belarus increased sequentially from 1986 through 199328,29 (Fig. 26-4). By 1996, more than 500 cases had been diagnosed in children younger than 15 years." The disease in the exposed children initially showed an equal sex distribution; 83 of 84 cases involved papillary thyroid cancer and 1 involved medullary thyroid cancer." Histologically, lesions that occurred soon after exposure were aggressive, with capsular invasion in 89% and lymph node metastases in 88%. Later, in 1998, Farahati and colleagues examined the agespecific effects of radiation on disease severity in 483 children living in Belarus and younger than 8 years of age at the time ofthe accident." They found that the frequency of thyroid carcinoma was highest among infants and children younger than 3 years and decreased rapidly with the advancing age at the time of exposure. There was a higher incidence of differentiated thyroid cancer among females compared with males (1.6). Follicular cancer represented only 3.6% of the cases, which may be explained by a longer latency period for this variant. Age at exposure was inversely related to disease severity. The study confirmed that younger patients had more extrathyroid disease, lymph node involvement, and distant metastasis. The latency period, however, did not differ by age group. The inverse relationship between disease severity and age at the time of exposure is postulated to be due to the small volume of thyroid tissue in children
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FIGURE 26-4. The number of cases of pediatric thyroid cancer in Belarus from 1986 to 1993 showing increased incidence since the April 1986 Chemobyl disaster. (Adapted from Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the Chemobyl disaster. Cancer 1994;74:748. Copyright © 1994, American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)
Factors That Predispose to Thyroid Neoplasia - - 245
younger than 2. The small volume of tissue would lead to a proportionately larger radiation dose at the same level of exposure. Data for the radioactive exposure by ingestion from the Marshall Islands, Nevada test sites, and Chernobyl show a clear increased risk of thyroid cancer; the important variables of age at exposure and dose of exposure contribute to the risk. This increase in incidence contrasts with the data presented previously regarding medically administered 1311, which even at high doses has minimal effect. 20•22 One difference is that, contrary to 1311, radioactive fallout has shortlived high-energy beta isotopes, which may cause more injury over a short period of time to the thyroid parenchyma than an equivalent exposure dose of only 13IJ.26 However, Baverstock pointed out that the negative data concerning medical 131 1 use and thyroid cancer come almost exclusively from an adult population of patients.P Little information is available regarding medical exposure in children, who are rarely treated or scanned with 1311. As the data from Chernobyl continue to mature, the characteristics of increased risk in both younger and older populations exposed to this high dose of fallout will become clearer. Some investigators have suggested that the increased incidence of pediatric thyroid cancer in and around Chernobyl is due to increased surveillance.F A French study of a population near a long-term nuclear power plant at Chooz showed no increased incidence in terms of proximity to this plant and the exposure from normal operations near a nuclear plant." However, the situation at Chernobyl with early, very aggressive lesions documented in exposed children is incontrovertible and argues that this acute intense exposure has significantly increased thyroid cancer incidence, which will probably continue over the next several decades.
Molecular Carcinogenesis The pathogenesis of radiation-induced thyroid cancer has not yet been elucidated. Gene rearrangements may play an important role in the process. Nikiforova and associates found that radiation-induced tumors had a 4% prevalence of BRAF point mutations and a 58% prevalence of RET/PTC rearrangements, and sporadic papillary thyroid cancers demonstrated a 37% prevalence of BRAF point mutations and only a 20% prevalence of RET/PTC rearrangements.r' Similarly, RET/PTC3 rearrangement was found in aggressive tumors that occurred less than 10 years after the Chernobyl accident. 35 Elisei and coauthors also found a prevalence of 38% of RET/PTC rearrangements in adenomas found within radiation-exposed glands, implying that this rearrangement is not restricted to the malignant phenotype but may be a step in the development of malignant transformation of radiationinduced thyroid tumors. 36
Other Factors A summary of the characteristics of radiation exposure and thyroid cancer is given in Table 26-2. Although a sizable body of data clearly defines this risk factor, most patients currently with thyroid cancer have no history of radiation exposure.'
A study from the Connecticut tumor registry showed that only 9% of thyroid cancers could be related in any way to radiation exposure. Other risk factors include dietary intake, sex hormones, other environmental exposures, lifestyle factors, and increased genetic susceptibility. The epidemiologic data on well-differentiated thyroid cancer may offer some clues to other etiologic factors. First, females are affected more frequently than males. Second, certain geographic regions have a significantly higher incidence, particularly Iceland, Switzerland, coastal Norway, and Hawaii." Unfortunately, studies of these populations in regard to dietary, hormonal, and environmental factors yielded very inconsistent results. Some studies reported opposite results, with some showing that certain factors increased the incidence of thyroid cancer, whereas other investigators showed a decrease risk from the same factors (Table 26-3). Dietary influences contributing to thyroid cancer have been extensively studied, focusing particularly on goitrogens and iodine-deficient or iodine-excessive diets. Animal models document that increased thyroid-stimulating hormone (TSH) levels result in thyroid neoplasia, and dietary factors may exert their effects by increasing TSH in one of three ways." Iodine deficiency leads to compensatory higher TSH levels; high-goitrogen diets (e.g., vegetables from the cruciferous family) may block iodine uptake and incorporation and lead to thyroid hypertrophy under the influence of TSH or to direct anterior pituitary effects that release TSH. Although theoretically these dietary influences can increase the risk of thyroid cancer, in reality the data are mixed. Both low-iodine diets and high-iodine diets have been reported to increase risk." Large intake of shellfish and other seafoods that are quite high in iodine content occurs in areas of the highest incidence of thyroid cancer such as Iceland, Norway, and Hawaii. 39,40 However, studies from northern Italy show that high intake of fish exerts a protective effect; increased risk is associated with starchy foods such as potatoes, rice, pasta, and bread." except in one study in which pasta was shown to have a protective effect." Lifestyle factors have been studied with regard to the development of thyroid neoplasms. Although consumption of alcohol can cause TSH release directly, it does not appear to be associated with increased risk." In fact, one study actually found a reduced risk among women who consumed
246 - - Thyroid Gland
at least 12 drinks per year," Cigarette smoking has also been evaluated as a potential carcinogen; however, the association between cigarette smoking and thyroid cancer has either been nonexistent or found to be protective against the development of thyroid neoplasia. 42-45 The mechanisms of this finding have not yet been elucidated. Caffeine-containing beverages have also been examined without evidence for any association with thyroid neoplasia. Finally, working in the wood-processing, pulp, and paper-making industry has been shown to be associated with an elevated risk of thyroid cancer." Hydrocarbons have been suggested to be the causative agent in this setting, but this has not been adequately studied. A second area of associated risk factors specific for females is the influence of sex hormone status. Different factors such as parity, early "artificial" menopause, oral contraceptive use, abortions, and late age at first birth have been reported to be associated with an increased risk of thyroid cancer.47,48 However, not all studies have come to the same conclusions (see Table 26-3). For example, two large studies from Norway showed different results in terms of parity.49.50 One study showed a proportional increased risk between zero and four children born, whereas a second study showed no association with parity. One consistent finding in several studies related to hormonal status is body weight. 1\\10 investigators have reported that obese patients in both younger and older age groups, and particularly females, have an increased risk for thyroid neoplasia.v-" The precise mechanism of this effect, whether dietary or hormonal, is unclear. Finally, the presence of benign nodular thyroid disease is clearly associated with thyroid cancer. I This finding may be related to a screening or selection bias or may be related to common factors that lead to both nontoxic nodular goiter and thyroid cancer. If only this subgroup of goiter patients is analyzed (nontoxic nodular), there is a reported incidence of thyroid cancer as high as 17% in one study; others report the development of thyroid cancer in 9% to 11% of this population. 52Associations between thyroid cancer and other malignancies suggest possible genetic influences. An association with familial polyposis of the colon, as well as melanoma and testicular and bladder cancers, has been reported.
Summary The only clearly documented risk factor for thyroid neoplasia is radiation exposure; a majority of patients acquiring this disease have no known risk factors. Major questions for the future include the definition of other genetic or environmental risk factors. Progress in this epidemiologic area will go hand in hand with increased understanding of the molecular biology of thyroid cancer (see Chapters 30 and 31). In patients with radiation-related thyroid cancer, investigators must determine whether the large population exposed as infants or children who are now in their sixth or seventh decade of life will continue to have a higher incidence of thyroid cancer 40 to 60 years after exposure and, if so, whether these radiation-induced thyroid cancers will have the same more aggressive natural history as non-radiation-induced cancers occurring in the elderly population of patients.
REFERENCES I. Franceschi S, Boyle P, Maisonneuve P, et al. The epidemiology of thyroid carcinoma. Crit Rev Oncog 1993;4:25. 2. Shore RE. Issues and epidemiological evidence regarding radiationinduced thyroid cancer. Radiat Res 1992;131:98. 3. Ron E, Kleinerman RA, Boice lD lr, et al. A population-based case-control study of thyroid cancer. 1 Natl Cancer Inst 1987;79:1. 4. Langsteger W, Koltringer P, Wolf G, et al. The impact of geographical, clinical, dietary and radiation-induced features in epidemiology of thyroid cancer. Eur 1 Cancer 1993;29A: 1547. 5. Duffy Bl lr, Fitzgerald Pl. Cancer of the thyroid in children: A report of 28 cases. 1 Clin Endocrinol Metab 1950;10:1296. 6. Clark DE. Association of irradiation with cancer of the thyroid in children and adolescents. lAMA 1955;159:1007. 7. Winship T, Rosvoll RY. Thyroid carcinoma in childhood: Final report on a 20 year study. Clin Proc Child Hosp 1970;26:327. 8. Schneider AB. Radiation-induced thyroid tumors. Endocrinol Metab ClinNorthAm 1990;19:495. 9. Shore RE, Woodard E, Hildreth N, et al. Thyroid tumors following thymus irradiation. 1 Natl Cancer Inst 1985;74:1177. 10. Ron E, Modan B, Preston D, et al. Thyroid neoplasia following low-dose radiation in childhood. Radiat Res 1989;120:516. 11. Schneider AB, Recant W, Pincky SM, et al. Radiation-induced thyroid carcinoma: Clinical course and results of therapy in 296 patients. Ann Intern Med 1986;105:405.
Factors That Predispose to Thyroid Neoplasia - - 247 12. Schneider AB, Ron E, Lubin J, et al. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 1993;77:362. 13. Perkel VS, Gail MH, Lubin J, et al. Radiation-induced thyroid neoplasms: Evidence for familial susceptibility factors. J Clin Endocrinol Metab 1988;66:1316. 14. Pottern LM, Kaplan MM, Larsen PR, et al. Thyroid nodularity after childhood irradiation for lymphoid hyperplasia: A comparison of questionnaire and clinical findings. J Clin EpidemioI1990;43:449. 15. Tucker MA, Jones PHM, Boice JD Jr, et al. Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res 1991; 51 :2885. 16. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 1991;325:599. 17. Boice JD Jr, Engholm G, Kleinerman RA, et al. Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 1988;116:3. 18. Hallquist A, Hardell L, Degerman A, et al. Medical diagnostic and therapeutic ionizing radiation and the risk for thyroid cancer: A casecontrol study. Eur J Cancer Prev 1994;3:259. 19. Dobyns BM, Sheline GE, Workman 18, et al. Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: A report of the cooperative thyrotoxicosis therapy follow-up study. J Clin Endocrinol Metab 1974;38:976. 20. Holm LE, Dahlqvist I. Israellson A, Lundell G. Malignant thyroid tumors after iodine-13I therapy. N Engl J Med 1980;303:188. 21. Holm LE, Hall P, Wiklund K, et al. Cancer risk after iodine-131 therapy for hyperthyroidism. J Natl Cancer Inst 1991;83: 1072. 22. Holm LE, Wiklund KE, Lundell GE, et al. Thyroid cancer after diagnostic doses of iodine-131: A retrospective cohort study. J Natl Cancer Inst 1988;80:1132. 23. Prentice RL, Kato H, Yoshimoto K, Mason M. Radiation exposure and thyroid cancer incidence among Hiroshima and Nagasaki residents. Natl Cancer Inst Monogr 1982;62:207. 24. Takeichi N, Ezaki H, Dohi K. A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Thyroid cancer: Reports up to date and a review. J Radiat Res (Tokyo) 1991;32(Suppl):180. 25. Wang Z, Boice JD Jr, Wei L, et al. Thyroid nodularity and chromosome aberrations among women in areas of high background radiation in China. J Natl Cancer Inst 1990;82:478. 26. Hamilton TE, van Belle G, LoGerfo JP. Thyroid neoplasia in Marshall Islanders exposed to nuclear fallout. JAMA 1987;258:629. 27. Kerber RA, Till JE, Simon SL, et al. A cohort study of thyroid disease in relation to fallout from nuclear weapons testing. JAMA 1993;270:2076. 28. Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after the Chernobyl disaster. Cancer 1994;74:748. 29. Baverstock KF. Thyroid cancer in children in Belarus after Chernobyl. World Health Stat Q 1993;46:204. 30. Mettler FA Jr, Williamson MR, Royal HD, et al. Thyroid nodules in the population living around Chernobyl. JAMA 1992;268:616. 31. Farahati J, Demidchik EP, Biko J, Reiners C. Inverse association between age at the time of radiation exposure and extent of disease in cases of radiation-induced childhood thyroid carcinoma in Belarus. Cancer 2000;88: 1470. 32. Furmanchuk AW, Roussak N, Ruchti C. Occult thyroid carcinomas in the region of Minsk, Belarus: An autopsy study of 215 patients. Histopathology 1993;23:319. 33. Rekacewicz C, de Vathair F, Delise MJ. Differentiated thyroid carcinoma incidence around the French nuclear power plant in Chooz. Lancet 1993;341:493.
34. Nikiforova, A, Ciampi R, Salvatore G, et al. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett 2004;209: 1. 35. Rubino C, Cailleux F, et al. Thyroid cancer after radiation exposure. Eur J Cancer 2002;38:645. 36. Elisei R, Romei C, Vorontsova T, et al. RETIPTC rearrangements in thyroid nodules: Studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 2001;86:3211. 37. Franceschi S, Talamini R, Fassina A, Bidoli E. Diet and epithelial cancer of the thyroid gland. Tumori 1990;76:331. 38. Franceschi S, Levi F, Negri E, et al. Diet and thyroid cancer: A pooled analysis of four European case-control studies. Int J Cancer 1991;48:395. 39. Glattre E, Haldorsen T, Berg JP, et al. Norwegian case-control study testing the hypothesis that seafood increases the risk of thyroid cancer. Cancer Causes Control 1993;4: 11. 40. Kolonel LN, Hankin JH, Wilkens LR, et al. An epidemiologic study of thyroid cancer in Hawaii. Cancer Causes Control 1990;1:223. 41. Markaki I, Linos D, Linos A. The int1uence of dietary patterns on the development of thyroid cancer. Eur J Cancer 2003;39: 1912. 42. Rossing MA, Cushing KL, Voigt LF, et al. Risk of papillary thyroid cancer in women in relation to smoking and alcohol consumption. Epidemiology 2000; 11:49. 43. Hallquist A, Hardell L, Degerman A, Boquist L. Occupational exposures and thyroid cancer: Results of a case-control study. Eur J Cancer Prev 1993;2:345. 44. Mack WJ, Preston-Martin S, Dal Maso L, et al. A pooled analysis of case-control studies of thyroid cancer: Cigarette smoking, and consumption of alcohol, coffee and tea. Cancer Causes Control. 2003;14:787. 45. Kreiger N, Parkes R. Cigarette smoking and risk of thyroid cancer. Eur J Cancer 2000;36:1969. 46. Fincham SM, Ugnat AM, Hill GB, et al. Is occupation a risk factor for thyroid cancer? J Occup Environ Med 2000;42:318. 47. Levi F, Franceschi S, Gulie C, et al. Female thyroid cancer: The role of reproductive and hormonal factors in Switzerland. Oncology 1993;50:309. 48. Preston-Martin S, Jin F, Duda MJ, Mack WJ. A case-control study of thyroid cancer in women under age 55 in Shanghai (People's Republic of China). Cancer Causes Control 1993;4:431. 49. Kravdal 0, Glattre E, Haldorsen T. Positive correlation between parity and incidence of thyroid cancer: New evidence based on complete Norwegian birth cohorts. Int J Cancer 1991;49:831. 50. Akslen LA, Nilssen S, Kvale G. Reproductive factors and risk of thyroid cancer: A prospective study of 63,090 women from Norway. Br J Cancer 1992;65:772. 51. Goodman MT, Kolonel LN, Wilkens LR. The association of body size, reproductive factors and thyroid cancer. Br J Cancer 1992;66: 1180. 52. Cole WHo Incidence of carcinoma of the thyroid in nodular goiter. Semin Surg Oncol 1991;7:61. 53. Zivaljevic V, Vlajinac H, Marinkovic J, et al. Cigarette smoking as a risk factor for cancer of the thyroid in women. Tumori. 2004;90:273. 54. Zivaljevic V, Vlajinac H, Jankovic R, et al. Case-control study of female thyroid cancer-Menstrual, reproductive and hormonal factors. Eur J Cancer Prev 2003;12:63. 55. Memon A, Varghese A, Suresh A. Benign thyroid disease and dietary factors in thyroid cancer: A case-control study in Kuwait. Br J Cancer 2002;86: 1745. 56. Bosetti C, Kolonel L, Negri E, et al. A pooled analysis of case-control studies of thyroid cancer. VI. Fish and shellfish consumption. Cancer Causes Control 2001;12:375.
Predictors of Thyroid Tumor Aggressiveness Blake Cady, MD
The antecedents of attempts to predict thyroid cancer behavior date back to the 1930s, when the concept of "lateral aberrant thyroid'v-' was established, because thyroid tissue appearing in lymph nodes in the neck was known to be associated with an innocent clinical behavior pattern in a vast majority of cases. As a result, these cases were considered to be not cancer but an arrested embryonic migration phenomenon, until Crile convincingly demonstrated small primary papillary cancers in such cases.' That was also an era when 15% to 20% of all thyroid cancers were of an anaplastic variety that was almost uniformly and rapidly fatal"; median survival associated with anaplastic cancers was only 3 or 4 months, and all but a few patients were dead within 6 months. This wide range of clinical behavior from cancers arising from the same thyroid follicular cell was noteworthy, even then, in displaying the extremes of tumor biologic behavior. Currently, of course, we have several well worked-out and easily clinically applicable indicators of risk group assignment to predict accurately the biologic behavior of cancers of the thyroid gland.>!" Arriving at these unique, clinically discernible risk estimations is a simple process in thyroid cancer, whereas clinical predictors of outcome are much less accurate and effective in other human cancers, particularly in defining a preponderance of patients at very low risk. It is important for surgeons to recognize the striking differences in behavior of thyroid cancers originating from an identical cell so that appropriate surgical techniques can be applied to patients to minimize morbidity and to restore and maintain normal life in the vast majority of patients currently being treated for differentiated thyroid carcinoma.
Epidemiology A number of epidemiologic features in thyroid carcinoma may have implications regarding thyroid cancer behavior. Beginning in the 1950s, it became well established that there was an increased incidence of differentiated thyroid carcinoma in patients who had received therapeutic radiation as infants and children. IS Such therapeutic radiation in the
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1930s and the 1940s was frequently given for thymic, adenoid, and tonsillar enlargement, facial acne, and even tinea capitis. As many as 30% to 40% of such patients later operated on for thyroid nodules were discovered to have differentiated thyroid carcinoma, usually papillary and often only microscopic." When this etiologic association became apparent, such low-dose radiation therapy disappeared from clinical practice, and as a result few patients today are seen with a history of radiation treatment. Thyroid gland abnormalities in survivors of the nuclear bomb explosions in Japan and the Pacific atolls are well described. I? These nodules were both benign and malignant, but in almost half of the cases of cancer, the lesion was a microscopic or small focus in thyroid tissue adjacent to a benign nodule. In the geographic area downwind of the Chernobyl nuclear accident, an appreciable number of children exposed to radioactive fallout have acquired thyroid carcinoma. 18 It is now evident that these cases represent a real increase in thyroid cancer (Fig. 27-1). A peculiar aspect of the Chernobyl reports has been the very short latency period of only a few years to the appearance of these cancers'? and iodine deficiency.20.21 The median time to appearance of thyroid carcinoma associated with childhood radiation therapy in previous reports has been about 20 years, and it appears to increase for at least 3 decades after exposure. No cases of thyroid carcinoma have been reported from the Three Mile Island nuclear accident in Pennsylvania. Although there are vast differences in background cosmic radiation between sea level and mountain communities and between house construction of brick or stone compared with wood frame, there have never been adequate data indicating that increased background cosmic radiation has been associated with an increased incidence of human thyroid carcinoma. Although widespread childhood radiation is no longer an issue in the United States, childhood Hodgkin's disease is frequently treated with a mantle radiation port that includes the thyroid gland; these patients have an increased risk for the development of differentiated thyroid cancer." Radiation-associated thyroid cancers appear to exhibit biologic behavior similar to that found in patients with thyroid cancer who have not received radiation.
Predictors of Thyroid Tumor Aggressiveness - - 249
radiation-induced thyroid cancer, has received much attention28-33 and continues to elicit genetic analysis and definitions.
100 90
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1986 1987 1988 1989 1990 1991 1992 1993 1994
Year FIGURE 27-1. Sharp increase. Childhood thyroid cancer is rising in three republics most affected by Chemobyl. (Redrawn with permission from Balter M. Chemobyl's thyroid cancer toll. Science 1995;270:1758. Copyright 1995, American Association for the Advancement of Science.)
The basic iodine content in the diet has been linked to varying patterns and incidences of thyroid carcinoma. 20 ,23-25 In regions with low dietary iodine, there is an increased proportion of follicular carcinoma and a high incidence of anaplastic carcinoma compared with areas with adequate dietary iodine, where papillary carcinoma predominates and anaplastic carcinoma is uncommon. There seem to be other subtle differences in the pattern of both differentiated and undifferentiated thyroid carcinoma in iodine-rich areas compared with iodine-poor areas. Historically, because of the presence of large "goiter belts" in the United States, an experiment was carried out in Akron, Ohio, in the 1920s in which schoolgirls were given iodine supplements, which produced a marked reduction in endemic goiter incidence. By the mid-1930s, the United States had established routine iodinization of household salt to control endemic goiter. As a result, 70 years later we have had two generations of our population growing up with adequate iodine in their diet. During this time there has been an increasing preponderance of papillary carcinoma of the thyroid in the United States and the virtual disappearance of anaplastic carcinoma.v? Conversion of long-standing or recurrent papillary carcinoma to anaplastic cancer of the thyroid with resultant death was a well-recognized phenomenon in the 1930s and 1940s but is now uncommon in patients born and raised in this country with adequate dietary iodine. This phenomenon of ensuring adequate dietary iodine represents a major public health accomplishment in preventing goiter and is undoubtedly a major cause of the changes in presentation of thyroid carcinoma since 1930. Many immigrants to the United States come from iodine-poor regions, however, and may display a pattern of disease that mimics the American experience of the 1930s. Other subtle environmental factors in the epidemiology of differentiated thyroid carcinoma may exist and have effects on outcome but have not been defined adequately to be recognized as a problem.P-" The role of genetic abnormalities in thyroid cancer, particularly
Pathology Understanding the pathology of thyroid carcinoma is critical to appreciating the biologic behavior of the various neoplasms arising from the thyroid follicle cell and allowing predictions of aggressiveness. Papillary and follicular thyroid carcinomas are the most common thyroid cancers worldwide. Differentiated thyroid carcinomas that have both papillary and follicular thyroid elements are classified as papillary carcinomas because they have the same biologic behavior as that of papillary carcinoma.v' In our series," whether the carcinomas were pure papillary or mixed papillary and follicular with varying proportions of follicular components, including follicular predominant forms, the clinical behavior was identical. In contradistinction, follicular carcinoma should describe thyroid cancers of a pure follicular pattern. Follicular carcinoma of poor differentiation has a poor prognosis but must be separated from anaplastic carcinomas consisting of giant and spindle cells. Undifferentiated thyroid carcinoma is a uniquely aggressive form of carcinoma consisting of spindle and giant cell anaplastic lesions, as well as some cases of small cell carcinomas.' Although the diagnosis of small cell undifferentiated carcinoma was used frequently in the 1930s, 1940s, and 1950 in contemporary studies using histochemical staining, many of these were either medullary carcinomas (first described in 1957) or lymphomas of the thyroid. Thus, the proportion of undifferentiated thyroid cancers that are of the small cell variety is quite small. Lymphoma of the thyroid is a recognized presentation of extranodal non-Hodgkin's lymphoma.P-" Patients with such lesions should have extensive diagnostic evaluation to rule out disseminated lymphoma with thyroid involvement. Thyroid lymphomas arise more often in patients with Hashimoto's thyroiditis and lymphoid hyperplasia. Histologic differentiation between these entities may be difficult, may cause diagnostic confusion, and may require sophisticated histochemical staining and electromicroscopy for accurate diagnosis. Patients with thyroid lymphoma can be treated for cure using surgical resection, if possible, but primarily through chemotherapy and radiation therapy." Rare types of thyroid carcinoma, such as sarcoma and squamous cell carcinoma, also occur. Melanoma and cancers of the lung, breast, and kidney are the tumors that most often metastasize to the thyroid gland. At present, in the United States, differentiated thyroid cancers make up about 95% of cases of thyroid malignancy, of which at least 80% are papillary; anaplastic carcinoma makes up less than 2%, and thyroid lymphoma makes up about 1%. Medullary carcinoma of the thyroid arises from parafollicular C cells, rather than thyroid follicle cells, and makes up less than 4% of all thyroid cancers.v'? Many reports in the literature indicate higher proportions of medullary carcinoma in a particular institution, but this represents the phenomenon of selection by diagnosis of familial clusters in the inherited form of the disease. Overall, medullary carcinoma represents less than 4% of all thyroid gland carcinomas.
250 - -
Thyroid Gland
Differentiated Thyroid Carcinoma Follicular Carcinoma Pure follicular carcinoma appears to be decreasing in frequency and now makes up about 10% of differentiated thyroid cancers. This proportion may be different in geographic areas with insufficient dietary iodine or with different pathologic definitions.P'" Follicular cancers are diagnosed by the invasion of the follicular cells into or through the veins or tumor pseudocapsule or into metastatic sites. Minor tumor pseudocapsular involvement or only minor vessel involvement within the tumor itself may define follicular carcinoma, but such technically defined follicular adenocarcinomas have little, if any, risk of recurrence, metastases, or death from disease, regardless of age or risk group. Such a follicular cancer with minor capsular involvement may be found in retrospect in a patient presenting with distant metastases, but this is rare. Extensive data from the Mayo Clinic" and Lahey Clinic 9,34 confirm the essential absence of risk of recurrence or death in such patients. In the 1930s and 1940s, the phenomenon of "benign metastasizing follicular adenoma" was described but represented inadequate sampling of the primary thyroid tumor pseudocapsule to discern completely the extent of capsular involvement in such metastatic cancers. However, major tumor pseudocapsular involvement represents a far more aggressive type of follicular thyroid cancer.34 Thus, gross breaching of the thyroid tumor pseudocapsule, particularly with extension outside the thyroid gland itself into surrounding structures (strap muscle, esophagus, soft tissues, laryngeal or tracheal wall), clearly represents a type of follicular adenocarcinoma with a worse prognosis. Such pathologic extension through the tumor pseudocapsule is a phenomenon that is somewhat linked with size, so that large follicular adenocarcinomas frequently have extension outside the thyroid gland and into surrounding structures, and minor tumor pseudocapsular involvement usually occurs in smaller lesions that are intraglandular. However, on occasion, even small follicular adenocarcinomas demonstrate gross involvement of the thyroid gland capsule and invasion of surrounding tissues. Such follicular adenocarcinomas, with major tumor pseudocapsular involvement and extraglandular extension, have a poor prognosis regardless of size. This poor prognostic implication of extensive tumor pseudocapsular involvement by follicular carcinoma applies across all age ranges, including a few patients who otherwise might be considered at low risk, but in older patients is particularly ominous. Thus, the mortality rate in the few younger patients is about 25%, but in older patients, who are more frequently affected, it may be as high as 75%. Overall, patients with follicular carcinoma have the same prognosis as patients with papillary carcinoma. 9,34042 We do not separate Htirthle cell cancer from other follicular cancers." Whether patients with Hiirthle cell cancer have a unique risk of recurrence or death is debatable."
Papillary Carcinoma Mention was previously made of the concept of lateral aberrant thyroid, which represented a phenomenon with such an
innocent long-term outlook that for many years it was considered an embryonic abnormality rather than a cancer.' This history represents one aspect of the difficulty of prognostication in thyroid cancer. It is important to realize that occult papillary cancers are extremely common in autopsy studies and in apparently normal thyroid tissue and have no impact or risk of clinical cancer or death from cancer. These occult lesions are seen in between 6% and 18% of American patients and are even more common in other countries.r' Now, of course, with rare exceptions, we recognize the presence of even benign-appearing thyroid tissue in lymph nodes of the neck as metastatic disease, frequently with an occult primary in the thyroid gland. More than 75% of young patients with papillary thyroid cancer have lymph node metastases when node dissections are performed. Twenty-five percent of young patients present because of a palpable lymph node in the neck rather than because of a tumor in the thyroid gland. 34045 Although the initial presentation with a palpable lymph node metastasis in all other head and neck carcinomas represents a poor prognosis and the presence of lymph node metastases in all other human cancers indicates a worse prognosis than cases that have negative nodes, the implication of nodal metastases is uniquely different in young patients with low-risk papillary carcinoma of the thyroid. Indeed, with some exceptions,704M7 reports of multifactorial analysis of differentiated thyroid carcinoma prognosis and risk groups fail to find lymph node metastases as a significant factor, and none of the risk group scoring systems include lymph node metastases. Many surgeons, endocrinologists, and physicians, however, still have difficulty in accepting such a uniquely different implication of nodal metastases.v"
Risk Groups in Differentiated Thyroid Cancer The phenomenon of a relationship between age and outcome in differentiated thyroid carcinoma dates back to reports from the 1940s and earlier," Clinically, it became obvious that the outcome of patients younger than 45 years was distinctly different from that of patients in older age groups. It is now apparent that there is a strong relationship between increasing age and worsening prognosis with age greater than 40, 45, or 50 years, variously defined in different reports.lv" Thus, in our reports,"!' all patients older than 70 years had an extremely high risk of recurrence and death (67%) from disease regardless of the individual features of the cancer, such as size, extent of disease, pathologic type, and extent of surgery. In all the multifactorial risk group designations published over the past 20 years, age has been one of the major prognosticating features, if not the major one. When other primary tumor features, such as extent of disease, size, grade, completeness of surgery, and flow cytometry," are included with age, uniquely effective separations of the benign-behaving preponderance of low-risk cases from higher risk groups, which represent a minority of cases, can be established. Early attempts at such prognostication by clinical phenomena were represented by the International Union Against Cancer tumor, nodes, and metastases (TNM) staging system" and the European Oncology Research for the Treatment of Cancer staging system published in the 1970s. 7
Predictors of Thyroid Tumor Aggressiveness - -
In the late 1970s and early 1980s, two other systems of clinical assessment of risk were published-AGES (age, grade, extent, and size) by the Mayo Clinic 8 and AMES (age, metastases, extent, and size) by the Lahey Clinicf--; that illustrated uniquely simple and effective postoperative prognostic scoring systems. The latter two systems demonstrated that the basic risk group assessment superseded the prognostic effect of type of surgery, use of radioactive iodine, use of external radiation therapy, presentation of primary disease, presentation of recurrent or metastatic disease, and perhaps even use of thyroid-stimulating hormone (TSH) suppression by thyroid hormone administration. The addition of flow cytometry to the AMES category (DAMES) I I was proposed as yet another sophisticated prognostication in individual cases but was not routinely clinically applicable at the time of surgery because of the need for a postoperative tumor analysis by flow cytometry. A major report by Shah and colleagues'? at Memorial Hospital in New York again confirmed all the basic features of the previously published multifactorial risk groups (age, metastases, extent, size). Finally, a Mayo Clinic study published by Hay and coauthors 14 has incorporated completeness of surgical removal of the primary thyroid cancer in the most recent iteration of their multifactorial analysis: MACIS (metastases, age, completeness of surgery, invasion of cancer, and size). Of all their MACIS patients with papillary cancer, 84% fall into a low-risk group, which has only a 3% 10-year recurrence rate and a 1% 20-year death rate. Such a low death rate is identical to that for an age-adjusted similar population without thyroid carcinoma. Three further levels of risk group assignment in this MACIS system have progressively worse prognoses, culminating in the highest scoring patients, who have a 75% risk of cause-specific mortality. The MACIS system is the only one that includes surgical resection, but it is important to understand that the operative features relate only to completeness of cancer removal and do not in any way demonstrate a difference in survival when total thyroidectomy and lesser procedures are compared. The outcome after incomplete surgical resection is heavily dependent on age. We have noted that only 11% of young or low-risk patients who had incomplete removal of the primary cancer died of disease when monitored for a minimum of 15 years, whereas high-risk or older patients had a risk of death of greater than 90% if the cancer was not grossly completely resected." Thus, even the results after incomplete surgical removal are heavily dependent on basic biologic phenomena, principally age and basic risk group.
Surgical Therapy of the Primary Cancer and Lymph Node Metastases Most multifactorial studies.>!" as well as many other reports,50-61 document that the extent of thyroid gland resection, the extent of lymph node resection, and the number of lymph node metastases involved had no bearing on patients' survival. There may be a higher risk of local recurrence in patients treated by thyroid lobectomy," but a recurrence in the remnant thyroid tissue never caused a death in the Mayo Clinic report. 57 No other human cancer represents such a lack of relationship between survival and lymph node metastases
251
or the presence of residual cancer at the conclusion of the surgical procedure as in young, low-risk patients with thyroid carcinoma. Indeed, even distant metastatic disease in differentiated carcinoma is not uniformly fatal in children or young adults 49,61 and can be treated for cure in a high proportion (>50%) of low-risk patients with radioactive iodine therapy.62-64 To have effective treatment in these patients, the remnant thyroid tissue must be removed or ablated. It should be noted that, regarding outcome and prognosis, medullary carcinoma of the parafollicular C cells does not display this unique lack of relationship between lymph node metastases and outcome. Medullary carcinoma of the thyroid does display some age association with prognosis but has the usual relationship between increasing lymph node involvement and poorer long-term survival." Thus, even cancers arising from different cells within the same gland display uniquely different biologic phenomena. This merely reemphasizes the fact that lymph node metastases in almost all human cancers are "indicators but not governors'P" of poor outcome. In patients with differentiated thyroid carcinoma, the indicator function is less precise, and the prognosis either is not affected by or, in one report, is even better in cases with lymph node metastases." Lymph node metastases are extremely common in papillary cancer, and two thirds of recurrences in the low-risk cancer are lymph node metastases." None of these presentations of lymph node metastases (occult, palpable, multiple, or recurrent) have deleterious effects on the prognosis of low-risk patients with differentiated thyroid carcinoma. In high-risk thyroid cancer patients, however, there may well be an association between lymph node metastases and a worse prognosis.f the usual relationship, again displaying the unique features of lowrisk patients.
Radioactive Iodine Clearly, in the presence of unresectable local disease, recurrent local disease, and distant metastases to the lungs, bones, or other sites, the potential curability of patients is almost totally dependent on the success of radioactive iodine (RAI) therapy.67.68 Not all differentiated carcinomas of the thyroid take up RAI, but when they do, the nuclear dose of radiation therapy is extraordinarily high (20,000 to 30,000 cGy) and, therefore, highly successful in ablating metastatic deposits. When tumors cannot be induced to take up RAI, however, therapeutic effectiveness is absent. In younger patients (low risk) and in children with distant metastases, metastases frequently take up RAI in therapeutically significant amounts,63.64 and long-term disease-free life can be achieved. This represents the unique phenomenon of a "homing" compound (iodine) carrying a lethal cellular poison (radiation-emitting isotope) that can seek out and destroy cancer cells throughout the body, even in disseminated metastases. Such an idealized cancer treatment remains the model and the elusive goal of cancer therapy and, to date, has seldom been duplicated in any other human cancer on a regular basis. Because the avidity of the normal thyroid gland for iodine and its radioactive isotopes is many magnitudes higher than that of even the most efficient iodine metabolism
252 - - Thyroid Gland of differentiated thyroid cancer, all normal thyroid tissue has to be eliminated to attempt therapeutic utilization of RAI. In patients with metastases or unresectable local disease, the need for total thyroidectomy, either surgical or radiotherapeutic, is unquestioned. After total thyroidectomy, with avoidance of removal or devascularization of the parathyroid glands, diagnostic RAI scans are used to detect residual normal thyroid tissue, which can be eliminated with small therapeutic doses of RAI (-30 mCi). After ablation of normal remnant thyroid tissue, iodine 131 can be used in hypothyroid patients with high serum TSH levels to ablate metastatic deposits. The curability of patients with metastatic thyroid carcinoma is related to their basic risk group,49.63.64 but all patients with distant metastases should receive treatment with RAI. In low-risk or young patients, the curability of pulmonary metastases is extremely high after appropriate RAI use, but in older or high-risk patients successful and effective treatment of distant metastases by RAI seldom results in a long-term disease-free state because other metastases develop or the original metastases regrow. Despite the acknowledged value of RAI for treatment in advanced, high-risk, recurrent, or metastatic cases of differentiated thyroid carcinoma, there is little evidence that routine adjuvant use of RAI in low-risk patients is of any benefit. 67.68 Hay and colleagues'" have questioned the routine adjuvant use of RAI in low-risk patients and found no evidence of improved cause-specific survival with RAI.
Changing Presentation of Thyroid Cancer The clinical presentation of thyroid carcinoma has changed dramatically over the years. The median size of all differentiated thyroid carcinomas has declined progressively, so that by 1980 and continuing currently only 10% of older and 6% of younger patients presented with lesions larger than 3 em in diameter, and almost 66% of the younger patients and 60% of the older patients presented with primary cancers smaller than 2 em in diameter." Clearly, such earlier disease presentation has improved the overall prognosis. Several authors have reported a better overall prognosis beginning about 195034 or 1960 5 1.62 for reasons that may be related to earlier diagnosis and, therefore, better risk group definition but are primarily related to the declining incidence of conversion of papillary to anaplastic carcinoma and the presence of less aggressive cancers that occur in populations with adequate dietary iodine. Thus, patients seen in the 1990s had a far better prognosis overall but, when separately defined by a multifactorial risk group, were seen to have a clinical behavior similar to that in previous decades." The better overall prognosis, then, is related to a higher proportion of cancers that can be completely resected, the smaller cancers diagnosed, the decreased frequency of extension outside the thyroid gland, and a lower proportion of patients presenting initially with distant metastases. In the 1930s, as many as 6% of patients initially presented with distant metastases, usually pulmonary, but the proportion is currently less than 1%. A multifactorial risk group assessment is also applicable to patients with large or advanced cancers from third-world countries (R. S. Rao, personal communication, 1994). Lowrisk patients by the AMES multifactorial classification still have an excellent prognosis.
Children Although frequently presenting with relatively advanced local, nodal, or metastatic disease, young children and teenagers have an extremely good prognosis.sl'" In some reports, more children die of pulmonary fibrosis secondary to RAJ treatment of the pulmonary metastases than die of thyroid carcinoma. Children younger than 7 years may have a poorer prognosis. Pulmonary metastases in children usually take up RAI, and these children can usually be cured with appropriate treatment.
Recurrence The term recurrent thyroid carcinoma is expected to imply some decrement in outcome and prognosis. However, if the "recurrence" is actually a new primary tumor in residual contralateral thyroid tissue.? the prognosis is no different from that for a primary carcinoma in any other presentation and risk group assignment. True recurrent carcinoma in the bed of the previously resected thyroid gland may be a difficult pattern of disease to treat; most such true local recurrences are not readily surgically resectable, but resection should be attempted. If RAI in therapeutic doses was not used initially, its potential use should be investigated by diagnostic scans and elimination of all residual normal thyroid. Reoperation for the completion of a total thyroidectomy at this time in the few patients who display such local tumor bed recurrence should be performed or the residual thyroid gland ablated by RAI. Occasionally, persistent disease in the wall of a trachea or larynx, with progressive growth, may cause airway encroachment and require surgical therapy."? Resection of a small segment of trachea is sometimes required and can be accomplished successfully. On rare occasions, laryngectomy for recurrent disease with airway obstruction may be required. Such extensive surgery should rarely be performed initially because of the excellent therapeutic outcome achieved with RAI, which can result in a good disease-free, long-term survival in low-risk or young patients." Thus, although recurrence is a poor prognostic sign in high-risk patients, it is not invariably an indication of fatal outcome, and indeed low-risk patients may do quite well." In our study, 80% of low-risk patients with recurrent disease survived, whereas 80% of older high-risk patients died. This is a further example of the risk group assuming more importance than the particular presentation of disease, type of recurrence, or type of therapy. Shaha has given a contemporary summary of risk group relationship to outcome."
Metastases Distant metastatic disease usually appears after treatment of a patient with an advanced primary cancer; it is rarely the presenting complaint of patients with a small or an obscure primary thyroid carcinoma, particularly older or high-risk patients. Low-risk patients with pulmonary metastases have better than 50% long-term disease-free survival after treatment with 131 1 and TSH suppression.49.63.64.72.73 As mentioned earlier, pulmonary metastases are far less common todayy·34.49 Whether earlier detection and treatment in a preclinical
Predictors of Thyroid TumorAggressiveness - - 253 stage by diagnostic scanning (which requires total thyroid ablation) and treatment when detected later by chest radiography are equivalent in outcome after RAI therapy is a matter of some debate." Patients with distant metastases other than to the lung tend to have a very poor outcome over the long term, although aggressive resection of isolated bone metastases with postresection RAI therapy is sometimes effective. Long-term outcome in these patients is also influenced by age and basic risk group.49,63.64,72,73 High-risk patients may have prolonged disease courses, but eventually almost all older patients with distant metastases die of disease.
Clinical Application of Indicators of Thyroid Tumor Aggressiveness The ready application of a variety of risk group definitions (AMES, AGES, MACIS) indicates that all patients should be so characterized before initial surgery and again at completion of surgery. Age and tumor size can be determined preoperatively, whereas local invasion, distant metastases, resectability, and tumor histology or grade are usually determined postoperatively. By characterizing the risk group, the surgeon can make an initial preoperative estimate of the need for and extent of thyroid and regional lymph node resection and, postoperatively, the need for RAI treatment. When the risk of recurrence is only 3% and the risk of death only I % in the low-risk MACIS, AMES, or AGES risk definition categories, it is impossible to prove the advantage of total thyroidectomy with RAI in contrast to a more limited or unilateral operation. Although no randomized trial has been conducted because of the infrequency of thyroid carcinoma even in young patients, studies addressing the issue of extent of surgical resection in low-risk patients find no consistent evidence of improved prognosis in patients undergoing total thyroid removal.P''" The critical need in patients who are young and have little or no risk of death is to have an operation that avoids, as much as possible, the chances of morbidity.57.75,76 In low-risk patients, the use of RAI scanning in surgical follow-up appears to be unnecessary because it contributes nothing to improvement in the near-perfect outcome. 66,68 Indeed, even the value of thyroid hormone administration in such patients is now questioned,68,77 except, of course, in patients who initially undergo total or near-total thyroidectomy. Because all studies of long-term medication indicate poor compliance by patients after many years, one needs either to monitor such patients closely throughout the rest of their lives by repeated TSH testing to prevent subtle hypothyroidism or iatrogenic hyperthyroidism or to leave enough thyroid tissue so that the patient is euthyroid in the absence of thyroid hormone administration. In older or high-risk patients and in low-risk patients with extensive or bilateral disease, strong consideration should be given to performing a total thyroidectomy initially because postoperative RAI therapy almost certainly should be attempted and TSH suppression therapy used. Total thyroidectomy in these situations is used primarily to facilitate the use of RAI.
Because lymph node metastases do not appear to influence patients' outcomes adversely and their cells do not implant in surgical wounds, it seems illogical to focus too greatly on maximizing the extent of lymph node resections, and selected nodal removal is adequate. Good functional and cosmetic results should be the principal goals. Reports from Sweden documenting prolonged microscopic surgical dissection of extensive regional lymph node areas in patients with medullary thyroid cancers seem illogical. No biologic rationale for such an endeavor in differentiated thyroid carcinoma exists, and the results of such reports should be critically evaluated. A convenient clinical approach to regional lymph node metastases in low-risk patients indicates that, for preoperatively palpable lymph node metastases in the neck, a function-preserving modified neck dissection is adequate. Such a functional neck dissection would include, at the very least, preservation of the spinal accessory nerve and the submandibular area with the ramus mandibularis. In addition, preservation of the sternocleidomastoid muscle and jugular vein should be attempted because limited selective dissection of the lymph nodes themselves is adequate, The phenomenon of wound implantation with differentiated thyroid carcinoma is rare. If lymph node metastases are not felt preoperatively but are observed or are palpable at the time of thyroid surgery, these nodes and the central compartment containing fat and nodes should be removed without extending the thyroid incision. Limited lateral neck dissection should be done to include palpable node metastases. Such central compartment or restricted node removal can be accomplished with minimal to no morbidity. As a corollary to the generally good prognosis and lack of relationship of lymph nodes to outcome, it should be noted that any functioning recurrent laryngeal nerve should be preserved at all costs, even if it has to be carefully dissected out from surrounding conglomerate lymph node metastases. Finally, if no obvious lymph node metastases are noted either before or at surgery, no formal lymph node removal needs to be performed. It is worth commenting on the fact that any young person presenting with a palpable lymph node in the neck should have as the first diagnostic maneuver a needle aspiration, not an excision, of the lymph node that is palpable. Well-trained cytopathologists can uniformly make the diagnosis of thyroid carcinoma using needle aspiration cytology of lymph node metastases. If the diagnosis is made by aspiration, even though the primary thyroid cancer is not palpable, operative strategy and treatment can be planned effectively with avoidance of a separate node biopsy. When an appropriate neck dissection has been performed, recurrence of cervical node metastases is very uncommon. Overall, most recurrences (two thirds) in low-risk patients are in the form of palpable lymph node metastases in the absence of previous neck dissection. Because lymph node metastases have little bearing on prognosis, the surgical or therapeutic RAI treatment of node metastases is associated with an excellent outcome, in keeping with the basic risk group definition. Although either surgical approaches or RAI may be suitable, there are advantages in performing a cosmetically acceptable and function-preserving neck dissection because (1) not all of these tumors take up RAI,
254 - - Thyroid Gland (2) treatment with RAI is prolonged and complicated and may require hospitalization and a previous total thyroidectomy, and (3) the results are not as good as with surgical removal. The use of serum thyroglobulin determination as a tumor marker has been encouraged as a component of the postoperative management of thyroid carcinoma. It seems illogical to perform expensive technologic tests for careful follow-up in the low-risk patients because the 20-year mortality is only I % and total thyroid ablation is required for the utilization of thyroglobulin determinations. Repeated RAI diagnostic scans require a hypothyroid state each time and should be avoided in low-risk patients, in whom such repeated periods of hypothyroidism are disabling. Thus, a simplified followup approach would avoid any kind of intensive technical follow-up in the 85% to 90% of patients at low risk, as judged by the MACIS or AMES scoring systems. In highrisk patients in whom more extensive surgery was used, the use of thyroglobulin determination and RAI scanning postoperatively appears to be justified in an attempt to increase long-term disease-free survival, but almost all distant metastases eventually prove fatal. Finally, several attempts78-80 to define differentiated thyroid cancer aggressiveness further are too recent to evaluate their feasibility for clinical use, particularly when such efficient practical clinical risk groups exist.
Summary Most patients with papillary and follicular thyroid cancer can be classified into low-risk groups by the AGES, AMES, TNM, or MACIS classifications. These low-risk patients have an excellent prognosis, so that total thyroidectomy is not required for patients with cancers confined to one lobe. Lymph node metastases should be removed by a functional neck dissection preserving the spinal accessory nerve, the internal jugular vein, and the sternocleidomastoid muscle. High-risk patients may benefit from total or near-total thyroidectomy as well as postoperative use of RAI adjuvant treatment, serum thyroglobulin determination, and TSH suppression therapy.
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121 LNM 1 EJ LNM 2
o Primary Tumor
TSH CON~~~~~
o
2
cAMP (pmol/well)
FIGURE 29-5. Homologous desensitization of cyclic adenosine monophosphate (cAMP) to thyroid-stimulating hormone (TSH) stimulation in neoplastic thyroid cells from six patients. Cells were cultured in 24 well plates for 3 days and for the last 24 hours in medium lacking TSH and fetal calf serum until 95% confluence. These cells were preincubated for 4 hours in either control medium without TSH (CON) or in medium supplemented with TSH (10 mU/mL) and washed three times with phosphate-buffered saline, pH 7.4. The cells were then incubated for 30 minutes in control medium and in medium supplemented with TSH (10 mU/mL) and I mM isobutylmethylxanthine. Intracellular cAMP was then measured by radioimmunoassay. Each bar represents the mean ± SD of 18 experiments. Neoplastic thyroid cells (white bar) showed desensitization after pretreatment with TSH for 4 hours, whereas two of three metastatic cell lines (type I, hatched bar) had an increased cAMP level in response to TSH stimulation, and both failed to desensitize. The third metastatic cell line both failed to increase cAMP level in response to TSH and failed to desensitize (type II). P < .002. (Data courtesy of Tezelman S, Shaver JK, Grossman RF, et al. Mechanism of homologous and heterologous desensitization in human neoplastic thyroid cells. Unpublished personal data, 1996.)
274 - - Thyroid Gland of phorbol ester-binding studies in many cell types.l" The effects of PKC downregulation on TSH-stimulated iodide organification have been demonstrated in porcine thyroid cells. 189 Like TPA, EGF had no direct effect on cAMP levels, but it did cause desensitization of cAMP production to subsequent TSH stimulation.'?" The EGF-induced desensitization of TSH-AC signal transduction system was abolished by coincubation with EGF-R antibody (EGF-R monoclonal antibody 528) and by genistein.l'" Desensitization apparatus, phosphodiesterase expression, and CREB may be activated in functioning thyroid adenomas.P"!"
Interaction (Cross-Talk) of the Different Signal Transduction Systems Cellular responses to external stimuli involve an integration of inputs from hormones, neurotransmitters, and growth factors. This integration is able to interact with distinct second messengers. The effect of one signal transduction system may alter the response of another, as already mentioned. This is called cross-talk. Although TSH stimulates both the AC system and the phosphoinositide turnover-calcium systems in animal cell cultures and human neoplastic membranes,43.106 the response patterns of protein phosphorylation to TSH and TPA are different and not reproduced by elevating cAMP by IBMX. 194 TSH and TPA had no additive effect on the proliferation of dog thyroid cells. 195.196 TPA, however, reduced the cAMP response to TSH when both agonists were incubated in dog and pig thyroid cells.197-199 TSH decreased cAMPdependent PKA activity in dog thyroid cells,2oo but the simultaneous presence of TPA and TSH, in contrast, inhibited TSH-induced downregulation of PKA 1.197 TPA had a biphasic effect on TSH-induced stimulation of cAMP production in pig thyrocytes.l'" TPA potentiated the effect of TSH when pig thyroid cells were exposed simultaneously to TSH and TPA for 10 minutes, but after 20 minutes TPA inhibited the cAMP response to TSH.198 TPA blocked the TSH effect and prevented cAMP-dependent PKA activity.!" Graves' disease IgG can increase PLC activity as well as cAMP production in rat FRTL-5 thyroid cells. PKC modulates different signal transduction systems, leading to positive or negative cross-talk with calmodulin kinase.P' Increased activation of calmodulin kinase by PKC results from PKCmediated phosphorylation of calmodulin-binding proteins.i" Studies demonstrated that when neoplastic thyroid cells are coincubated with TPA and TSH for 4 hours or longer, TPA decreased the cAMP response compared with that when cells are stimulated with TSH alone.I" This effect of TPA is abolished by coincubation with staurosporine.P? Although EGF does not change the level of cAMP directly, TSH increases cAMP levels, which then stimulates the production of EGF-Rs.I53·154 TSH induces proliferation and differentiation expression in dog thyroid cells, whereas EGF and TPA induce proliferation and dedifferentiation. When dog thyrocytes were simultaneously exposed to both TSH and EGF, the expression of protooncogenes, such as c-myc, was lower than with exposure to either EGF or TSH alone. 203 Pretreatment with TSH or forskolin increases the
response of pig thyroid cells to EGF, probably because of increasing numbers of EGF receptors.'>' TSH increases both thyroid cell growth and differentiation, whereas EGF increases only thyroid cell growth and inhibits cell differentiation. EGF also inhibits TSH-mediated thyroglobulin synthesis, morphologic differentiation, and iodide uptake, as well as organification. I44•204-206 In general the PKC- and PTK-mediated pathways are triggered by TPA and EGF.207 Increased concentrations of intracellular cAMP block activation of raf-; and MAPK in fibroblasts.l'" Thus, EGFdependent MAPK activation was blocked by forskolin or IBMX. PKA probably phosphorylates and inactivates MAPKs. Dibutyryl cAMP blocks DNA synthesis and also signal transmission from ras by inhibiting raj activation. 132 The incubation of EGF and TSH together induced a significant decrease in cAMP response to TSH compared with the cAMP response that resulted after stimulation with TSH alone. 190 Thus, EGF inhibits TSH-stimulated cAMP production. The inhibition of cAMP was abolished when neoplastic thyroid cells were incubated with TSH, EGF, and EGF-R-monoclonal antibody 528. 190 Natriuretic peptides (NPs) and their receptors (NP-R) have been identified in thyroid gland. 208 Although atrial natriuretic factor inhibits cAMP formation and thyroglobulin production in primary thyrocyte cultures through subsequent activation ofGi NAPs, binding to NP-R can activate AC.209
Summary The growth pattern of thyroid cells is complex and is under the control of various signal transduction systems, including the AC-cAMP-PKA system, the PLC-PKC-system, the Ca-CaM-kinase system, and the growth factor-tyrosine kinase system. Extracellular signals such as hormones, neurotransmitters, and growth factors bind to their specific receptors and stimulate intracellular transduction systems into second messengers. The TSH-AC signal transduction system has been well investigated in benign and malignant thyroid tumors. The TSH-PLC and EGF-tyrosine kinase system, as well as other signal systems, has also been studied. Derangements in the signal transduction systems cause abnormal growth and behavior of thyroid follicular cells. The interactions or cross-talk between signaling systems play an important role in the growth pattern of normal and abnormal thyrocytes. A better understanding of the various factors that influence the particular signal transduction system and of specific alterations in signaling that correlate with changes in behavior should lead to new therapies.
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eukaryotic cells provides evidence that homologous desensitization to thyrotropin stimulation requires a cell-specific factor. Endocrinology 1990;127:1240. Tezelman S, Shaver JK, Grossman RF, et al. Desensitization of adenylate cyclase in Chinese hamster ovary cells transfected with human thyroid stimulating hormone receptor. Endocrinology 1994;134:1561. Tezelman S, Hoelting T, Jossart G, et al. Influence ofphospholipase-C signal transduction system on the desensitization of the TSH-adenylate cyclase signal transduction system. Presented at the Annual Meeting of the American Association of Cancer Research, San Francisco, April 16-19, 1994. Kraft AS, Anderson WB, Cooper H, et al. Decrease in cytosolic calcium/phospholipid-dependent protein kinase activity following phorbol ester treatment of EU thymoma cells. J Bioi Chern 1982;257:13193. Ginsberg J, Murray PG. Phorbol ester and phospholipase C-mediated differentiated thyroid function in vitro: The effects of protein kinase C inhibition and down-regulation. Thyroid 1991;1:195. Tezelman S, Siperstein AE, Duh QY, et al. Cross-talk between epidermal growth factor and thyrotropin-induced desensitization of adenylate cyclase in human neoplastic thyroid cells. Poster presented at the 67th Annual Meeting of the American Thyroid Association, Tampa, Florida, November 10-14, 1993. Voight C, Holzapfel HP, Paschke R. Expression of ~-arrestins in toxic and cold thyroid nodules. FEBS Lett 2000;486:208. Persani L, Lania A, Alberti L, et al. Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas. J Clin Endocrinol Metab 2000;85:2872. Brunetti A, Chiefari E, Filetti S, et al. The cyclic AMP response elements binding protein (CREB) is functionally reduced in human toxic thyroid adenomas. Endocrinology 2000;141:722. Tanabe A, Nielsen TB, Dheela-Rani CS. Thyroid cell responses to thyrotropin and 12-0-tetradecanoyl-phorbol-13-acetate: Translocation of protein kinase C and phosphorylation of thyroid cell polypeptide substrates. Arch Biochem Biophys 1985;243:92. Roger PP, Reuse S, Servais P, et al. Stimulation of cell proliferation and inhibition of differentiation expression by tumor-promoting phorbol esters in dog thyroid cells in primary culture. Cancer Res 1986;46:898. Lamy F, Roger PP, Lecocq R, et al. Protein synthesis during induction of DNA replication in thyroid epithelial cells: Evidence for late markers of distinct mitogenic pathways. J Cell Physiol 1989; 138:568. Roger PP, Breton MF, Dumont JE, et al. Epidermal growth factor and phorbol ester actions on the TSH-induced down-regulation of the isoenzyme I (PKA I) of cyclic AMP-dependent protein kinases in dog thyroid cell primary cultures. Cell Signal 1991;3: 145. Omri B, Breton MF, Haye B, et al. Phorbol esters prevents the thyroid-stimulating hormone-induced but not the forskolin-induced decrease of cAMP-dependent protein kinase activity in thyroid cell cultures. Eur J Biochem 1988;175:125. Rani CSS, Field JB. Comparison of effects of thyrotropin, phorbol esters, norepinephrine, and carbachol on iodide organification in dog thyroid slices, follicles, and cultured cells. Endocrinology 1988;122:1915. Breton MF, Haye B, Omri B, et al. Decrease in cAMP-dependent protein kinase activity in suspension cultures of porcine thyroid cells exposed to TSH or forskolin. Mol Cell Endocrinol 1988;55:243. Hidika A, Okajima F, Ban T, et al. Receptor cross-talk can optimize assays for autoantibodies to the thyrotropin receptor: Effector of phenylisopropyladenosine on adenosine 3',5'-monophosphate and inositol phosphate levels in rat FRTL-5 thyroid cells. J Clin Endocrinol Metab 1993;77:1164. MacNicol M, Shulman H. Cross-talk between protein kinase C and multifunctional Ca 2+/calrnodulin-dependent protein kinase. J Bioi Chern 1992;267:12197. Reuse SC, Maenhaut C, Dumont JE. Regulation of protooncogenes c-fos and c-myc expressions by protein tyrosine kinase, protein kinase C, and cyclic AMP mitogenic pathways in dog primary thyrocytes: A positive and negative control by cyclic AMP on c-myc expression. Exp Cell Res 1990;189:33. Eggo MC, Bachrach LK, Fayet G, et al. The effects of growth factors and serum on DNA synthesis and differentiation in thyroid cells in culture. Mol Cell EndocrinoI1984;38:141. Errick JE, Eggo MC, Burrow GN. Epidermal growth factor inhibits thyrotropin-mediated synthesis of tissue-specific proteins in cultured bovine thyroid cells. Mol Cell Endocrinol 1985;43:51.
Signal Transduction in Thyroid Neoplasms - - 279 206. Roger PP, Dumont JE. Epidermal growth factor controls the proliferation and the expression of differentiation in canine thyroid cells in primary culture. FEBS Lett 1982;144:209. 207. Heimrich R, Kraiem Z. The protein kinase pathway inhibits c-jun and c-fos protooncogene expression induced by the protein kinase C and thyrosine kinase pathway in cultured human thyroid follicles. J Clin Endocrinol Metab 1997;82:1839. 208. Tseng YCL, Lahiri S, Selsiti OF, et al. Characterization by affinity cross-linking of a receptor for atrial natriuretic peptide in cultured
human thyroid cells associated with reduction in both adenosine 3' -phosphate production and thyroglobulin secretion. J Clin Endocrinol Metab 1990;70:528. 209. Selliti OF, Perrella G, Doi SQ, et al. Natriuretic peptides increase cAMP production in human thyrocytes via the natriuretic peptide clearance receptor (NPR-C). Regul Pept 2001;97:103.
Oncogenes in Thyroid Tumors Peter E. Goretzki, MD • Victor Gorelev, MD • Dietmar Simon, MD • Hans-Dietrich Roeher, MD
The knowledge that a variety of environmental conditions, such as exposure to external radiation or chemicals, or chronic inflammatory processes and viral infections can induce neoplasms initiated studies seeking the explanation for these associations. Cells can be infected with RNA- or DNA-containing viruses, and the viral genome becomes inserted into the genetic code of the host cell.' As the cells divide, the viral DNA is transcribed and translated, producing a protein that may act as a growth factor, as a growth factor receptor, in signal transduction, or in the transcription of other genes. In the latter situation, it may interfere with apoptosis. Tumor development after viral infection occurs as a result of insertion and activation of viral oncogenes in host cells. 1 Subsequent investigation documented that eukaryotic cells harbor genes similar to viral oncogenes, which started the hunt for additional protooncogenes. Radiation and chemical toxins lead to tumor development and malignancy by causing multiple genetic changes that accumulate in affected cells (Fig. 30-1). These genetic changes may be single base pair changes (i.e, point mutations), insertions, deletions, rearrangements, and translocations. These genetic modifications affect encoded protein structure (i.e., mutations) or amplify certain genes (i.e., translocation), which then alter normal regulatory processes, turning protooncogenes into oncogenes.' Protooncogenes can be defined as genes involved in cell growth and cell differentiation that gain oncogenic potential and support tumor development and tumor propagation when amplified or structurally modulated. Thyroid tumors of follicular cell origin appear to develop by means of multiple genetic changes in cells rather than by activation of a single oncogene.v' Oncogene products can be divided into different protein families with specific cellular functions (e.g., growth factor, growth factor receptor, signal-transducing protein), and they may act on cell surfaces, within the cell cytoplasm, or within the nucleus-that is, inhibitors and activators of transcription (Fig. 30_2).2.5 Some variations of these general rules are related to the physiologic characteristics of specific tissues. Oncogenes can be deduced from their similarity to viral genes and from genes encoding proteins involved in the physiologic pathways of cell stimulation.P" Constitutive activation by specific mutations was demonstrated in vitro for the thyroid-specific growth factor receptor (i.e., thyrotropin or thyroid-stimulating
280
hormone [TSH] receptor) and the signal-transducing protein (gsp) connected to this receptor (i.e., alpha subunit of the Gs protein [Gs-a]). The field of oncogene research focuses on genetics and incorporates information from microbiology (e.g., viral infectious diseases), embryology, physiology (e.g., proteins important in growth and differentiation), epidemiology (e.g., prevalence of thyroid cancer in Russia before and after the Chernobyl catastrophe), toxicology, and radiology (e.g., effect of radiation on oncogene structure and expression). In this chapter, we review the roles of oncogenes in human thyroid tumors.
Oncogenes Connected to Thyroid-Stimulating Hormone Thyroid-Stimulating Hormone Receptor Mutations The idea that physiologic pathways may be constitutively activated by genetic alterations of single components of these pathways was compelling but hard to prove. For thyroid tumors, the TSH receptor (TSH-R) had to be cloned before studies of the structure and expression of this receptor could be performed. Cloning of the human TSH-R by Parmentier and colleagues in 1989 9 was an important breakthrough in this field. The knowledge that all G protein-related receptors develop from a common progenitor and demonstrate specific protein structures (i.e., an intracellular carboxyterminal end, an extracellular ligand-specific end, and a seven-transmembrane loop region) made it possible to use experiences from p-adrenergic receptor studies for TSH-R investigations. Liggett'? and Hausdorff"! and their colleagues used sitespecific deletions of the p-adrenergic receptor. They were able to modulate specifically hormone-stimulated cyclic adenosine monophosphate (cAMP) production of transfected cells with wild-type or deleted p-adrenergic receptors.F Because various groups had demonstrated the growthstimulating effect of TSH in human tumors and had demonstrated an enhanced cAMP response to TSH in differentiated thyroid tumors.P:" the question arose whether tumorspecific changes in the cAMP response were caused by TSH-R mutations. Several groups screened human thyroid
Oncogenes in Thyroid Tumors - - 281
FIGURE 30-1. Multistep mutation
theoryof thyroidtumordevelopment. Mutations A-M and N-W are mutations that lead to cell death or early apoptosis (i.e., programmed cell death). Mutation X provides growth advantage but no immortalization (i.e.,cooperative mutationsin benign tumor development). Y-Z mutations cooperate in tumor development, including mutations that interfere with apoptosis and may lead to immortalization and to uncontrolled malignant tumor growth.
UNCONTROLLED GROWTH
tumors for activating mutations in the TSH-R gene, and Parma" and Paschke'? and their coworkers found somatic mutations in the TSH-R gene from the DNA of autonomously functioning thyroid adenomas. Kopp and colleagues" demonstrated TSH-R mutations in a patient with congenital hyperthyroidism and an autonomously functioning goiter; the mutated genes increased basal cAMP production when transfected into COS cells. Nonhyperfunctioning thyroid adenomas and differentiated thyroid cancer, however, lacked the stimulating mutations of the TSH-R gene, as demonstrated by Matsuo and associates.'? Activating TSH-R mutations are restricted to some benign thyroid tumors with functional hyperactivity.
FIGURE 30-2. Oncogenes in human thyroid tumors.
Oncogeneproducts may be divided into receptor proteins, proteins for transducingsystems, and nuclear transcription factors or inhibitors of transcription. Known protooncogenes for thyroid tumors activated by mutation, translocation,or amplificationare the gene for the thyroidstimulating, hormone receptor (leading to benign hyperfunctioning adenomas); genes for receptors with tyrosine kinase activity, such as egf-r, trk, ret, and neu (demonstrated in differentiated thyroid cancer [DTC] and medullary thyroid cancer [MTC]; the PDGF-r gene (demonstratedin anaplastic thyroid cancer); and genes for proteins in transducing systems with guanosine triphosphatase activity, such as ras and gsp (demonstrated in benign and malignant thyroid tumors). Intranuclear protooncogenes,such as c-myc, c-fos, and c-jun, are amplified by external stimulation, but their primary importance in the development and propagationof human thyroid tumors has not been proved.
G Protein Mutations Activating mutations of the alpha subunit of the G protein that enhances cellular cAMP were first demonstrated in growth hormone-secreting pituitary tumors by Vallar and coworkers in 1987.20 Further investigations by Landis" and Masters" and their colleagues biochemically identified and characterized the effect of these stimulating mutations that inhibit G protein-specific guanosine triphosphatase (GTPase) activity. The mutated stimulating G protein (Gs) has a much lower GTPase activity than wild-type Gs. The reduced susceptibility of GTP to hydrolysis may increase the period of Gs in the GTP-bound state. Because Gs-GTP
FUNCTION
ONCOGENE
TUMOR TYPE
RECEPTOR
tsh-r egf-r; trk ret; neu pdgf-r
BENIGN DTC;MTC
TRANSDUCING SYSTEM
ras; gsp
BENIGN & DTC.MTC
NUCLEAR FACTOR
myc; fos; jun second. effects
UNDIF.CA
282 - - Thyroid Gland 1)
PRIMER
c201
I
236bp
BstZ1
2)
PRIMER
BstZ1
190bp 220bp
•
rt 201 rnut201
DNA AMPLIFICATION BY PCR
DIGESTION BY BstZ1
3)
PRIMER
106 bp PRIMER
AMPLIFICATION OF MUTANT DNA mut201 wt201 ssDNA
wt201/mut201 nondigested 1.PCR product
FIGURE 30-3. Detection of gsp mutations at codon 201 by two-step restriction fragment length polymorphism-dependent polymerase chain reaction (PCR). In the first step, PCR primers are used to amplify a part of the gsp gene, including codon 201, with a tota11ength of 236 base pairs (bp). This product demonstrates two restriction sites for the enzyme BstZ1, with one inside codon 201 at the 5' end and one at the 3' end. In the second step, digesting the product with BstZl causes a new product of 190 bp in the case of wild-type (wt) gsp at codon 201 and a product of 220 bp in the case of mutated (mut) gsp at codon 201. However, parts of undigested wild-type gsp genes may still be present, even in optimal reaction conditions. In the third step, a second PCR with the first 5' end primer and an inner 3' end primer amplifies only mutant gsp and uncut wild-type gsp, yielding a product of 106 bp. A second digestion with BstZl does not change the 106-bp product in the case of the mutant gsp at codon 20 I, but it gives rise to an additional 60-bp product in the case of noncut wild-type gsp.
represents the biologically active protein, some Gs mutations enhance the amount of biologically active Gs protein. In 1990, Lyons and coauthors-' demonstrated an activating Gs protein mutation (i.e., mutation of the gsp gene) in an autonomously functioning multinodular goiter, a finding that was confirmed by Suarez and colleagues.s' Sullivan and associates.P and our group.! Unlike pituitary tumors, multinodular goiter and various benign and malignant thyroid tumors are polyclonalv-" and demonstrate a low level of gsp.8 Specific techniques were applied to isolate and amplify gsp mutations in thyroid tumors: mutation-specific oligonucleotide hybridization of asymmetric polymerase chain reaction products" and two-step restriction fragment length polymorphism methods (Figs. 30-3 and 30_4).29 By correlating these results with subcloning techniques, we demonstrated gsp mutations in 35% of all 86 investigated differentiated thyroid cancers and C-cell carcinomas of the thyroid (Table 30-1). The proportion of cells bearing gsp varies between 3% and 43%.30 When sensitive molecular biologic technique's are applied, gsp mutations can frequently be detected in differentiated thyroid tumors of patients from low-iodine areas. Whether these results are different in tumors from patients with sufficient iodine supplementation, as hypothesized by us in 1992,8 awaits further investigation. We demonstrated enhanced expression of Gs-a when the gene is mutated (Table 30_2).30 This contrasts with the effect of chronic external Gs stimulation. For example, cholera toxin causes tachyphylaxis, and Gs-a expression decreases with time." Activating mutations of the TSH-R and Gs-a enhance basal cAMP production directly and enhance it indirectly by the lack of downregulation and overexpression of mutated gsp-encoded protein.
Low abundant mutation detectable (Lane 9 and 11)
FIGURE 30-4. Two-step restnction fragment length polymorphism method. Seven thyroid tumor tissues were tested by electrophoresis before and after the second digestion of the polymerase chain reaction (PCR)-amplified gsp gene, including codon 201. Lane 7 shows the DNA ladder for checking the length of PCR products. Lanes I, 3, 5, 8, 10, 12, and 14 demonstrate undigested second PCR products of gsp with lengths of about 220 bp (upper arrow). Lanes 2, 4, 6, 9, 11, 13, and 15 demonstrate DNA after the second BstZI digestion, with partial digestion at lanes 2, 4, 6, 13, and 15 but no digestion of the DNA product at lanes 9 and 11 (lower arrow). These two tissues (8/9 and 10111) harbor mutant gsp at codon 201, but tissues 1/2,3/4,5/6, 12/13, and 14/15 do not. The sensitivity of detecting gsp mutations at codon 201 was less than 3% (controlled by subcloning).
Oncogenes in Thyroid Tumors - - 283
Stimulating mutations of Gs-a, demonstrable in benign (especially autonomous nodules) and malignant differentiated thyroid tumors, are important somatic mutations in the development and propagation of thyroid tumors. The mutations increase cAMP production and Gs-a expression, which stimulates cellular growth.
ras Family Oncogenes Activating point mutations in three human ras genes (i.e., Harvey ras [H-ras] on chromosome 11, Kirsten ras [K-ras] on chromosome 12, and N-ras on chromosome 1) have been demonstrated in numerous tumors, including thyroid tumors.Approximately 40% to 50% of colon cancers, more than 80% of pancreatic cancers and cholangiocarcinomas, and 30% to 40% of lung cancers harbor specific ras mutations.P'" Ras encodes a small protein, p21, of 21,000 D that has no intrinsic GTPase activity. p21 forms a complex with a GTPase-activating protein, GAP, that enhances the GTPase activity of p21 more than 4000 times. This GAPinduced GTP hydrolysis is reduced by a factor of 1000 by mutant ras-encoded proteins when the mutations occur at codon 12, 13, or 61. Although ras mutations in colon, pancreatic, and other cancers are mainly restricted to one or two different ras genes, some researchers dealing with thyroid tumors have found all three ras genes (on three different chromosomes) mutated at different sites (Table 30_3).8.35-40 Although some
groups mainly found H-ras mutations, others predominantly demonstrated N-ras mutations (see Table 30-3). Some of these differences may be explained by variations in methodology, with possible errors generated when only hybridization techniques were applied. Hybridization techniques can yield false-positive and false-negative results, as demonstrated by Chen and Viola.41 Even in cases of comparable technical procedures, results vary significantly between groups. The prevalence of ras mutations in thyroid tumors therefore remains questionable. Most studies have shown that the prevalence of ras mutations was not significantly different in benign and malignant thyroid tumors, nor was it different in tissues from patients living in low- or highiodine areas (Table 30_4).8.30 Exposure to low-dose therapeutic radiation seems to increase the K-ras mutations in histologically normal thyroid tissues and in tissues from thyroid tumors. Fogelfeld and colleagues'? demonstrated an increase in K-ras mutations in thyroid tumor tissue from 0% (0 of 18 patients) to 62% (8 of 13 patients) after radiation therapy. Confirmation of this interesting finding is pending. Nevertheless, some of the differences in the prevalence of ras mutations in thyroid tumors may be caused by regional differences in environmental conditions.>' similar to aflatoxin-induced hepatocellular carcinomas occurring in Asia but not in Europe.
Oncogenes Acting as Growth Hormone Receptors with Tyrosine Kinase Activity Thyrocyte-activating growth factors not related to the cAMP system, such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF), act by stimulating membrane receptors with tyrosine kinase activity." These receptors by themselves may acquire oncogenic potential through truncation of regulatory elements, producing secondary overactivity,44 or by protein overexpression after gene translocation and rearrangement with other promoter regions. The latter mechanism has been demonstrated for ret (ligand still unknown) and trk products (i.e., nerve growth factor receptor) in human papillary thyroid cancer.45,46 Point mutations of the kinase domain of ret also change this protooncogene to an effective oncogene, causing C-cell carcinomas and
284 - - Thyroid Gland
pheochromocytomas in multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and medullary thyroid carcinoma (MTC).47
Epidermal Growth Factor Receptor and Neu/HER2/Erb-B2 and coMet EGF has been demonstrated to be one of the most efficient growth factors for thyrocytes in vitro and in vivo in numerous experiments.w'" EGF-receptor (EGF-R) overexpression, compared with that in normal tissue from the same patients, has been found in membrane fractions from thyroid tumors.V-? No mutation-induced activation of EGF-R has been demonstrated in thyroid tumors, questioning the role of EGF-R in thyroid tumor development and propagation. Further studies were initiated when an EGF-R-related truncated receptor, Neu/HER2/Erb-B2, was discovered in breast cancer patients and predicted early hematogenous spread of tumor and a bad prognosis.P>' Few studies of neuencoded protein expression in human thyroid cancers exist, and their results are controversial. Haugen and coworkers'" found increased messenger RNA (mRNA) and overexpression of neu-encoded protein in 12 of 17 (71%) papillary
thyroid cancers but not in follicular adenomas (0 of 5) or in follicular carcinomas (0 of 5). Simon and associates'? demonstrated overexpression of neu-encoded protein in only 5 of 23 (22%) papillary tumors but in 6 of 17 (35%) follicular thyroid cancers. Studies of Lemoine" and Auguste'" and their colleagues failed to demonstrate amplified mRNA or overexpressed neu-encoded protein in 20 follicular thyroid cancers and 21 thyroid adenomas (Table 30-5). The EGF-R-related oncogene neu/HER2/erb-B2 is therefore of questionable importance in differentiated thyroid cancers. Additional interest was generated by studies of the hepatocyte growth factor receptor (HGF-R), which is expressed in liver tissue and in various other human tissues, including the thyroid. The high levels of c-met mRNA in thyroid tissues contrasts with low or undetectable HGF-R protein expression. 59 The reason for this inhibited translation in normal thyroid tissue is unknown. In papillary thyroid carcinomas, HGF-R protein is expressed 100-fold more than in normal thyroid tissue, making this protein and its c-met gene a good candidate in the search for thyroid oncogenes.Pv" Further studies with more tumor samples and using thyrocyte transfection assays are needed to prove this hypothesis.
Oncogenes in Thyroid Tumors - - 285
ret and trk Oncogenes Transfection experiments by Donghi'" and Grieco" and their colleagues in 1989 and 1990 demonstrated a papillary thyroid carcinoma-specific oncogene (pte) that transformed fibroblasts (NIH 3T3 cells) into colony-forming cells. The gene was cloned and identified as the ret protooncogene by Takahashi and Cooper in 1985. 62 The gene was translocated and rearranged on the same chromosome 10 to an unknown 5' sequence.P The expression of the trk protooncogene, which codes for the receptor for nerve growth factor, was detected in a few thyroid carcinomas, but little other information is available. About 30% of papillary thyroid carcinomas from patients in Italy have a ret rearrangement, but no other thyroid tumors from Italian patients and no nonthyroid tumors had ret rearrangements.s'r'" Further studies of thyroid tissues from the United States and Asia confirmed the almost complete specificity of pte (i.e., ret rearrangement) to papillary thyroid carcinomas, although with a prevalence of only 5% to 17% and 0% to 3%, respectively (Table 30_6).67-69 Nevertheless, the ret oncogene has oncogenetic potential proved by transfection assay and has tissue specificity to papillary thyroid cancer. Whether the ret oncogene initiates the primary step from normal thyrocyte to papillary thyroid carcinoma or from highly differentiated papillary thyroid carcinoma to a less differentiated tumor state is unknown. The pte oncogene gained general interest when it was mapped to the same region on chromosome 1Oq11-12 as the MEN 2A gene. Studies of the tyrosine kinase domain of the ret protooncogene by Mulligan and coworkersf'-" revealed that specific germline mutations of ret led to MEN 2A, MEN 2B, and familial MTC. Further investigations demonstrated somatic mutations of ret in sporadic MTC as well, but these and the mutations in patients with MEN 2B were located at sites of ret different from those of the mutations identified in MEN 2A patients." In 1994, Lips and associates.F using the same molecular genetic techniques, documented that patients who have a ret protooncogene mutation develop MTC and that ret-negative patients are not at risk. Documentation of the presence or absence of ret oncogenes is a more accurate method than using stimulated calcitonin determinations for detecting this disorder. It is the first molecular genetic test in thyroidology with direct clinical importance (i.e., early thyroidectomy), and it should save lives and money.
Intranuclear Oncogenes Nuclear protooncogenes involved in thyroid growth are c-myc, c-jun, and c-fos. They were characterized by their similarity to viral oncogenes. Unlike most oncogenes encoding cell surface receptors or signal-transducing proteins, nuclear protooncogenes function by means of gene amplification. Because external stimulation of cells by growth factors activates cellular receptors, signal-transducing proteins, second messengers, and nuclear protooncogenes by means of increased gene expression, it is difficult to determine whether alterations in nuclear protooncogenes are primary or secondary cellular phenomena. For example, it is difficult to know whether increased staining for c-mye in thyroid adenomas and thyroid carcinomas, as demonstrated by Auguste and associates." is a primary or secondary phenomenon. In general, c-mye and c-fos protooncogenes are expressed after stimulation of the thyroid by TSH and cAMP, which increase thyroid growth and differentiation. EGF and TPA cause thyroid growth and dedifferentiation mainly by enhancing c-jun protooncogene expression. C-fos and c-jun expression can inhibit the thyroid hormone receptor. The thyroid hormone receptor, however, may inhibit the induction of C-fOS 73,74 and thus play the role of an antagonist to cell-specific protooncogenes. Understanding this direct regulatory loop of tissue-specific and growth-inhibiting intranuclear hormone receptors with intranuclear protooncogenes may increase our knowledge of thyroid growth and tumor development in low-iodine areas. In 1991, Heldin and Westermark" demonstrated the loss of a specific tumor suppressor gene, which coded for a nuclear thyroid-specific transcription factor (TIFI), in anaplastic thyroid carcinomas.
Summary Molecular biologic studies have gathered substantial information about the pathogenesis of thyroid neoplasia. Activ~ting mutations of the TSH-R and the signal-transducing protem encoded by gsp have been identified in thyroid neoplasms. These activating mutations enhance cellular cAMP production, which stimulates thyrocyte growth. TSH-R-activating mutations result in the development of autonomously functioning thyroid adenomas, and activating
286 - - Thyroid Gland
gsp mutations are found in benign and malignant thyroid tumors. Activating mutations of other GTP-binding proteins, such as the ras oncogene product p2I, have also been detected in benign and malignant thyroid tumors. The prevalence and the distribution of H-ras, N-ras, and K-ras mutations vary considerably among studies. Different results have also been obtained for growth factor receptors with tyrosine kinase activity, such as EGF-R, neu (also called erb-B2 or HER2) proteins, and HGF-R, which were found to be overexpressed in some malignant thyroid tumors, but all lacked any mutations or deletions that might have predicted the altered receptors could result in thyroid neoplasia. ret rearrangements contribute to the development of papillary thyroid cancer, and point mutations in ret cause the MEN 2A and MEN 2B syndromes and familial form of MTC. Genetic testing is a simple and effective method for detecting affected family members. Whether the interaction of the nuclear thyroid hormone receptor and nuclear protooncogenes can explain goiter development and thyroid tumors in iodinedeficient areas awaits further investigation. This exciting research should lead to important advances in our understanding and treatment of patients with thyroid neoplasia. Recently B type Raf kinase (BRAF) activating mutations have been identified in papillary thyroid cancers. Raf kinase is a key component of the Ras-+Raf--+MEK--+MAP/ERK signaling pathway involved in cell growth and tumorigenesis. BRAF is the strongest activator of this signaling system and is located on chromosome 7. The most frequent BRAF mutation is a Tl796A transversion point mutation in exon 15 which causes a V599E aminoacid missense mutation resulting in activation of BRAF kinase. 76 •77 BRAF mutations occur in approximately 35 to 70% of papillary thyroid cancers. It is not found in follicular thyroid cancer, Hurthle cell cancer, or benign thyroid adenomas, and occurs in about 20% of anaplastic thyroid cancers.Y'? There does not appear to be any overlap between BRAF, RETIPTC and ras mutations in papillary thyroid cancers.
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12. Hausdorff WP, Hnatowich M, O'Dowd BF, et al. A mutation of the ~2-adrenergic receptor impairs agonist activation of adenylyl cyclase without affecting high affinity agonist binding. J Bioi Chern 1990;265:1388. 13. Goretzki PE, Frilling A, Simon D, et al. Growth regulation of normal thyroids and thyroid tumors in man. Recent Results Cancer Res 1990;118:48. 14. Ledent C, Parmentier M, Maenhaut C, et al. The TSH cyclic AMP cascade in the control of thyroid cell proliferation: The story of a concept. Thyroidology 1991;3:97. 15. Clark OH, Gerend PL, Davis M, et al. Characterization of the thyrotropin receptor-adenylate cyclase system in neoplastic human thyroid tissue. J Clin Endocrinol Metab 1983;57:140. 16. Parma J, Duprez L, VanSande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993;365:649. 17. Paschke R, Tonacchera M, VanSande J, et al. Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid. J Clin Endocrinol Metab 1994; 79:1785. 18. Kopp P,VanSande J, Parma J, et al. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 1995;332:150. 19. Matsuo K, Friedman E, Gejman PV, et al. The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: Structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms. J Clin Endocrinol Metab 1993;76:1446. 20. Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 1987; 330:566. 21. Landis CA, Masters SB, Spada A, et al. GTPase inhibiting mutations activate alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989;340:692. 22. Masters SB, Miller RT, Chi MH, et al. Mutations in the GTP-binding site of Gs alter stimulation of adenylyl cyclase. J Bioi Chem 1989;264:15467. 23. Lyons J, Landis CA, Harsh G, et al. Two G-protein oncogenes in human endocrine tumors. Science 1990;249:655. 24. Suarez HG, DuVillard JA, Caillou B, et al. Gsp mutations in human thyroid tumours. Oncogene 1991;6:677. 25. O'Sullivan C, Barton CM, Staddon SL, et al. Activating point mutations of the gsp oncogene in human thyroid adenomas. Mol Carcinog 1991;4:345. 26. Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990;71:1427. 27. Namba H, Matsuo K, Fagin J. Clonal composition of benign and malignant thyroid tumors. J Clin Invest 1990;86:218. 28. Gorelov VN, Roher HD, Goretzki PE. A method to increase the sensitivity of mutation specific oligonucleotide hybridization using asymmetric polymerase-chain reaction (PCR). Biochem Biophys Res Commun 1994;200:365. 29. Goretzki PE, Gorelov V, WeiAmann K, et al. Mutation and expression of alpha Gs in differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC). Exp Clin Endocrinol 1993;101:54. 30. Gorelov VN, Gyenes M, Neser F, et al. Distribution of Gs-alpha activating mutations in human thyroid tumors measured by subcloning. J Cancer Res Clin Oncol 1996;122:453. 31. Milligan G, Unson CG, Wakelam JO. Cholera toxin treatment produces down-regulation of the alpha-subunit of the stimulatory guanine-nucleotide-binding protein (Gs). Biochem J 1989;262:643. 32. Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancer. Nature 1987;327:293. 33. Bos JL. Ras oncogenes in human cancer: A review. Cancer Res 1989; 49:4682. 34. Anderson MW, Reynolds SH, You M, et al. Role of proto-oncogene activation in carcinogenesis. Environ Health Perspect 1992;98:13. 35. Lemoine NR, Mayall ES, Wyllie FS, et al. High expression of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989;4:159. 36. Suarez HG, DuVillard JA, Caillou B, et al. Detection of activated ras oncogenes in human thyroid carcinomas. Oncogene 1988;2:403. 37. Wright PA, Lemoine NR, Mayall ES. Papillary and follicular thyroid carcinomas show a different pattern of ras oncogene mutation. Br J Cancer 1989;6:576.
Oncogenes in Thyroid Tumors - - 287 38. Namba H, Gutman RA, Matsuo K, et aI. H-ras protooncogene mutations in human thyroid neoplasms. J Clin Endocrinol Metab 1990; 71:223. 39. Schark C, Fulton N, Jacoby R, et al. N-ras 61 oncogene mutations in Hiirthle cell tumors. Surgery 1990;108:994. 40. Karga H, Lee JK, Vickery AL, et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991; 73:832. 41. Chen J, Viola MV. A method to detect ras point mutations in small subpopulations of cells. Anal Biochem 1991;195:51. 42. Fogelfeld L, Merchant PS, Zitman R, et al. Prevalence of K-ras point mutations in radiation-induced thyroid cancer [Abstract 66). American Thyroid Association Meeting, Tampa, Florida, 1993. 43. Ullrich A, Schlesinger S1. Tyrosine-kinase receptors. Cell 1990; 61:203. 44. King CR, Borrello I, Bellot F, et al. EGF binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3. EMBO J 1988;7:1647. 45. Bongarzone I, Pierotti MA, Monzini N, et aI. High frequency of activation of tyrosine oncogenes in human papillary thyroid carcinoma. Oncogene 1989;4:1457. 46. Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990;60:557. 47. Mulligan LM, Kwok JBJ, Healey CS, et al. Germ-line mutations of the ret proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458. 48. Westermark K, Karlsson FA, Westermark B. Epidermal growth factor modulates thyroid growth and function in culture. Endocrinology 1983;112:71. 49. Tseng YCL, Burman KD, Schaudies RP, et al. Effects of epidermal growth factor on thyroglobulin and adenosine 3',5'-monophosphate production by cultured human thyrocytes. J Clin Endocrinol Metab 1989;71:771. 50. Hoelting T, Siperstein AE, Clark OH, et al. Epidermal growth factor enhances proliferation, migration, and invasion of follicular and papillary thyroid cancer in vitro and in vivo. J Clin Endocrinol Metab 1994;79:401. 51. Duh QY, Gum ET, Gerend PL, et al. Epidermal growth factor receptors in normal and neoplastic thyroid tissue. Surgery 1985;98:1000. 52. Masuda H, Sugenoya A, Kobayashi S, et al. Epidermal growth factor receptor on human thyroid neoplasm. World J Surg 1988;12:616. 53. DePotter CR, Beghin C, Makar AP, et aI. The neu-oncogene protein as a predictive factor for haematogenous metastases in breast cancer patients. Int J Cancer 1990;45:55. 54. Kury F, Sliutz G, Schemper H, et al. Her-2 oncogene amplification and overall survival of breast carcinoma patients. Eur J Cancer 1990;26:946. 55. Haugen DRF, Akslen LA, Varhaug lE, et al. Expression of c-erbB-2 protein in papillary thyroid carcinoma. Br J Cancer 1992;65:832. 56. Simon D, Goretzki PE, Roher HD. The significance of c-neu and p53 in endocrine tumors. Langenbecks Arch Chir Suppl 1993;2:69. 57. Lemoine NR, Wyllie FS, Lillehaug JR, et al. Absence of abnormalities of the c-erbB-I and c-erbB-2 proto-oncogenes in human thyroid neoplasia. Eur J Cancer 1990;26:777. 58. Auguste LJ, Masood S, Westerband A, et al. Oncogene expression in follicular neoplasms of the thyroid. Am J Surg 1992;164:592.
59. DiRenzo MF, Narsimhan RP, Olivero M, et al. Expression of the metlHGF receptor in normal and neoplastic human tissues. Oncogene 1991;6:1997. 60. Prat M, Narsimhan RP, Crepaldi T, et al. The receptor encoded by the human cometoncogene is expressed in hepatocytes, epithelial cells and solid tumors. Int J Cancer 1991;49:323. 61. Donghi R, Sozzi G, Pierotti MA, et aI. The oncogene associated with human papillary thyroid carcinoma (PTC) is assigned to chromosome IOqI I -q 12 in the same region as multiple endocrine neoplasia type 2A (MEN 2A). Oncogene 1989;4:321. 62. Takahashi M, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985;42:581. 63. Fabien N, Paulin C, Santoro M, et al. Detection of ret oncogene activation in human papillary thyroid carcinomas by in situ hybridisation. Br J Cancer 1992;66:1094. 64. Santoro M, Carlomagno F, Hay ill, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer study type. J Clin Invest 1992;89:1517. 65. Santoro M, Sabino N, Ishizaka Y, et al. Involvement of RET oncogene in human tumours: Specificity of RET activation to thyroid tumours. Br J Cancer 1993;68:460. 66. Jhiang SM, Caruso DR, Gilmore E, et al. Detection of PTe oncogene in human thyroid cancers. Oncogene 1991;7:1331. 67. Namba H, Yamashita S, Pei HC, et al. Lack of PTC gene (ret protooncogene rearrangement) in human thyroid tumors. Endocrinol Jpn 1991;38:627. 68. Waijwalku W, Nakamura S, Hasegawa Y, et al. Low frequency of rearrangements in the ret and trk proto-oncogenes in Japanese thyroid papillary carcinomas. Jpn J Cancer Res 1992;83:671. 69. Zou M, Shi Y, Farid NR. Low rate of ret proto-oncogene activation (PTC/ret-TPC) in papillary thyroid carcinomas from Saudi Arabia. Cancer 1994;73: 176. 70. Mulligan LM, Eng C, Healy CS, et al. Specific mutations of the ret proto-oncogenes are related to disease phenotype in MEN2A and FMTC. Nat Genet 1994;6:70. 71. Zedenius J, Wallin G, Hamberger B, et al. Somatic and MEN2A de novo mutations identified in the ret proto-oncogene by screening of sporadic MTCs. Hum Mol Genet 1994;3:1259. 72. Lips CJM, Landsvater RM, Hoeppener JWM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994;331:828. 73. Rascle A, Ghysdael J, Samarut 1. c-Erb, but not v-ErhA, competes with a putative erythroid repressor for binding to the carbonic anhydrase II promoter. Oncogene 1994;9:2853. 74. Zhang XK, Wills KN, Husmann M, et al. Novel pathway for thyroid hormone receptor action through interaction withjun andfos oncogene activities. Mol Cell Bioi 1991;11:6016. 75. Heldin NE, Westermark B. The molecular biology of the human anaplastic thyroid carcinoma cell. Thyroidology 1991;3: 127. 76. Xing M, Vasko V, Tallini G, et al. BRAF TRI796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab 2004; 89:1365. 77. Kimura ET, Nikiforova MN, Zhu Z, et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RETIPTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63:1454.
Thyroid Oncogenesis Electron Kebebew, MD
Genetic alterations are the cornerstone of carcinogenesis. Genetic changes can be due to hereditary predisposition, acquired from viral infections (viral oncogenes), and result from environmental exposures to external or ionized radiation or even from chronic inflammatory conditions. The resulting genetic alterations ultimately lead to "transformation" of the cell toward a state of uncontrolled cell growth, disrupted normal cellular differentiation or apoptosis, and an invasive and metastatic cellular phenotype. The multistep hypothesis of carcinogenesis has been the framework on which genetic alterations have been investigated. 1The accumulation of multiple genetic events results in the developmentof cancer (Fig. 31-IA).1.2 These genetic modifications can be point mutations (single base pair changes), insertions, deletions, rearrangements, or translocations. When such genetic changes occur, they can lead to an oncogene, which can function in a dominant or recessive manner. An oncogene has the potential to induce or unsuccessfully suppress oncogenesis. A protooncogene is a gene that regulates cellular growth and/or cell differentiation that, when altered or amplified, leads to the development or progression of a neoplasm ("dominant" or "gain of function" genetic change). The functional products of protooncogenes have been classified at the cellular level as (I) growth factors, (2) membrane or intracellular receptors, (3) signal transduction system proteins, and (4) nuclear transcriptional activators or inhibitors. In contrast to dominant or gain of function oncogenes, tumor suppressor genes function to control cellular growth, but in a recessive fashion. The loss of function of the tumor suppressor gene product leads to unregulated cellular growth. Protooncogenes and tumor suppressor genes can occur as germline or somatic genetic mutations. The integrated study of molecular biology, epidemiology, embryology, physiology, and clinical medicine has led to significant advances in our understanding of oncogenesis. Many investigators have helped provide insight into the genetic mechanisms involved in thyroid tumorigenesis and its potential for clinical application in determining the prognosis of patients with thyroid cancer and in identifying individuals at risk of developing thyroid cancer. A working oncogenesis model has been proposed for thyroid cancers of follicular cell
288
origin (Fig. 31-lB).3 The main genetic abnormality (germline RET protooncogene point mutations) that occurs in the less
common thyroid cancer of parafollicular cell origin (medullary thyroid cancer) is well characterized and has led to earlier screening and treatment of patients with hereditary medullary thyroid cancer (see Chap. 15). This has translated into improved patient outcome." This chapter discusses our current knowledge of oncogenesis in follicular cells of the thyroid, a working model for thyroid carcinogenesis, and the potential clinical applications of these findings. The important growth factors and signal transduction factors that also influence the initiation or progression of thyroid neoplasms are discussed in Chapters 28 and 29.
Oncogenesis in Thyroid Cancers of Follicular Cell Origin Oncogene Receptor Proteins THYROID-STIMULATING HORMONE RECEPTOR
The thyroid-stimulating hormone (TSH) receptor is a transmembrane glycoprotein that is G protein coupled. TSH, acting through its receptor, is the main regulator of thyrocyte function and growth. Its function is mediated via the adenylate cyclase and phospholipase C intracellular pathways.' Constitutively activating mutations in the TSH receptor occur in the transmembrane segment and intracytoplasmic loop in hot thyroid nodules (""30%) but are usually absent in cold thyroid nodules or thyroid cancers (Table 31_1).5-10 Unfortunately, the frequency of TSH receptor-activating mutations observed in hot thyroid nodules has been variable, ranging from 3% to 82%.5-12 This discrepancy is likely due to several factors such as small sample size, screening of only part of the TSH receptor gene, less sensitive screening techniques (single-strand conformation polymorphism), inaccurate characterization of thyroid nodule function, and the quality of DNA in tissue samples studied.P In general, TSH receptor-activating mutations lead to some benign hot nodules but not to malignant thyroid neoplasms or cold thyroid nodules. 13
Thyroid Oncogenesis - -
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Mitosis, accumulation of genetic alterations leading to unregulated proliferation and differentiation
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FIGURE 32-4. Epidermal growth factor (EGF) stimulates invasion by thyroid cancer cells in vitro. Cells treated with EGF, AG 1478 (tyrosine kinase inhibitor), GM-6001 (peptidomimetic matrix metalloproteinase [MMPj inhibitor), and Col-3 (tetracycline MMP inhibitor). EGF was administered at a dose of 10 ng/ml., AG 1478 at 10 11M, and GM-6001 at 100 j.lM. Col-3 was administered at 5 and 10 j.lg/mL, as indicated. Data expressed as mean ± 1 standard deviation. Brackets indicate pairwise comparisons. **p < .0001 by analysis of variance.
MMP-9 and MTl-MMP expression in these cells and that MMP-2 activation in the extracellular space parallels MTl-MMP expression.P" EGF-stimulated invasion in thyroid cancer cell lines is antagonized by both synthetic MMP inhibitors and EGF receptor tyrosine kinase inhibitors (Fig. 32-4), but not by the serine protease inhibitor aprotinin. Our findings suggest that EGF acts by altering MMP gene transcription downstream of its receptor and that, at least in our model, serine proteases do not contribute significantly to invasion.
Regulators of Invasion Several growth factors have been identified as important paracrine regulators of cancer growth and spread. Chief among these are those that bind receptor tyrosine kinases, such as EGF, hepatocyte growth factor/scatter factor (HGF/SF), transforming growth factors, and platelet-derived growth factor. Elevated expression of EGF receptors (EGFRs) and related Erb-B receptors has been found in many human malignancies. In cancers of the breast, head and neck, urogenital tract, and other tissues, Erb-B receptor overexpression is associated with poor prognosis." The Erb-B2 receptor, also known as Her-2/neu, is of particular interest because of its ability to form cell surface heterodimers with other Erb-B family receptors, thus augmenting receptor tyrosine kinase signaling." Our initial interest in studying the role of EGF in thyroid cancer stemmed from the fact that EGF is highly expressed in the normal human thyroid, at levels more than twice those found in other major organs." Several groups, including our own, have identified Erb-B receptors on the surface of thyroid cancer cells, and we have found that thyroid cancer cell lines overexpress both the EGFR and Erb-B2 when compared with normal thyrocytes. As mentioned
Both EGF and HGF/SF have been shown to increase protease expression and invasion in human cancers.V" Furthermore, they are reported to induce the dismantling of adherens junctions, possibly by disrupting the cadherincatenin linkage to the actin cytoskeleton." Similar paracrine signals are known to regulate the epithelial-mesenchymal transformation during normal embryonal development, which mirrors the pathologic events of malignant progression in many ways. Thus, proteins that maintain normal epithelial cell architecture, such as E-cadherin and catenin, are now being seen as invasion or metastasis suppressors. Stromal cells have been recognized as having an active role in both the progression and inhibition of malignant invasion. Stromal cells secrete a variety of proteases, and cancer cells may stimulate them to synthesize MMPs in a paracrine fashion by releasing growth factors and human extracellular matrix metalloproteinase inducer (EMMPRJN76). Coculture with activated stromal cells can confer a malignant phenotype on immortal cells that generally display benign behavior.T" On the other hand, tumor stroma has in many cases been found to harbor large quantities of protease inhibitors,"? suggesting that normal fibroblasts may mount an adaptive "tumoristatic" response.
Molecular Cross-Talk in Malignant Progression As previously mentioned, although adhesion, proteolysis, and migration can be considered individually, the three are actually inseparable events in the process of invasion. Likewise, research has shed light on a myriad of interlinkages between the processes of cancer growth, survival, invasion, and angiogenesis. What follows is a brief discussion of molecular cross-talk between these systems, with particular reference to the adhesion molecules and proteases mentioned previously. Angiogenesis, a process central to tumor growth and survival, is an MMP-dependent process. As cancer cells employ MMPs to invade into adjacent normal tissues, endothelial cells stimulated by proangiogenic tumor signals require MMP activity to invade into the tumor substance. Both endogenous and synthetic MMP inhibitors have been shown to block angiogenesis by interfering with endothelial cell attachment, proliferation, migration, and growth. Small molecules released by proteolysis of the extracellular matrix, including growth factors and angiostatin, act as both positive and negative regulators of angiogenesis.t" The activation of pro-MMPs is a critical step in the regulation of extracellular matrix proteolysis. MMP-2 activation is known to take place on the cell surface, where MTl-MMP cleaves pro-MMP-2 into its active form in the presence of permissive concentrations of TIMP-2. Studies of cancer cells and angiogenic endothelial cells suggest that aV~3 integrin binds the carboxyterrninal PEX domain of MMP-2 and
Mechanisms and Regulation of Invasion in Thyroid Cancer - -
301
that this interaction may localize proteolytic activity to the invasive front of cells. 81,82 Treatment of cancer cells with anti-integrin antibodies has been shown to increase MMP-2 secretion as well as cell invasiveness, and other studies suggest that signaling through FAK upregulates MMP_9. 83,84 Integrins and the uPAIuPAR system are known to interact and exert reciprocal regulatory actions on one another, but these processes are just beginning to be understood. As mentioned before, aV~3 integrin is expressed on activated endothelial cells. Antagonists of aV~3 integrin are known to disrupt blood vessel formation in the chick allantoic membrane and other bioassay systems. In vivo, Uv~3 integrin antagonists block tumor angiogenesis and, in some cases, can cause tumor regression.f The role of cadherin-catenin signaling in promoting tumor growth and MMP-7 expression has already been mentioned. E-cadherin is also a substrate for MMP-3 and MMP-7. Cleavage of E-cadherin results in release of the soluble extracellular E-cadherin fragment, which has been found to promote tumor cell invasion by acting in a paracrine manner.f" The soluble E-cadherin fragment is thought to interfere with normal E-cadherin function in nearby cells and possibly to activate other signaling pathways that remain to be identified.
Trastuzumab (Herceptin), a humanized monoclonal antibody directed against Erb-B2 (Her-2), has undergone several phase II and phase III clinical trials that have demonstrated a survival benefit in patients with Her-2-overexpressing breast cancers." These studies have led to the licensing of trastuzumab in many countries for use in combination with paclitaxel. EGFR antagonists are also being aggressively investigated. Cetuximab (IMC-225, Erbitux), a monoclonal antibody that binds the extracellular domain of EGFR, has been investigated in phase II and phase III trials in colorectal cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinomas of the head and neck. Early results show good response rates and few toxicities. ZD1839 (Iressa) is a synthetic inhibitor ofthe EGFR tyrosine kinase. It belongs to a growing list of small-molecule receptor tyrosine kinase inhibitors that display high specificity for certain receptor tyrosine kinase subtypes. ZD 1839 has undergone phase I and II trials in the treatment of NSCLC and glioblastoma multiforme. It is generally well tolerated and appears to have some antitumor effect. Imatinib mesylate (Gleevec), which inhibits the KIT tyrosine kinase, has been approved in the United States for the treatment of chronic myeloid leukemia and stromal tumors of the gastrointestinal tract.
Implications for Clinical Therapeutics
Summary
Pharmacologic agents targeting specific mechanisms of tumor growth, invasion, and angiogenesis represent an emerging class of anticancer therapies. Although the vast majority of such drugs are in the preclinical or early clinical investigative stages, their great potential warrants pursuit from clinicians and scientists. The cadherin-catenin system has received the most attention in colorectal carcinoma, in which nonsteroidal anti-inflammatory drugs have been shown to exert an antineoplastic effect that may be mediated by reductions in intracellular ~-catenin.87 Interest in integrin antagonists has generally focused on their antiangiogenic activity. Medi-522 (Vitaxin), a monoclonal antibody with activity against aV~3 integrin, has entered phase IIII clinical trials in patients with advanced solid tumors and lymphoma. Proteases are an attractive potential target for cancer chemotherapy because they lie at the crossroads of several central processes in malignant progression. Antagonists of the uPAIuPAR system, which include small-molecule serine protease inhibitors and a truncated form ofuPAR, are undergoing early clinical trials. Synthetic MMP inhibitors, including marimastat, batimastat, BMS-275291, BAY 12-9566, Col-3, and others, have received substantial interest and were utilized in several phase III trials during the late 1990s. Unfortunately, results of these studies have been largely disappointing, with several studies terminating early because of adverse outcomes.f Such findings have highlighted the complex actions of MMPs as both positive and negative regulators of cancer progression; further understanding of their functions is needed at the basic science level. Perhaps the greatest immediate potential for emerging anticancer therapy lies with growth factor antagonists.
The process whereby malignant cancer cells invade and metastasize is complex, but current studies are elucidating the cellular mechanisms in each step of the involved pathways. Cancerous cells must detach from their primary tumors, disrupt restraining basement membrane barriers, and move into their surrounding matrix to enter the blood and lymph channels, allowing distant spread. Each of the mechanisms involved is a normal cellular property that has been coopted to promote malignant progression. Research has shed light on the complex and pleiotropic effects of adhesion molecules, proteases, and growth factors in cancer. Rational drug design has allowed clinicians and scientists to make promising early inroads into novel therapies that target tumor growth, angiogenesis, and invasion. Further basic science and clinical research are required before viable treatments for advanced malignancies become a reality.
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35. Ruoslahti E, Giancotti FG. Integrins and tumor cell dissemination. Cancer Cells 1989;1:119. 36. Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992;69: II. 37. Akiyama SK, Larjava H, Yamada KM. Differences in the biosynthesis and localization of the fibronectin receptor in normal and transformed cultured human cells. Cancer Res 1990;50: 1601. 38. Demeure Ml, Doffek KM, Rezaee M, et al. Diminished expression of the alpha 5 beta I integrin (fibronectin receptor) by invasive clones of a human follicular thyroid cancer cell line. World J Surg 1994;18:569. 39. Owens LV, Xu L, Craven RJ. Overexpression of the focal adhesion kinase (p125 FAK) in invasivehuman tumors. Cancer Res 1995;55:539. 40. Weiner TM, Liu ET, Craven RJ, Cance WG. Expression of focal adhesion kinase gene and invasive cancer. Lancet 1993;342:1024. 41. Frisch SM, Vuori K, Ruoslahti E, Chan Hui PY. Control of adhesiondependent cell survival by focal adhesion kinase. J Cell BioI 1996;134:793. 42. Hie 0, Furuta Y, Kanazawa S, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995;377:539. 43. Shapiro L, Fannon AM, Kwong PO, et al. Structural basis of cell-cell adhesion by cadherins. Nature 1995;374:327. 44. Bremnes RM, Veve R, Hirsch FR, Franklin WA. The E-cadherin cellcell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer 2002;36:115. 45. Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 1998;58:4086. 46. Hajra KM, Fearon ER. Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer 2002;34:255. 47. Behrens 1, Mareel MM, van Roy FM, Birchmeier W. Dissecting tumor cell invasion: Epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Bioi 1989;108:2435. 48. Vleminckx K, Vakaet LJ, Mareel MM, et al. Genetic manipulation with E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991;66:107. 49. Brabant G, Hoang- Vu C, Cetin Y, et al. E-cadherin: A differentiation marker in thyroid malignancies. Cancer Res 1993;53:4987. 50. Scheumann GF, Hoang-Vu C, Cetin Y, et al. Clinical significance of E-cadherin as a prognostic marker in thyroid carcinomas. J Clin Endocrinol Metab 1995;80:2168. 51. Graff JR, Greenberg VE, Herman lG, et al. Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hiirthle's cell, and poorly differentiated human thyroid carcinoma. Cancer Res 1998;58:2063. 52. Lamlum H, Hyas M, Rowan A, et al. The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: A new facet to Knudson's 'two-hit' hypothesis. Nat Med 1999;5:1071. 53. Muller T, Choidas A, Reichmann E, Ullrich A. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. J Cell Bioi 1995;130:67. 54. He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509. 55. Tetsu 0, McCormick F. Beta-catenin regulates expression of cyclin 01 in colon carcinoma. Nature 1999;398:422. 56. Crawford HC, Fingleton BM, Rudolph-Owen LA, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene 1999;18:2883. 57. Gottardi CJ, Wong E, Gumbiner BM. E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesionindependent manner. J Cell Bioi 2001 ;153:1049. 58. Osawa M, Kemler R. Molecular organization of the uvomorulincatenin complex. 1 Cell Bioi 1992;116:989. 59. van de Wettering M, Barker N, Harkes IC, et al. Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 2001;61:278. 60. Werb Z. ECM and cell surface proteolysis: Regulating cellular ecology. Cell 1997;91:439. 61. Coussens LM, Werb Z. Matrix metalloproteinases and the development of cancer. Chern Bioi 1996;3:895. 62. Irnren S, Kohn DB, Shimada H, et al. Overexpression of tissue inhibitor of metalloproteinases-2 by retroviral-mediated gene transfer in vivo inhibits tumor growth and invasion. Cancer Res 1996;56:2891.
Mechanisms and Regulation of Invasion in Thyroid Cancer - - 303 63. Nakamura H, Ueno H, Yamashita K, et al. Enhanced production and activation of progelatinase A mediated by membrane-type I matrix metalloproteinase in human papillary thyroid carcinomas. Cancer Res 1999;59:467. 64. Shi Y, Parhar RS, Zou M, et al. Tissue inhibitor of metalloproteinases-I (TIMP-I) mRNA is elevated in advanced stages of thyroid carcinoma. Br J Cancer 1999;79:1234. 65. Duffy MJ, Maguire TM, McDermott EW, O'Higgins N. Urokinase plasminogen activator: A prognostic marker in multiple types of cancer. J Surg OncoI1999;71:130. 66. Schmitt M, Harbeck N, Thomssen C, et al. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: Prognostic relevance and target for therapy. Thromb Haemost 1997;78:285. 67. Smit JW, van der Pluijm G, Romijn HA, et al. Degradation of extracellular matrix by metastatic follicular thyroid carcinoma cell lines: Role of the plasmin activation system. Thyroid 1999;9:913. 68. Hoelting T, Siperstein AE, Clark OH, Duh QY. Epidermal growth factor enhances proliferation, migration, and invasion of follicular and papillary thyroid cancer in vitro and in vivo. J Clin Endocrinol Metab 1994;79:401. 69. Yeh MW, Rougier JP, Park JW, et al. Thyroid cancer cell invasion is regulated though epidermal growth factor receptor-dependent activation of MMP2/gelatinase A. Cancer Res (submitted). 70. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37(SuppI4):S9. 71. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550. 72. Kajikawa K, Yasui W, Sumiyoshi H, et al. Expression of epidermal growth factor in human tissues. Immunohistochemical and biochemical analysis. Virchows Arch A Pathol Anat Histopathol 1991;418:27. 73. Hoelting T, Tezelman S, Siperstein AE, et al. Biphasic effects of thyrotropin on invasion and growth of papillary and follicular thyroid cancer in vitro. Thyroid 1995;5:35. 74. Harvey P, Clark 1M, Jaurand MC, et al. Hepatocyte growth factor/ scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases. Br J Cancer 2000;83: 1147. 75. O-Charoenrat P, Modjtahedi H, Rhys-Evans P, et al. Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells. Cancer Res 2000; 60: 1121.
76. Guo H, Zucker S, Gordon MK, et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Bioi Chern 1997;272:24. 77. Atula S, Grenman R, Syrjanen S. Fibroblasts can modulate the phenotype of malignant epithelial cells in vitro. Exp Cell Res 1997;235:180. 78. Skobe M, Fusenig N. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci USA 1998;95: 1050. 79. Chang C, Werb Z. The many faces of metalloproteases: Cell growth, invasion, angiogenesis and metastasis. Trends Cell Bioi 2001; II :S37. 80. Stetler-Stevenson WG. Matrix metalloproteinases in angiogenesis: A moving target for therapeutic intervention. J Clin Invest 1999; 103:1237. 81. Brooks PC, Stromblad S, Sanders LC, et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3.Cell 1996;85:683. 82. Brooks PC, Silletti S, von Schalsa TL, et al. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 1998;92:391. 83. Seftor RE, Seftor EA, Stetler-Stevenson WG, Hendrix MJ. The 72 kDa type IV collagenase is modulated via differential expression of alpha v beta 3 and alpha 5 beta I integrins during human melanoma invasion. Cancer Res 1993;53:3411. 84. Shibata K, Kikkawa F, Nawa A, et al. Both focal adhesion kinase and e-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cells. Cancer Res 1998;58:900. 85. Eliceiri BP, Cheresh DA. The role of alpha v integrins during angiogenesis: Insights into potential mechanisms of action and clinical development. J Clin Invest 1999; 103:1227. 86. Noe V, Fingleton B, Jacobs K, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001;114:111. 87. Bright-Thomas RM, Hargest R. APC, beta-catenin, and hTCF-4; an unholy trinity in the genesis of colorectal cancer. Eur J Surg Oncol 2003;29: 107. 88. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 2002;295:2387. 89. Harries M, Smith 1. The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer 2002;9:75.
Surgical Management of Recurrent and Intrathoracic Goiters Antonio Sitges-Serra, MD • Juan J. Sancho, MD
Recurrent and intrathoracic goiters may pose considerable problems to the surgeon. Surgery is often indicated because local complications are common, and it requires thorough knowledge of the potentially distorted anatomy found at exploration. An appropriate preoperative assessment is essential because thyroid function may be abnormal, there may be sequelae from previous surgery, and precise anatomic definition of the lesion is important for a safe and expeditious operation. Symptoms may differ considerably from those found in uncomplicated goiters and may include airway compression, superior vena cava syndrome, and dysphonia, simulating a thyroid malignancy. Finally, the highest rates of postoperative vocal cord paralysis are reported after surgery for recurrent and complex intrathoracic goiters, suggesting that there is still room for improvement of surgical technique in this area. In this chapter, the pathogenesis, clinical presentation, preoperative assessment, and surgical approach to recurrent and intrathoracic goiters are discussed.
Recurrent Goiter Prevalence Palpable recurrence of nontoxic nodular goiter is seen in 2.5% to 20% of patients who have had previous thyroid surgery for the same condition; there seems to be a trend toward higher recurrence rates and probably more clinically complicated recurrences with longer follow-up. 1 Miccoli and colleaguesreported palpable recurrences in up to 25% to 30% of their patients after 3 years of follow-up, and this figure increased to 75% when strict echographic criteria were used for detecting small nodules. Although these authors noted that the aim of their surgical intervention was to "completely remove the thyroid nodules detected in the preoperative ultrasound," many surgeons would agree that such a high incidence of recurrent benign goiter was somehow related to an excessively conservative initial operation. Cohen-Kerem and coworkers- carefully observed 100 patients operated on for
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multinodular goiter with a less than total thyroidectomy for a mean of 93 months. The recurrence rate in this group was 21%, although only 4% of patients with a recurrence required a reoperation within that period.
Causes of Goiter Recurrence EXTENT OF THE INITIAL SURGICAL PROCEDURE
It has been known for a century that conservative surgery for multinodular goiter is associated with goiter recurrence. Kocher reported an 18% recurrence rate after enucleation of thyroid nodules." For this reason, bilateral thyroid resection had already been advocated by pioneers in thyroid surgery, such as Johann Mikulicz, Donald Balfour, Charles Mayo, George Crile, and Thomas Dunhill." From those times until 2 decades ago, subtotal thyroidectomy was considered the standard surgical treatment for multinodular goiter and for Graves' disease. Recurrences are still observed, however, because either this time-honored principle is ignored or goiter recurs in the contralateral lobe after total lobectomy for apparently uninodular disease. Furthermore, prolonged follow-up of large series of patients has shown that even bilateral subtotal thyroidectomy is associated with a substantial recurrence rate. Conservative initial operation can be incriminated as the main cause of goiter recurrence. Inadequate resections, such as isthmusectomy, nodule enucleation, subtotal lobectomy, and bilateral resection preserving the upper pole of the thyroid lobes, are still frequently found to have been the initial operations in patients with goiter recurrence. In the study by Bistrup and associates,' a recurrence rate of 19% was probably related to the number of atypical surgical procedures (six isthmusectomies and seven enucleations). In Anderson and colleagues' report," 38 subtotal lobectomies were followed by eight recurrences, independent of whether thyroxine (T 4 ) was administered postoperatively. These atypical surgical procedures on the thyroid gland should be abandoned. Recurrence after total lobectomy or appropriate subtotal
Surgical Management of Recurrent and Intrathoracic Goiters - -
bilateral thyroidectomy poses more conceptual questions. Did lobectomy miss significant contralateral disease? If so, should the extent of surgery be dictated by preoperative ultrasonographic findings? Should the contralateral lobe be thoroughly explored at the time of planned lobectomy? Do the remnant size and location determine recurrence? Most surgeons believe that when nodules are not palpable in the contralateral lobe preoperatively, a lobectomy is all that is required. Excessive reliance on lobectomy, however, may predispose to recurrence as a result of untreated contralateral disease-"; up to 45% of clinically solitary nodules show other associated nodules on echography." The extent of surgery for multinodular goiter is also questioned; subtotal bilateral, total on one side and subtotal on the other, and total thyroidectomy are currently practiced by experienced endocrine surgeons. A very low (2.5%) recurrence rate (l % after lobectomy and 3% after bilateral operation) was reported by Kraimps and colleagues- after a selectively aggressive policy. These authors carried out lobectomy only if the contralateral lobe did not have palpable nodules during the operation. They performed total lobectomy of the most affected lobe plus subtotal resection of the contralateral lobe in multinodular goiters. In their opinion, recurrence was almost always due to growth of nodules left behind at the initial operation. If we compare these results with the 10% recurrence rate reported in the comprehensive study by Berglund and coworkers," two facts deserve attention and may substantiate the opinion of the French group: (1) the time for the recurrence to appear was double in French patients (8 versus 4 years after the initial thyroidectomy) and (2) more extensive surgery was carried out by the French team (45% lobectomy and 53% bilateral operation versus 76% lobectomy and 24% bilateral operation, respectively). In a 7-year followup study after thyroidectomy," patients with recurrent goiter were compared with those without goiter. Again, unilateral resection had been performed more often in patients with recurrence (85%) than in patients without recurrence (61%). These data suggest that the extent of the initial procedure is probably a crucial factor in determining recurrence and support the contention that conservative initial procedures are associated with higher and earlier recurrence as a result of growth of preexistent nodules. From only the point of view of recurrence, total thyroidectomy would be the preferred surgical treatment for multinodular goiter. to In the hands of Reeve and colleagues, this operation has resulted in almost no permanent complications and more and more endocrine surgeons are using this approach.'! It should be stressed, however, that recurrent laryngeal nerve palsy or permanent hypoparathyroidism should not occur after thyroidectomy for benign disease, and that surgical judgment and experience are essential when a radical approach is considered. THE CONTROVERSY OF POSTOPERATIVE THYROXINE SUPPLEMENTATION
Whether T4 supplementation influences goiter recurrence rate after thyroidectomy is a matter of controversy. T4 replacement therapy is compulsory for patients rendered hypothyroid by thyroidectomy, and there is no question about giving these patients replacement therapy to keep their thyroid-stimulating hormone (TSH) levels in the normal range. On the other
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hand, there are no hard clinical data to support T 4 supplementation in euthyroid patients to prevent recurrence. Because TSH may stimulate thyroid remnant growth, there may be sound theoretical reasons to keep the serum TSH concentrations low after thyroidectomy. Success with this approach, however, has been far from uniform because factors other than TSH influence thyroid growth and, eventually, goiter recurrence.v'? Despite some contrary evidence, 13 during the 1980s some authorities were recommending routine T 4 supplementation to prevent recurrences after surgery for nontoxic goiter,":" This recommendation was largely empirical and based on the understanding of the effects of TSH on thyroid tissue growth." More recent reports, however, do not support the benefit of routine T4 supplementation in preventing goiter recurrence. In a retrospective study, Berglund and colleagues? showed no difference in recurrence rates between patients who received T4 and those who did not after partial thyroidectomy for benign goiter. The recurrence rate was 10% in 29 patients receiving "prophylactic" T4, 7% in 46 patients receiving replacement T4 treatment, and 11% in 186 patients not receiving T4. There were no differences in the TSH levels between patients with and without recurrence. A prospective, randomized study by Bistrup and colleagues' evaluated 100 patients consecutively operated on for nontoxic goiter. The treatment group received 100 ug of L-thyroxine per day. Sixty-nine patients had completed a 9-year follow-up, and the rate of palpable recurrence was 14.5% in treated patients versus 21.8% (not significant) in untreated patients. As in Berglund's series, recurrence was independent of TSH status. An aggressive TSH suppression approach was proposed by Miccoli and coauthors.? who randomly assigned their patients to substitutive (100 ug/day) or suppressive (2.2 to 3 ug/kg per day) T 4 therapy. At 3 years, a 78% recurrence rate (palpable plus echographically detected) was observed in the former group and 21% in the TSH-suppressed group. These recurrence rates are the highest reported to date, and doubts were expressed by discussants of the article about the appropriateness of the initial operation. It is unlikely that TSH-suppressive T4 therapy will ever be widely adopted to prevent recurrence of benign thyroid disease. It requires close monitoring for life as well as fine adjustment of the T4 dosage. It demands strict compliance with the assigned treatment and can have detrimental side effects. 1 Subclinical hyperthyroidism induced by suppressive doses of T4 may increase skeletal bone loss, particularly in postmenopausal women, and may have adverse effects in elderly persons with heart disease.l?"? Because many patients operated on for nontoxic goiter are young, it is difficult to justify suppressive treatment for life, whereas appropriate surgery may result in long-term recurrence rates below 5%. From the data reviewed, it is our opinion that prevention of recurrence ultimately depends on more aggressive resection. Routine postoperative T 4 supplementation seems unjustified.P OTHER FACTORS INFLUENCING GOITER RECURRENCE
Family history has been implicated in the postoperative recurrence of goiter, and some authors recommend T 4 supplementation if there is a positive family history." In the study by Berghout and colleagues," a family history of
306 - - Thyroid Gland goiter was found twice as often in patients with recurrent goiter at follow-up as in those without recurrence (65% versus 37%). Familial history was not found to influence recurrence in the series by Kraimps and associates'': patients with a positive family history had the same recurrence rate as those without a positive family history. Note, however, that the recurrence rate in this series of patients treated with extensive operations was only 2.5%. It has been claimed that recurrences may be higher in patients living in iodinedeficient regions and that this happens even when suppressive doses of T4 are administered.' On the other hand, Steiner and Zimmermann.P working in an endemic area, reported a reduction of recurrence by postoperative T4 supplementation. There are no obvious reasons for these discrepancies. A more recent issue is related to the intrinsic growth behavior of recurrent goiters. Harrer and coworkers'? found that most nodules within multinodular goiters that had regrown after a first subtotal thyroidectomy were of polyclonal rather than monoclonal composition. This suggests that these lesions are generated by de novo proliferation of cohorts of different thyrocytes sharing the common trait of an exceedingly high intrinsic growth rate or, alternatively, by unknown growthstimulating molecular events acting focally on clusters of cells derived from different ancestors.
the initial procedure. These cases, however, usually represent delayed treatment of a known, long-standing recurrence. COMPARTMENTAL SYNDROMES
Fibrosis resulting from previous surgery around the recurrent goiter and adjacent structures can cause severe compressive symptoms, even in the absence of a large thyroid mass. Fixation of strap muscles to the trachea closes the thyroid bed medially, preventing central bulging of the goiter, and contributes to an increase of the thyroid compartment pressure. In contrast, multinodular goiters that have not been operated on can expand quite freely in the neck and may attain a considerable size before causing compression syndromes. Dysphagia, dyspnea, and dysphonia are among the most common symptoms in patients with benign recurrent goiters referred for surgery (see Table 33-1). Vocal cord paralysis is occasionally seen as a manifestation of compartmental syndrome in patients who do not recall voice changes after the initial procedure until some years later. The following is an illustrative example.
Clinical Presentation Recurrent goiter may arise with symptoms and signs varying from a barely palpable asymptomatic nodule to a large cervicothoracic mass causing compartmental syndromes. Clinical presentation is different if patients are diagnosed during a regular follow-up study, in which recurrences are often asymptomatic, or if they come from surgical series, in which more severe symptoms are commonly required. In Berglund's follow-up study," only 4 of the 26 recurrences observed required surgery: 2 because of suspicion of malignancy and 2 because of compression symptoms. In the remaining 22 patients, recurrences were small and of little clinical significance. On the other hand, in the surgical series of Roeher and Goretzki," three quarters of patients complained of severe compressive symptoms (Table 33-1). TIME AFTER INITIAL SURGERY
The interval between thyroidectomy and clinical recurrence or reoperation varies. Clinical recurrence after a correct initial operation is rarely seen before 4 to 6 years. The mean interval from reported series varies from 4 to 9 years, but many patients are referred to the surgeon 15 to 20 years after
When it occurs on the same side as the recurrent goiter, vocal cord paralysis does not necessarily imply that the nerve was injured at the initial operation; it may be compressed or stretched and may regain its function when the thyroid remnant has been removed. Recovery rate in this circumstance has been reported to be 38%.24 HYPERTHYROIDISM
Dorbach and Schicha" evaluated thyroid function in 69 patients with recurrent goiter a mean of 13.8 years after thyroidectomy. A continuous increase in thyroid autonomy was noted at the rate of about 4% per year. At 20 years, 70% of recurrent goiters were functionally autonomous; thereafter, the prevalence of thyroid autonomy increased only marginally to reach about 90% in the 40th postoperative year. In the Roeher and Goretzki series,'> 18% of patients had clinical hyperthyroidism. It appears that more and more cells become autonomous over time in recurrent goiter, and this is another argument for early surgical treatment.
Preoperative Assessment Physical examination of patients with recurrent goiters may reveal a hard cervical mass, barely movable on swallowing,
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sometimes resembling a carcinoma. Fine-needle aspiration confirms the diagnosis of benign goiter in virtually all cases, although occasionally carcinoma may be suspected. On the other hand, a recurrent thyroid nodule after partial thyroidectomy for cancer may represent a benign nodule arising in the contralateral lobe." If possible, the operative notes and pathology reports from the initial thyroidectomy should be obtained. Initial conservative surgery (isthmusectomy, enucleation) makes re-exploration easier than initial extensive surgery, which may involve both sides of the neck. One or more parathyroid glands may have been resected with the thyroid, and this information may change the surgical strategy to prevent permanent hypoparathyroidism. Laryngoscopy should be performed routinely to ascertain whether prior surgery or recurrent goiter may have caused vocal cord paralysis. Normal voice should not prevent the surgeon from ordering a laryngoscopy because contralateral vocal cord compensation may minimize the clinical sequelae of previous nerve injury. Results of laryngoscopy should be made known to the patient when the physician discusses the risk of postoperative complications. As in other thyroid diseases, thyroid function should be determined before surgery. Patients presenting with hyperthyroidism should be treated with antithyroid drugs. Because most, if not all, thyroid tissue will be removed, the patient must be aware that T4 replacement therapy will be necessary for life. Serum calcium measurements are recommended. Patients with recurrent goiters are usually normocalcernic, but the true status of each parathyroid gland cannot be ascertained from preoperative calcium or parathyroid hormone (PTH) studies. Consequently, the surgeon must be extremely careful to identify and to preserve all viable parathyroid tissue. Preoperative or intraoperative PTH assays on blood drawn from the lowermost part of both internal jugular veins could be used to determine whether parathyroid glands are missing on one side. This might help the surgeon in planning a more conservative surgery or in proceeding to parathyroid autotransplantation if viability of identified parathyroid glands seems doubtful.
Surgical Approach Surgeons dealing with recurrent goiters need to be experienced in regular thyroid surgery and versatile enough to recognize potential dangers, prevent technical mishaps, and adapt their surgical strategy to the often unforeseen findings at cervical exploration. The aim of surgical treatment for recurrent goiter is to relieve the patients from compression symptoms and to prevent any further recurrence. Total thyroidectomy is thus the treatment of choice. This principal aim should be balanced against the risk of nerve injury and hypoparathyroidism. The surgeon should be satisfied carrying out a lesser procedure if, because of local conditions, risk of injuring the recurrent nerve or the parathyroid glands seems too high. In these cases, exhaustive hilar dissection can be avoided and an intracapsular near-total or subtotal resection can be performed. The surgical approach to recurrent goiters depends mainly on three factors: the type of initial procedure and the size and location of the recurrence.
If the initial procedure was a conservative operation (isthmusectomy or nodule enucleation), reoperation should not be too difficult because the dorsal aspects of both thyroid lobes were probably left undisturbed. A midline or lateral approach for total or subtotal resection is usually possible, and surgery is similar to a standard procedure for multinodular goiter. The ease of finding the recurrent nerve and parathyroid is influenced by the size and anatomy of the underlying goiter. If the initial procedure was a totallobectomy, chances are the contralateral lobe was not mobilized, and total thyroidectomy may be carried out with little difficulty with few, if any, postoperative complications.P In these cases, a lateral approach facilitates the exposure of the upper pole and dorsal aspect of the remaining lobe. The prior collar incision should be used. The skin flaps are elevated, and the lateral space of the neck is entered. The superficial neck fascia is divided sharply between the anterior border of the sternocleidomastoid muscle and the sternothyroid muscle. The dissection is deepened and the intermediate tendon of the omohyoid muscle transected. The medial cervical fascia is then incised along the vascular sheaths, and the middle thyroid vein is identified and ligated. At this stage, if the goiter is large or if the patient's neck is short or difficult to hyperextend, exposure of the upper thyroid vessels may require dividing the strap muscles lateral to the thyroid cartilage. The upper pole vessels are ligated on the surface of the thyroid to avoid injury to the superior laryngeal nerve, and the thyroid is mobilized medially. Locating and encircling the main trunk of the superior thyroid artery at this stage helps to define better the anatomy of the goiter and to identify the recurrent laryngeal nerve. The upper parathyroid gland and the recurrent nerve are found, and the dissection is continued downward. If the thyroid has an intrathoracic extension, the hilum may lie very posteriorly, and it may be preferable at this stage to pull the thyroid out of the thorax before identifying the recurrent laryngeal nerve (see later discussion of surgical approach to intrathoracic goiter). Care is taken to identify the thyrothymic ligament and ligate it on the surface of the thyroid to avoid damaging an intrathymic inferior parathyroid. The lower pole of the thyroid is inspected to uncover any subcapsular inferior parathyroid gland that may require dissection or resection and autotransplantation if preservation of its blood supply is not feasible. Medial rotation is completed, and the remaining isthmus is peeled off the trachea and the strap muscles that are usually adherent to it. The most difficult procedure for recurrent goiter is completion thyroidectomy after subtotal unilateral or bilateral resection and reoperation to excise a remnant that has developed into a large thyroid nodule. In these cases, the surgeon should proceed laterally. The most difficult step of this procedure is dissecting the relapsing thyroid nodule off its dorsal and lateral (vascular) adhesions and dissecting the hilum of the inferior thyroid artery where the recurrent nerve and the upper parathyroid gland may be encased in fibrous tissue. Identifying the nerve in the lowermost part of the neck and tracing it to the vascular hilum, where it intertwines with the terminal branches of the inferior thyroid artery, may be a helpful maneuver. Alternatively, if dissection is deemed too dangerous, the surgeon may perform subtotal or near-total intracapsular resection,8.15.26 leaving
308 - - Thyroid Gland 0.5 to 2 g of thyroid tissue. In contrast to thyroidectomy for cancer, there is no absolute need for total resection in benign recurrent goiter, particularly if this increases the risk of postoperative complications. As discussed earlier, when operating on patients with prior vocal cord paralysis, one should always attempt to identify and preserve the recurrent laryngeal nerve. Large recurrent goiters often have an intrathoracic extension because the undisturbed structures of the upper mediastinum allow the enlarging thyroid mass to expand caudally. Their management is discussed later in this chapter.
and a 1.2% rate by Al-Suliman and colleagues.P It is not possible to know with certainty how much viable parathyroid tissue remains, and where it remains, in a patient with recurrent goiter. One of our patients experienced permanent hypoparathyroidism after a completion thyroidectomy after a prior total lobectomy.
Postoperative Complications At the beginning of this century, Theodor Kocher warned against the risks of reoperative thyroid surgery." Beahrs and Sakulsky'? reported a high incidence of nerve palsies when recurrent diffuse toxic goiter was treated by repeated thyroidectomy. Although reoperation for Graves' disease is no longer performed because of the alternative of radioiodine ablation, reoperation for compressive or hyperfunctioning recurrent goiter still accounts for about 5% of thyroidectomies in specialized units. This is currently the type of thyroid operation with the highest rate of permanent recurrent nerve palsy and hypoparathyroidlsm.P'P'" The risk of permanent vocal cord paralysis was evaluated by Weitensfelder and colleagues in a series of 525 thyroidectomies." The probability of recurrent nerve injury increased in the following sequence: uncomplicated nodule < goiter < thyroid cancer < recurrent goiter. Early palsies (3.2%) were more frequent than permanent ones (0.8%); only one in four early palsies became permanent. This 75% recovery rate was similar to the 86% rate reported by Jatzko and colleagues." The prevalence of permanent vocal cord paralysis after repeated thyroidectomy for recurrent benign goiter in reports from specialized thyroid units is shown in Table 33-2. Permanent nerve injury is observed in very experienced hands, even when subtotal resections were performed at reoperation. Permanent hypoparathyroidism seems to be a problem of less importance than recurrent nerve injury. In the series of Levin" and Jatzko-? and their coworkers, no patient experienced permanent hypoparathyroidism after repeated thyroidectomy for recurrent benign goiter. A 3% permanent hypocalcemia rate was reported by Kraimps and colleagues"
Uncertainty about prior parathyroid status should make the surgeon very cautious when identifying and dissecting the parathyroid glands, particularly if the initial operation was done in a nonspecialized setting. As suggested earlier, intraoperative bilateral PTH assays may assist the surgeon in decision making.
Intrathoracic Goiter Mediastinal extension is common in large, bulky, multinodular goiters. Negative intrathoracic pressure and gravity facilitate the descent of an enlarged thyroid gland. Intrathoracic goiter is rarely «2%) a purely mediastinal tumor developing in an embryonic ectopic remnant or in a fragment of goiter left behind after an initial thyroidectomy.W" Because lateral and medial expansion may be limited after previous surgery, recurrent goiters often have more mediastinal prolongation. Between 3% and 20% of all intrathoracic goiters have undergone previous thyroid resections and are recurrent goiters.24.33-37
Definition and Prevalence Review of the definitions of intrathoracic goiter shows no consensus on when a goiter should be considered intrathoracic. The most commonly accepted definition would include all goiters with a lower pole lying below the thoracic outlet." Other groups refer to substernal goiter only in cases in which at least 50% of the thyroid mass is located below the thoracic inlet. 33.34 The Lahey Clinic group defined mediastinal goiters as "those with a major intrathoracic component that required reaching into the mediastinum for its dissection.v" This lack of agreement is reflected in the reported prevalences for intrathoracic goiter, which range from 4% to 20% of all operations for multinodular goiters. Intrathoracic goiters are also referred to as substernal goiters. Although the majority of intrathoracic goiters are anteriorly situated and thus are truly substernal, others may lie in the posterior mediastinum. Consequently, the term intrathoracic is preferred.
Surgical Management of Recurrent and Intrathoracic Goiters - - 309
Clinical Presentation Intrathoracic goiters usually occur late in life and have a peak incidence in the sixth decade. The average ratio between females and males is 3 to 4:1.38,39 In 20% to 30% of patients, the thyroid can be barely palpable or not palpable at all in the neck (grades I and II), and the thoracic extension represents most of the bulk of the goiter.35.36 Between 6% and 40% of patients reported in surgical series have no symptoms but have undergone thyroidectomy as prophylaxis against the potentially severe complications of a large intrathoracic thyroid mass. In these asymptomatic cases, substernal goiters are usually incidentally discovered on a plain chest radiograph.f The most common clinical manifestations of substernal goiters are related to compression or displacement of the adjacent visceral, neural, and vascular structures (Table 33-3). Tracheal obstruction and resulting upper airway compression symptoms were observed in 20% to 56% of the patients operated on for intrathoracic goiter in some reports. Ranging from mild to severe, these symptoms are isolated dyspnea, dyspnea with cyanosis, dyspnea with cyanosis prohibiting physical efforts, suffocation, and choking requiring immediate resuscitation." Dyspnea or cough may be worsened by some positions, such as lying flat or rolling on one side. The mechanism leading to airway obstruction is compression of the trachea by a goiter expanding between bone structures (spine, sternum, and first rib). Melliere and colleagues" observed severe airway compression by goiters in 58 patients (2% of their thyroidectomy cases). Fifteen were thyroid malignancies and 43 were benign goiters, of which 16 had an intrathoracic substernal extension compressing the airway. Shaha and coworkers'? cared for 24 patients admitted during a 4-year period with acute life-threatening airway distress resulting from thyroid enlargement (in 9 patients, immediate intubation was required). Twenty of these patients had benign goiter, 15 of them with marked substernal extension. In patients requiring emergency care for acute airway obstruction, surgery should be performed as soon as possible, and patients should not be weaned from the ventilator before surgery because this may be followed by acute asphyxia." Occasionally, dyspnea resulting from upper airway obstruction can mimic lung disease. In these cases, it may be difficult to determine precisely which component is the main reason for the dyspnea. Lung function tests aided by flow-loop studies may be very helpful in determining the degree of airway obstruction.
Stephenson and associates'? determined peak expiratory flow to investigatethe functional impact of substernal goiters. The preoperative peak expiratory flow ratio (observed to predicted) was significantly lower in patients with intrathoracic goiter, with a positive predictive value of 90%. This reduced peak expiratory flow improved after thyroidectomy. This test, along with failure of the peak airflow and forced expiratory volume to respond to bronchodilators, may be helpful in identifying the patients with respiratory disease and associated intrathoracic goiters who may benefit from thyroidectomy. The following is an illustrative example.
Entrapment of the recurrent laryngeal nerve or laryngeal distortion may be the major cause of hoarseness found in about one third of patients who have undergone thyroidectomy for intrathoracic goiter. Cho and coauthors-! reported that vocal cord paralysis from benign thyroid conditions may be particularly prevalent among patients with large substernal goiters, and they attributed this to nerve compression, ischemia, or stretching. The true prevalence of preoperative vocal cord paralysis in substernal goiters,
310 - - Thyroid Gland
FIGURE 33-1. A, Chest radiograph of a 72-year-old woman with dyspnea, reduced peak expiratory flow, and a massively calcified cervicothoracic goiter. B, Computed tomography (CT) scan section at the level of the subcricoid trachea showing narrowing of the airway lumen. C, CT scan section showing marked narrowingof the trachea at the thoracic outlet. D, Downward extension of the goiter to the aortic arch 2 em above the carina,
however, is difficult to determine because laryngoscopy has been carried out very selectively in symptomatic patients. Furthermore, the rate of hoarseness is probably higher than that of well-documented vocal cord dysfunction. As discussed earlier, vocal cord paralysis can be reversed by thyroidectomy.24,28,35,37 Thus, when operating on patients with intrathoracic goiter and dysphonia, the surgeon should identify the nerve and free it from surrounding fibrosis and adjacent compressive structures. Occasionally, however, nerve injury during a previous procedure or infiltration by an adjacent malignancy makes the recovery of vocal cord function impossible. Lateral and posterior displacement of the esophagus causes dysphagia in about one fourth of patients being operated on for bulky intrathoracic goiters. However, these symptoms do not severely interfere with swallowing; aspirative complications and malnutrition have not been reported. Esophagograms show esophageal compressions and displacement by the thyroid mass but add little information to the management of these patients. Less frequently (10% of cases), obstruction of venous return gives rise to a fully or partially developed superior vena cava syndrome. This can be obvious with cyanosis, dilation of superficial
facial and neck veins, and descending collateral venous circulation (Fig. 33-2). Subclinical venous compression can be diagnosed by having the patient raising the arms (Marafion's maneuver or Pemberton's sign) and observing distention of the external jugular and superficial neck veins. Collateral circulation may rarely involve the upper esophagus with "downhill" varices developingtv'" and causing an upper gastrointestinal hemorrhage. Superior vena cava syndrome is reversed by thyroidectomy and is considered to be an absolute indication for surgery." Gross multinodular goiters, whether in the neck or mediastinum, tend to develop autonomous nodules, particularly in patients with a prolonged history.15,25 Although in some reports no patients with hyperthyroidism were observed,24.33,36 in others biochemical or clinical evidence of thyroid hyperfunction was found in a significant (15 % to 40%) proportion of patients. 34,35,40 Hyperthyroidism is more common in elderly patients. In Cougard and colleagues' series of 218 intrathoracic goiters.'? hyperthyroidism developed in 35% of patients 70 years or older and in only 17% of those younger than 70 years, Hyperthyroidism in elderly patients can have potentially lethal cardiac complications such as congestive heart failure, arrhythmias, and worsening of
Surgical Management of Recurrent and Intrathoracic Goiters - -
311
FIGURE 33-2. A and B, Superior vena cava syndrome in a patient with intrathoracic goiter. A pyramid-shaped bilateral intrathoracic goiter could not be retrieved through a collar incision, and thyroidectomy through a combined cervicomediastinal approach was carried out, with complete relief of caval compression.
ischemic heart disease. Thyrotoxicosis may develop simultaneously as a result of hyperfunctioning "hot" nodules (Plummer's disease), after administration of iodinated contrast medium, or after T 4 is given in an attempt to inhibit further growth of the goiter. Thus, it is important to identify patients with hyperthyroidism because they should receive definitive treatment, preferably surgical, as soon as possible. Radioactive iodine has been used to control hyperthyroidism in multinodular goiters, but it is often ineffective, repeated doses are required, and long periods of time elapse before obtaining the desired effects. Furthermore, radiation thyroiditis may occur soon after the administration of iodine 131 and may precipitate an emergency situation in the patient with airway obstruction.t' In several series, the prevalence of cancer in intrathoracic goiters ranged from 3% to 17% (Table 33-4), including both overt malignancies and occult papillary carcinomas. It is difficult to make an accurate preoperative diagnosis of carcinoma because the intrathoracic component cannot be reached by a fine needle. Furthermore, the exact location of the malignant nodule is difficult to ascertain. A relatively high proportion of thyroid lymphomas (6 of 102 substernal goiters) has been observed in the two series with the highest prevalence of malignancy.v-" Advanced intrathoracic thyroid carcinoma
may pose significant surgical problems if infiltrating surrounding structures; biopsy plus tracheostomy, palliative resection, and total thyroidectomy with or without laryngeal or segmental tracheal resection have all been performed in these circumstances. Review of unusual clinical presentations of intrathoracic goiters reveals a fair number of severe, albeit rare, complications. The following cases were collected from the literature by Lawson and Biller38: hematemesis from downhill esophageal varices, abscess formation, Homer's syndrome, chylothorax from thoracic duct occlusion, and transient ischemic attacks resulting from a "thyroid steal syndrome." Fatal hematemesis has been described in a patient with fullthickness ulceration of the esophagus by a posterior substernal goiter." Axillosubclavian vein thrombosis was found in one patient with substernal goiter compressing the innominate vein."? Injury to the membranous portion of the trachea at intubation for general anesthesia has occurred in at least two patients as a result of the trachea being angulated anteriorly by a posterior intrathoracic goiter" (1. M. Rodriguez, personal communication); thyroidectomy and tracheal repair were performed through sternotomy in both cases.
Preoperative Imaging and Assessment Various reports have emphasized the usefulness of chest radiographs and airway films in assessing the extent of tracheal displacement and obstruction caused by intrathoracic goiters. 4 1,42 Chest radiographs were abnormal in 60% to 90% of patients included in four studies.33.35-37 Lateral chest radiographs should also be taken to demonstrate any anterior displacement of the trachea, which may render orotracheal intubation dangerous (Fig. 33-3). Occasionally, lung metastasis from a thyroid carcinoma can be observed.P''? Extrinsic pressure on mediastinal structures is best shown by CT scanning, which is the most sensitive imaging technique for diagnosing intrathoracic goiter extension. 36,38-40,42 It should be obtained in patients with a history suggesting
312 - - Thyroid Gland
Iodine 131 scintigraphy should always precede CT scanning because intravenous iodine administered for vascular enhancement blocks iodine uptake by the goiter. Technetium 99m scintigraphy does not depend on iodine uptake by
FIGURE 33-3. Lateral cervicothoracic radiographic projection showing marked anteriordisplacement of the trachea, widening of the tracheovertebral space, and airway compression against the sternal manubrium by a large (580 g) intrathoracic goiter.
compression symptoms and in those with nonpalpable lower thyroid borders, particularly if chest radiographs show an abnormal mediastinal outline or marked tracheal deviation. CT scanning gives important information to the surgeon regarding (I) the precise location of the intrathoracic extension; (2) the presence, extent, and situation of the continuity between the cervical and the thoracic components of the goiter; (3) definition of the limits of the lesion; (4) areas of calcification; (5) degree of heterogeneity and cystification of the intrathoracic portion; and (6) level and degree of tracheal lumen reduction. Nuclear magnetic resonance imaging may be superior" because, in addition to the information provided by CT scanning, it has two advantages: it offers sagittal and coronal tomographic cuts, which further clarify the anatomy of the intrathoracic goiter, and it delineates more precisely the relations among the goiter, the whole length of the trachea, and the mediastinal vessels. Vascular invasion by a thyroid malignancy may also be detected. Thyroid scintigraphy has limited value in the preoperative assessment of intrathoracic goiters. Iodine 131 scintigraphy often fails to show the mediastinal prolongation24•36,38,40 and adds little to the management of intrathoracic goiter. In patients with subclinical or overt hyperthyroidism, it may show hot hyperfunctioning nodules. The most useful indication for 131I scintigraphy is to clarify the nature of an isolated mediastinal mass, and it should be ordered for patients in whom CT scanning does not show mass continuity between the mediastinum and the neck. The following is an example.
FIGURE 33-4. Chest radiograph (A) and iodine 131 scmtigram
(B) in a case of recurrent intrathoracic goiter independent of the neck approached through a median sternotomy. Subtotal thyroidectomy was performed 22 years before. The mass was situated behind the ascending aorta.
Surgical Management of Recurrent and Intrathoracic Goiters - - 313
the goiter, but because of the proximity of the goiter to the thoracic cardiovascular blood pool, the findings may be difficult to interpret. Its sensitivity has been reported to be only 33%.49 Laryngoscopy should be carried out in patients presenting with hoarseness or dysphonia and in those who have had prior neck surgery. Vocal cord paralysis may result from (1) previous surgery, (2) compartmental syndrome, or (3) invasion of the recurrent laryngeal nerve by a thyroid malignancy. These different possibilities should be borne in mind during operation. Thyroid function tests must be performed before surgery because hyper- or hypothyroidism may be associated with large intrathoracic goiters. Hyperthyroid patients should be treated with antithyroid drugs before surgery. Some authors" add steroids to the antithyroid drugs to prevent worsening of compartmental syndromes resulting from goiter inflammation. This practice, however, is not widespread, and most surgeons would prefer to operate on patients not receiving steroids. Failure to measure a recent thyroid hormone concentration may precipitate perioperative metabolic problems. One of our patients experienced postoperative acute myxedema despite a near-normal hormone concentration 1 month before surgery.
Surgical Treatment Thyroidectomy is the preferred treatment for intrathoracic goiter (Table 33-5). T4 treatment has repeatedly proved ineffective in reducing goiter volume" and may result in hyperthyroidism. A clinical trial using suppressive doses of L-thyroxine(2.5 ug/kg per day) to reduce the size of sporadic nontoxic goiters has shown that after 9 months of continued treatment 58% of the patients responded (as determined by ultrasonography). The mean reduction of goiter size was 25%. This benefit, however, was short lasting; 9 months after
the treatment was discontinued, the goiter volume regained its basal value" Evidence supports a growing consensus against the use of L-thyroxine treatment for goiter size reduction or goiter growth prevention." CERVICAL APPROACH
More than 90% of intrathoracic goiters can be removed through a standard collar incision. Several maneuvers facilitate approaching, dissecting, and delivering huge goiters into the cervical wound. These are summarized in the following description of a "standard" bilateral resection for multinodular intrathoracic goiter. The best position of the patient on the operating table is the semisitting Kocher position with hyperextension of the neck. This reduces venous pressure in the upper trunk and helps to minimize blood loss. To reduce further the pressure in the neck, it may be helpful to divide the sternal head of the sternocleidomastoid muscle and the strap muscles. This maneuver also gives a wide exposure for approaching the upper pole and the laterodorsal aspects of the goiter. Before any attempt is made to mobilize the intrathoracic extension, the upper thyroid vessels and lateral middle veins should be divided on both sides. The surgeon then decides which is the smaller of the two lobes and rotates it medially to identify and encircle its inferior thyroid artery. The posterolateral surface of the lower pole should be carefully inspected to detect any subcapsular parathyroid gland that may require autotransplantation in the sternocleidomastoid muscle. During mobilization of bulky thyroid lobes, we have found it useful to apply a small bulldog vascular clamp to the trunk of the inferior thyroid artery. Perithyroid and hilar dissection can then be carried out with a minimal blood supply to the thyroid; the clamp is released after lobectomy is finished. Pressure in the neck is greatly relieved at this stage, and resection of the mobilized lobe can be accomplished. Tracheal attachments of the dorsum of the thyroid are severed as completely as possible without endangering the contralateral recurrent laryngeal nerve. Having freed as many cervical attachments as possible, the surgeon now approaches the lobe with a major intrathoracic component. Access to the hilum may be difficult before the intrathoracic extension has been brought up. If this is the case, no heroic efforts should be
314 - - Thyroid Gland made to identify the recurrent nerve at this stage; attention is focused instead on delivering the thoracic goiter extension into the neck. This is done by gently pulling up the thyroid lobe while the surgeon frees loose adhesions surrounding the mediastinal portion of the goiter with the index finger and applies caudal to cephalad pressure onto it. If this proves difficult, two additional maneuvers may be helpful: (l) the finger of the surgeon can be replaced by. a sterile "soup spoon," which breaks negative intrathoracic pressure, reaches lower, and occupies less space th~n the surgeon's finger 34•52 ; and (2) intracapsular fragmentation of the thyroid (morcellation) was proposed by Lahey to reduce the size and soften the intrathoracic goiter extension and facilitate its removal through the neck. This technique has two drawbacks: major bleeding and tumor spillage. When the goiter is obviously cystic and no fear of malignancy exists, Allo and Thompson" occasionally used a variation of this technique by introducing a metal suction device through small capsular incisions. Katlic and colleagues-' also used morcellation, aspiration, or both, in 5 of their 80 operations for intrathoracic goiter, with good results. After the intrathoracic portion has been delivered into the neck, the operation proceeds in a standard manner, identifying the recurrent laryngeal nerve and the upper parathyroid gland. Use of closed suction drains is advisable to evacuate blood from the large remaining mediastinal cavity. If the intrathoracic part is very difficult to mobilize before the recurrent nerve is identified and the tracheal attachments of the thyroid lobe are severed, the surgeon may identify the nerve close to the inferior hom of the thyroid cartilage where it enters the larynx and dissect it downward. This is followed by section of the tracheal attachments. By so doing, the cervical part is completely free and more efficient upward traction, without fear of injuring the nerve, can be exerted on the thoracic part of the goiter. Identification of the recurrent nerve at the level of the cricoid cartilage, however, is technically demanding and should not be attempted by the less experienced surgeon.
STERNOTOMY AND COMBINED MEDIASTINAL APPROACH
The anterior chest wall should be prepared and draped in all patients undergoing thyroidectomy for large intrathoracic goiters should sternotomy be required. Sternoto.my can be carried out as a last resort or maneuver, or, better, It should be planned electively for patients in whom preoperative imaging demonstrates very bulky, low-lying, solid goiters with complex anatomic relations. Between 2% and 11% of intrathoracic goiters have required removal through a combined cervical and sternotomy approach. 32-42,49.53 Indications for this combined approach include a large discrepancy between the diameter of the thoracic inlet and that of the goiter (pyramidal or pearshaped intrathoracic extensions; see Fig. 33-5), superior vena cava syndrome, retroesophageal extension, deepseated tumors reaching the carina, invasive carcinoma, and acute respiratory distress. The specific reasons for performing sternotomy given in a number of studies are su~m~zed in Table 33-6. The main advantage of sternotomy IS Widening of the thoracic inlet. Widening facilitates deeper blunt dissection and exteriorization of large thyroid masses that otherwise would require fragmentation. It may also help to control bleeding in the occasional case in which mediastinal vessels to the goiter are identified. If a carcinoma is present, invading the lower trachea, sternotomy may be required to achieve a radical resection.lv" If sternotomy is used, the cervical part of the operation is done first to control the major thyroid vessels. Leaving sternotomy to the end of the operation also has the advantage of shortening the wound exposure time, thus reducing the risk of infection. In cases of superior vena cava syndrome, however, early sternotomy may be required to decompress the large neck veins effectively. Partial or full median sternotomy is carried out. Partial sternotomy has the advantage of being more cosmetic. It can be done by raising the lower skin flap over the sternal manubrium, thus sparing a presternal skin wound.
Surgical Management of Recurrent and Intrathoracic Goiters - - 315
The following case history represents a good example of a patient with recurrent giant intrathoracic solid goiter who underwent total thyroidectomy through a combined cervicomediastinal approach.
Widening the thoracic outlet by sternum splitting may decrease the risk of recurrent laryngeal nerve injury in difficult cases. In a study by Cougard and colleagues/" no permanent nerve palsy was observed in 16 patients who had sternotomy, whereas a 6.8% palsy rate was noted in patients operated on through only a cervical incision.
THORACOTOMY A half-century ago, there was uncertainty as to the best route for resecting large intrathoracic goiters when access to the chest was required.> Thoracotomy (usually right) was proposed mainly by thoracic surgeons such as Clagett, Sweet, and Ellis in the belief that most intrathoracic goiters represented isolated thoracic masses and that posterior goiters could not be safely removed through a neck incision. Since then, experience has shown that approaching the intrathoracic goiter through posterolateral thoracotomy should be discouraged. There are several reasons for this. Posterior thoracic goiters are no longer per se an indication for thoracotomy because they can usually be delivered through collar incision or median sternotomy. Major thyroid vessels cannot be appropriately controlled from the thorax, and the cervical extension of the goiter cannot be dissected free from the adjacent structures. It is because of these
FIGURE 33-5. Recurrent goiter
witha largeintrathoracic extension of the right lobe. A, Chest radiograph film shows lateral displacement of the trachea by a large mediastinal mass. B, Computed tomography scan shows downward prolongation of the goiter past the aortic arch. C. Sagittal section in a nuclear magnetic resonance scan showsthe relationshipof the intrathoracic goiterwith the venous innominate trunk, the spine, and the right mainbronchus. D. Coronal section shows tracheal compression, pleural thickening around the goiter, and relationship withthecarina. Median sternotomy was performed to allow blunt finger dissection of the lower pole of the right lobe lying behind the vena cava on the right main bronchus.
316 - - Thyroid Gland technical difficulties that thoracotomy is associated with substantial risk of recurrent laryngeal nerve injury.37,55.56 If a thoracotomy is carried out because an incorrect diagnosis of purely posterior mediastinal "tumor" has been made, it often requires conversion to a neck incision.'? Shahian and Rossi'? made the case for exceptional circumstances that may require thoracotomy: at the Lahey Clinic, two patients had a cervical and thoracotomy approach in a 20-year period. Both presented with a right posterosuperior mediastinal goiter extending from a left thyroid lobe passing behind the trachea and the esophagus. In our experience, however, these "corkscrew goiters" can also be approached by a full median sternotomy and opening of the right pleural cavity. Gentle pressure on the posterior thyroid mass helps to untwist the goiter around the tracheoesophageal axis. SUMMARY
It is usually difficult to foresee which patients will require a thoracic approach when operating on an intrathoracic goiter. It is therefore advisable to prepare the surgical field for sternotomy in cases of huge thoracic thyroid masses, especially if they are posterior, suspicious of being malignant, or recurrent." Further studies based on preoperative imaging techniques, anatomic landmarks, and volumetric studies may serve to delineate further the subset of patients who require a thoracic approach.
Postoperative Complications The morbidity rate after surgery for intrathoracic goiters ranges between 4% and 12% in various series from referral institutions. The most common significant complications are listed in Table 33-7. Patients with the highest complication rates are those with thyroid malignancies and those undergoing a combined cervicomediastinal approach. Despite the extensive perithyroidal dissection required to resect these large goiters, permanent hypoparathyroidism is unusual in the hands of experienced surgeons. To achieve these results, knowledge of the altered anatomy is essential, as is proper identification and eventually autotransplantation of any parathyroid gland in the surface of the thyroid whose blood supply cannot be guaranteed. Recurrent laryngeal nerve paralysis results from not identifying the nerve and inadvertent injury or from stretching during blunt dissection of large intrathoracic masses. As previously stated, efforts to identify the nerve before the
intrathoracic goiter is fully mobilized may result in inadvertent injury. If the nerve is not transected, vocal cord paralysis is usually (75%) temporary. Tracheal softening leading to tracheal collapse and respiratory failure (tracheomalacia) is being reported exceptionally, even in series of patients operated on for airway compression. In several major studies 32-3M1,42 encompassing 298 patients (including two series of patients operated on for respiratory distress), only 2 patients were diagnosed with tracheomalacia and required postoperative tracheostomy.3M2 Of the seven patients with tracheomalacia reported by Geelhoed.l? three had recurrent goiters and one had a longstanding multinodular goiter. Methods for management of tracheomalacia are extensively reviewed in this study. External splinting by custom-made rings or Marlex mesh has also been tried.59 Tracheostomy, however, remains the standard treatment whenever tracheal softening is identified at surgery.
Summary Operations on recurrent and intrathoracic goiters are associated with increased intraoperative technical difficulties and permanent sequelae. Because compression symptoms are common or may develop with time, surgery becomes the only rational therapy. An appropriate preoperative assessment, including laryngoscopy, CT scanning, and thyroid function tests, and an experienced surgeon are essential for minimizing perioperative complications. Safe thyroid resection is the aim, and the incidence of permanent vocal cord paralysis and hypocalcemia should be near zero when treating these benign conditions.
REFERENCES I. Burman KD. Is long-term levothyroxine therapy safe? Arch Intern Med 1990;15:2010. 2, Miccoli P, Antonelli A, Iaconi P, et al. Prospective, randomized, double-blind study about effectiveness of levothyroxine suppressive therapy in prevention of recurrence after operation: Result at the third year of follow-up. Surgery 1993;114: 1097. 3. Cohen-Kerem R, Schachter P, Sheinfeld M, et al. Multinodular goiter: The surgical procedure of choice. Otolaryngol Head Neck Surg 2000;122:848. 4. Welbourn R. The History of Endocrine Surgery. New York, Praeger, 1990, p 44. 5. Bistrup C, Nielsen JD, Gregersen G, Franch P. Preventive effect of levothyroxine in patients operated for non-toxic goitre: A randomized trial of one hundred patients with nine year follow-up. Clin Endocrinol (Oxf) 1994;40:323. 6. Anderson PE, Hurley PR, Rosswick P. Conservative treatment and long-term prophylactic thyroxine in the prevention of recurrence of multinodular goiter. Surg Gynecol Obstet 1990;171:309. 7. Berglund J, Bondesson L, Christensen SB, et al. Indications for thyroxine therapy after surgery for nontoxic benign goitre. Acta Chir Scand 1990;156:433. 8. Kraimps JL, Marechaud R, Gineste D, et al. Analysis and prevention of recurrent goiter. Surg Gynecol Obstet 1993;176:319. 9. Berghout A, Wiersinga WM, Drexhage HA, et al. The long-term outcome of thyroidectomy for sporadic nontoxic goiter. Clin Endocrinol (Oxf) 1989;31: 193. 10. Reeve TS, Delbridge L, Cohen A, et al. Total thyroidectomy: The preferred option for multinodular goiter. Ann Surg 1987;206:782. I I. Delbridge L, Guinea AI, Reeve TS. Total thyroidectomy for bilateral benign multinodular goiter: Effect of changing practice. Arch Surg 1999;134:1389.
Surgical Management of Recurrent and Intrathoracic Goiters - 12. Duh QY, Clark OH. Factors influencing the growth of normal and neoplastic thyroid tissue. Surg Clin NorthAm 1987;67:281. 13. Geerdsen JP, Frolund L. Recurrence of nontoxic goitre with and without postoperativethyroxine medication. Clin Endocrinol (Oxf) 1984;21:221. 14. Goretzki P, Roeher HD, Horeyseck G. Prophylaxis of recurrent goiter by high-dose L-thyroxine. World 1 Surg 1981;5:855. 15. Roeher HD, Goretzki PE. Management of goiter and thyroid nodules in an area of endemic goiter. Surg Clin North Am 1987;67:233. 16. Goretzki PE, Clark OH. Thyroid-stimulating hormone receptor studies. Prog Surg 1988;19:181. 17. Stall GM, Harris S, Sokoll U, et al. Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine. Ann Intern Med 1990;113:265. 18. Adlin EV, Maurer AH, Marks AD, et al. Bone mineral density in postmenopausal women treated with L-thyroxine. Am 1 Med 1991;90:360. 19. Ross DS. Subclinical thyrotoxicosis. In: Mazzaferri EL, Bar RS, Kreisberg RA (eds), Advances in Endocrinology and Metabolism. St. Louis, CV Mosby, 1991. 20. Smith SA, Gharib H. Thyroid nodule suppression. In: Mazzaferri EL, Bar RS, Kreisberg RA (eds), Advances in Endocrinology and Metabolism. St. Louis, CV Mosby, 1991. 21. Martina B, Staub JJ, Gemsenjager E. Long-term follow-up after thyroidectomy: Incidence of recurrent goiter and functional results. Schweiz Med Wochenschr 1992;122:1753. 22. Steiner H, Zimmermann G. Reinterventions an der Schilddriise. Cited in Roeher HD, Goretzki PE. Management of goiter and thyroid nodules in an area of endemic goiter. Surg Clin North Am 1987;67:233. 23. Harrer P, Broecker M, Zint A, et al. Thyroid nodules in recurrent multinodular goiters are predominantly polyclonal. 1 Endocrinol Invest 1998;21:380. 24. Cho HT, Cohen IP, Som ML. Management of substernal and intrathoracic goiters. Otolaryngol Head Neck Surg 1986;94:282. 25. Dorbach M, Schicha H. Frequency and temporal occurrence of a functional autonomy in recurring goiter. Nuklearmedizin 1993;32:316. 26. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;III :604. 27. Beahrs OH, Sakulsky SB. Surgical thyroidectomy in management of exophthalmic goiter. Arch Surg 1968;96:512. 28. AI-Suliman NN, Graversen HP, Blicher-Toft M. Surgical treatment of benign recurrent goiter: Technique, complications and permanent sequelae. Ugeskr Laeger 1994;156:165. 29. latzko GR, Lisborg PH, Miiller MG, Welle VM. Recurrent nerve palsy after thyroid operations: Principal nerve identification and a literature review. Surgery 1994;115:139. 30. Menegaux F, Turpin G, Dahman M, et aI. Secondary thyroidectomy in patients with prior thyroid surgery for benign disease: A study of 203 cases. Surgery 1999;126:479. 31. Weitensfelder W, Lexer G, Aigner H, et aI. Long-term laryngoscopic follow-up in vocal cord paralysis following struma surgery. Chirurgie 1989;60:29. 32. Shahian DM. Surgical treatment of intrathoracic goiter. In: Cady B, Rossi RL (eds), Surgery of the Thyroid and Parathyroid Glands. Philadelphia, WB Saunders, 1991, p 215. 33. Katlic MR, Grillo HC, Wang Cc. Substernal goiter. Am 1 Surg 1985;149:283. 34. Allo MD, Thompson NW. Rationale for the operative management of substernal goiters. Surgery 1983;94:969.
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35. Michel LA, Bradpiece HA. Surgical management of substernal goitre. Br 1 Surg 1988;75:565. 36. Sanders LE, Rossi RL, Shahian DM, Williamson WA. Mediastinal goiters: The need for an aggressive surgical approach. Arch Surg 1992;127:609. 37. Maruotti RA, Zannini P,Viani MP, et aI. Surgical treatment of substernal goiters. Int Surg 1991;76:12. 38. Lawson W, Biller HF. Management of substernal thyroid disease. In: Falk SA (ed), Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. New York, Raven Press, 1990, p 389. 39. Rodriguez 1M, Hernandez Q, Pinero A, et aI. Substernal goiter: Clinical experience of 72 cases. Ann Otol Rhinol LaryngoI1999;108:501. 40. Cougard P, Matet P, Goudet P, et al. Substernal goiters: 218 operated cases. Ann Endocrinol (Paris) 1992;53:230. 41. Melliere D, Saada F, Etienne G, et al. Goiter with severe respiratory compromise: Evaluation and treatment. Surgery 1988;I03:367. 42. Shaha A, Alfonso A, laffe BM. Acute airway distress due to thyroid pathology. Surgery 1987;102:1068. 43. Stephenson BM, Shandall AA, Griffith GH. Peak expiratory flow in the detection ofretrosternal goiter. Ann R Coli Surg Engl 1991;73:215. 44. Kelly TR, Mayors Dl, Bontsicaris RS. "Downhill" varices: A cause of upper gastrointestinal hemorrhage. Am Surg 1982;48:35. 45. Sorokin JJ, Levine SM, Moss EG, Biddle CM. "Downhill" varices: Report of a case 29 years after resection of a substernal thyroid gland. Gastroenterology 1977;73:345. 46. Parker DR, el-Shaboury AH. Fatal haematemesis due to benign retrosternal goiter. Postgrad Med 11992;68:756. 47. Santos GH, Ghalili K. Axillosubclavian vein thrombosis produced by retrosternal thyroid. Chest 1990;98: 1281. 48. Dubost C, D' Acremont B, Potter C, et al. Tracheal injury caused by intubation for compressive endothoracic goiter. 1 Chir (Paris) 1991;128:109. 49. Al-Suliman NN, Graversen HP, Blicher-Toft M. Intrathoracic goiter: Diagnostic aspects, surgical complications and permanent sequelae. Ugeskr Laeger 1994;156:1646. 50. Berghout A, Wiersienga WM, Drexhage HA, et al. Comparison of placebo with L-thyroxine alone or carbimazole for treatment of sporadic goiter. Lancet 1990;336: 193. 51. Gharib H, Mazzaferri EL. Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998;128:386. 52. Landreneau RI, Nawarawong W, Boley TM, et al. Intrathoracic goiter: Approaching the posterior mediastinal mass. Ann Thorac Surg 1991;52:134. 53. Mussi A, Ambrogi MC, Iacconi P, et al. Mediastinal goitres: When the transthoracic approach? Acta Chir Belg 2000;100:259. 54. Daou R. Substernal goitre. Chirurgie 1991;117:43. 55. ludd ES, Beahrs OH, Bowes DE. A consideration of the proper surgical approach for substernal goiters. Surg Gynecol Obstet 1960;110:90. 56. Ellis FH lr, Good CA, Seybold WD. Intrathoracic goiter. Ann Surg 1952;135:79. 57. Shahian DM, Rossi RL. Posterior mediastinal goiter. Chest 1988;94:599. 58. Monchik 1M, Materazzi G. The necessity for a thoracic approach in thyroid surgery. Arch Surg 2000;135:467. 59. Geelhoed GW. Tracheomalacia from compressing goiter: Management after thyroidectomy. Surgery 1988;I04: 1100.
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract H. Dralle, MD • M. Brauckhoff, MD • A. Machens, MD • O. Gimm, MD
Thyroid cancer invading the aerodigestive tract is uncommon (Table 34-1). Apart from distant metastases, extrathyroid invasion is the dominating risk factor for tumor recurrence and mortality in thyroid cancer. [-3 Among the patients with extrathyroid extension of thyroid cancer, those with tracheal or esophageal invasion have a worse prognosis in terms of survival than those with invasion of other extrathyroid structures." Apart from tumor extension, the extent of primary surgery as the mainstay of therapy in differentiated and medullary thyroid carcinoma significantly affects tumor recurrence and survival.v' In an investigation regarding cancer-specific cause of death in thyroid cancer, local complications from tumor growth accounted for 35% of fatalities, distant metastases for 34%, local and metastatic disease jointly for 28%, and complications related to therapy for 4%.7 By direct tumor extension, thyroid cancer may take three main directions of spread: (1) the central route, involving the paratracheallymph nodes, the recurrent laryngeal nerve, and the aerodigestive axis; (2) the lateral route, involving lymph nodes of the lateral compartment, the carotid sheath; and the lateral nerves; and (3) the mediastinal route, involving the upper mediastinal lymph nodes, the great vessels, the thymus, and other mediastinal organs. The four main types of thyroid cancer, papillary, follicular, medullary, and undifferentiated thyroid carcinoma, differ with regard to tumor biology and disease progression not only from each other but also from squamous cell carcinoma of the head and neck. Consequently, the efficacy of adjuvant treatment modalities such as radioiodine therapy and percutaneous irradiation varies significantly according to the tumor entity. Unlike involvement of the lateral neck and mediastinum, invasion of the aerodigestive tract has stirred considerable controversy concerning indications, technique, and extent of resection. Because patients with aerodigestive tract invasion are generally older than patients without aerodigestive tract
318
invasiont'? and the aerodigestive tract is vitally important, surgery in this setting poses a real challenge for both the surgeon and the patient. Prevention and elimination of airway obstruction are the primary objectives of surgical therapy, while striving at the same time to preserve the patient's voice capacity and quality of life. As in other complex diseases, optimal selection of patients and outcome for thyroid cancer invading the aerodigestive tract can be accomplished only in a multidisciplinary approach. The preoperative work-up for local and distant tumors relies on joint radiologic and nuclear medicine expertise. The surgical resectability depends on the cooperation of surgeons with anesthesiologists; ear, nose, and throat specialists; and plastic, vascular, and thoracic surgeons. Postoperative care requires the combined expert knowledge from fields as diverse as radiology and nuclear medicine (radioiodine therapy, percutaneous irradiation) and advanced endoscopy (e.g., intraluminal stenting, laser ablation). During the past 4 decades, sophisticated surgical techniques of laryngotracheal resection have been developed and have become the prerequisite to perform extended resections with minimal morbidity and mortality. Optimal survival can be achieved by radical resection of the primary tumor at the first operation.' Hence, a thorough preoperative ascertainment of tumor spread and a speedy referral of patients to specialized centers for primary surgery are the mainstay of therapy for thyroid cancer invading the aerodigestive tract.
Preoperative Assessment of Local and Distant Disease As invasion of the aerodigestive tract by thyroid cancer remains asymptomatic for a long time, the diagnosis of visceral infiltration is often not made preoperatively.
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 319
A heightened index of suspicion is warranted in patients who have either sonographic evidence of airway invasion or clinical symptoms of extrathyroid tumor growth such as hoarseness, hemoptysis, and dysphagia. These patients should undergo a thorough work-Up, including fine-needle aspiration cytology, computed tomography, and/or magnetic resonance imaging. In this setting, flexible laryngotracheobronchoscopy, pharyngoesophagoscopy, and endolurninal biopsy are helpful in verifying full-thickness invasion of the aerodigestive tract and mapping the longitudinal and circumferential extension of tumor involvement. In the absence of transmural involvement radiologically, endoscopy is unlikely to yield additional information. Indirect laryngoscopy and direct laryngoscopy provide information on preoperative vocal cord function (Fig. 34-1). Every patient with locally advanced thyroid cancer should be evaluated for his or her cardiovascular and pulmonary performance and also undergo intensive imaging to identify or exclude distant metastases (Fig. 34-2). Lung and bone are the most common sites of distant metastases in thyroid carcinoma.P Remarkably, only half of patients with pulmonary metastases die because of respiratory insufficiency.' Bone metastases account for 30% to 40%7.14,15 and brain metastases for 3% to 20%7,16-18 of cancer-specific fatalities.
FIGURE 34-1. Radiologic and endoscopic diagnosis of intramural and intraluminal invasion of upper airway in advanced thyroid cancer. A and B. A 62-year-old woman with follicular thyroid carcinoma, insular type, invading the left wall of the cricoid and trachea (MRI). C and D, A 35-year-old woman with recurrent follicular thyroid cancer with intraluminal invasion of the right lateral part and pars membranacea of the upper trachea (MRI). E and F, A 61-year-old woman with recurrent papillary thyroid cancer invading the posterior part of the larynx and upper trachea, endoscopy (E) and MRI (F).
320 - - Thyroid Gland Resectability:
Clinical check Cervical US
assessment of tumor type and local extension
FNAC
Tracheal, esophageal wall invasion
Operability: assessment of physical condition and systemic tumor extension
Complete medical evaluation of physical condition
FIGURE 34-2. Preoperative evalu-
ation of resectability and operability in thyroid cancer patients with aerodigestive invasion (ADI). CT = computed tomography; FNAC = fine-needle aspiration cytology; MRI = magnetic resonance imaging; PET = positron emission tomography; US = ultrasonography.
Imaging of lung, liver, bone, brain (CT/MRI,
PET)
MUltiple progressive lung and/or other distant, mets Walt and see
or palliation
Evidence suggests that fluorodeoxyglucose (FOG) positron emission tomography (PET) may be suitable to detect metastatic deposits from differentiated thyroid cancer in patients who have elevated thyroglobulin levels but negative radioiodine scans. The detection rate of FOG-PET in this setting was 70% to 80%. False-negative results were obtained in patients who displayed low serum thyroglobulin levels and/or minimal cervical lymph node enlargement. 19.20 On multivariate analysis, patients with a metastatic FDGPET volume of more than 125 mL had a significantly reduced survival." FDG-PET may also be useful to detect metastatic deposits from medullary thyroid carcinoma"
Selection of Patients For patients with locally advanced thyroid cancer, especially when it invades the aerodigestive tract, the key to success is the selection of the best operation for the individual patient. This allocation of the best operation must incorporate aspects as diverse as technical resectability of the tumor, progression of disease, and the patient's physical condition and social background.
Local Resectability Modem imaging techniques are highly accurate in determining the extent of local disease, not only in respect to soft tissue and vascular invasion but also in terms of laryngeal, tracheal, or esophageal invasion.23•24 Therefore, not only must palliative versus curative interventions be balanced against each other but also various types of resection (see Fig. 34-2). In contrast to primary squamous carcinoma, which requires wide excisions, resectability of invasive thyroid carcinoma can often be achieved, leaving only small margins of normal tissue. When resection margins are involved histologically, the microscopic tumor deposits can sometimes be ablated subsequently with radioiodine therapy provided the residual tumor takes up iodine. Irresectability from a technical point of view is ill defined but mostly present in patients with mediastinal involvement of the great vessels, including the innominate artery, trachea, and esophagus. With widespread neck involvement, extensive surgical procedures on the visceral axis are of limited value, especially when tumor widely invades the carotid sheath. In general, multiple distant metastases, undifferentiated carcinoma, or non-Hodgkin's lymphoma precludes extensive
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 321
surgery on the aerodigestive tract. There are only a few reports of successful resections on the aerodigestive tract for undifferentiated thyroid carcinomas, associated with a long-term palliation of 3 to 7 years. 12.25
Progression of the Disease In patients with recurrent disease and poorly differentiated carcinoma, progression of the disease should be considered. This may be difficult because reliable biomarkers for tumor progression are nonexisting. The role of distant metastases is hard to evaluate. Patients with metastases confined to the lung have an improved survival rate compared with those with multiple-organ involvement, bone metastases only, or other single-organ involvement.Fv" Only half of the patients in the first group succumb to their pulmonary metastases." Accordingly, most authors do not recommend excluding surgery on the aerodigestive tract when the metastatic disease is stable or only slowly progressing and confined to the lung. 9,IO,28-31 Except for clinical risk factors such as disease progression or local or distant tumor spread, there is only limited knowledge about biologic or molecular markers indicative of a dire prognosis in thyroid cancer. Poorly differentiated tumors.F an aneuploid DNA pattern," and nuclear atypia!' have been encountered more frequently in patients with than without tracheal invasion. The prognostic suitability of these and others parameters such as p53,32 CD97,33 or E-cadherin34-36 remains to be elucidated. Owing to the lack of suitable prognostic biomarkers, clinical decision making continues to be based on the presence or absence of clinical risk factors.
Physical and Mental Condition of the Patient Aerodigestive tract invasion is often associated with two major pro~lems: poorly differentiated thyroid cancers and elderly patients. Although papillary thyroid carcinoma prevails in all published series on aerodigestive invasion (Table 34-2), ~oorly differentiated thyroid carcinomas may be more susceptible to laryngotracheal invasion than their well-differentiated counterparts. 8,II,12,37,38 In addition, patients with aerodigestive invasion are on average 5 to 10 years older than those without aerodigestive invasion. 9,10-12 These increments in patients' age require a careful evaluation of the patient's cardiovascular and pulmonary performance and physical condition, all of which tend to deteriorate with increasing age (see Fig. 34-2). . In inoperable cases, a "wait and see" policy may be supenor to tracheostomy when the obstruction of the airway is tolerable. In patients with progressive airway obstruction and local irresectability, construction of a tracheostomy should be avoided because of the associated decline in the patient's quality of life. Instead, intraluminal stenting and tumor ablation (e.g., by laser surgery) should be attempted before resorting to permanent tracheostomy.
Surgical Approach The first surgical attempts at trachea resections were reported at the end of the 19th century by Gluck and Zeller (1881 )39 and Colley (1895).40 These authors used dogs for their experiments on segmental resections of the neck trachea.
322 - - Thyroid Gland Reconstruction was performed using either circular anastomoses in a three-stage operation'? or a bayonet-shaped anastomosis in a one-stage operation." V. Eiselsberg, in 1896, was the first to publish a circular tracheal resection with primary anastomosis that was successful; the patient was a 46-year-old man. Before that period, tracheal stenoses were treated only with tracheal dilatation, longitudinal tracheal splitting, and/or placement of tracheal tubes." The milestones on the road toward a systematic approach to tracheal resections were the development of intubation anesthesia in the 1940s and 1950s42-44 and the technique of tracheal release described in 1946.45
Preparation of the Patient The patient is prepared for a cervical or cervicomediastinal procedure. When a cervical evisceration is envisaged, the preparation also involves the upper abdomen for a median abdominal incision to harvest the intestinal graft. Intubation is achieved either orally or through a preexisting tracheostomy. In the latter instance, the indwelling tracheal cannula is exchanged for an oral endotracheal tube when there is no proximal obstruction. For most extended cervical operations, a low U-shaped collar incision is preferred, which can be extended down to the xiphoid for complete median sternotomy and mediastinal dissection. The cervical cutaneous flap is developed upward to reach the cranial larynx.
Cervical Exploration The aim of cervical exploration is to determine resectability and, when the tumor is resectable, to mobilize the tumor in a centripetal direction, a procedure referred to as "encircling the enemy." This technique affords an en bloc resection of the whole surgical specimen, thus avoiding piecemeal resection of the tumor. Usually, the dissection starts at the anterior and medial aspect of the jugular vein and carotid artery on the side with the most tumor. Precluding extensive visceral resections, invasion of the carotid artery is a rare phenomenon (Table 34-3), often indicative of poorly differentiated cancer. Combining carotid artery resection with
cervicovisceral resection carries a high risk of lethal complications, notably carotid rupture, and thus should be avoided. Concomitant lateral lymph node metastases should be dissected appropriately. Prophylactic dissections are not recommended in order to preserve the soft tissues.
Surgical Technique of Radical Resection of Aerodigestive Invasion Tracheoesophageal invasion is often the result of direct invasion from the primary tumor but rarely arises from lymph node metastases.v'" According to pathoanatomic studies of Shin and coworkers" and Salassa and colleagues, this mode of visceral invasion may be due to (1) the proximity of the posterior thyroid capsule and the pretracheal fascia, (2) the paucity of lymphatics and lymphatic invasion by thyroid cancers of the posterior thyroid fascia, and (3) the presence of potential lines of weakness in the tracheal wall where the vessels penetrate perpendicular to the lumen (Fig. 34-3), opening avenues for tumor invasion. Considering these preformed pathways of tumor invasion, Shin and coworkers devised an anatomic staging system according to the depths of tracheal invasion. This system may be relevant not only for surgical decisions on the extent of resection but also for estimating the prognosis for the individual patient (Fig. 34-4). In their series, the prognosis for patients with stages 1 to 3 (invasion of tracheal wall without infiltration of the entire thickness of the mucosa) was significantly better than that for patients with stage 4 disease (invasion of tracheal wall with complete mucosal invasion)." The human arterial blood supply of the tracheoesophageal axis is organized in a segmental fashion and substantially differs from that in mammals, especially dogs. It has been extensively studied by Miura and Grillo (1966) and Salassa and coworkers (1977). From their studies, it can be concluded that the vascular pedicles of the lateral trachea, which are essential for the nutrition of the tracheal cartilages, arise from branches of the inferior thyroid, supreme intercostal, subclavian, internal mammary, innominate, and bronchial arteries (see Fig. 34-3). These vessels interconnect along the lateral tracheal wall, forming a longitudinal anastomosis that
34-3. Macro- and microarchitecture of arterial blood supply of the tracheoesophageal tract. A. Left anterior view. B, Right anterior view. C, Microscopic blood supply. (From Salassa JR, Pearson BW, Payne WS. Gross and microscopical blood supply of the trachea. Ann Thorac Surg 1977;24:100.) FIGURE
324 - - Thyroid Gland
FIGURE 34-4. Staging system for thyroid carcinoma invading the trachea. (From Shin DH, Mark EJ, Suen He, Grillo He. Pathologic
staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic mannerof extension to the trachea: A clinicopathologic study basedon 22 patients who underwent thyroidectomy and airway resection. Hum Pathol 1993;24:866.)
gives rise to the transverse intercartilaginous arteries of each tracheal segment. The submucosal capillary plexus that is fed by the transverse intercartilaginous arteries supplies the posterior tracheal wall. Therefore, preservation of the lateral vascular pedicles is of utmost importance when performing tracheoesophageal resection. Unlike anterior dissection, vascular division close to the lateral wall is not recommended. Only the vessels that supply the segment to be resected may be ligated in order to maintain a sufficient blood supply. It should also be noted that the removal of the thyroid gland, although indicated in most patients with advanced thyroid cancer, may be detrimental in some instances, because the inferior thyroid artery largely contributes to the tracheal blood supply. The esophagus can safely be separated from the posterior tracheal wall without compromising arterial blood supply when the lateral pedicle is preserved. Technically, the extent and type of laryngotracheal resection depend on (I) localization of the invading cancer (larynx, cricoid, or cervical trachea), (2) tumor extension in longitudinal and horizontal directions, and (3) tumor extension through
the tracheal wall (Shin grades I to 3 versus grade 4). Considering the rates of involved structures in advanced thyroid cancer without and, in particular, with aerodigestive invasion, unilateral tracheal invasion with ipsilateral involvement of the recurrent laryngeal nerve is by far the most prevalent form of aerodigestive tract invasion from thyroid cancer (see Table 34-3). Laryngeal and/or esophageal invasion is less frequent. In contrast, invasion of the strap muscles and the internal jugular vein in isolation is rather common. Depending on the respective combination of the aforementioned resection criteria, six principal types ofstage- and localization-oriented laryngotracheal tumor resections with or without reconstruction can be distinguished (Fig. 34-5, Table 34-4): Type 1: Unilateral circumscribed tumor invasion at the laryngotracheal angle, often associated with involvement of the ipsilateral recurrent laryngeal nerve. Tumor invasion should not exceed more than 2 em in the longitudinal direction and no more than one third of the laryngotracheal circumference. This type of resection
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - -
325
FIGURE 34-5. Types of laryngotracheal resection and reconstruction in invasive thyroid cancer.
("window" resection) can be reconstructed with a sternocleidomastoid flap covering the laryngotracheal wall defect. A suprahyoidallaryngeal release is not necessary. Type 2: Extent of tumor invasion is comparable to that in type 1 but localizedinferiorto the laryngocricoidregion.
Reconstruction is similar to that in type 1 except for the higher division of the sternocleidomastoid muscle. In both types of reconstruction, a circular, airtight, rnusculotracheal anastomosis is fashioned, suturing the external muscular fascia onto the anastomosis. To this
326 - - Thyroid Gland end, a monofilic absorbable thread (3-0) and fullthickness running sutures are used. Type 3: Unilateral tumor invasion involving more than 2 em in length and/or more than one third of the laryngotracheal circumference is best treated with a circular laryngotracheal (type 3) or tracheal resection (type 4). Because preservation of at least one recurrent laryngeal nerve is of paramount importance, type 3 requires an oblique, sometimes S-shaped transection of the trachea above and below the tumor, allowing congruent approximation of the resection margins.29.30.38.52.53 The tracheal anastomosis is usually constructed with a monofilic absorbable thread (3-0) and full-thickness interrupted sutures. Because of the proximity of resection anastomosis to the contralateral vocal cord, a transient protective (mini)tracheotomy with sufficient distance to the anastomosis'" is fashioned (Fig. 34-6). Type 4: Tumor invasion of the cervical trachea that extends more than 2 em in length and more than one third of the tracheal circumference to one or both sides of the trachea is best dealt with by circumferential trachea resection and primary tracheal reconstruction. Types 3 and 4 require to some extent careful tracheal mobilization and, in most cases, a suprahyoidal release of the larynx. 55.56 We and others suggest avoiding extensive mediastinal mobilization to facilitate construction of the cervical anastomosis so as not to disrupt the vascular blood supply of the trachea.57 By a combination of anteflexion and mobilization of
both trachea and larynx, about 7 cm of resectional length can be gained. 58,59 In type 4, routine tracheostomy is frequently unnecessary provided that at least one recurrent laryngeal nerve is intact. To verify recurrent laryngeal nerve integrity, we routinely monitor the recurrent laryngeal and vagal nerves intraoperatively using an electromyographic neuromonitoring device. In both types of circumferential tracheal resection, we routinely protect the tracheal anastomosis with a sternocleidomastoid muscle flap. Covering the tracheal suture lines with a protective muscle flap is crucially important in combined tracheoesophageal resections, where the esophageal anastomosis directly adjoins the tracheotracheal anastomosis, to decrease the risk of esophagotracheal fistula formation. Type 5: In types 5 and 6, the airway cannot be reconstructed because of extensive bilateral tumor invasion of the laryngocricoid area. When the pharyngoesophageal segment is not involved, laryngectomy without cervical esophagectomy is adequate. A terminal suprajugular tracheostomy is constructed. Type 6: In bilateral laryngocricoid and transmural pharyngoesophageal tumor invasion, total laryngotracheoesophagectomy and construction of a terminal tracheostomy are inevitable. When only the cervical digestive tract is involved, a free jejunal flap seems to be the reconstruction of choice. 6o- 64 In this instance, we prefer to connect the mesenteric artery of the graft to the ipsilateral external carotid artery and the mesenteric
FIGURE 34-6. Oblique sleeve resection of the trachea with primary anastomosis (type 3). This 50-year-old woman had recurrent papillary thyroid carcinoma (PTC) invading the left cricoid portion and the trachea. A, Preoperative magnetic resonance imaging scan. B, Tumor invasion of the left cricoid and upper trachea with infiltration of the left recurrent laryngeal nerve. C, View of the right portion of larynx and trachea that shows no tumor invasion; the right recurrent laryngeal nerve remained intact. D, Oblique sleeve resection of the left cricoid with resection of the cervical trachea. E, Primary anastomosis after laryngeal release. F, Resected specimen showing intraluminal tumor invasion.
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 327
vein of the graft to the internal jugular vein. It is of utmost importance to free only very short vascular segments from the mesenteric fat pad to protect the vascular anastomosis from incidental kinking and ultimately graft ischemia. The microvascular anastomoses are fashioned using running sutures and a monofile, nonabsorbable thread (8-0) (Fig. 34-7). Only in the event of jejunal graft failure or mediastinal extension of esophageal resection would we opt for a gastric graft65.66 or colon graft67,68 supplied by the left colonic artery for digestive reconstruction. The general placement of a soft drainage is not recommended. Although some of the numerous surgical details may be controversial and subject to discussion, the following principles are of major importance.
Encircling the Front of Invasion at the Aerodigestive Level and En Bloc Resection. En bloc resection is the
cornerstone of oncologic surgery, because it minimizes tumor spillage and thus diminishes the risk of local recurrence. In contrast to primary aerodigestive malignancies, thyroid cancer invades the aerodigestive tract from the outside. Hence, the first step of en bloc resection consists of encircling the extraluminal specimen and dissecting it off adjacent structures in a centripetal fashion. The aerodigestive tract should be transected only after the extraluminal portions of the tumor have been freed, thus ensuring that the whole tumor is resected as a single specimen, with extraluminal and intraluminal tumor extensions in continuity. To accomplish this goal, the front of tumor invasion is narrowed down to the point where the tumor penetrates the aerodigestive axis. This crucial step of preparation is achieved by using optical magnification, as for the entire operation.
Protection of the Ipsilateral Recurrent Laryngeal and Vagal Nerve. The ipsilateral recurrent laryngeal nerve
is involved in up to 50% of advanced thyroid carcinomas (see Table 34-3). Therefore, preserving nerve integrity on at least one side is highly important to maintain postoperative speech and respiration. Intraoperative neuromonitoring helps to identify and preserve the nerve,69,70 especially at its point of entry at the laryngotracheal angle. Most experts agree that perineural tumor infiltration in differentiated thyroid cancer does not warrant resection of the nerve, in particular when the nerve is still functioning.P'P Minimal residual disease at the nerve can be treated with postoperative radioiodine ablation without incurring higher rates of recurrence or poorer surviva1.9.10.72 Nonfunctioning nerves, however, should be resected, because nerve function will not recover postoperatively when the nerve is infiltrated. This situation is different from that in the nerve palsies encountered in benign goiter, which may recover when the nerve is released. When bilateral palsy of the recurrent laryngeal nerve cannot be avoided, we and others recommend medialization of one vocal cord, which can be performed during the same session or in the early postoperative period." Window Resection. Window resection, as opposed to circumferential (sleeve, circular) resection, denotes a fullthickness wedge resection leaving intact the continuity of the residual trachea. Although most experts in tracheal resection have incorporated window resections into their armamentarium (Table 34-5), this type of resection continues to spark controversial debates. The main disadvantages of this type of
resection may be insufficient tracheal stability and a higher risk of residual disease at the tracheal margins. Several techniques have been developed to prevent instability of the residual trachea: coverage of the resectional defect with fascia lata, either in isolation or supported by a muscle flap,74-76 a myoperiosteal flap from the sternocleidomastoid muscle," or autologous grafts from distant sites,?8-81 Window resection may be indicated for small, circumscribed, invading tumors, especially when located at the laryngotracheal angle, that do not exceed more than 2 em in length and one third of the tracheal circumference. More extensive tumor invasions should be treated with sleeve resection with circular reconstruction. Shaving Procedures. Shaving procedures summarize all resectional techniques on the aerodigestive tract that preserve wall continuity while risking leaving residual cancer. Shaving procedures are contraindicated in patients with intraluminal invasion when the intent is curative but may be adequate in terms of long-term survival in patients who have only superficial tracheal wall infiltration,4.9.10,25.37,71,73.82-86 The drawbacks of shaving procedures are the impossibility to assess reliably the extent of tracheal invasion and the risk of producing tracheal ischemia, a disastrous complication that can emerge when the trachea is too vigorously shaved, In an era of growing expertise in laryngotracheal resections, the need to shave should be limited to patients who either are unable to tolerate transmural resections or have extensive local or distant disease precluding extended resections from an oncologic point of view, Another subgroup who might benefit from shaving are patients who have only superficial but not intraluminal laryngeal invasion that otherwise would require laryngectomy. Intraoperative Frozen Section, Safety Margins. The purpose of obtaining frozen sections in thyroid cancers invading the aerodigestive tract is to better define the tumor type and to ensure that all surgical margins of the resectional specimen are free of tumor. Although it should be possible in most instances to discriminate at least between differentiated, medullary, and undifferentiated thyroid cancers, it may not always be feasible on frozen section to exclude reliably minimal invasive disease at the margins, which may become apparent only on conventional histopathology. In the study of Nishida and colleagues (1997), 11 of 40 patients who had negative margins on frozen section were eventually found to have positive margins on postoperative histopathology. At least some of those patients who have positive margins develop local recurrences. 31.87,88 Despite the lack of systematic studies, minimal margins of normal tissue seem to be adequate in differentiated and poorly differentiated thyroid cancers from an oncologic standpoint. This is in contrast to squamous cell and anaplastic carcinomas of the upper aerodigestive tract. Mediastinal Tracheal Resection. Mediastinal tracheal resection in thyroid cancer is rarely indicated. Tracheal invasion below the offspring of the innominate artery is often associated with involvement of the great mediastinal vessels, a constellation that frequently precludes radical resection on oncologic grounds. The rare exceptions where resection of the mediastinal trachea may be warranted include short-distance invasions related to local recurrence or lymph node metastases. In addition to a complete sternal split, resections on
328 - - Thyroid Gland
FIGURE 34-7. Cervical evisceration (type 6). This 69-year-old woman had recurrent follicular cancer. The patient came to operation with tracheostomy and feeding tube via gastrostomy. A, Cervical exploration with assessment of resectability. E, Resection of larynx, cervical trachea, and esophagus. C, Resected specimen showing tumor invasion of laryngotracheal (left) and pharyngoesophageal (right) areas.
D, First step of jejunal free graft transplantation: jejunoesophagostomy (end to end). E, Second step: hypopharyngojejunostomy (end to end). F, Third step: arterial anastomosis with mesenteric artery and external carotid artery (end to end). G, Fourth step: venous anastomosis with mesenteric vein and internal jugular vein (end to side). H, Gastrografin demonstration of intact digestive anastomoses at the seventh postoperative day.
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 329
the mediastinal trachea necessitate a complete release of the cervical and mediastinal trachea. This resection is fraught with an increased risk of anastomotic leakage when the cuff of the endotracheal tube is positioned over the tracheotracheal anastomosis. Pharyngoesophageal Invasion. Pharyngoesophageal invasion only is less frequent (see Tables 34-3 and 34-5) and usually does not require reconstructions as complex as invasions of the upper airway. Because of its position behind the trachea, transmural invasionof the esophagus mainly occurs in combination with extensive laryngotracheal or tracheal invasion. In most instances, however, extramucosal esophageal resection eradicates the tumor. The esophageal defect is closed by simple approximation and primary suture of the extramucous esophageal wall. When a transmural esophageal resection is necessary, the remaining distance between the margins after esophageal release determines whether simple approximation and primary suture are adequate or whether a jejunal free graft is required for reconstruction. Postoperative Care. Apart from the complexity of the procedures themselves, the association between old age and aerodigestive tract invasion demands the dedication of surgeons, surgical residents, nurses, and ancillary staff involved in postoperative care. Except for rare patients in whom prolonged intubation and mechanical ventilation are required for other reasons, patients with tracheal anastomoses should be extubated immediately after the operation. Because of the inevitable contamination with the flora of the upper aerodigestive tract, antibiotics should be routinely administered preoperativelyfor prophylaxis. In laryngocricoid resections, the moderate use of systemic steroids may reduce
laryngeal edema. When patients undergo prolonged intubation, both cuff pressure and cuff position relative to the tracheal anastomosis must be repeatedly checked to avoid local tracheal ischemia. After reconstructions using a free jejunal graft, the jejunal graft must be closely inspected for mucosal ischemia as an indicator of compromised graft perfusion, especially in the immediate postoperative period. Vascular complications are exceptional after the second postoperative day. Parenteral feeding can be resumed 6 days after the jejunal transfer when anastomotic leakage has been ruled out by a diatrizoate meglumine (Gastrografin) swallow. Complications. After such complex procedures, serious early and late complications may ensue. The management of these complications requires extensive experience and skills. In 317 cervicovisceral resections reported on during the last 3 decades, hospital mortality was approximately 4% (see Table 34-5). The impact of the learning curve on morbidity was demonstrated in a multi-institutional study from Japan." In this series, the complication rate of tracheoplasty that was performed for a variety of conditions (l 0% of which involved thyroid cancer) progressively declined since the 1960s. The complication rate increased significantly with the extent of tracheal resection and was excessive after resection of more than eight tracheal rings. Tracheal anastomosis with resorbable sutures tended to involve less complications than that with nonresorbable sutures. Surgical experience obviously mattered more than the type of suture used. Anastomotic dehiscence was the second most common complication (33% of complicated cases), associated with a 48% death rate.
330 - -
Thyroid Gland
Apart from the high lethality of anastomotic dehiscence, arterial rupture of the right common carotid artery or innominate artery, albeit rare, may emerge after tracheal resection, typically during the second half of the first postoperative week. First published by Korte" (1879) after simple tracheostomy, this disastrous complication can develop after tracheal resection, mediastinal tracheostomy, cervical reoperation, and after external irradiation with or without preceding cervical operation.P" Risk factors predisposing to arterial rupture include lymphatic fistula, hematoma, and wound infection.46-50 In some wound infections, Staphylococcus aureus was identified as the infectious agent. Arterial rupture is a highly dramatic and life-threatening event that necessitates immediate intervention to save the patient from instant exsanguination. Median sternotomy must be performed to obtain control of the proximal innominate and subclavian arteries. The arterial defect can be resected and then reconstructed, using, for instance, a saphenous vein autograft.v" Palliative Local Procedures. Palliative local procedures are reserved for end-stage disease in patients with thyroid cancer invading the aerodigestive tract when radical surgery is not feasible or is contraindicated. With the advent of interventional techniques, in particular intraluminal stenting and laser ablation,46-5o,96 extensive although not radical resections that leave gross tumor at the resection margin are rarely indicated. Moreover, these new techniques relegate permanent tracheostomy to a last-resort procedure reserved for desperate situations. Tracheostomy may not be a simple procedure in patients who have extensive involvement of the aerodigestive tract and, thus, patients are at an increased risk for major complications such as bleeding, infection, obstruction, or tracheoesophageal flstula.97,98 Therefore, tracheostomy should no longer be portrayed as the one and only palliative alternative to radical surgery. Additive Treatment (Radioiodine Therapy. External Irradiation). Radioiodine treatment and external irradiation are recommended as additive therapies for thyroid cancer patients who reveal bulky or minimal residual disease. However, the efficacy of both modalities in achieving local control of tumor is doubtful and unproved in this setting. Radioiodine treatment in differentiated thyroid cancer responsive to radioiodine may be an effective adjunct to shaving procedures when the residual tracheal invasion is minimal. Conversely, some suggest that radioiodine treatment is not effective for local tumor control after nonradical surgery.82 Some tumors also fail to recur after subtotal resection despite positive surgical margins and the failure to initiate postoperative radioiodine ablation,87.88 Likewise, external irradiation for aggressive thyroid cancers has not always improved survival. 99-102 Nevertheless, there are also proponents of external radiotherapy in differentiated thyroid carcinoma with extrathyroidal growth. 103-105 In most of these studies, the benefit was limited to local recurrence only, but survival was not improved,I06-108 Considering these data, radioiodine treatment seems to be useful in minimal residual disease after shaving procedures or tracheal resections and for patients with distant metastases that take up 131I. Whether external irradiation has a role in patients with major aerodigestive tract invasion is still to be elucidated. When gross residual tumor remains after partial resection,
external radiotherapy may be unable to prevent local recurrence." Therefore, external radiotherapy should be reserved for patients who have irresectable progressive local disease and patients who have positive tumor margins after extensive resection.
Long-Term Results after Surgery In aerodigestive tract invasion, the type of thyroid cancer, the presence of nonpulmonary distant metastases at initial resection, the extent of local tumor invasion, and the patient's age are the four universally recognized determinants of survival. 5,8,12,29,3o Unfortunately, all clinical studies comparing different surgical strategies, such as shaving procedures, radical, incomplete, and palliative resections,4.9,IO,12,25,7I,73,8287,109,110 are retrospective and uncontrolled. In addition, the populations studied are not comparable with regard to the biologic determinants of survival (Table 34-6). None of the studies excluded patients with intraluminal airway invasion, whose survival is much lower. 5I For cure, these patients would require complete resection of the involved part of the airway. Given the rarity of thyroid cancer in general and of aerodigestive tract invasion in particular (see Table 34-1), it is virtually impossible to set up a controlled prospective trail large enough to yield unbiased results for different types of treatment. Summarizing the data shown in Table 34-6, the following conclusions can be drawn: at present, there are only eight studies available that compare different surgical strategies for thyroid cancers invading the aerodigestive tract. All studies are retrospective and fail to specify known determinants of survival such as patients' age, extent of tumor invasion, type and differentiation of thyroid cancer, or presence or absence of distant metastases. Keeping these shortcomings in mind, shaving procedures, complete resections, or both clearly fared better than incomplete resections in all seven pertinent studies. 4,25,82,83,87,109,111 This finding was significant in three studies,83,I09,l11 Comparing shaving and complete resections, four of six studies found no difference in terms of surviva1.4,83,109,11O In only one of these six studies, survival was significantly better in the complete resection group than in the shaving group. III In conclusion, incomplete resections are associated with local recurrence and decreased survival. Nevertheless, some patients may enjoy a remarkably long life after palliative resection. With the exception of one study, complete resection and shaving procedures produced comparable results in terms of survival. Although incomplete or shaving resections are not indicated in patients with intraluminal invasion of thyroid cancer, shaving resections may be beneficial in case of superficial laryngotracheal invasion. In experienced hands, deep wall invasion of the aerodigestive tract may be treated by radical resection. In addition, owing to the lack of controlled and unbiased data, the decision about the extent of resection has to be based on individual factors such as patient's age, type of tumor, progressive distant disease, and physical and mental condition. Given the tremendous challenge posed by aerodigestive involvement, every effort must be undertaken to prevent this disastrous condition by detecting
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 331
and eliminating thyroid cancer before it invades the aerodigestive tract.
Summary Aerodigestive tract invasion by thyroid cancer affects approximately 6% of patients with thyroid cancer, representing one of the most demanding disease-related complications in endocrine surgical oncology. Two thirds of patients with advanced thyroid cancer suffer from invasion of the upper airway, whereas pharyngoesophageal involvement accounts for only approximately 20% to 25%. Because of the more aggressive biology of the tumors and older age of the patients, aerodigestive tract involvement signifies a "negatively" selected group of thyroid cancer patients. Aerodigestive invasion poses a real challenge to both surgeon and patient. Because the aerodigestive tract is located at the crossroads of various medical disciplines, a joint interdisciplinary effort is essential for the best outcome in these patients with advanced thyroid cancer. When combined, modem diagnostic
technologies can often differentiate among extramural, intramural, and intraluminal as well as local and distant tumor invasion. Preoperative work-up of the patient is directed at determining technical resectability and operability, both of which are prerequisites for surgery. The surgical approach to the upper aerodigestive tract is dependent on the extent of wall invasion and, for visceral resection, on the anatomy and adequacy of the arterial blood supply to the larynx, trachea, and esophagus. Accordingly, there are six types of upper airway resection: type 1, window resection at the laryngocricoid level; type 2, window resection of the trachea; type 3, oblique sleeve resection of the laryngocricoid; type 4, horizontal sleeve resection of the trachea; type 5, laryngectomy; and type 6, cervical evisceration. Resection with curative intent aims at removing the extraluminal, intramural, and intraluminal portions of the tumor in a single surgical specimen. As in other solid cancers, centripetal preparation and en bloc resection are the principles of oncologic surgery in thyroid cancer. Shaving procedures violate these basic rules of surgical oncology. Nonetheless, shaving procedures may be indicated in
332 - - Thyroid Gland elderly patients with partial-thickness invasion and/or progressive multiple distant metastases that are not amenable to resection.
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84. Fujimoto Y, Obara T, Ito Y, et al. Aggressive surgical approach for locally invasive papillary carcinoma of the thyroid in patients over forty-five years of age. Surgery 1986;100:1098. 85. Musholt TJ, Musholt PB, Behrend M, et aI. Invasive differentiated thyroid carcinoma: Tracheal resection and reconstruction procedures in the hands of the endocrine surgeon. Surgery 1999; 126: 1078. 86. Park CS, Suh KW, Min JS. Cartilage-shaving procedure for the control of tracheal cartilage invasion by thyroid carcinoma. Head Neck 1993;15:289. 87. Ishihara T, Kobayashi K, Kikuchi K, et al. Surgical treatment of advanced thyroid carcinoma invading the trachea. J Thorac Cardiovasc Surg 1991;102:717. 88. Ozaki 0, Sugino K, Mimura T, Ito K. Surgery for patients with thyroid carcinoma invading the trachea: Circumferential sleeve resection followed by end-to-end anastomosis. Surgery 1995; 117:268. 89. Dickmann PS, Nussbaum E, Finkelstein JZ. Arteriotracheal fistula in patients treated for lymphoma. Pediatric Pathol 1989;9:329. 90. Iannuzzi R, Metson R, Lofgren R. Carotid artery rupture after twice-aday radiation therapy. Arch Otolaryngol Head Neck Surg 1989;100:621. 91. Ishihara T, Yamazaki S, Kobayashi K, et al. Resection of the trachea infiltrated by thyroid carcinoma. Ann Surg 1982; 195:496. 92. Neville WE. Reconstruction of the trachea and stem bronchi with Neville prosthesis. Int Surg 1982;67:229. 93. Orringer MB. Anterior mediastinal tracheostomy with and without cervical exenteration. Ann Thorac Surg 1992;54:628. 94. Reiter D, Piccone BR, Littman P, Lisker S. Tracheoinnominate artery fistula as a complication of radiation therapy. Otolaryngol Head Neck Surg 1979;87:185. 95. Scheumann GFW, Maschek HJ, Dralle H. Arteriotracheal fistula as a fatal complication after tracheal resection and twice-a-day-irradiation for thyroid carcinoma. Acta Chir Aust 1993;4:278. 96. Grillo HC, Zannini P, Michelassi F. Complications of tracheal reconstruction. J Thorac Cardiovasc Surg 1986;91:322. 97. Djalilian M, Beahrs OH, Devine KD, et al. Intraluminal involvement of the larynx and trachea by thyroid cancer. Am J Surg 1974; 128:500. 98. Holting T, Meybier H, Buhr HJ. Probleme der Tracheotomie beim organiiberschreitenden anaplastischen Carcinom. Langenbecks Arch Chir 1989;374:72. 99. Benker G, Oblricht T, Reinwein D, et al. Survival rates in patients with differentiated thyroid carcinoma. Influence of postoperative external radiotherapy. Cancer 1990;65:1517. 100. Lerch H, Schober 0, Kuwert T, Saur HB. Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol 1997;15:2067. 101. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: A 10 year follow-up report of the impact of therapy in 576 patients. Am J Med 1981;70:511. 102. Staunton MD. Thyroid cancer: A multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 1994;20:613. 103. Tsang RW, Brierley JD, Simpson WJ, et al. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 1998;82:375. 104. Tubiana M, Schlumberger M, Rougier P, et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 1985;55:794. 105. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer-Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer 1996;77:172. 106. Mueller Gaertner HW, Brzac HT, Rehpenning W. Prognostic indices for tumor relapse and tumor mortality in follicular thyroid carcinoma. Cancer 1991;67:1903. 107. Phlips P, Hanzen C, Andry G, et aI. Postoperative irradiation for thyroid cancer. Eur J Surg OncoI1993;19:399. 108. Lipton RJ, McCaffrey T, van Heerden J. Surgical treatment of invasion of the upper aerodigestive tract by well-differentiated thyroid carcinoma. Am J Surg 1987;154:363. 109. Simpson WJ, Panzarella T, Carruthers JS, et al. Papillary and follicular thyroid cancer: Impact of treatment in 1578 patients. Int J Radiat Oncol BioI Phys 1988;14:479. 110. Segal K, Abraham A, Levy R, Schindel J. Carcinomas of the thyroid gland invading larynx and trachea. Clin OtolaryngoI1984;9:21. III. Friedmann M, Danielzadeh JA, Caldarelli DD. Treatment of patients with carcinoma of the thyroid invading the airway. Arch Otolaryngol Head Neck Surg 1994;120:1377.
Potentially New Therapies in Thyroid Cancer Jin-Woo Park, MD • Quan-Yang Duh, MD • Orlo H. Clark, MD
Differentiated thyroid cancer (DTC) of follicular cell origin is a fascinating tumor because of its varying aggressiveness. Fortunately, most patients with these cancers, despite regional metastasis, can be cured by surgical resection, radioiodine ablation, and thyroid-stimulating hormone (TSH) suppression therapy. Unfortunately, patients with poorly differentiated thyroid cancers or anaplastic thyroid cancers usually fail to respond to this combined therapy. These tumors usually grow rapidly, invade adjacent structures, and spread to other parts of the body. During the dedifferentiation process, they lose thyroid-specific gene expressions, including the ability to take up and organify radioiodine and to make thyroglobulin (TG). The methods used to treat patients with DTC are therefore usually not effective in these patients. These tumors also usually fail to respond to alternative treatment with external radiation or systemic cancer chemotherapy. Medullary thyroid carcinomas are also highly aggressive, and there is no alternative if patients do not respond to surgical treatment. We therefore need to develop novel treatments for these unfortunate patients. Advances in molecular and cellular biology make it possible to develop new therapeutic approaches to thyroid cancer. These approaches can be divided largely into two categories regarding treatment targets. Redifferentiation therapy targets thyroid-specific genes to restore thyroid-specific differentiated function and to make the tumors respond to conventional therapy. The other possible category of treatment targets several cancer-related genes or their products that do not depend on thyroid-specific genes but depend on altered characteristics of thyroid cancer cells during tumorigenesis (Fig. 35-1). Therapeutic approaches described in this chapter have established effects in vitro, but the majority of them are not ready for medical practice yet. Careful clinical trials and analyses should be performed.
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Restoration of Differentiated Thyroid Function Redifferentiating Agents DTCs of follicular cell origin (papillary and follicular cancers) are usually well differentiated and behave in a nonaggressive manner. However, some lose differentiated functions (dedifferentiation) and behave more aggressively. These cancers become refractory to thyroid-specific therapies that are based on differentiated thyroid function such as radioiodine therapy and thyrotropin (TSH)-suppressive therapy. Restoring differentiated functions in these tumors may not only slow tumor growth but also resensitize tumors to thyroid-specific therapy such as treatment with radioactive iodine. Redifferentiating therapies are tissue specific and generally less toxic than nonspecific chemotherapy. There are several redifferentiating agents for thyroid cancers: (1) retinoids, (2) aromatic fatty acids, (3) peroxisome proliferator-activated receptor y (PPARy) agonists, and (4) histone deacetylase inhibitors. RETINOIDS
Retinoids have been shown to modulate cell growth and differentiation by binding to their receptors' The mechanism of action of retinoids is not completely understood. There are two classes of receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). Each class has three subtypes, o, ~' and y.Although RAR and RXR function as either homodimers or heterodimers, RAR-RXR heterodimers and RXR-RXR homodimers are predominant. To activate transcriptional activity, RAR-RXR heterodimers bind to RA response element (RARE) and RXR homodimers bind to retinoid X response element (RXRE) (Fig. 35-2).2,3 RXRs also heterodimerize with the vitamin D receptor (VDR), thyroid hormone receptor (T3R), and PPAR.4
Potentially New Therapies in Thyroid Cancer - LOH 3p, 7q21.1-7q31.1, 10q, 17p, T(2;3)(q13;p25)
Functioning follicular adenoma
Follicular carcinoma
Follicular adenoma FIGURE 35-1. Proposed multistep tumorigenesis model for thyroid carcinoma. LOH = loss of heterozygosity; TSH-R =TSH receptor. (Modified from Learoyd DL, Messina M, Zedenius J, et al. Molecular genetics of thyroid tumors and surgical decision-making. World J Surg 2000;24:923.)
335
Poorly differentiated carcinoma
Thyrocyte
p53
Anaplastic carcinoma
RET/PTe, trk met, res, gsp Braf
There are several natural retinoids or ligands such as alltrans-retinoic acid (all-trans-RA), 13-cis-RA, and 9-cis-RA. All-trans-RA binds only with RAR, but 9-cis-RA binds with both RAR and RXR. 13-cis-RA converts to all-trans-RA in vivo. There are also synthetic ligands such as LGD1550 (RAR a1~/y agonist), tazarotene (RAR ~/y agonist), AM80 (RAR ex agonist), and LGDl069 (RXR agonist). The antiproliferative and redifferentiating effects of retinoids have been demonstrated in many human cancers, including thyroid cancer.5 ,6 RA induces cell cycle arrest in
FIGURE 35-2. Basic mechanisms of action of retinoids and peroxisome proliferatoractivated receptor y (PPARy). The retinoid receptors are activated by specific ligands: retinoic acid receptor (RAR) by all-transretinoic acid (all-trans-RA) or 9-cis-retinoic acid (9-cis-RA); retinoid X receptor (RXR) by 9-cis-RA. The PPARy is activated by specific ligands such as thiazolidinedione (TZD) derivatives or aromatic fatty acids. Activated receptors bind with each other and form homo- or heterodimers. These in turn bind to specific response elements to promote the transcription of target genes: retinoic acid response element (RARE), retinoid X response element (RXRE), and PPAR response element (PPRE). The transcription of these genes then induces growth inhibition and redifferentiation.
the Gon phase with a reduced level of cyclin D1 and cyclindependent kinase 2 (CDK-2) messenger RNA (mRNA) and protein, which leads to reduced phosphorylation of the retinoblastoma protein." RA treatment increased mRNA for the sodium-iodide symporter (NIS) and radioactive iodine uptake in vitro in human thyroid cancer cells."!" In clinical trials, about 40% of patients treated with RA have had increased radioiodine uptake. 11 Although these effects are generally reversible and usually do not result in a dramatic clinical response, some patients
336 - - Thyroid Gland are helped by this treatment and combined treatment with other drugs may improve the effect of this therapy. AROMATIC FATTY ACIDS: PHENYLACETATE, PHENYLBUTYRATE
There is increasing evidence that aromatic fatty acids such as phenylacetate and phenylbutyrate induce tumor growth inhibition and redifferentiation in vitro, in vivo, and also in some clinical trials. 12-15 Aromatic fatty acids act through multiple mechanisms. They can block the tumor cell access to free glutamine and also block the isoprenylation of ras family proteins. 16 Histone deacetylase inhibition and PPARy activation are other suggested mechanisms of action. 17-19 Phenylacetate is a metabolite of phenylalanine. It accumulates in phenylketonuria and is associated with brain damage. It has been used to treat children who have urea cycle disorders. Phenylbutyrate metabolizes to phenylacetate in humans. Phenylacetate often induces differentiation and apoptosis in human cancer cell lines at concentrations that have been safely used in humans. Phenylbutyrate seems to be more potent in inducing apoptosis than phenylacetate." It is also reported that aromatic fatty acids can modulate sensitivity to chemotherapy when combined with chemotherapeutic drugS.21-23 Kebebewand colleagues reported that phenylacetate induced cytostasis in the GOII cell phase and induced radioiodine uptake in thyroid carcinoma cell lines.24 They also reported that phenylacetate decreased the TSH growth response, TG secretion, and the secretion of vascular endothelial growth factor (VEGF) in the thyroid cancer cell lines. Differentiating agents can be synergistic or additive in combination with other differentiating agents acting by other mechanisms. A combination of RA and phenyl acetate had synergistic antiproliferative effects in follicular thyroid cancer cell lines," Phenylbutyrate also seems to induce more apoptosis than phenylacetate at the same concentration in thyroid cancer cell lines. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR YAGONIST
PPAR belongs to the nuclear hormone receptor superfamily implicated in inhibition of cell proliferation and induction of cell redifferentiation-" PPAR has three isoforms, ex, 8, and y. They are ligand-dependent transcription factors that must form heterodimers with the RXR receptor in order to bind to their response elements (PPREs) and activate transcription (see Fig. 35-2).27 Among numerous PPARy agonists, thiazolidinedione (TZD) derivative antidiabetic drugs such as troglitazone, pioglitazone, and rosiglitazone are newly discovered potent PPARy agonists.P-" Investigations have shown that TZD derivatives are not only insulin sensitizers but also inhibit proliferation of human breast, prostate, bladder. colon, lung, and gastric cancer cells in vitro. in vivo, or both. 30-35 In thyroid carcinogenesis, PPARyappears to play an important role, especially in follicular thyroid cancer. A chromosomal translocation creating a fusion protein of PAX8-PPARyl was found in five of eight follicular thyroid carcinomas but not in follicular thyroid adenomas or papillary thyroid carcinomas, and this abnormal fusion protein is a dominant negative suppressor of wild-type PPARyactivity.36
Ohta and colleagues reported antiproliferative effects in vitro and growth inhibition in vivo of troglitazone in papillary thyroid cancer cell lines.37 In our investigations, human thyroid cancer cell lines express PPARy variably, and chromosomal translocations involving PPARy are uncommon. Troglitazone induced antiproliferation in papillary, follicular, Hilrthle cell, and anaplastic thyroid cancer cell lines. Its action can be explained in part by cell cycle arrest in the GOII phase and apoptotic cell death. We also demonstrated downregulation of CD97, a thyroid dedifferentiation marker, in thyroid cancer cell lines treated with troglitazone." Treatment with PPARy agonists might be a useful new medical therapy for patients who have poorly differentiated thyroid cancers by inducing growth inhibition and redifferentiation. HISTONE DEACETYLASE INHIBITOR
Histone acetylation and deacetylation can modulate chromatin structure and regulate gene expression related to DNA replication, transcription, differentiation, and apoptosis." Reversible acetylation of s-amino groups of lysine residues in the aminoterminus of histone is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Fig. 35-3). HATs lead to the relaxation of chromatin structure and transcriptional activation, whereas HDACs lead to chromatin condensation and transcriptional repression of target genes.'? There is increasing evidence that a disorder in equilibrium of histone acetylation can be associated with tumor development." HDAC inhibitors such as depsipeptide (FR901228), trichostatin A, and suberoylanilide hydroxarnic acid (SAHA) are promising new anticancer agents. HDAC inhibitors induce hyperacetylation of chromatin and activate genes that are related to differentiation and apoptosis in cancer cells. 42,43 Depsipeptide (FR901228) is currently in phase I clinical studies and the results of treatments are promising.r' In thyroid cancer cells, HDAC inhibitors inhibit cell proliferation by inducing apoptosis through activation of the caspase cascade and cell cycle arrest at G[ and G 2/M by a reduction in cdk2- and cdkl-associated kinase activities." In addition to the antiproliferative effects, HDAC inhibitors can modulate expression of several genes. Thyroid-specific genes can be transcriptional targets controlled by the acetylation status of histones. In particular, Kitazono and coauthors reported that depsipeptide markedly increased the mRNA level of NIS and resultant radioiodine uptake in low concentrations." Zarnegar and colleagues demonstrated NIS expression in different thyroid diseases. They also demonstrated that trichostatin A dramatically increases NIS expression and resultant radioiodine uptake in low concentrations. Trichostatin A inhibits cell proliferation by inducing apoptosis and cell cycle arrest at the G 2/M phase in a dose-dependent manner," Methylation is another mechanism of transcriptional repression of certain genes. Combinations of inhibitors for these processes might be synergistic because these two epigenetic processes are closely linked."
Gene Therapy Cancer gene therapy is the transfer of nucleic acids that can replace defective genes or introduce suicide genes or immune modulator genes. During the past several years, there have
Potentially New Therapies in Thyroid Cancer - -
337
FIGURE 35-3. Reversible acetylation of histones by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Acetylation status can affect transcriptional activity of the specific gene by transcriptional factor (TF).
been remarkable technical advances in terms of transfection efficiency and tissue specificity, Gene therapy for cancer has moved from success in laboratory practice to clinical trials. Several genes have been considered as candidates for gene therapy in thyroid cancer, Differentiation-related genes such as p53, 1TF-l, PAX-S, and NIS were introduced to retard cancer cell growth or induce redifferentiation. Thyroidspecific promoter and HDAC inhibitors have been used to increase transcriptional activity and tissue specificity in thyroid cancer cell lines.49,50 Currently, many investigators are trying to improve the efficiency of tissue-specific, multigene, transfection therapy.
differentiation-related genes or other effective genes might be needed, In addition to the role of wild-type p53 in dedifferentiation of thyroid cancers, thyroid-specific transcriptional factors, such as TTF-l, TTF-2, and PAX-8, are closely related to thyroid-specific differentiated functions such as radioiodine uptake. 58-6o It was reported that overexpression of TTF-l and PAX-8 restored TG gene promoter activity in thyroid cancer cell Iines."' Further investigations are necessary to determine whether cotransfection of wild-type p53 and thyroid-specific genes is more effective in inducing redifferentiation.
P53, TTF-l, PAX-B
After surgical resection of the thyroid gland and tumor in patients with DTC of follicular cell origin, regional or distant metastases are often effectively treated with radioiodine, Iodide uptake by thyrocytes is mediated by NIS. Most differentiated thyroid carcinomas express NIS, and NIS expression correlates with clinical radioiodine uptake.f However, some differentiated and most undifferentiated thyroid carcinomas fail to express NIS, These tumors lack the ability to take up iodide and are thereby refractory to radioiodine therapy.63.64 Many investigators have tried to restore NIS expression in thyroid cancer cells. 10,24,58 There are two remarkable advances in this field: HDAC inhibitors and gene therapy using the NIS gene. Cloning and characterization of the NIS gene made it possible to try gene therapy using this gene in both thyroid and nonthyroid malignancies. Several clinical trials using NIS gene transfection for triggering significant iodide uptake in nonthyroid tumors are under way.65-67 In thyroid cancer, transduction of human NIS (hNIS) in a follicular thyroid cancer cell line (FfC-133) induced high uptake of radioiodine in vitro and also in vivo in a xenograft model/" Although the transduction of the hNIS gene can induce radioiodine influx, it is followed by rapid efflux.
Most DTCs do not have p53 gene mutations, whereas some poorly differentiated thyroid cancers, most anaplastic thyroid cancers, and established thyroid cancer cell lines have p53 mutations.?' Several investigations suggest that undifferentiated thyroid carcinomas originate from differentiated ones, It therefore appears that p53 mutations occur as a late genetic event associated with dedifferentiation of thyroid tumor cells and immortalization of cell lines. Gene therapy with wild-type p53 in thyroid carcinoma cells in culture that had a p53 mutation showed that it (1) induced growth arrest (not apoptosisj.P (2) increased thyroid-specific gene expression" (3) enhanced the response to chemotherapy and radiation therapy,54,55 and (4) downregulated expression of thrombospondin (TSP) 1 (not VEGF),56,57 However, it seems unlikely that gene therapy with wild-type p53 gene alone will become an effective treatment in patients who have poorly differentiated thyroid cancer or anaplastic thyroid cancer. It induced growth arrest rather than apoptotic cell death in most studies and it rarely induced thyroid-specific gene expression, especially for radioiodine uptake. For it to be an effective treatment, cotransfection of
SODIUM-IODIDE SYMPORTER (NIS) GENE
338 - - Thyroid Gland Inhibition of iodide efflux has to be added for a therapeutic application of the hNIS gene. Iodide efflux could be inhibited by cotransfection of the thyroperoxidase gene (TPO), decreasing pendrin (PDS) gene activity, or combination with lithium treatment. 69,70 For transcriptionally targeted gene therapy, the TG promoter can be used. Thyroid-specific transcription factors such as TIF-l, TTF-2, or PAX-8 closely interact with the TG promoter. TG promoter activity, however, may not be enough in poorly differentiated and anaplastic thyroid cancer cells that also have defects in these transcriptional factors. Cotransfection of these genes may enhance TG promoter activity."
Treatments Independent of Differentiated Thyroid Function Cytotoxic Drugs GEMCITABINE
Gemcitabine is a new antimetabolite drug. Gemcitabine is a deoxycytidine analog and induces antiproliferative activity by phase-specific killing of cells undergoing DNA synthesis and blocking the cell cycle progression through the GI/S phase. Gemcitabine has dose-dependent synergistic activity with cisplatin. Data from two randomized clinical studies support the use of combined treatment with gemcitabine and cisplatin for treatment of patients with locally advanced or metastatic cancers including non-small cell lung cancer and prostatic cancer. n ,73 Combination of gemcitabine and other cytotoxic drugs such as vinorelbine, cyclophosphamide, or paclitaxel is also currently under clinical study. Antitumor activity of gemcitabine is also observed in thyroid cancer cells in vitro. Gemcitabine induced apoptosis, cell cycle arrest in the S phase, and upregulation of Fas in poorly differentiated or anaplastic thyroid cancer cell lines.r'-" A multimeric form of gemcitabine appears to be more potent for inhibition of tumor cell growth than the monomeric form in thyroid cancer cells in vitro." In a medullary thyroid cancer cell line, IT, gemcitabine also induced an antiproliferative effect and decreased neuroendocrine activity." Gemcitabine and cisplatin in combined treatment are also synergistic in thyroid cancer cell lines. Voigt and colleagues reported that combined treatment is schedule dependent and effective only when gemcitabine is followed by cisplatin, not vice versa, in anaplastic thyroid cancer cell lines." Although small numbers of patients with thyroid cancer were included in phase I clinical trials using gemcitabine, further clinical studies are required to confirm the safety and effectiveness of regimens including gemcitabine." GELDANAMYCIN
Geldanamycin is a specific inhibitor of heat shock protein 90 (Hsp90). Hsp90 is one of the most abundant chaperone proteins in the cytosol of eukaryotic cells. It helps newly synthesized proteins make stable conformations (maturation) or helps translocate them to their ultimate locations."? It plays an important role in stress such as heat shock, and it is associated with the mitogen-activated signal cascade.
It is also an essential component for fundamental cellular processes such as hormone signaling, cell cycle control, proliferation, and differentiation under physiologic conditions.P Although Hsp90 is essential for eukaryotic cells and its inhibition may cause significant toxicity, cancer cells appear to be more sensitive to inhibition of this chaperone's activity, Hsp90 expression can be upregulated by mitogen or growth factor stimulation, and it is higher in tumors than in normal tissues." Hsp90 may therefore playa critical role in tumor cell growth or survival, or both. Several oncoproteins, such as Raf-l, erbB family receptors, and mutant p53 proteins, are reported to be substrates for Hsp90, and they can change their conformation and be stabilized by Hsp90. 82-84 The National Cancer Institute screened drug sensitivity to geldanamycin in 60 tumor cell lines in vitro and reported that geldanamycin is a promising anticancer drug effective at nanomolar concentrations." Our investigations using human thyroid cancer cell lines demonstrated that geldanamycin inhibited cell proliferation, downregulated oncoproteins, and inhibited epidermal growth factor (EGF)-induced invasion. 86 Although geldanamycin is a novel anticancer drug based on differential dependence on Hsp90 between cancer cells and normal cells, significant side effects related to inhibition of diverse substrates for Hsp90 are inevitable and may limit its clinical usefulness, However, continued characterization of the ansamycin binding site on Hsp90 will make it possible to develop more substrate- or tissue-specific Hsp90 inhibitors. The results of a phase I clinical trial using the geldanamycin analog 17-allylamino-17-dernethoxygeldanamycin (l7-AAG) were reported by Memorial SloanKettering Cancer Center.s? They suggested that clinically achievable concentrations of 17-AAG exceed those that were effective in preclinical models. Structurally different Hsp90 binding drugs such as radicicol have also been introduced as a second class of Hsp90 inhibitors.
Gene Therapy Gene therapy in thyroid cancer can be designed to kill cancer cells independent of thyroid-specific function. Suicide gene therapy was designed to kill the thyroid cancer cells by chemosensitization. Immune modulatory genes such as interleukin 2 (IL-2) and IL-12 have been studied for immunotherapy. A thyroid-specific promoter such as TG promoter can make the gene therapy more tissue specific, and multigene transduction can make the gene therapy more effective. SUICIDE GENE
Suicide gene therapy is the transduction of chemosensitization genes that can transform a nontoxic form of a drug (prodrug) into a toxic substance. A classic example of this therapy is transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene with nucleoside analogs, such as acyclovir or ganciclovir. It is, however, difficult to transfect all of the target cells. A bystander effect is therefore an important aspect of suicide gene therapy.V With a bystander effect, this strategy has been evaluated for possible treatment of localized tumors. Suicide gene therapy is currently in clinical trials for several human cancers including melanoma, glioblastoma, and breast cancer.":"
Potentially New Therapies in Thyroid Cancer - - 339
HSV-tk and prodrug therapy has been reported to induce antitumor activity in thyroid cancer cell lines in vitro and in vivo/? A thyroid-specific promoter such as TG promoter with or without the Cre-IoxP system (site-specific recombination system) increased tissue specificity and decreased toxicity.93-95 INTERLEUKIN 2 AND INTERLEUKIN 12
IL-2 is associated with augmentation of antitumor T-cell and natural killer cell activity; IL-12 also plays an important role in the development of cellular immunity. Although systemic administration of recombinant interleukins has demonstrated antitumor activity, systemic toxicity with increasing dosage and longer exposure has been observed. 96.97 Appropriate local production of interleukins without systemic toxicity can be achieved by gene therapy. Gene therapy using IL-2 or IL-12 has been well studied in medullary thyroid cancer models. In rat and mouse medullary thyroid cancer models, transduction of IL-2 or IL-12 resulted in tumor regression and loss of tumorigenicity without significant toxicity.98-IOO Gene therapies in these models also induced regression of an established tumor at a distant site and longlasting tumor-specific immunity. Furthermore, combining suicide and immunoregulatory gene therapies (IL-2) enhanced tumor growth inhibition and immune reaction in a rat xenograft model.'?' Immunoregulatory genes can be added in multigene therapy in combination with a thyroid-specific promoter.
ErbB Family of Tyrosine Kinase Receptors The tyrosine kinase receptors of the ErbB family are important receptors involved in cellular proliferation, differentiation, and survival and are widely expressed in malignant tissue. Overexpression of EGF receptor (EGFR) has been associated with cell proliferation, invasion, angiogenesis, and both chemoresistance and radioresistance. It is therefore natural to target these receptors in cancer therapy. EGFR and ErbB2 are frequently expressed in papillary thyroid cancer and are reported to be associated with lymph node metastases and recurrence. 102-105 Haugen and colleagues suggested autocrine stimulation of EGFR by transforming growth factor a (TGF-a) in papillary thyroid cancers.l'" EGF and TGF-a enhanced invasion and growth of DTC cells in vitro and in vivo by binding to the EGF receptors. EGF- and TGF-a-mediated effects were blocked by a monoclonal antibody to EGF receptor (Mab528) or genistein, a tyrosine kinase inhibitor.l'" However, treatment with anti-EGFR antibody alone failed to induce growth inhibition. 108 Anti-EGFR antibody treatment may be effective for therapeutic use in combination with other chemotherapeutic agents or conjugation with radioiodine. Transduction of a normal human ErbB2 gene changed the growth property of rat thyrocytes. Thyroid cells transformed with ErbB2 can grow in the absence of thyrotropin and do not respond to the growth-inhibitory effect of TGF_~.109 Ligand binding of both thyroid hormone (T3) and RA receptors inhibited the transcriptional activity of EGF receptor and ErbB2 prornoter.!'? Several compounds targeting the ErbB family or its downstream cascade are in clinical studies and demonstrate promising results (Fig. 35-4). IMC-225 (cetuximab,
anti-EGFR) and trastuzumab (Herceptin, anti-HER2/neu) are monoclonal antibodies, and ZD1839 (Iressa) and OSI-774 (Tarceva) are selective EGFR-tyrosine kinase inhibitors.Ul-l'? To our knowledge, the therapeutic utility of these drugs in patients with thyroid cancer has not been evaluated.
Metalloproteinase Inhibitor Matrix metalloproteinases (MMPs) and the plasmin activation system are proteolytic enzymes that play a crucial role in extracellular matrix (ECM) degradation in many cancers. This degradation is very important in tumor growth, invasion, and metastasis. Angiogenesis requires MMPs that degrade ECM for endothelial cell invasion. On the other hand, MMPs also produce anti angiogenic protein fragments. I13 MMP activity depends on interaction between MMPs, membrane-type MMPs (MT-MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), and ECM metalloproteinase inducer (EMMPRIN). Stromal cells make most MMPs in cancers. Cancer cells induce synthesis of MMPs by stromal cells through EMMPRIN and cytokine stimulatory mechanisms. 114 Thyroid cancer cells overexpress MMP-l, MMP-2 (or increase the proMMP-2 activation ratio), MMP-9, and MTlMMP. Overexpression usually correlates with more aggressive behavior such as advanced stage, tumor invasion, and lymph node metastases.I'>!'? Cytokines, growth factors, and hormones can stimulate cancer cell invasion in vitro. This stimulation occurs in part through MMP activity. The modulation of MMPs appears to depend on the cell lines and stimulator.Us!'? Thyroid cancer cell invasion can be
FIGURE 35-4. Strategies for ErbB family inhibition. mAb = monoclonal antibody.
340 - - Thyroid Gland stimulated by IL-l, tumor necrosis factor a (TNF-a), EGF, and TSH.I17,120.121.122 MMP-9 was induced by IL-l, TNF-a, and phorbol esters but MMP-2 was not.'!? Growth factors generally upregulate expression of MMP-2 and MMP-9, but EGF stimulation appears to increase invasion in part through MMP-l in thyroid cancer cell lines.P' The effects of TSH on growth, migration, and invasion of thyroid cancer cells were biphasic, with an increase at low and a decrease at high concentrations.120 TSH induced invasion of thyroid cancer cells through the activation of urokinase-like plasminogen activator (uPA) and basement membrane type IV collagenase.P? but TSH inhibited EGF-induced MMP-l expression.'!' Interaction between thyroid cancer cells and tumor-derived fibroblasts also appears to be important in the balance of MMP activity.'!" Inhibition ofMMP activity has been studied as a new anticancer therapy. TlMPs are important in the homeostasis of ECM by regulating the activity of MMPs. However, there is increasing evidence that TlMPs are also involved in cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis through MMP-dependent or MMP-independent pathways. A treatment strategy using TlMPs is not appropriate because of their paradoxical role in tumorigenesis.F'P" Several orally active MMP inhibitors (MMPIs) have been developed: marimastat (BB-25l6), prinomastat (AG3340), BAY 12-9566, CGS-27023A, and Col-3 (6-deoxy-6-demethyl4-dedimethylamino tetracycline). These drugs have demonstrated anti-invasive, antimetastatic, and antiangiogenic effects in preclinical studies. 125- 127 Among doxycycline and modified tetracyclines, Col-3 (metastat) is the most potent MMPI. Col-3 induced cell cycle arrest at the GOIl phase, apoptosis, and necrosis in vitro. Col-3 also decreased MMP-2, TIMP-l, and TIMP-2 secretion in vitro and inhibit cancer invasion in vitro.P? In clinical studies, COL-3 demonstrated antitumor activity in several human cancers. The most common adverse event was dose-related photosensitivity.F'P? Yeh and coworkers demonstrated that Col-3 effectively inhibited thyroid cancer cell invasion in vitro at the clinically achievable concentration with no significant apoptotic cell death.!" Some clinical trials using orally active MMPIs, however, failed to achieve survival gain in phase III trials, although results of these studies are incomplete.P" MMP activity appears to be more important in early local invasion or micrometastasis than established metastasis.'!' It is therefore still possible that MMPI treatment may be helpful in early-stage cancer, after chemotherapy or radiation therapy, or both. Further studies are needed in thyroid cancers.
Vascular Endothelial Growth Factor Inhibitors VEGF is a potent stimulator of endothelial cell proliferation in vitro, promotes neoangiogenesis in vivo, and increases vascular permeability. VEGF is overexpressed in most human malignancies in which elevated VEGF expression is associated with a more aggressive cancer. High expression of VEGF was found in both chronic lymphocytic thyroiditis and DTCs but not in poorly differentiated cancers. 131.132 Although it is controversial, there is considerable evidence that VEGF overexpression in DTCs is associated with aggressive clinical features, such as a larger
tumor and local and distant metastases. 133-135 Endothelial cells lining tumor-embedded microvasculature express VEGF receptors. 136 Transduction of VEGF to a thyroid cancer cell line in vitro demonstrated that VEGF indirectly promotes the growth of thyroid tumors by stimulating angiogenesis. 137 TSH can promote growth of thyroid cancer cells in part by stimulating VEGF secretion, but short-term TSH stimulation with recombinant human TSH (rhTSH) did not increase serum VEGF levels significantly. 138.139 Redifferentiating agents such as phenylacetate inhibit VEGF secretion in human thyroid carcinoma cells." The neutralization of VEGF by anti- VEGF monoclonal antibody inhibited tumor growth and neovascularization markedly in the dermal matrix angiogenesis model in vivo.140 Manumycin (a famesyltransferase inhibitor) also decreased VEGF and inhibited endothelial cell proliferation. These effects were enhanced by a combination of manumycin and paclitaxel (a microtubule inhibitor) in an anaplastic thyroid carcinoma mouse xenograft model. 141 A VEGF inhibitor appears to be attractive treatment for thyroid cancers.
Conclusion There are many potentially new medical treatments that appear promising in vitro, in vivo, and in preclinical studies. Clinical trials and more basic scientific research are necessary, but there is optimism about their effectiveness. We hope that these new therapies and clinical trials will result in their use for patients who do not respond to conventional therapy and open the way to investigating novel treatment targets based on newly extended molecular and cytogenetic understanding of cancer.
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122. Packman KS, Demeure MJ, Doffek KM, et al. Increased plasminogen activator and type IV collagenase activity in invasive follicular thyroid carcinoma cells. Surgery 1995; 118:1011. 123. Jiang Y, Goldberg ID, Shi YEo Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 2002;21:2245. 124. Yoshizaki T, Sato H, Furukawa M. Recent advances in the regulation of matrix metalloproteinase 2 activation: From basic research to clinical implication [Review]. Oncol Rep 2002;9:607. 125. Bonomi P. Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer. Semin OncoI2002;29(1 SuppI4):78. 126. Tonn JC, Kerkau S, Hanke A, et al. Effect of synthetic matrixmetalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro. Int J Cancer 1999;80:764. 127. Lokeshwar BL, Selzer MG, Zhu BQ, et al. Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral nonantimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. Int J Cancer 2002;98:297. 128. Cianfrocca M, Cooley TP, Lee JY, et al. Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: A phase I AIDS malignancy consortium study. J Clin Oncol 2002;20:153. 129. Rudek MA, Figg WD, Dyer V, et al. Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J Clin OncoI2001;19:584. 130. Yeh MW, Rougier JP, Park JW, et al. Invasion by thyroid cancer cells is regulated by signaling through the EGF receptor and effected by activated gelatinases. Submitted to Cancer Res. 131. Soh EY, Duh QY, Sobhi SA, et al. Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J Clin Endocrinol Metab 1997;82:3741. 132. Klein M, Picard E, Vignaud JM, et al. Vascular endothelial growth factor gene and protein: Strong expression in thyroiditis and thyroid carcinoma. J EndocrinoI1999;161:41. 133. Fenton C, Patel A, Dinauer C, et al. The expression of vascular endothelial growth factor and the type I vascular endothelial growth factor receptor correlate with the size of papillary thyroid carcinoma in children and young adults. Thyroid 2000;10:349. 134. Lennard CM, Patel A, Wilson J, et al. Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 2001;129:552. 135. Klein M, Vignaud JM, Hennequin V, et al. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J Clin Endocrinol Metab 2001;86:656. 136. Viglietto G, Maglione D, Rambaldi M, et al. Vpregulation of vascular endothelial growth factor (VEGF) and downregulation of placenta growth factor (PIGF) associated with malignancy in human thyroid tumors and cell lines. Oncogene 1995;11:1569. 137. Belletti B, Ferraro P, Arra C, et al. Modulation of in vivo growth of thyroid tumor-derived cell lines by sense and antisense vascular endothelial growth factor gene. Oncogene 1999;18:4860. 138. Soh EY, Sobhi SA, Wong MG, et al. Thyroid-stimulating hormone promotes the secretion of vascular endothelial growth factor in thyroid cancer cell lines. Surgery 1996; 120:944. 139. Tuttle RM, Fleisher M, Francis GL, et al. Serum vascular endothelial growth factor levels are elevated in metastatic differentiated thyroid cancer but not increased by short-term TSH stimulation. J Clin Endocrinol Metab 2002;87:1737. 140. Soh EY, Eigelberger MS, Kim KJ, et al. Neutralizing vascular endothelial growth factor activity inhibits thyroid cancer growth in vivo. Surgery 2000;128:1059. 141. Xu G, Pan J, Martin C, Yeung Sc. Angiogenesis inhibition in the in vivo antineoplastic effect of manumycin and paclitaxel against anaplastic thyroid carcinoma. J Clin Endocrinol Metab 2001; 86:1769.
Comparative Genomic Hybridization in Thyroid Neoplasms Daishu Miura, MD • Nobuyuki Wada, MD • Laurent Brunaud, MD
Thyroid tumors of follicular cell origin serve as a good model for studying possible genetic events in tumor initiation, transformation, and progression. Fagin 1 and WynfordThornas-? proposed the multistep model of genetic alterations for thyroid tumors that arise from follicular cells (Fig. 36-1). They proposed a model with two main pathways: from follicular adenoma to follicular carcinoma and from low-risk papillary carcinoma to high-risk papillary carcinoma. Subsequently, these differentiated thyroid carcinomas may transform to anaplastic thyroid carcinoma. The latter change, from differentiated to anaplastic, is associated with p53 mutations.F' Comparative genomic hybridization (CGH) is a genome scanning technique that allows identification of changes in a relative copy number of DNA sequences (gains or losses), using DNA extracted from clinical tumor samples or cell lines (Fig. 36-2).6 The fluorescence in situ hybridization (FISH) reaction can also be used to detect gains and losses. FISH, however, is restricted to the analysis of metaphase nuclei only, whereas CGH is able to analyze interphase nuclei from cells that are not actively proliferating. In cancer cells, gains and losses of oncogenes and tumor suppressor genes can be mirrored by chromosomal abnormalities such as chromosomal deletions, monosomies, duplication, polysomies, and gene amplifications such as homogenously staining regions or double-minute chromosomes.'
Methods DNA Extraction High-molecular-weight whole genomic DNA (>4 kb) was obtained for reference DNA from healthy female and male donors and also for test DNA from samples. The normal reference DNA was prepared from peripheral lymphocytes, and the test DNA was from tissue samples. DNA was extracted after overnight proteinase K digestion followed by the phenol chloroform isoamyl method and alcohol precipitation. 344
The concentration of reference and test DNA were measured with a fluorometer.
Preparation of Metaphase Spreads The quality of the normal metaphase spreads, to which reference and test DNA were hybridized, strongly influence the reliability and sensitivity of CGH analyses. Metaphase spreads were prepared from synchronized cultures of peripheral blood cells from a healthy male donor (Fig. 36-3). T lymphocytes in RPMI 1640 medium were stimulated with phytohemagglutinin and cultured for 72 hours. The cells were then synchronized by treatment with 10-7 M methotrexate (MTX) for 15 hours to inhibit DNA replication, followed by 10-5 M thymidine for 5 hours to release the cells synchronously from the MTX-induced block. Colcemid (l ug/ml.) was added during the final 30 minutes of thymidine release. Lymphocytes were fixed in a 3:1 solution of methanol and acetic acid and dropped on precleaned microscope slides. The slides were air-dried using a Thermotron environmental chamber.
Comparative Genomic Hybridization CGH was performed according to the protocol described by Kallioniemi and associates," with slight modifications using fluorochromes conjugated to dUTP for standard nick translation (see Fig. 36-2).8 Test and reference DNA were labeled using the nick translation reaction with fluorescein-12 (FITC)-dUTP and Alexa Fluor 568-5-dUTP, respectively. The size of DNA fragments was adjusted from 500 to 1500 bp for hybridization, depending on the amount of DNA polymerases and incubation time. Approximately 200 ng each of FITC-labeled test and Alexa-568-labeled reference DNA samples were hybridized to the normal metaphase spreads. Twenty micrograms of unlabeled Cot-l DNA was used to block the binding of repeated DNA sequences. The DNA was denatured for 5 minutes at 73°C in hybridization solution (50% formamide, 10% dextran
Comparative Genomic Hybridization in Thyroid Neoplasms - - 345
FIGURE 36-1. Carcinogenesis in thyroid tumors.
sulfate, and 2X SSC, pH 7.0). Metaphase slides were also denatured in a denaturing solution (70% formarnide, 2X SSe. pH 7.0) for 3 to 5 minutes at 73°C and dehydrated with ethanol.Hybridizationwas performed in a chamber at 37°C for 2 or 3 days. Posthybridization slides were washed three times in washing solutions (50% formarnide, 2X sse, pH 7.0), once in 2X SSC at 45°C, once in 2X sse at room temperature, twice in a PN buffer (0.1 M NazHP04, 0.1 M NaHzP04, 0.1% NP-40, pH 8.0), and once in distilled water at room temperature. The slides were counterstained with 10 ul, of 0.4 I-1M 4',6-diarnidino-2-phenylindole (DAPI) in an antifade solution.
Digital Image Acquisition and Analysis The three-color images-blue (DAPI), green (FITC), and red (Alexa-568)-with appropriate light source and filters were acquired using several different image acquisition systems (Figs. 36-4 and 36-5). At least 10 images of metaphase
FIGURE 36-2. Technique of comparative genomic hybridization. Equal amounts of the fluorochrome-labeled test and reference DNA were hybridized to normal metaphase spreads with unlabeled Cot-l DNA to block the binding of repeated DNA sequences.
FIGURE 36-3. Schema of cell cycle.
spreads were used for each hybridization. These three-color images were analyzed to determine the ratio of green and red fluorescence intensity along each chromosome. Image analysis typically involved normalizing the intensity of green and red images, chromosome segmentation, background subtraction, medial axis calculation, integration of fluorescence intensity in bands perpendicular to the medial axis across each chromosome, and calculation of green-tored ratios along each medial axis. The green-to-red ratio indicated the relative DNA sequence copy number at each point in the test genome. At least six metaphase spreads were analyzed per hybridization and the results were averaged. The regions with a green-to-red ratio of more than 1.20 were interpreted as gains and those with a ratio less than 0.80 as losses. However, the results were dependent on the cutoff values. Cot-l DNA inhibited binding of the labeled DNA to the centromeric and heterochromatic regions, so that the centromeric areas of chromosome 1, 9, 16, and Y and the
346 - - Thyroid Gland Normal metamorphosis chromosomes
FIGURE 36-4. Schema in digital image acquisition and analysis.
p arm of acrocentric chromosomes (chromosomes 13-15, 21, and 22) could not be analyzed in this study. A positive control with known chromosomal abnormalities and a negative control using normal human male and female DNA were used in each hybridization as controls to verify the reliability of this method.
Papillary Thyroid Carcinoma DNA copy number changes are uncommon in papillary thyroid carcinomas as compared with other poorly differentiated and well-differentiated thyroid carcinomas. Papillary thyroid
carcinomas in CGH studies have variable rates of genetic aberrations and specific sites of aberrations. Nonetheless, several common aberrations have been identified, including gains on chromosomes lq, 5q, 6q 9q 13q, 19q, 2lq, 4 and 7, and losses on chromosomes lp, 9q, 16q, 17, 19, and 22.9- 11 Hemmer and associates 10 found genetic aberrations in only 3 (12%) of 26 papillary thyroid carcinomas and reported a positive correlation between the presence of aberrations and older age (>70 years) and cervical lymph node metastasis. Singh and colleagues!' identified genetic aberrations in 10 (48%) of 21 papillary thyroid carcinoma cases. They reported that the loss of chromosome 22 was found only in younger patients «45 years) and was associated
FIGURE 36-5. Comparative genomic hybridization image. The high intensity of green and red images demonstrates gains and losses on chromosomes, respectively.
Comparative Genomic Hybridization in Thyroid Neoplasms - - 347
with a higher rate of regional lymph node metastasis. In our study, no chromosomal aberration was found in 6 welldifferentiated papillary thyroid carcinomas, but 3 (43%) of 7 poorly differentiated papillary thyroid carcinomas had chromosomal aberration. The most common chromosomal site was a gain on lq in 2 (29%) of the 7 poorly differentiated papillary thyroid carcinomas (Table 36-1). This region of lq abnormalities harbors a gene that encodes one of the receptors for the nerve growth factor (NTRKl), which is activated in about 15% of papillary thyroid carcinomas.'? Clonal chromosomal aberrations have been identified in almost half of the cytogenetically examined papillary thyroid carcinomas by other methods than CGH. The most frequent alteration has been an intrachromosomal rearrangement, a paracentric inversion in lOq (RET/PTC). This site is frequently the only change, and it is not detectable by CGH.IO.13-21
Follicular Thyroid Tumor Thyroid tumors of follicular cell origin serve as a good model for studying possible genetic events regarding tumor origin, transformation, and progression. Multiple genetic events appear to be responsible for the progression from adenoma to carcinoma in some tumors (see Fig. 36-1).1.2.22.23 Follicular adenomas have close cytologic and morphologic similarity to follicular carcinomas; the defining difference is the presence of capsular invasion and/or vascular invasion in carcinomas. Because of this similarity, it has been proposed that follicular carcinomas originate from preexisting adenomas. Follicular adenomas could represent premalignant tumors that could transform into carcinomas, through copy number changes in critical genes controlling invasion, angiogenesis, and metastasis. Clinical evidence that follicular carcinomas are obviously larger than follicular adenomas supports this theory. Hemmer and coworkers>'found that copy number changes were more frequent in follicular carcinomas (9 [69%] of 13) than in histologically benign follicular adenomas (14 [48%] of 29) using CGH. However, the average number of copy number changes was less in follicular carcinoma (1.6 changes
per case, range 0 to 6) than in follicular adenoma (2.5 changes, range 0 to 12). On the other hand, Frisk and associates-" subsequently described that the frequency of aberrations was similar in follicular adenomas (8 adenomas, 1.9 changes/mean) and follicular carcinomas (13 carcinomas, 1.5 changes/mean), as well as in 8 minimally invasive follicular carcinomas (1.5 changes/mean) and 5 widely invasive follicular carcinomas (1.6 changes/mean). Hemmer and colleagues" reported that a loss of chromosome 22 or 22q was particularly common in carcinomas (6 [46%] of 13) whereas a loss of chromosome 22 was found in only 2 (7%) of 29 adenomas. Moreover, loss of the chromosome 22 was present in 7 (54%) of the 13 widely invasive follicular carcinomas but in none of the 7 minimally invasive carcinomas (P = 0.04).10 Loss of chromosome 22 was also common in older than in younger patients (P =0.01). A loss of lp was frequent in follicular carcinomas (20%), whereas gains in chromosomes 5, 7, 12, 14, and X were common in follicular adenomas but not found in follicular carcinomas.s' A DNA copy number loss was also common in l3q in follicular carcinomas (25%).10 The common regions for DNA copy number gain were in lq (25%) and in l7q (20%) for follicular carcinomas. Papillary carcinomas that also arise from follicular cells have fewer chromosomal aberrations, especially losses, than follicular carcinomas. 10 One candidate for the tumor suppressor gene in chromosome 22q is neurofibromatosis type 2 (NF2) located at 22q 12, and there may be another putative suppressor gene distal to NF2. The significance of these and other suppressor genes located in 22q in the genesis of follicular carcinoma is currently unknown. Although formation of fusion genes PAX8-PPARyl caused by a t(2;3)(q13;p25) has been observed in several cases of follicular carcinomas." unfortunately it is difficult to identify these chromosomal translocations using CGH.
Hurthle Cell Thyroid Tumor Hiirthle cell thyroid tumors comprise 1% to 5% of all thyroid neoplasms and have been classified as variants of follicular thyroid tumors. They differ from follicular thyroid carcinomas by their inability to trap radioiodine and by
348 - - Thyroid Gland
HOrlhle cell adenomas
Left: losses Right: gains
FIGURE 36-6. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 15 Hiirthle cell adenomas and 13 Hiirthle cell carcinomas.
HOrlhle cell carcinomas
the accumulation of mitochondria and eosinophilic cytoplasm on histology. They are also more likely to be multifocal, have nodal metastasis, and appear to be clinically aggressive. Hiirthle cell carcinomas are similar to follicular thyroid carcinomas in that they usually cannot be diagnosed by fine-needle aspiration biopsy or frozen section. It is also difficult to distinguish Hiirthle cell adenomas from carcinomas preoperatively or intraoperatively. Some investigators previously recommended that all Hiirthle cell tumors should be considered as malignant and be treated aggressively because of their malignant potential. 27.28 Others suggested that Hiirthle cell tumors are separated into adenomas (which have no capsular and vascular invasion) and carcinomas, using similar criteria as used for follicular tumors. 29-32 Some studies have suggested that patients with Hiirthle cell carcinoma do not necessarily have a worse prognosis than patients with follicular thyroid carcinorna.Pr" Hemmer and coworkers/" reported 3 of 4 Hiirthle cell adenomas had chromosomal aberrations. Frisk and associates"
also reported that 2 of 3 Hiirthle cell adenomas had chromosomal aberrations, as did 3 of 4 Hiirthle cell carcinomas. Similarly, Tallini and colleagues-' documented that 6 of 7 adenomas and 3 of 4 carcinomas had chromosomal aberrations. We found chromosomal aberrations in 9 of 15 Hiirthle cell adenomas and in 8 of 13 Hiirthle cell carcinomas." The mean number of chromosomal gains and losses were 2.1 and 0.7 in 15 adenomas versus 4.2 and 0.8 in 13 carcinomas. Although Hiirthle cell adenomas were more likely to have fewer chromosomal aberrations than Hiirthle cell carcinomas, in our study, this difference was not significant (P > 0.05) (Fig. 36-6 and Table 36-2). Our investigations have found that whole or focal chromosomal gains are relatively common in chromosomes 5, 7, 12, 17, 19, and 20 and losses are in chromosomes 2 and 9 in both Hiirthle cell adenomas and carcinomas (see Fig. 36-6).36 Frisk and colleagues'" reported that loss of 9q 13-q21.3 was a specific aberration in Hiirthle cell carcinomas. In our study, gains in chromosome 12 were more common in Hiirthle cell
Comparative Genomic Hybridization in Thyroid Neoplasms - - 349
carcinomas than in Hiirthle cell adenomas and, in particular, gains in l2q occurred more frequently in patients with Hiirthle cell carcinomas who developed recurrent disease (P < 0.001).36 Roque and coworkers'? have reported an increased frequency of gains in chromosome 7 and 12 among different thyroid tumors (e.g., goiters, follicular adenomas, and follicular carcinomas). These findings support the concept that some thyroid neoplasms develop in a multistep process. We also found that gains in 5p, 7, 19p, 19q, and 20p were associated with a higher risk of tumor recurrence as well as l2q in patients with Hiirthle cell carcinoma (Table 36-4).36 The presence of these chromosomal aberrations in primary Hiirthle cell carcinoma may predict developing recurrent disease. Erickson and associates'" reported
that loss of chromosome 22, by FISH, was associated with deaths due to Hiirthle cell carcinoma.
Anaplastic Thyroid Carcinoma Anaplastic thyroid carcinoma is an extremely aggressive cancer, with a median survival after diagnosis of just a few months.l? The outcome is so poor that the American Joint Committee on Cancer (AJCC) classifies all patients with this tumor as having stage 4 thyroid cancer. Fortunately, anaplastic thyroid carcinoma accounts for less than 2% of all thyroid carcinomas in the United States and has been decreasing in incidence.f'-"
350 - - Thyroid Gland
Hemmer and colleagues, to as previously mentioned, reported that more chromosomal aberrations occurred in follicular thyroid carcinomas than in papillary thyroid carcinomas. They studied DNA copy number changes by CGH in 69 patients with thyroid carcinoma. Among the 20 follicular thyroid carcinomas, there were 22 deletions and 26 gains (median changes 2, range 0 to 8, for one sample). In contrast, among the 26 papillary thyroid carcinomas, there were no deletions and 6 gains (median changes 0, range 0 to 4, for one sample). Among the 13 anaplastic thyroid carcinomas, there were 5 deletions and 27 gains (median changes 2, range 0 to 13, for one sample). Their documentation of more gains than losses in anaplastic thyroid carcinomas is similar to our results. By CGH analysis of 10 anaplastic thyroid carcinomas, chromosomal aberrations were found in 5 of the 10 anaplastic thyroid carcinomas (Table 36-5).8 We identified 24 chromosomal aberrations, of which 22 were gains and 2 were losses (Fig. 36-7). The two anaplastic thyroid carcinomas (cases 9 and 10) that had the greatest number of chromosomal aberrations (6 and 13) were found histologically in association with follicular thyroid carcinoma. The others with no chromosomal abnormalities (cases 1, 2, and 6), or two or fewer chromosomal abnormalities (cases 3, 4, and 5) were histologically associated with papillary thyroid carcinoma. The median numbers of chromosomal aberrations were 9.5 for anaplastic thyroid carcinoma associated with follicular thyroid carcinoma versus 0.5 for those associated with papillary thyroid carcinoma; this difference was significant (P = 0.046). Two of the anaplastic thyroid carcinomas without known association with follicular or papillary thyroid
carcinoma had no chromosomal aberrations. We found that DNA copy number changes in anaplastic thyroid carcinomas appear to parallel those of the associated follicular or papillary thyroid carcinomas. Thus, after transformation from follicular thyroid carcinoma or papillary thyroid carcinoma to anaplastic thyroid carcinoma, the cells appear to retain their cytogenetic profile. We found no significant correlation between the presence of chromosomal aberrations and overall survival or other clinicopathologic characteristics in our investigation (see Table 36-5).8 The most common chromosomal aberrations were gains in chromosome lq2l-qter in 3 of 10 anaplastic thyroid carcinomas and gains in chromosome lOp and Xp in 2 of 10 anaplastic thyroid carcinomas (see Fig. 36-7). Two of 3 anaplastic thyroid carcinomas that had a gain in lq were associated with papillary thyroid carcinoma (see Table 36-5), but neither had a known history of radiation exposure. The region of lq aberrations found in these 3 anaplastic thyroid carcinomas harbors a gene that encodes one of the receptors for the nerve growth factor (NTRKI), which is activated in about 15% of papillary thyroid carcinomas.P Activation of NTRKI has been reported to be present in papillary thyroid carcinomas that occur after exposure to radiation in children, as well as RET/PTe chromosomal rearrangements.P'v"? Human thyroid cancer cell lines had more chromosomal aberrations than did frozen thyroid cancer samples in our studies, consistent with other studies (Fig. 36-8 and Table 36_6).8,10.48.49 More alterations may be required to establish an immortalized cell line or that cultivating of cells leads to the selection of cells that have more chromosomal aberrations.P No common chromosomal aberrations by
Comparative Genomic Hybridization in Thyroid Neoplasms - -
351
FIGURE 36-7. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 10 anaplastic thyroid carcinomas.
CGH in anaplastic thyroid carcinoma were apparent when we compared our findings to those reported in the literature (see Table 36-6).
Medullary Thyroid Carcinoma Apart from the RET protooncogene (RET) point mutation of chromosome 10, no other genes have been found to be involved in the original growth of medullary thyroid carcinomas. Germline RET mutations have been identified in about 98% of patients with familial medullary thyroid carcinoma, and somatic RET mutations have been frequently detected in sporadic medullary thyroid carcinomas.t! In sporadic medullary thyroid carcinomas, the RET gene is mutated in codon 918, where a methionine is substituted to a threonine (M918T). Chromosomal aberrations have been detected by CGH in approximately 50% to 60% of the patients with medullary thyroid carcinoma.P>' The number of chromosomal aberrations in medullary thyroid carcinoma appears to be lower than in other thyroid carcinomas that arise from thyroid follicular cells.'? Frisk and coworkers>' reported that chromosomal regions 19q, 19p, 13q, and llq may be involved in medullary thyroid carcinogenesis but that medullary thyroid carcinoma is a relatively genetically stable tumor. Overall, the results of CGH investigations in medullary thyroid carcinomas have suggested a normal modal number of chromosomes with a marked tendency to random hypodiploidy.P Hypodiploidy has also been found in medullary thyroid carcinoma cell lines. 53
Limitations and Difficulties of Comparative Genomic Hybridization CGH only detects genomic aberrations that involve loss or gains of DNA sequences. Balanced translocations or inversions are therefore not detectable, nor are small intragenic rearrangements and point mutations. CGH also only detects DNA sequence copy number changes relative to the average copy number in the entire tumor sample. The relative green-to-red ratios can be transformed to indicate actual copy numbers if the absolute copy number in several loci are independently determined or if the ploidy is determined by DNA content analysis. 6•54 Pericentromeric and heterochromatic repeat regions, unfortunately, cannot be reliably evaluated by CGH because unlabeled Cot-I DNA blocks binding of the labeled DNA to the pericentromeric and heterochromatic regions. These DNA sequences are highly polymorphic in copy number between individuals. Thus, ratio changes at or near these regions should be interpreted cautiously, especially when the test and reference DNA samples come from different individuals.> CGH, unfortunately, cannot detect single-copy losses or gains unless the extent of the region in loss/gain is greater than about 10 Mb, Moreover, the CGH ratio may not be a quantitative measure of the number of copies lost or gained unless the involved region is much greater than 10 Mb in extent. Similar to other methods based on extracted DNA, CGH requires that the tumor specimens be relatively free from
352 - - Thyroid Gland
- - - FTC cell lines (FTC133, FTC236 , FTC238) •
• ATC cell line (AR081-1)
............ PTC cell line (TPC-1)
FIGURE 36-8. Summary of chromosomal aberrations analyzed by comparative genomic hybridization (CGH) in five thyroid cancer cell lines: (I) FfC-133 was derived from a primary follicular thyroid cancer (FfC); (2) FfC-236 was derived from a lymph node metastasis of FfC from the same patient as in FfC-133; (3) FfC-238 was derived from a lung metastasis ofFfC from the same patient as in FfC-133; (4) AR081-1 was derived from an anaplastic thyroid cancer (ATC); and (5) TPC-I was derived from a papillary thyroid cancer (PTC).
Comparative Genomic Hybridization in Thyroid Neoplasms - - 353
surrounding normal tissues that dilute the green-to-red ratio changes. If the normal tissue contribution is greater than 50% of the total DNA content, reliable detection of the ratio becomes increasingly difficult. In addition to normal cell contamination, intratumor genetic heterogeneity may also dilute the green-to-red ratio changes detected by CGH. This technique detects the average copy number of sequences in all cells included in the specimen, so those aberrations that are homogenously present (clonal) in the tumor cells are more readily detected. In most cases, this is an advantage, because the clonal changes are likely to represent the early and most important changes. However, in multiclonal tumors, the different genetic aberrations present in the individual clones may sometimes balance one another or exist at too Iowa frequency to be detected. 54
Conclusions Investigations using CGH have identified several regions of the genome with gains and losses that havepreviously not been suspected to be involved in thyroid carcinoma. These regions may contain important novel genes that are responsible for thyroid tumor development and progression. Further investigations using higher resolution CGH analysis and a larger series of tumors are required to validate and refine the locations of the common regions of loss and gain in each chromosome and to evaluate the significance of these genetic events in the multistep model of thyroid carcinogenesis.
REFERENCES 1. Fagin JA. Genetic basis of endocrine disease: III. Molecular defects in thyroid gland neoplasia. J Clin Endocrinol Metab 1992;75:1398. 2. Wynford-Thomas D. Molecular basis of epithelial tumorigenesis: The thyroid model. Crit Rev OncoI1993;4:1. 3. Wynford-Thomas D. Origin and progression of thyroid epithelial tumours: Cellular and molecular mechanisms. Horm Res 1997;47:145. 4. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal tumor development. N Engl J Med 1988;319:525. 5. Fagin JA, Matsuo K, Karmakar A, et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993;91:179. 6. Kallioniemi A, Kallioniemi OP, Sudar D, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 1992;258:818. 7. Ried T, Heselmeyer-Haddad K, Blegen H, et al. Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: A phenotype/genotype correlation. Genes Chromosomes Cancer 1999;25:195. 8. Miura D, Wada N, Chin K, et al. Anaplastic thyroid cancer: Cytogenetic patterns by comparative genomic hybridization. Thyroid 2003;13:283. 9. Chen X, Knauf JA, Gonsky R, et al. From amplification to gene in thyroid cancer: A high-resolution mapped bacterial-artificial chromosome resource for cancer chromosome aberrations guides gene discovery after comparative genome hybridization. Am J Hum Genet 1998;63:625. 10. Hemmer S, Wasenius VM, Knuutila S, et al. DNA copy number changes in thyroid carcinoma. Am J Pathol 1999;154:1539. 11. Singh B, Lim D, Cigudosa JC, et al. Screening for genetic aberrations in papillary thyroid cancer by using comparative genomic hybridization. Surgery 2000;128:888. 12. Said S, Schlumberger M, Suarez HG. Oncogenes and anti-oncogenes in human epithelial thyroid tumors. J Endocrinol Invest 1994; 17:371. 13. Antonini P, Venuat AM, Linares G, et al. A translocation (7;10) (q35;q21) in a differentiated papillary carcinoma of the thyroid. Cancer Genet Cytogenet 1989;41:139.
14. Bondeson L, Bengtsson A, Bondeson AG, et al. Chromosome studies in thyroid neoplasia. Cancer 1989;64:680. 15. Jenkins RB, Hay ill, Herath JF, et al. Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Cancer 1990;66:1213. 16. 01ah E, Balogh E, Bojan F, et al. Cytogenetic analyses of three papillary carcinomas and a follicular adenoma of the thyroid. Cancer Genet Cytogenet 1990;44:119. 17. Teyssier JR, Liautaud-Roger F, Ferre D, et al. Chromosomal changes in thyroid tumors: Relation with DNA content, karyotypic features, and clinical data. Cancer Genet Cytogenet 1990;50:249. 18. Herrmann ME, Mohamed A, Talpos G, Wolman SR. Cytogenetic study of a papillary thyroid carcinoma with a rearranged chromosome 10. Cancer Genet Cytogenet 1991;57:209. 19. Herrmann MA, Hay ill, Bartelt DH Jr, et al. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin Invest 1991;88:1596. 20. Sozzi G, Bongarzone I, Miozzo M, et al. Cytogenetic and molecular genetic characterization of papillary thyroid carcinomas. Genes Chromosomes Cancer 1992;5:212. 21. Sozzi G, Bongarzone I, Miozzo M, et al. A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma. Genes Chromosomes Cancer 1994;9:244. 22. Farid NR, Shi Y,Zou M. Molecular basis of thyroid cancer. Endocr Rev 1994;15:202. 23. Learoyd DL, Twigg SM, Zedenius JV, Robinson BG. The molecular genetics of endocrine tumours. J Pediatr Endocrinol Metab 1998; 11:195. 24. Hemmer S, Wasenius VM, Knuutila S, et al. Comparison of benign and malignant follicular thyroid tumours by comparative genomic hybridization. Br J Cancer 1998;78:1012. 25. Frisk T, Kytola S, Wallin G, et al. Low frequency of numerical chromosomal aberrations in follicular thyroid tumors detected by comparative genomic hybridization. Genes Chromosomes Cancer 1999; 25:349. 26. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARyl fusion oncogene in human thyroid carcinoma [corrected]. Science 2000;289: 1357. 27. Thompson NW, Dunn EL, Batsakis JG, Nishiyama RH. Hiirthle cell lesions of the thyroid gland. Surg Gynecol Obstet 1974;139:555. 28. Gundry SR, Burney RE, Thompson NW, Lloyd R. Total thyroidectomy for Hiirthle cell neoplasm of the thyroid. Arch Surg 1983;118:529. 29. Gosain AK, Clark OH. Hurthle cell neoplasms: Malignant potential. Arch Surg 1984;119:515. 30. Grossman RF, Clark OH. Hiirthle cell carcinoma. Cancer Control 1997;4:13. 31. DeGroot U, Kaplan EL, Shukla MS, et al. Morbidity and mortality in follicular thyroid cancer. J Clin Endocrinol Metab 1995;80:2946. 32. Arganini M, Behar R, Wu TC, et al. Hiirthle cell tumors: A twenty-fiveyear experience. Surgery 1986; I00: 1108. 33. Sanders LE, Silverman M. Follicular and Hiirthle cell carcinoma: Predicting outcome and directing therapy. Surgery 1998;124:967. 34. Sugino K, Ito K, Mimura T, et al. Hiirthle cell tumor of the thyroid: Analysis of 188 cases. World J Surg 2001;25:1160. 35. Tallini G, Hsueh A, Liu S, et al. Frequent chromosomal DNA unbalance in thyroid oncocytic (Hiirthle cell) neoplasms detected by comparative genomic hybridization. Lab Invest 1999;79:547. 36. Wada N, Duh QY, Miura D, et al. Chromosomal aberrations by comparative genomic hybridization in Hiirthle cell thyroid carcinomas are associated with tumor recurrence. J Clin Endocrinol Metab 2002;87:4595. 37. Roque L, Serpa A, Clode A, et al. Significance of trisomy 7 and 12 in thyroid lesions with follicular differentiation: A cytogenetic and in situ hybridization study. Lab Invest 1999;79:369. 38. Erickson LA, Jalal SM, Goellner JR, et al. Analysis of Hiirthle cell neoplasms of the thyroid by interphase fluorescence in situ hybridization. Am J Surg Pathol 2001;25:911. 39. Haigh PI, ltuarte PH, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 2001;91:2335. 40. Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996: U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 2000;89:202.
354 - - Thyroid Gland 41. Clark OH. Predictors of thyroid tumor aggressiveness. West J Med 1996;165: 131. 42. Greco A, Miranda C, Pagliardini S, et al. Chromosome I rearrangements involving the genes TPR and NTRKI produce structurally different thyroid-specific TRK oncogenes. Genes Chromosomes Cancer 1997;19:112. 43. Pierotti MA, Bongarzone I, Borello MG, et al. Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 1996;16:1. 44. Ron E, Modan B, Preston D, et al. Thyroid neoplasia following lowdose radiation in childhood. Radiat Res 1989;120:516. 45. Shore RE, Woodard E, Hildreth N, et al. Thyroid tumors following thymus irradiation. J Nat! Cancer Inst 1985;74:1177. 46. Schneider AB, Ron E, Lubin J, et al. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 1993;77:362. 47. Perkel VS, Gail MH, Lubin J, et al. Radiation-induced thyroid neoplasms: Evidence for familial susceptibility factors. J Clin Endocrinol Metab 1988;66:1316. 48. Komoike Y, Tamaki Y, Sakita I, et al. Comparative genomic hybridization defines frequent loss on 16p in human anaplastic thyroid carcinoma. IntJ OncoI1999;14:l157.
49. Wilkens L, Benten D, Tchinda J, et al. Aberrations of chromosomes 5 and 8 as recurrent cytogenetic events in anaplastic carcinoma of the thyroid as detected by fluorescence in situ hybridisation and comparative genomic hybridisation. Virchows Arch 2000;436:312. 50. Mark J, Ekedahl C, Dahlenfors R, Westermark B. Cytogenetical observations in five human anaplastic thyroid carcinomas. Hereditas 1987;107:163. 51. Frisk T, Zedenius J, Lundberg J, et al. CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome. Int J OncoI2001;18:1219. 52. Wurster-Hill DH, Pettengill OS, Noll WW, et al. Hypodiploid, pseudodiploid, and normal karyotypes prevail in cytogenetic studies of medullary carcinomas of the thyroid and metastatic tissues. Cancer Genet Cytogenet 1990;47:227. 53. Tanaka K, Baylin SB, Nelkin BD, Testa JR. Cytogenetic studies of a human medullary thyroid carcinoma cell line. Cancer Genet Cytogenet 1987;25:27. 54. Kallioniemi OP, Kallioniemi A, Piper J, et al. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer 1994; 10:231.
Sodium-Iodide Symporter and Radioactive Iodine Therapy Rasa Zarnegar, MD
The treatment of patients with well-differentiated thyroid cancer (WDTC) includes three modalities: thyroidectomy, radioiodine (1311) ablation, and thyrotropin (thyroid-stimulating hormone, TSH) suppression. Unfortunately about 25% of WDTCs are initially resistant to 131 1, and about 50% of recurrent thyroid cancers are also resistant to 131 1 treatment. These patients have a worse prognosis, and several investigators have attempted to enhance radioiodine uptake in thyroid cancer cells of follicular cell origin.P Thyroid iodide uptake plays a critical role in the diagnosis and treatment of a variety of thyroid disorders. Since the cloning of the sodium-iodide symporter (NIS), research has been focused on methods of enhancing the uptake of iodide in thyrocytes. NIS is an intrinsic plasma membrane glycoprotein located on the basolateral membrane of thyroid follicular cells and is responsible for iodine uptake into thyroid cells (Fig. 37-1).3,4 It plays a critical role in the active transport of iodide from the blood stream into thyrocytes and in a number of nonthyroid tissues, including the mammary glands during lactation, stomach, kidneys, and salivary glands. Functional NIS expression on thyroid tissue is essential for the concentration of iodide in thyrocytes against a concentration gradient. Iodide is a component of the thyroid hormones triiodothyronine (T 3) and thyroxine (T 4), which playa role in the metabolism, growth, and maturation of a variety of organ systems.! When thyroid cells transform into cancer cells, their ability for iodine uptake is decreased." This is true for both papillary and follicular thyroid carcinomas. Most Hurthle cell carcinomas fail to take up enough 1311 for treatment to be effective. Three mechanisms have been proposed for poor iodide uptake in thyroid carcinoma: (I) NIS gene mutations, (2) suppression of NIS gene expression, and (3) posttranscriptional modifications of the NIS protein. Therefore, research is focused on increasing NIS symporter function in a variety of tumors using specific drugs or gene therapy followed by radioactive iodine ablation.
Molecular Characterization of the NIS Gene The molecular characterization of NIS was accomplished in 1996 when Dai and colleagues cloned the transporter' from Xenopus laevis oocytes, using the complementary DNA (eDNA) libraries derived from FRTL-5 cells (functional rat thyroid-derived cell line). The eDNA encoding the human NIS (hNIS) gene was identified on the expectation that hNIS would be highly homologous to rat NIS'? The hNIS gene is located on chromosome 19p12-13.2. It comprises 1929 base pairs encoding a 643-amino acid glycoprotein with a molecular weight of 70 to 90 kd. The variable molecular weight depends on the level of glycosylation of the protein. The coding region of hNIS contains 15 exons and 14 introns and codes for a 3.9-kb messenger RNA (mRNA).8 NIS is a membrane protein with 13 transmembrane domains with an extracellular NHz terminus and an intracellular COOH terminus (Fig. 37-2). The configuration of the NH z and COOH termini have been confirmed by immunohistochemistry." There are three potential asparagine (ASN) glycosylation sites at positions 225, 485, and 497. 10 However, glycosylation has not been shown to affect the functionality, targeting, or stability of the NIS protein." Findings derived from NIS mutations that cause congenital iodide transport deficiency (lTD) show that a spontaneous single amino acid substitution of proline (Pro) instead of threonine (Thr) at position 354 (T354P) is the cause of congenital lack of iodide transport in several patients.U'" This suggests that a hydroxyl group at the ~ carbon position (Thr-354) is essential for NIS function.14 In the same patients, a mutation from valine-59 to glutamate has also been discovered.P Subsequent to the cloning of hNIS, cDNAs encoding NIS have also been isolated from two other species, pig" and mouse." Mouse NISI6 and rat NIS3 contain 618 amino acid residues, whereas human NIS7 and pig NISI5 contain 643. A highly conserved homologue among all isolated NIS proteins exists.
355
356 - - Thyroid Gland Colloid
FIGURE 37-1. Schematic representation of the iodide uptake and
biosynthetic pathways of thyroidhormones in thyrocytes. Iodine is actively accumulated across the basolateral plasma membrane of the thyrocyte in a processcatalyzed by the sodium-iodide symporter (NIS). This transportis driven by the Na" gradientgenerated under adenosine triphosphate (ATP) hydrolysis by Na+,K+-ATPase. The iodideis passively translocated across the apical membrane of the thyrocyte by the pendrin (PDS)proteininto the colloid, where it is used to iodinate thyroglobulin (Tg). Iodine organification is catalyzed by thyroid peroxidase (TPO) and requires H202• The iodinated Tg, containing thyroid hormones, is stored in the colloid. Thyroid hormones, thyroxine (T4 ) and triiodothyronine (T3) , are released from Tg and secretedin the blood.All steps in the thyroid hormone biosynthetic pathway are stimulated by thyroid-stimulating hormone (TSH).TSH-R = TSH receptor. NIS gene expression is high in thyroid, gastric, and lactating mammary glands, and lower levels are present in other tissues including brain, small intestines, testes, skin, spleen, ovary, and prostate."
Regulation of NIS Gene Expression and Function It has been known for decades that pituitary-derived TSH increases iodide transport into the thyroid cells by way of an adenylate cyclase-cyclic adenosine monophosphate (cAMP)-mediated pathway.' Thyrotropin-releasing hormone from the hypothalamus stimulates the release of TSH, whereas T 3 and T 4 inhibit it. TSH binds the TSH receptor (TSHR) on the basolateral membrane of the follicular cells, causing the accumulation of iodide through the cAMP-mediated increase of NIS transporter synthesis (see Fig. 37-1).17 Upregulation of thyroid NIS expression and iodide uptake activity by TSH have been shown in in vitro and
animal modelsp-2o After withdrawal, a reduction in both intracellular cAMP and iodide uptake activity is observed. TSH stimulation has also been shown to affect cell polarization and spatial organization, leading to redistribution of the NIS transporter from the cytoplasm to the cell membrane. Therefore, TSH not only stimulates NIS transcription and biosynthesis but also is required for NIS targeting to the plasma membrane. The NIS protein is targeted to the basolateral membrane of follicular cells. Although the mechanism of this targeting is not fully elucidated, several sorting signals in the COOH terminus have been identified including the PDZ, dileucine, and acid-based motifs. 21-23 Localization of NIS at the basolateral plasma membrane is important not only for iodide transport in the thyroid gland but also for effective treatment of thyroid disease with radioactive iodine. Impaired targeting is one mechanism by which thyroid cancers have decreased iodide uptake. 24.25 Therefore, it is important for the treatment of thyroid cancer to determine the mechanisms that regulate the subcellular distribution of NIS. Phosphorylation, a common cellular mechanism for modulating protein activity, subcellular localization, and degradation, has been shown to playa role in the post-transcriptional stabilization of the NIS protein. In the presence and absence of TSH, the phosphorylation pattern of the NIS protein is different." Although studies have not shown a role of phosphorylation in the targeting and stability of the NIS protein, its role has been shown in the function of other transporters. Iodide has also been shown to be a major regulator of iodide uptake by the thyroid gland. In 1923, Plummer" noted that high doses of iodide block thyroid function in patients with hyperactive thyroid disease. However, it was Wolff and Chaikoff who, in 1948, reported that the binding of iodide in the rat thyroid in vivo was blocked when iodide plasma levels reached a critical high threshold, a phenomenon known as the acute Wolff-Chaikoff effect.28 Raben showed that the acute inhibition of organic iodide binding is dependent on intrathyroid rather than plasma concentrations of iodide by blocking iodide transport with thiocyanate." Studies went on to show that the inhibitory effects of iodide on the organification of iodine last 2 days, after which there is an adaptation or escape from the effect" The Wolff-Chaikoff effect and the ensuing escape constitute a highly specialized autoregulatory system that protects the thyroid from iodide overload but at the same time ensures adequate iodide uptake for thyroid hormone synthesis. The regulatory role of iodide in NIS function has been explored with studies indicating that NIS transcription is inhibited by iodide. 31.32 Eng and colleagues.P>' however, showed that iodide does not affect NIS gene transcription but rather increases the rate of turnover of the NIS protein. However, it is more likely that iodide affects NIS transporter protein at multiple levels, inhibiting transcription and also increasing turnover of the protein. Although the major regulators of the NIS transporter are TSH and iodide, there are associations between NIS regulation and cytokines including tumor necrosis factor a. (TNF-a.), TNF-~, interferon-y, interleukin-l a. (IL-l o), IL-I~, IL-6, and transforming growth factor ~2' All these cytokines have been shown to play an inhibitory role in NIS protein expression and iodide uptake through decreased NIS gene transcription.31.35.36
Sodium-Iodide Symporter and Radioactive Iodine Therapy - - 357
FIGURE 37-2. Schematic model of the human sodium-iodide symporter, which represents an intrinsic membrane protein with 13 transmembrane and 14 extramembranous domains and 3 potential N-linked glycosylation sites. ExM = Extramembranous domains.
NIS and Thyroid Cancer As previously mentioned, the treatment of patients with WDTC includes three modalities: thyroidectomy, radioiodine (1311) ablation, and TSH suppression. Unfortunately, about 25% ofWDTCs are initially resistant and about 50% of recurrent thyroid cancers are resistant to 1311 treatment. These patients have a worse prognosis, and many studies have attempted to enhance radioiodine uptake in thyroid cancer cells in such patients. 1•2,34,37,38 Since the discovery of the NIS gene, much attention has been focused on the symporter because it is a marker for differentiation and also the mechanism by which radioactive iodide therapy works. Thyroid diseases directly affect the function of the NIS symporter. Three mechanisms, as previously stated, have been proposed for poor iodide uptake in thyroid carcinoma: (I) NIS gene mutations.t? (2) suppression of the NIS gene expression,6.39-44 and (3) post-transcriptional modifications of the NIS protein. 24,26 Congenital lTD is an infrequent autosomal recessive condition caused by mutations in the NIS gene. The clinical picture consists of hypothyroidism, goiter, low thyroid iodide uptake, and low saliva-to-plasma iodide ratio. The incidence of lTD is 1 per 4000 neonates. It has an irreversible effect on the growth and development of the neonate, leading to cretinism. Mutations in thyroid-specific molecules such as thyroid peroxidase, thyroglobulin, and TSHR have been identified. 45-47 NIS mutations have also been reported in congenital hypothyroidism resulting in the absence of the functional NIS symporter. Kosugi and coworkers" reported that a T354P NIS gene mutation was found in seven Japanese
patients from five unrelated families. To date, approximately 60 cases of lTD belonging to 33 families have been reported. Twenty-seven cases from 13 families studied have been shown to have NIS gene mutations. 12.39,48-50 Thyroid cancer has not been shown to involve the mutations seen in congenital lTD. Russo and colleagues" performed direct sequencing of NIS cDNA from five papillary and two follicular thyroid cancers and found no mutations in the NIS gene. The proposed mechanism of reduced radioactive uptake in thyroid cancer has been associated with decreased expression of the NIS gene. Bidart and associates'? showed that NIS protein immunostaining is increased in Graves' disease and reduced in Hashimoto's and thyroid cancer. Our own studies have confirmed that NIS gene expression is increased in Graves' disease and hyperactive adenomas and reduced in Hashimoto's disease. Also, expression of the NIS symporter is reduced in papillary, medullary, and follicular thyroid cancers. Schmutzler'" found that the redifferentiation effect of retinoic acid in thyroid cancer cells is associated with increased NIS gene expression. NIS gene expression not only may be deceased in thyroid cancer but also may affect post-transcriptional targeting of the NIS protein. Saito and colleagues" showed that 7 of 17 papillary thyroid carcinomas overexpressed the NIS gene, but the NIS protein was located in the cytoplasm and not on the cell membrane. In contrast, NIS protein expression was barely detected in the paratumoral normal tissue. Contrary to the results of Saito and colleagues, several investigators have found absent or intermediate expression staining of the NIS protein in differentiated thyroid cancer. 54,55
358 - -
Thyroid Gland
Loss of polarization and impaired membrane targeting of other membrane proteins have been described in malignant thyroid cancer. The epidermal growth factor receptor, as detected by immunohistochemistry, was overexpressed and localized not only pericellularly but also intracellularly rather than exclusively localized on the basolateral membrane as in normal cells. NIS must be expressed, targeted, and retained in the appropriate plasma membrane surface in polarized epithelial cells for active iodide transport to occur. TSH regulates NIS distribution between the plasma membrane and intracellular membrane compartments. In thyroid cancer cells, iodide transport can still be present even in the absence of cell polarization, but targeting to and retention in the plasma membrane remain essential if active iodide transport is to take place. Therefore, elucidating the mechanisms involved in proper targeting and retention of NIS at the plasma membrane is essential to enhancing iodide uptake in thyroid cancer cells.
Enhancing NIS Gene Expression The NIS gene has become the focus of much attention in the past decade as new drugs have been developed that can enhance its expression. Retinoic acid (RA) was the first drug identified to enhance NIS gene expression. 1,53.56-60 9-cis-RA, a ligand for both retinoic acid receptor (RAR)/retinoic X receptor (RXR) heterodimers and RXRIRXR homodimers, markedly induced NIS mRNA expression in a dose- and time-dependent fashion, with maximal levels occurring at 12 hours. All-trans-RA, an RAR-specific ligand, had similar potency. Combining an RAR with an RXR-selective ligand enhanced both NIS mRNA expression and iodide uptake. Similarly, a ligand for peroxisome proliferator-activated receptor y (PPARy), when combined with 9-cis-RA, synergistically increased both NIS mRNA levels and iodide uptake. Schmutzler and colleagues" showed that RA increased radioiodine transport in two different follicular thyroid carcinoma cell lines (FTC-l33 and FTC-238), suggesting that RA may cause redifferentiation of advanced thyroid carcinoma. However, clinical trials with RA at our institution have not mirrored the results seen in cell studies. Histone deacetylase inhibitors are a group of anticancer agents that function through mechanisms that are not yet fully elucidated. Both hyperacetylation and hypoacetylation of histones appear to play important roles in carcinogenesis through gene regulation. Histone deacetylase inhibitors are a unique group of drugs that are under investigation for their role in the regulation of gene expression. Acetylation of lysine residues within the arninoterrninal domains of the core histones has been associated with the regulation of gene transcription/" Histone hyperacetylation correlates with increased gene transcription, whereas hypoacetylation correlates with decreased gene transcription. Although histone acetylation does not disrupt individual nucleosomes, moderate levels of acetylation can destabilize the higher order folding of arrays of nucleosomes. Thus, acetylation of specific lysine residues can regulate the chromatin binding or the enzymatic activity of other nonhistone proteins. 63,64
A number of investigations, however, determined that the up- or downregulation of genes by histone acetylation is not ubiquitous for all genes in a cell. 64 Indeed, a global increase in core histone acetylation did not induce widespread gene transcription. 65 Histone acetylation neutralizes electrical charges, separating DNA from the histones, thus allowing nucleosomal DNA to become more accessible to transcriptional activators or repressors. Histone acetylation is believed to stabilize local nucleosomal structures, thereby allowing transcription factors and the basal transcriptional machinery access to DNA. Hyperacetylation of histones has been shown to open chromatin markedly, and it is required for transcriptional activation." Histone acetylation is a reversible process. Histone acetyltransferases (HATs) transfer the acetyl moiety from acetyl coenzyme A to lysine, neutralizing the positive charge in the histones. Histone deacetylases (HDACs) remove the acetyl groups, re-establishing the positive charge in the histones. In studies at our institution, we found that trichostatin A (TSA) enhanced NIS gene expression in thyroid cancer cell lines with an associated increase in radioactive iodide uptake in these cell lines.s? Depsipeptide (FR901228), another HDAC inhibitor, has also be shown to increase NIS gene expression in well-differentiated thyroid carcinoma cell lines derived from follicular thyroid carcinomas (FTC-l33, FTC-236) and anaplastic carcinomas (SW-1736, KAT-4).68 At low concentrations, these drugs have minimal cytotoxic effects in cell lines (Fig. 37-3). Our studies with TSA showed that at low concentrations this drug caused cells to FTC 133
Hours
FIGURE 37-3. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl tetrazolium bromide (MIT) assay for FfC-l33 after treatment with trichostatin A (TSA), n = 3. TSA concentrations of 0, 10,50, 100,250,and 1000ng/mLwere usedin the cell line.Cell proliferation wasmeasured relative to day 0 andrepresents an average measurement. The measurements were taken at 24, 48, and 72 hours. FfC-133 cell proliferation occurred in the presence of TSA at concentrations up to 50 ng/mL, growth inhibition at 100, 250, and 1000ng/mL. FfC = follicular thyroid carcinoma.
Sodium-Iodide Symporter and Radioactive Iodine Therapy - - 359
The identification of drugs that can enhance the expression of the NIS gene does not have limited application to differentiated thyroid cancers. NIS gene expression was identified and characterized in the mammary gland by Tazebay and coworkers.s? A report by Kagai and coauthors'? showed induction of NIS gene expression and radioiodine uptake in breast cancer cells following treatment with RA. In the estrogen receptor-positive human breast cancer cell line MCF-7, all-trans-RA treatment stimulated iodide uptake in a time- and dose-dependent fashion up to approximately 9.4-fold. However, in estrogen receptor-negative human breast cancer, no induction of iodide uptake was observed after RA treatment. RA also did not induce increased iodide uptake in prostate cancer cells (LNCaP), choriocarcinoma cells (JEG-3), and lung cancer cells (A549, H460). Therefore, the effect of RA is cell specific. The effects of HDAC inhibitors in nonthyroidal carcinomas with respect to iodide uptake have yet to be elucidated. Cloning the NIS gene further allows the development of novel cytoreductive gene therapy by directing the transfer of the NIS gene into different tumor cells followed by radioiodine therapy. Early studies in transformed rat thyroid cells (FRTL-Tc) without iodide transport activity showed that transfection restores radioiodine accumulation activity in vitro and in vivo." Mandell and colleagues" demonstrated iodide accumulation in vitro and in vivo in several cancer cell lines, including melanoma, liver, colon, and ovarian carcinoma cell lines, after retrovirus-mediated transfection with the rat NIS gene. An in vitro clonogenic assay was used to demonstrate that rat NIS-transduced cancer cell lines could be killed selectively by the accumulated l3ll. Prostate cancer cells (LNCaP) were shown to be killed selectively by accumulation of radioiodine after tissue-specific iodide uptake by prostate-specific antigen promoter-directed NIS expression in vitro." In a study using adenovirus-mediated intratumoral NIS gene delivery, 3 mCi of 1311 intraperitoneally injected 4 days after transfection in LNCaP xenografts showed a clear therapeutic advantage with an 80% reduction in volume." Rhenium 188, a chemical analog of technetium, with the NIS transporter has been shown to deliver a radiation dose 4.5 times higher than 1311. The next crucial step toward clinical application of NIS gene delivery followed by radioiodine therapy will involve the generation and investigation of safe and efficient gene delivery with vectors that can be administered systemically, targeting specific tissue without severe side effects.
C FIGURE 37-4. Apoptosis assay by annexin V/PI staining and flow cytometryusing trichostatin A (TSA) at concentrations of 0,50, 100, and 500 ng/mL for 24, 48, and 72 hours. Cells are classifiedas viable, early apoptosis, and nonviable. Treatmentwith up to 100 nglmLTSA did not significantly affectthe numberof apoptotic cells.At 500 nglmL TSA, 68.7% of the cells were nonviableafter 72 hours.
redifferentiate with an associated transient Gz/M arrest and at higher concentrations caused cells to progress to apoptosis (Fig. 37-4). If these results can be confirmed in vivo, these drugs may be used clinicallyin the treatment of thyroid cancer in combination with radioactive iodine therapy. Depsipeptide is involved in several clinical trials for tumor redifferentiation in advanced cancers, including thyroid cancer.
Conclusion NIS research has become an exciting field with the cloning of the NIS gene and investigations into the trafficking of the symporter. NIS was used extensively in the management of thyroid disease even before its molecular characterization for radioiodine ablation. However, several thyroid cancers have decreased NIS expression, and therefore radioiodine therapy is less effective in the treatment of these tumors. The investigation of RA and histone deacetylating inhibitors such as depsipeptide and TSA, the possibility of enhancing NIS gene activity, and methods to increase the effectiveness of radioactive iodine therapy are entering clinical trials.
360 - - Thyroid Gland Treatment of nonthyroid tumors by transfecting tumor cells with the NIS gene followed by radioiodine ablation is also a field that requires further investigation. It has become evident that continued study of the mechanisms involved in NIS transporter synthesis and trafficking as well as study of drugs and vectors for systemic administration of the NIS gene will considerably affect the future of cancer therapy.
REFERENCES 1. Schmutzler C, Winzer R, Meissner-Weigl J, Kohrle J. Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells. Biochem Biophys Res Commun 1997;240:832. 2. Lawrence JE, Emerson CH, Sullaway SL, Braverman LE. The effects of recombinant human TSH on the thyroid I23-iodide uptake in iodide treated normal subjects. J Clin Endocrinol Metab 2001;86:437. 3. Dai G, Levy 0, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature 1996;379:458. 4. Dohan 0, De la Vieja A, Carrasco N. Molecular study of the sodiumiodide symporter (NIS): A new field in thyroidology. Trends Endocrinol Metab 2000; II :99. 5. Carrasco N. Iodide transport in the thyroid gland. Biochim Biophys Acta 1993;1154:65. 6. Min JJ, Chung JK, Lee YJ, et al. Relationship between expression of the sodium/iodide symporter and 131J uptake in recurrent lesions of differentiated thyroid carcinoma. Eur J Nucl Med 2001;28:639. 7. Smanik PA, Liu Q, Furminger TL, et al. Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun 1996;226:339. 8. Smanik PA, Ryu KY, Theil KS, et al. Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. Endocrinology 1997;138:3555. 9. De la ViejaA, Ginter C, Carrasco N. Topology of the sodium/iodide symporter.Program of the 12th InternationalThyroid Congress, Kyoto, Japan, 2000;107. 10. Levy 0, De la Vieja A, Ginter CS, et al. N-linked glycosylation of the thyroid Na+/I-symporter (NIS). Implications for its secondary structure model. J BioI Chern 1998;273:22657. 11. Fujiwara H. Congenital hypothyroidism caused by a mutation in the Na+/I-symporter. Nat Genet 1997;17:122. 12. Fujiwara H, Tatsumi K, Moo K, et al. Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect. J Clin Endocrinol Metab 1998;83:2940. 13. Fujiwara H, Tatsumi K, Tanaka S, et al. A novel V59E missense mutation in the sodium iodide symporter gene in a family with iodide transport defect. Thyroid 2000;10:471. 14. Levy 0, Ginter CS, De la Vieja A, et al. Identification of a structural requirement for thyroid Na+/I-symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism. FEBS Lett 1998;429:36. 15. Ruby S, Watrin C, Rousset B. Molecular cloning and functional analyses of the pig sodium iodide symporter: Evidence for three forms generated by alternatesplicing. Program of the 12thInternationalThyroid Congress, Kyoto, Japan 2000;107. 16. Perron B, Rodriguez AM, Leblanc G, Pourcher T. Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues. J EndocrinoI2001;170:185. 17. Weiss SJ, Philip NJ, Ambesi-Impiombato FS, Grollman EF. Thyrotropin-stimulated iodide transport mediated by adenosine 3',5'monophosphate and dependent on protein synthesis. Endocrinology 1984;114:1099. 18. Levy 0, Dai G, Riedel C, et al. Characterization of the thyroid Na+/Isymporter with an anti-COOH terminus antibody. Proc Natl Acad Sci USA 1997;94:5568. 19. Kogai T, Curcio F, Hyman S, et al. Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. J EndocrinoI2000;167:125.
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Sodium-Iodide Symporter and Radioactive Iodine Therapy - 43. Lin JD, Chan EC, Chao TC, et al. Expression of sodium iodide symporter in metastatic and follicular human thyroid tissues. Ann Oncol 2000; II :625. 44. Ryu KY, Senokozlieff ME, Smanik PA, et al. Development of reverse transcription-competitive polymerase chain reaction method to quantitate the expression levels of human sodium iodide symporter. Thyroid 1999;9:405. 45. Bikker H, Vulsma T, Baas F, de Vijlder 11M.Identification of five novel inactivating mutations in human thyroid peroxidase gene by denaturing gradient gel electrophoresis. Hum Mutat 1995;6:9. 46. Leiri T, Cochaux P, Targovnik HM, et al. A 3' splice site mutation in the thyroglobulin gene responsible for congenital goiter with hypothyroidism. J Clin Invest 1991;88:1901. 47. Sunthornthepvarukui T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: Resistance to thyrotropin caused by mutations in the thyrotropin receptor gene. N Engl J Med 1995;332:155. 48. Fujiwara H, Tatsumi K, Miki K, et al. Congenital hypothyroidism caused by a mutation in the Na+/I- symporter. Nat Genet 1997;16:124. 49. Matsuda A, Kosugi S. A homozygous missense mutation of the sodium/iodide symporter gene causing iodide transport defect. J Clin Endocrinol Metab 1997;82:3966. 50. Kosugi S, Inoue S, Matsuda A, Jhiang SM. Novel, missense and lossof-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients. J Clin Endocrinol Metab 1998;83:3373. 51. Russo D, Manole D, Arturi F, et al. Absence of sodiumliodide symporter gene mutationsin differentiatedhuman thyroidcarcinomas.Thyroid 2001; 11:37. 52. Bidart lM, Mian C. Lazar V, et al. Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues. J Clin Endocrinol Metab 2000;85:2028. 53. Schmutzler C. Regulation of the sodium/iodide symporter by retinoids-A review. Exp Clin Endocrinol Diabetes 200 I; I09:41. 54. Jhiang SM, Cho JY, Ryu KY, et al. An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues. Endocrinology 1998;139:4416. 55. Castro MR, Bergert ER, Beito TG, et al. Monoclonal antibodies against the human sodium iodide symporter: Utility for immunocytochemistry of thyroid cancer. J Endocrinol 1999;163:495. 56. Volume 240, Number 3 (1997), in Article No. RC977715, "Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells," by C. Schmutzler, R. Winzer, J. Meissner-Weigl, and J. Kohrle, pages 832-838. Biochem Biophys Res Commun 1998;246:562. 57. Kogai T, Schultz 11, Johnson LS, et al. Retinoic acid induces sodium/ iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line. Proc Nat! Acad Sci USA 2000;97:8519. 58. Schmutzler C, Kohrle J. Retinoic acid redifferentiation therapy for thyroid cancer. Thyroid 2000;10:393.
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Parathyroid Embryology, Anatomy, and Pathology Miguel F. Herrera, MD • Armando Gamboa-Dominguez, MD
A small gland located in the vicinity of the thyroid gland was first described in 1880 by the Swedish anatomist Sandstrom, 1 who named it "glandula parathyroideae." The first anatomic descriptions of the parathyroid glands in humans were published by Welsh in 18982 and Halsted and Evans in 1907. 3 These authors demonstrated in their classic studies that there are typically four parathyroid glands (two on each side) with a relatively constant mutual location. It is essential for the surgeon dealing with endocrine surgery to be familiar with the embryology, anatomy, and histology of parathyroid glands to appreciate the rationale of certain surgical maneuvers and decisions.
Embryology The thyroid, the parathyroid glands, and the thymus originate from the embryonic pharyngeal region. The pharynx itself is initially an endodermally lined cul-de-sac that forms the cephalic extremity of the foregut. This is derived from a part of the yolk sac. The foregut diverticulum is divided into a more cranial pharynx and a more caudal proper foregut with the appearance of the primordium of the pulmonary apparatus as a small ventral outgrowth. When the embryo is approximately 26 days old, lateral walls of the pharynx show a nonuniform growth that forms five pairs of endodermally lined pouches." Only the first pouch persists as a large, hollow cavity to form at least the greater part of the middle ear cavity and the tympanic tube. The second pouch almost completely disappears. It is from the third and fourth pouches that the parathyroid and thymus glands develop, and they also contribute to the formation of the thyroid gland. The fate of the fifth pouch is uncertain. Each pair of parathyroid glands has a different origin. The inferior parathyroid glands originate from the third branchial pouch and, therefore, are designated as parathyroid III, whereas the superior parathyroid glands descend from the fourth branchial pouch and are referred to as parathyroid IV. Figure 38-1 schematically depicts the development and migration of the parathyroids.
Norris," basing his findings on a collection of 139 human embryos, fetuses, and newborn children, studied the morphogenesis of the parathyroid glands. He divided the developmental process into five stages, as described next.
Preprimordial Stage The preprimordial stage is represented by embryos from 4 to 8 mm in length. This stage makes up the embryonic development between the time of the formation of the pharynx (foregut) and the earliest appearance of a recognizable parathyroid anlage. The third and fourth pouches show slight dorsal extensions. The third pouch, which has the form of a tubelike lateral expansion from the embryonic pharynx, makes contact with the ectoderm of the branchial cleft and then continues its growth downward in the ventral direction.
Early Primordial Stage At this stage, the embryo is about 9 mm in length. The tissue destined to become the parathyroids can be recognized. Proliferation and differentiation of large, clear cells with sharply demarcated polygonal outlines occur in the third and four pouches. This proliferation results in a thickening of the third diverticulum wall. The early primordium of parathyroid IV adopts the form of a solid budlike nodule; the fourth pouch still exists as a tubular diverticulum from the pharynx.
Branchial Complex Stage At this stage, paired derivatives of the third and fourth pouches become separated from each other to take up independent positions. During the early stage, the branchial pouches are joined to the pharynx; subsequently, the pharyngobranchial ducts become drawn out, narrowed, and finally divided so that at each side of the midline there is a pair of lobulated bodies. One pair represents the thymus and parathyroid III (third branchial complex), and the other represents the lateral thyroid and parathyroid IV (fourth branchial complex).
365
366 - - Parathyroid Gland and parathyroid III is at about the level of the lower pole of the thyroid, parathyroid III increases in size and gradually becomes constricted at its base of attachment, and complete separation occurs. The two elements of the fourth complex also grow and become constricted until the interlobular stalk is divided. There is almost no descent of this complex, and the isolation of parathyroid IV occurs when the lateral and median thyroids become incorporated. The final position of parathyroid IV in relation to the thyroid gland is determined by the place at which the inclusion of the lateral thyroid body occurs. Isolation of the parathyroid glands is usually accomplished by the time the embryo is 20 mm in length.
Definitive Form Stage This stage is the period from the end of the stage of isolation to the time when the parathyroids assume their definitive form. Alteration in form from a spherical or globular body toward an ellipsoid shape occurs. The form of the parathyroid glands is ultimately determined by their relation to adjacent structures. This embryologic relationship of the parathyroids, the thyroid, and the thymus makes the location of most parathyroid glands predictable. FIGURE 38-1. Origin of parathyroid glands from the third and
fourth pharyngeal pouches.
The median thyroid, which descended in an earlier stage from a median diverticulum of the floor of the pharynx, begins to grow out laterally and cephalocaudally in the form of a flat plate that extends to both sides of the midline. This plate begins to bend dorsally at its lateral edges and extends more and more dorsally to intervene between the laterally placed third branchial complex and the more medially placed fourth branchial complex. At the beginning of the branchial complex stage, the thymus primordium and the parathyroid primordium are intimately joined; however, the thymus enters into a period of rapid ventral growth until it makes contact with the pericardium. Parathyroid III, on the other hand, does not grow as rapidly as the thymus and remains as a budlike projection from the upper end of the thymus cord. Finally, parathyroid III takes a spherical shape, intimately attached to the cephalic pole of the thymus cord. At the end of this stage, the third branchial complex migrates through the entire extent of the embryonic neck, and separation of the parathyroid from the thymus begins. The position of the fourth complex in relation to the median thyroid depends on changes in form, size, and position of the rapidly growing lateral lobe of the median thyroid. During this time, parathyroid IV is still attached to the lateral thyroid body. The brachial complex stage ends when the embryo is approximately 18 to 20 mm in length.
Isolation Stage This stage is characterized by separation of each branchial complex. When the thymus and parathyroids have descended
Anatomy Most humans have four parathyroid glands. The percentage of individuals with supernumerary glands varies from 2.5% to 22%. The presence of as many as eight parathyroid glands has been reported, and different series have determined that there is a wide variation in the number of individuals with fewer than four glands. The exact number of individuals with fewer than four glands may be impossible to determine because the surgeon or researcher may not be able to find one or more glands, and a missing gland could represent an unobserved rather than an absent gland. The parathyroid glands usually lie on the posterior surface of the thyroid gland, each with its own connective tissue capsule surrounded by lighter colored fat globules. Figures 38-2 and 38-3 depict the normal location of parathyroid glands with emphasis on their anatomic relations. The superior parathyroid gland is normally located on the posteromedial aspect of the thyroid gland near the tracheoesophageal groove. The majority of these glands are located within a circumscribed area 2 em in diameter, about 1 em above the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. They may be either intimately associated with the cricothyroid junction or tucked behind the upper and middle thirds of the thyroid. When a gland is in intimate association with the cricothyroid junction, it is suspended by a small pedicle and enveloped by a pad of fatty tissue. When they are located on the posterior surface of the upper pole, parathyroid glands are invariably beneath a thyroid-investing fascial sheath. Superior parathyroid glands can be located farther down, sometimes obscured by the inferior thyroid artery or the recurrent laryngeal nerve. A rather unusual location is above the upper thyroid pole in the posterior aspect of the neck, the retropharyngeal or retroesophageal space. True superior intrathyroidal glands are rarely seen.
Parathyroid Embryology, Anatomy, and Pathology - - 367
FIGURE 38-2. Frontal view of the anatomic location of parathy-
roid glands.
The inferior parathyroid glands are more widely distributed. They are normally located on the posterolateral aspect of the inferior pole of the thyroid gland, below the inferior thyroid artery, although they may be located anterior, inferior, or lateral to the inferior thyroid pole. They are usually surrounded by fat and sometimes may be in a fatty
FIGURE 38-3. Lateral viewof the anatomic location of upperand
lower parathyroid glands. A, Right. B, Left.
appendage of the inferior thyroid pole. Some of these inferior glands can be found high up on the thyroid lobe. Another common location of the inferior parathyroids is the region inferior to the thyroid, close to the thyrothymic ligament or within the cervical part of the thymus. Inferior glands can also be located farther down in the thymus or in the fatty tissue of the anterior mediastinum, at the carotid bifurcation, or within the substance of the thyroid gland. Most anatomic studies have not involved serial sections of the thyroid gland, but Thompson and colleagues'' carefully sliced all thyroid lobectomy specimens during a 10-year period and found truly intrathyroid parathyroid glands in 3% of the cases. They were all located in the lower third of the thyroid and, therefore, were considered inferior parathyroid glands. Failure of an inferior parathyroid gland to descend during its embryonic development may result in a gland located higher up in the neck, even above the upper thyroid pole. These glands are usually surrounded by a remnant of thymic tissue. When supernumerary glands exist, the fifth gland is most often located in the thymus or in relation to the thyrothymic ligament."? Figure 38-4 graphically demonstrates the frequency of anatomic locations of both superior and inferior parathyroid glands as reported by Gilmour in a study on 527 autopsies. 10 As previously stated, parathyroid glands can be either extracapsular or intracapsular. When the gland is located underneath the fibrous capsule of the thyroid, it is designated intracapsular; whereas when it lies outside the capsule it is termed extracapsular. This anatomic feature has great surgical importance. When an intracapsular gland is diseased, it expands locally within the confines of the thyroid capsule and remains in its place. An enlarged extracapsular parathyroid gland, on the other hand, tends to be displaced to the area of least resistance. Thus, an extracapsular gland at the cricothyroid junction falls into the posterior mediastinum and an extracapsular gland within the thymus disappears behind the clavicle and falls into the superior anterior mediastinum. Symmetry of parathyroid glands varies for parathyroids III and IV. Symmetry of superior glands is found in approximately 80% of the cases, whereas approximately 70% of inferior glands are symmetrical. Relative symmetry of all four glands is noted in approximately 60% of the cases. It is important to note that symmetry is less marked when the glands are located in an unusual site.? When two parathyroid glands are intimately related to each other and appear to be fused, they are known as "kissing pairs." This is a rare finding. A kissing-paired parathyroid can be differentiated from a bilobular gland by the presence of a cleavage plane present in the kissing pair and an intact capsule in the bilobulated gland. The parathyroid glands vary in size, shape, and color. They are spherical, somewhat flattened, or ovoid bodies whose shapes are modeled by pressure from the surrounding structures. The size of parathyroid glands varies from 4 to 6 mm in length and 3 to 4 mm in width. The average parathyroid gland is about 5 x 3 x I mm. When they are long, they tend to be narrow and thin. Conversely, when they are short, they are wide and thick. The average weight of a parathyroid is 35 to 40 mg, but it ranges from 10 to 70 mg. The color of the glands varies with age. In the newborn. they are gray and semitransparent. They are light pink in children,
368 - - Parathyroid Gland
FIGURE 38-4. Frontal view of the anatomic location of upper and lower parathyroid glands as reported by Gilmour,"
turning yellow in adults as their fat content increases. In older adults, they become darker,"!' Parathyroid glands may conceivably be confused with small lobules of fat, with accessory nodules of thyroid tissue, or even with lymph nodes. Several physical characteristics may help to distinguish one from the other. The parathyroid glands are faintly globular or oblong structures that are softer in consistency than the adjacent thyroid or lymph nodes. Fat lobules are more friable than parathyroid glands and do not have the gland consistency or the lacework of blood vessels on the surface. Lymph nodes have a more rounded configuration and are more adherent to the surrounding tissues. Thyroid nodules are always harder, more reddish, and less homogeneous than parathyroid glands. Parathyroid tissue is quite vascular, and on biopsy a "blush" or diffuse bleeding can be seen on the cut surface. Neither fat nor lymph nodes exhibit such a blush. 6,l 2,l 3 At surgery, the typical appearance of a parathyroid gland is that of a small "body" that moves inside its own fat capsule when gentle pressure on the surface is applied with a fine surgical instrument.
Relation between the Parathyroid Glands and the Recurrent Laryngeal Nerve Emphasis has been placed on the relationship of the parathyroid glands and the recurrent laryngeal nerve. A predictable relation of both the superior and inferior parathyroid glands to the recurrent laryngeal nerve is noted within a rectangular area that can be imagined visually when the lobe of the thyroid is rotated medially. The superior boundary of this rectangle is the most cephalad portion of the thyroid lobe; the inferior boundary is a point on the trachea 4 em below the inferior pole of the thyroid gland; posteriorly, the esophagus; and anteriorly, the surface of the thyroid lobe and trachea. The usual course of the recurrent laryngeal nerve should divide this rectangle into two triangles, one lying ventral and the other dorsal to the nerve. After analyzing 100 autopsy specimens, Pyrtek and Painter" found that 93%
of parathyroid glands were situated in a predictable relation to the recurrent laryngeal nerve (i.e., superior glands lying posterior and superior to the nerve and inferior glands lying anterior to the nerve). This supports the reliability of the recurrent laryngeal nerve as a guide for locating the parathyroid glands.
Arterial Blood Supply to the Parathyroids On the basis of the study of 357 parathyroid gland pedicles, Flament and colleagues" found a single artery supplying the parathyroids in 80% of the cases. This artery was simple in 65% of the cases, bifurcated before its entry into the gland in 30%, and divided into three branches in 5%. In 15% of the total group, two distinct arteries were observed, in 4% three were seen, and in 1%, even four separate arteries were found. The length of the artery is variable, usually between 8 and 12 mm. When long, the arteries are commonly tortuous; when the pedicle is short, it holds the parathyroid hard against its vessel of origin. Generally, pedicles of the superior parathyroid are shorter than those of the inferior ones. Both the superior and inferior parathyroid glands most frequently borrow their blood supply from the inferior thyroid artery. In particular, superior parathyroid glands receive their arterial blood supply from this artery in approximately 80% of the cases. In 15%, the blood supply is provided by the superior thyroid artery, and in 5%, by anastomoses running between the two systems. When the superior thyroid artery supplies the superior parathyroid, the supply almost always comes from the posterior branch or from an artery arising from the posterior branch and destined for the esophagus or the larynx. In approximately 10% of the cases, inferior parathyroid glands are vascularized by the superior thyroid artery, anastomosis of both systems, or Neubauer's artery." This figure is intimately related to the frequency of agenesis of the inferior thyroid artery, which occurs in 1% to 6% of cases. In terms of parathyroid blood supply, certain practical observations are worthwhile. A special tiny parathyroid
Parathyroid Embryology, Anatomy. and Pathology - - 369 artery always supplies the gland and is considered terminal. Superior and inferior parathyroid arteries usually arise from the glandular branch of the thyroid artery but can often arise from the muscular or the esophageal branches. They can also originate from an anastomosing channel between the inferior and superior thyroid vessels. Very few, if any, vascular connections between the parathyroid glands and the adjacent connective tissue normally exist. The fine branches that the parathyroid arteries give off to the surrounding fat end in the fatty tissue, thus making it easier to enucleate the glands with their involved fat than to liberate them from it. 3,14
Adenoma
Parathyroid glands consist of chief and oxyphil cells, fibrovascular stroma, and adipose tissue. Chief cells are identified in children and adults; oxyphil cells are mainly observed in adults. Chief cells constitute almost all the parenchyma and measure 6 to 8 urn in diameter; their cytoplasm contains argyrophilic granules and lipids. Clear cells have an optically clear cytoplasm as a result of glycogen loss during histologic processing. The total number of oxyphil cells grows with increasing age; however, this kind of cell is also identified in pediatric populations. It is associated with secretory functions, contrary to the usual point of view that these are degenerated cells. 15 Parenchymal cells are arranged in solid sheets, cords, tubular structures, or, in 2% to 50%, microcystic formations. The admixture of stromal and adipose elements varies with age and function. The parenchyma-to-stroma ratio is used as an indicator of a normocellular or hypercellular gland; the median ratio is 50%, but the adipose tissue content varies from 40% to 70% (Fig. 38-5). Therefore, some authors consider the stromal-parenchymal index inadequate for separating normal from abnormal glands.l's'? Primary hyperparathyroidism can be produced by three different pathologic lesions: adenoma, hyperplasia, and carcinoma. The frequencies of these vary, mainly because of the use of different criteria for their diagnosis in the various series.
An adenoma is a benign neoplasm composed of chief cells, oncocytic cells, transitional oncocytic cells, or a mixture of these cell types. They are responsible for 80% to 90% of hyperparathyroidism cases and usually affect a single gland. Adenomas are more frequent in females than males, at a ratio of 3:1. Macroscopically, the affected gland is enlarged, tan-brown, ovoid, well limited or encapsulated, and occasionally with areas of hemorrhage or cystic spaces (Fig. 38-6). In smaller adenomas, a rim of normal glandular tissue is identified. The remaining glands are normal or atrophic. I? Histologically, adenomas are encapsulated tumors composed of cohesive sheets of cells surrounded by a fine capillary network. Occasionally, insular, tubular, trabecular, or acinar patterns are observed. Stromal fat is scant or absent, and the large, thick-walled veins typical of normal parathyroid glands are lacking. However, these two criteria, classically considered diagnostic of adenoma, have been regarded as less relevant.F:" A rim of normal glandular tissue is always identified in small lesions but is sometimes absent in large adenomas even if serial sections are made. On the other hand, adenomas are occasionally confused with hyperplastic nodules admixed with normal glandular tissue in cases of parathyroid hyperplasia. Because of the poor reproducibility of histologic criteria to differentiate parathyroid adenoma from hyperplasia, close cooperation between the pathologist and surgeon is recommended.l? In conclusion, a remnant of normal tissue is no absolute prerequisite for a diagnosis of adenoma and is identified in only 50% to 60% of proven adenoma cases (Fig. 38-7). The precise histopathologic definition of parathyroid adenoma has remained elusive. Studies using molecular approaches have established that parathyroid adenomas are clonal proliferations. Some studies demonstrated clonal rearrangements of the parathyroid hormone gene and further evidence for clonality through the analysis of the hypoxanthine phosphoribosyltransferase gene." Thus, the monoclonality of adenoma cells is usually reflected by their monomorphic appearance, although cases with a mixed
FIGURE 38-5. A close l: 1 relation of epithelial and stromal cells is observed in normal glands from adults.
FIGURE 38-6. Macroscopic aspect of a parathyroid adenoma showing a nodular configuration with cystic degeneration in a brown gland.
Pathology
370 - - Parathyroid Gland
FIGURE 38-7. Parathyroid adenoma. A rim of normocellular parathyroid tissue with adipose cells surrounds a proliferation of chief and oncocytic cells.
FIGURE 38-8. Parathyroid hyperplasia. Nodular proliferation of parenchymal cells admixed with normocellular parathyroid tissue at the periphery of a hyperplastic gland.
cellular population exist. The cells are larger than normal, and the nuclei show hyperchromasia, atypia, and an increased DNA content." Focally, there is syncytia formation, with variable numbers of nuclei surrounded by basophilic cytoplasm, probably as a result of cell degeneration.
In classic chief cell hyperplasia, these cells are mixed with oncocytic and transitional oncocytic cells. Stromal fat cells are decreased, and vascular supply is provided by large, thick-walled vessels. The parenchymal cells frequently show a nodular arrangement, usually at the beginning of the disease. These nodules consist of polygonal cells with abundant cytoplasm and a medium-sized or small, centrally located nucleus. In the internodular tissue, parenchymal cells are mixed with stromal elements (Fig. 38-8). In the occult form of parathyroid hyperplasia, confusion with a parathyroid adenoma or a large normal parathyroid gland can occasionally occur, and its functional significance is uncertain. To distinguish between parathyroid hyperplasia and parathyroid adenoma, it is important to know the gross appearance of all glands at surgery. 17 In primary chief cell hyperplasia, enlargement of more than two parathyroid glands is frequently observed, whereas the great majority of adenomas involve a single gland. Hence, no single morphologic parameter is able to resolve the differential diagnosis (Table 38-1); instead, the distinction between adenoma and hyperplasia is based on the combination of gross features plus histologic parameters. When a normal parathyroid gland is documented histologically, most experts believe that the abnormal gland or glands are adenomas.
Adenoma Variants Oncocytic adenomas are rare neoplasms composed of oncocytic cells. Ultrastructural studies have revealed the presence of abundant mitochondria in the cytoplasm of oncocytic cells. The major criteria for the diagnosis of oncocytic adenomas, according to Wolpert and coworkers.P are as follows: (l) more than 90% of cells showing oncocytic features, (2) histologically normal parathyroid tissue in a biopsy of another gland, and (3) postoperative normocalcemia. Lipoadenomas (hamartomas) are lesions consisting of proliferation of stromal and parenchymal elements. Grossly encapsulated, lipoadenomas appear soft, yellow-tan, and lobulated. Histologically they are composed mainly of abundant adipose tissue with myxoid changes and fibrosis, admixed with chief and oncocytic cells arranged in thin branching cords."
Hyperplasia Primary parathyroid hyperplasia is defined as an absolute increase in chief cells, oncocytic cells, and transitional oncocytic cells mixed with stromal elements in multiple parathyroid glands, in the absence of a known stimulus for parathyroid hormone hypersecretion. 17 Clinically, parathyroid hyperplasia does not differ significantly from adenomas. However, parathyroid hyperplasia is associated with the dominantly inherited multiple endocrine neoplasia (MEN) types land 2. In contrast, parathyroid hyperplasia is generally absent in MEN 28. 23 In more than half of the cases, the hyperplastic glands weigh less than 1 g. According to macroscopic and microscopic morphology, three patterns of hyperplasia have been recognized: classic, pseudoadenomatous, and occult."
Parathyroid Embryology, Anatomy, and Pathology - -
371
(posterior) side of the thyroid and are adjacent to the recurrent laryngeal nerve (upper posterior and lower anterior). About 80% of patients with primary hyperparathyroidism have solitary parathyroid tumors (adenomas), 1% have carcinoma, and 19% have hyperplasia or more than one abnormal parathyroid gland.
REFERENCES
FIGURE 38-9. Parathyroid carcinoma. Nodular arrangement of neoplastic parathyroid cells surrounded by fibrous tissue. A, The centers of the nodules show ischemic necrosis and calcification. B, Intrathyroidal metastasis of parathyroid carcinoma: small nests of neoplastic cells mixed with thyroid follicles.
Carcinoma Parathyroid carcinoma is responsible for 0.5% to 2% of cases of primary hyperparathyroidism. It is a slow-growing neoplasm of the parenchymal cells.'? On gross examination, parathyroid carcinoma is an illdefined mass, usually larger than adenomas, with adherence to surrounding tissues. The cut surface is irregularly nodular, gray-tan, and firm. Microscopically, it consists of neoplastic parenchymal cells that show atypia, mitotic figures, capsular and vascular invasion, and, of paramount importance, thick fibrous bands interspersed among the neoplastic cells. Not all of these features can be observed in every case; fibrous bands are present in 90%, mitotic activity in 80%, capsular invasion in 75%, and vascular invasion in 10% of cases in some series.17,25 The tumor cells making up parathyroid carcinoma are arranged in trabecular, sheetlike, or rosette-like patterns. Occasionally, the neoplastic cells form nodular structures with central calcification and necrosis (Fig. 38-9). Nuclear morphology is variable, from minimal atypia to marked pleomorphism with clumped chromatin and enlarged nucleoli.'? Cytoplasm is clear, eosinophilic, and granular, sometimes mimicking the plasmacytoid cytoplasm of the cells of medullary thyroid carcinoma. Because cytologic features broadly overlap, the distinction between parathyroid carcinoma and parathyroid adenoma is mainly based on the invasive character of the former.17,25
Summary The parathyroid glands ongmate from the third (lower parathyroids) and fourth (upper parathyroids) branchial pouches. These four glands are usually situated on the dorsal
1. Alveryd A. Parathyroid glands in thyroid surgery. Acta Chir Scand 1968;389: 1. 2. Welsh DA. Concerning the parathyroid glands: A critical anatomical and experimental study. J Anat Physiol 1898;32:292. 3. Halsted WS, Evans HM. The parathyroid glandules. Their blood supply, and their preservation in operation upon the thyroid gland. Ann Surg 1907;46:489. 4. Boyd JD. Development of the thyroid and parathyroid glands and the thymus. Ann R Coli Surg Engl 1950;7:455. 5. Norris EH. The parathyroid glands and the lateral thyroid in man: Their morphogenesis, histogenesis, topographic anatomy and prenatal growth. Contrib EmbryoI1937;159:249. 6. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:814. 7. Akerstrom G, MaImaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:14. 8. Wang CH. The anatomic basis of parathyroid surgery. Ann Surg 1976;183:271. 9. McGarity WC, Bostwick 1. Technique of parathyroidectomy. Am Surg 1976;40:657. 10. Gilmour JR. Embryology of the parathyroid glands, thymus and certain associated rudiments. J Pathol Bacteriol 1937;45:507. 11. Gray SW, Skandalakis JE, Akin JT, et al. Parathyroid glands. Am Surg 1976;40:653. 12. Curtis GM. The blood supply of the human parathyroids. Surg Gynecol Obstet 1930;315:805. 13. Pyrtek LJ, Painter RL. An anatomic study of the relationship of the parathyroid glands to the recurrent laryngeal nerve. Surg Gynecol Obstet 1964;119:509. 14. F1ament JB, Delattre JF, Pluot M. Arterial blood supply to the parathyroid glands: Implications for thyroid surgery. Anat Clin 1982;3:279. 15. Abu-Jawdeh GM, Roth SI. Parathyroid glands. In: Sternberg SS (ed), Histology for Pathologists. New York, Raven Press, 1992,p 311. 16. Ghandur-Mnaymneh L, Cassady J, Hajianpour MA, et al. The parathyroid gland in health and disease. Am J Pathol 1986;125:292. 17. Delellis RA. Tumors of the parathyroid gland. In Atlas of Tumor Pathology, 3rd series, fascicle 6. Washington, DC, Armed Forces Institute of Pathology, 1993, p I. 18. Ghandur-Mnaymneh L, Kimura N. The parathyroid adenoma. A histopathologic definition with a study of 172 cases of primary hyperparathyroidism. Am J PathoI1984;115:70. 19. Bomstein-Quevedo L, Gamboa-DomfnguezA, Angeles-Angeles A, et aI. Histologic diagnosis of primary hyperparathyroidism: A concordance analysis between three pathologists. Endocr PathoI2001;12:49. 20. Arnold A, Staunton CE, Kim HG, et al. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 1988;318:658. 21. Mallette LE. DNA quantitation in the study of parathyroid lesions. A review. Am J Clin Pathol 1988;98:305. 22. Wolpert HR, Vickery AL Jr, Wang CA. Functioning oxyphil cell adenomas of the parathyroid gland. A study of 15 cases. Am J Surg Pathol 1989;13:500. 23. DeLellis RA, Dayal Y, Tischler AS, et al. Multiple endocrine neoplasia (MEN) syndromes: Cellular origins and interrelationships. Int Rev Exp Pathol 1986;28:163. 24. Black WC, Haff RC. The surgical pathology of parathyroid chief cell hyperplasia. Am J Clin PathoI1970;53:565. 25. Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases. Cancer 1973;31:600.
Parathyroid Hormone: Regulation of Secretion and Laboratory Determination Jonas Rastad, MD, PhD • Peter Ridefelt, MD, PhD • Wen T. Shen, MD
The parathyroid gland is exceptional among human tissues because its principal secretory product, parathyroid hormone (PTH), is involved in a direct feedback loop, which tightly regulates the serum calcium concentration. This secretion is potently inhibited by calcium through calcium sensors on the parathyroid cell surface, and PTH exerts its effects through a specific receptor in the peripheral target tissues. In the past, disturbances in this system were difficult to recognize clinically because of inadequate assays for PTH and calcitriol. Despite the improvements in these assays, however, management of patients with the broad spectrum of metabolic calcium disturbances is still complicated by limitations in knowledge. This chapter provides a background for subsequent chapters on hyperparathyroidism by outlining the normal physiologic regulation of PTH secretion, describing the derangements in PTH and calcium regulation in primary and secondary hyperparathyroidism (HPT), and defining the current methods for determining serum PTH values.
Physiologic Regulation of Parathyroid Hormone Release Several endogenous substances, including peptides, steroid hormones, and amines, have been found to influence PTH release.I-' It is apparent, however, that calcium is the most potent regulator of PTH secretion. Analyses of normal parathyroid cells have shown that acute changes in extracellular calcium concentration induce rapid changes in PTH release.v' Studies in vitro and in vivo5-9 support the concept that the dose-response relationship between calcium and PTH is inversely sigmoidal, with the steepest part of the curve corresponding to the physiologic concentration range for ionized calcium (Ca2+j) (Fig. 39-IA). Minor alterations within the physiologic calcium concentration range can thus induce considerable secretory responses (Fig, 39-2), and 372
reduction of ionized plasma calcium by 0.04 mmollL may elevate serum PTH by 100% or more. Circadian variation in serum PTH values differs between men and women, and blunting of this variation in HPT seems to occur in vivo,10,I 1 whereas the presence and pathophysiologic significance of rapid pulsations in the release of PTH await clarification. 12,13 Stepwise alterations in extracellular calcium concentration have suggested that more sudden changes may elicit greater PTH responses, whereas rapid decreases in plasma calcium may be counteracted most effectively." The amplitude and direction of the change in calcium concentration also influence the magnitude of the secretory response. 15,16 A nonsuppressible component of PTH secretion persists even when the extracellular calcium concentration is markedly elevated (see Figs. 39-IA and 39-2). The extent of this component is partly related to discrepant sensitivities of PTH assays to different portions of the PTH molecule. Under normal circumstances, the basal serum PTH value is positioned closer to the level of maximal suppression than stimulation, which implies a potential to counteract decreased plasma calcium levels." The steep slope of the dose-response relationship between external calcium and PTH release in euparathyroid patients also supports the notion that shifts in the position and slope of the doseresponse curve significantly influence the steady-state serum PTH value.S'? Chronic changes in serum calcium lead to a shift in the calcium-PTH dose-response curve, whereas acute changes in serum calcium move the PTH secretory responses along the prevailing dose-response curve.7,8.14.18 Moreover, chronic hypocalcemia is characterized by a maintained, albeit numerically reduced, stimulation of PTH secretion in response to a further reduction of the calcium concentration (Fig. 39-3). The rapid effect of extracellular calcium on PTH release suggests that calcium directly interferes with the PTH release process, but the nature of this interference has been
Parathyroid Hormone: Regulation of Secretion and Laboratory Determination - 30
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FIGURE 39-2. Inverse sigmoidal relationship between ionized plasma calcium and intact serum parathyroid hormone (S-PTH) in 22 healthy controls (0) and 26 patients with sporadic primary hyperparathyroidism (e) subjected to sequential citrate and calcium infusions. Values represent mean ± standard deviation. (From Schwartz P, Sorensen HA, Transbol 1. Interrelations between the calcium set-points of Parfitt and Brown in primary hyperparathyroidism: A sequential citrate and calcium clamp study. Eur J Clin Invest 1994;24:553. © 1994 by Blackwell Science.)
300
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B FIGURE 39-1. Effects of increases in extracellular ionized calcium on parathyroid hormone (PTH) release (A) and steady-state Ca2+i (B) of dispersed parathyroid cells from normal glands of adult cattle, parathyroid adenomas (n = 22), hyperplastic glands of sporadic primary hyperparathyroidism (HPT) (n = 9), and familial HPT of multiple endocrine neoplasia (MEN) type I (n =8), as well as hyperplastic glands of uremic patients with hypercalcemic HPT (n = 23). PTH release is expressed in percentages of the release at 0.5 mmol extracellular calcium, and cytoplasmic calcium is measured with quin-2 in a cuvette system. Values represent mean ± standard error and are recalculated and extended from Wallfelt and
colleagues."
only partially clarified. It has been demonstrated that external calcium mainly regulates secretion of newly synthesized hormone, which may bypass the relatively few secretory granules in the parathyroid cells.!? Intracellular degradation with release of carboxyterminal PTH fragments occurs especially at high extracellular calcium concentrations. This attenuates the biologic activity of the secretory product because the calcium-regulating properties of PTH reside in its aminoterminal portion. The secretion of PTH is also modulated by transcription of the PTH gene, which consists of three exons and is located in chromosome 11 (1lp15).2o PTH is synthesized as a precursor molecule (pre-pro-PTH) and undergoes sequential cleavage." The pre-pro-signal
peptide is important for cellular transport and extrusion of the intact (1-84) PTH molecule. A single amino acid mutation in this sequence has been found to cause insufficient PTH secretion in familial hypoparathyroidism.P Similar actions have also been ascribed to PTH itself, and this may partially explain the existence of the carboxyterminal portion of PTH. Messenger RNA (mRNA) levels for PTH are increased within hours by low extracellular calcium, consistent with
200
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Peripheral Parathyroid Hormone Metabolism Intact PTH 1-84 is rapidly cleared from the human circulation and has a half-life of only a few minutes.19.114 This degradation ensures that activation of the PTH receptor can be closely regulated by parathyroid cell secretion of PTH. Moreover, there is no evidence for dynamic regulation of peripheral PTH metabolism. PTH clearance mainly depends on high-capacity uptake of Kupffer cells in the liver and on glomerular filtration. A small amount of PTH, however, appears in the urine because of tubular reabsorption and proteolysis. Circulating PTH is molecularly heterogeneous and contains various carboxyterminal peptide sequences arising by cleavage, mainly at residues 33 to 43. Although only 15% of intact PTH 1-84 is metabolized to such circulating fragments, they make up at least half, and sometimes substantially more, of the immunoreactive PTH in the circulation. 1I5•1I6 This discrepancy is due to the release of such fragments from the parathyroid gland, sequestration from Kupffer cells, and slower clearance from the circulation than for intact hormone. The metabolism of these fragments depends only on intact renal function; consequently, the fragments are accumulated to a considerable degree in renal insufficiency. In contrast, very few aminoterminal PTH fragments exist in the circulation of euparathyroid individuals,
although these fragments may become appreciable in primary and secondary HPT.
Parathyroid Hormone Receptor To characterize normal and pathologic systemic calcium homeostasis, it is pertinent to clarify some aspects of the cloned PTH receptor,'!" Apart from the classic targets of PTH in bone and kidney, the receptor has been demonstrated in fibroblasts, chondrocytes, lymphocytes, smooth muscle cells, and fat cells. This allows PTH to induce hypotension and bowel relaxation and to influence chronotropism and inotropism of the heart in addition to its classic actions on bone turnover and calcium, phosphate, and vitamin D metabolism in the kidney. The receptor also binds PTHrP with similar efficiency. Because PTHrP exerts a variety of hitherto partially clarified functions, studies on the common PTH-PTHrP receptor and its actions are hampered by difficulties in determining the biologically relevant agonist. Activation of the PTH receptor's cAMP-generating capacity requires PTH amino acids 1-24, and PTH 1-34 is essentially as potent as the full-length peptide. I IS However, various PTH fragments may activate other second messenger systems of the receptor with variable efficiency, whereby complex modes of differential interactions may exist. Moreover, specialized binding sites for midregional and carboxyterminal PTH sequences of unknown functional significance may occur,'!" The PTH receptor belongs to the growing family of peptide receptors characterized by seven transmembrane domains and G protein coupling. Expression of this receptor is sensitive to PTH, and prolonged exposure to the ligand can reduce the number of available receptors, whereby target cell functions are less effectively activated. 120 HPT of uremia is a striking example in this phenomenon, with its frequently profound elevation of intact serum PTH levels and comparably modest rise in serum calcium values. Internalization and partial recycling of the receptor protein are the mechanisms for this modulation. 12l Decreased affinity for PTH and desensitization of the cAMP response may modulate the peripheral actions of PTH.122 Other substances such as glucocorticoids as well as vitamin A and D metabolites may interfere with PTH receptor expression, although their in vivo actions in humans remain to be established. Inherited variants of pseudohypoparathyroidism may be caused by dysfunctions in the PTH receptor, its associated G proteins, and different second messenger systems such as adenylate cyclase and phospholipase C. 123
Parathyroid Hormone Assays Assaying for PTH in vivo has been notoriously difficult because of its picomolar concentrations in the circulation as well as its molecular heterogeneity. This heterogeneity is due to parathyroid gland secretion of various carboxyterminal PTH fragments (especially when PTH release is suppressed), hepatic proteolysis, and accumulation of midregional and carboxyterminal fragments caused by slow renal clearance in
Parathyroid Hormone: Regulation of Secretion and Laboratory Determination - - 379
kidney disease. In principle, PTH may be assayed for bioactivity as well as by radioimmunologic and immunometric methods. Although the former two are currently of limited clinical interest, their mechanisms deserve mention. PTH bioassays use either directly analyzed cAMP concentrations in urine or cAMP production of cell systems to assess biologic PTH activity of patients' sera. l24,125 Although such assays may be sensitive in the range of picograms of PTH (per milliliter), they are limited in routine use. These techniques are laborious. They are hampered by the concomitant activation of the PTH-PTHrP receptor by both ligands despite their very limited sequence homology. PTHrP is the most common cause for humoral hypercalcemia of malignancy. PTH bioassays do not distinguish between these two hormones. Moreover, cAMP responses of the PTH-PTHrP receptor might mirror its activation only partially because of the involvement of multiple second messenger systems, whereby bioassays may underestimate activity of circulating PTH. Radioimmunoassays were previously the most widely used means of PTH determination. This technique primarily uses a polyclonal, high-affinity antibody to which binding of radioiodinated PTH is allowed to compete with PTH to be measured in serum. By generating standard curves for binding of the radioactive ligand as a function of its concentration, the amount of iodinated PTH not displaced from the antibody can be used to approximate the concentration of PTH in the serum sample. Naturally, a host of factors require characterization and optimization to secure performance of such analyses. Some of these factors are antibody affinity, radiolabeling of PTH without interference with its immunoreactivity, and stability of the tracer peptide to be displaced.!" Particular problems have been caused by the use of bovine PTH as a tracer. Bovine PTH was selected because of its availability and the presence of tyrosine residues suitable for iodination. To reduce other difficulties, results have been reported in equivalents of pooled human sera. Moreover, analysis with characterized human PTH fragments has demonstrated multiple immunoreactivity of available displacement assays despite their characterization as "aminoterminal," "midregional," or "carboxyterminal." In view of the substantially lower circulating concentration of intact PTH in comparison with fragments encompassing various portions distal to the aminoterminal region, radioimmunoassays have been dependent on satisfactory renal function for reliable use in vivo and are variably limited in the recognition of mild to moderate primary HPT as well as the discrimination of HPT from other causes of hypercalcemia. 127,128 Displacement assays separate patients with primary HPT from overtly euparathyroid control subjects, provided that renal function is normal.P? This separation, however, naturally depends on the biochemical decision levels by which HPT is considered to prevail and current limits for the application of operative treatment verifying existence of the disease. Even with these assays, however, some 20% of individuals with malignancy-associated hypercalcemia demonstrate false-positive PTH elevations. This phenomenon is possibly related to circumstances other than limited specificity toward PTHrP.129,130 Hypothetically, nonspecific interaction of serum in these patients cannot be excluded as
a cause of this phenomenon. It might also be related to disproportionally increased parathyroid gland secretion of midregional and carboxyterminal PTH fragments recognized by these assays. Moreover, the total weight of abnormal parathyroid tissue is generally strongly correlated with serum PTH measured by displacement assay, which indeed also applies to total serum calcium.v' Because the variation among patients is considerable, however, measurements from many patients are required to establish these relationships. Neither biochemical variable, therefore, should be expected to be applicable to predict the degree of glandular enlargement.
Immunometric Assays Routine diagnosis of primary HPT and evaluation of the extent of secondary HPT have been greatly facilitated by the development of immunometric "sandwich" assays. Briefly, these assays use a pair of antibodies that recognize different regions of PTH.131-134 One of these antibodies, preferentially monoclonal, is immobilized, whereas a polyclonal antiserum with greater affinity is labeled with radioiodine (immunoradiometric assay) or chemoluminescence. Because of cooperation of the antibodies, such a sandwich assay is more sensitive than either antibody alone in displacement radioimmunoassays. With careful selection of antibodies, the immunometric assays are specific and sensitive for intact PTH, which allows identification of insufficient PTH secretion of hypoparathyroidism as well as a wide range of PTH levels without sample dilution. Moreover, it is technically favorable to tag antibodies rather than peptides. A vast excess of PTH fragments might hinder a small fraction of intact PTH from binding to the immobilized antibody and from reacting in the assay, a circumstance that has been suggested to occur in analyses for PTH of rare parathyroid gland aspirates.P" The immunometric analyzing process is faster than with radioimmunoassays. By reducing incubation times, the analysis can be done in 15 to 30 minutes and, consequently, can be used intraoperatively.136-138 Such speed of processing, however, is accompanied by a reduction in assay sensitivity. Clinical analysis with immunometric PTH assays usually separates hypercalcemic patients with HPT from patients with other causes of hypercalcemia. This is particularly evident with respect to malignancies of nonparathyroid origin, although some 5% to 10% of these patients demonstrate intact serum PTH in the lower portion of the normal range. Nonparathyroid tumors that produce intact PTH are exceptionally rare. Examples of such tumors include ovarian and small cell carcinomas as well as thymomas.P''33) chloride-to-phosphorus ratio." As mentioned earlier, a mild hyperchloremic metabolic acidosis is often present. About 30% of patients with primary hyperparathyroidism have an increased uric acid level, and 15% have an elevated alkaline phosphatase level. 34,35 Most patients with primary hyperparathyroidism also have an increased or high-normal 1,25-dihydroxyvitamin D 3 level." It is also important to document the serum blood urea nitrogen and creatinine levels, and perform serum protein electrophoresis. The latter helps to eliminate the diagnosis of multiple myeloma. Patients with primary hyperparathyroidism who have increased bone alkaline phosphatase (with other normal liver enzymes) have high-turnover bone disease and are susceptible to postparathyroidectomy hypocalcemia. In patients with osteitis fibrosa cystica, the blood magn~sium and potassium levels can be low, and hypomagnesemia can contribute to postoperative tetany.
Normocalcemic Hyperparathyroidism Patients with primary hyperparathyroidism can also be normocalcemic. Most of these individuals are detected because of recurrent nephrolithiasis or osteoporosis.'? The reasons for normocalcemic hyperparathyroidism include (1) vitamin D deficiency, (2) low serum albumin, (3) pancreatitis, (4) increased phosphate intake, (5) excessive hydration, and (6) a low-normal blood calcium set point with an increase above the patient's normal calcium level but still within the normal range.'? The diagnosis of normocalcemic hyperparathyroidism is usually made by documenting an increased total PTH level with or without an increased blood ionized calcium level. However, patients with renal leak hypercalciuria must be excluded. The increased PTH level in patients with renal leak is secondary to the excessive calcium loss in the urine; one can diagnose renal leak hypercalciuric patients by treating them with thiazide diuretics, With treatment, the urinary calcium level falls and the secondary increase in the blood PTH also decreases to normal. In patients with normocalcemic hyperparathyroidism, the urine calcium and blood PTH remain elevated." Normocalcemic hyperparathyroidism is discussed in more detail Chapter 45.
Radiologic Investigations Patients with classic osteitis fibrosa cystica have subperiosteal bone resorption best observed on the radial aspect of the middle and distal phalanges on hand radiographs. Other skeletal manifestations of severe primary hyperparathyroidism include bone cysts, osteoclastomas or "brown tumors," pathologic fractures, and general demineralization. The skull may exhibit a finely mottled, ground-glass appearance, with loss of definition of the inner and outer cortices." Abdominal flat plates or ultrasonography may reveal renal stones. Bone densitometry studies are currently being performed more frequently and may be utilized in assessing the effects of primary hyperparathyroidism on bone. Primary hyperparathyroidism mainly leads to loss of bone at cortical sites such as the distal radius. Bone density is relatively preserved at sites such as the lumbar spine, which is rich in cancellous bone.'? This is in contrast to the bone density changes seen in menopause. In the latter, the lumbar spine is the major target of bone mineral loss. Despite these findings, lumbar spine density improves after parathyroidectomy.f-" Localizing tests such as ultrasonography, sestarnibi scanning, magnetic resonance imaging, or computed tomography scanning are used by some clinicians to make or confirm the diagnosis of primary hyperparathyroidism. One should emphasize, however, that the diagnosis of primary hyperparathyroidism is made by metabolic testing; localiza~ion te~ts often identify the tumor site but do not make the dIagnOSIS, because both false-positive and false-negative localization tests occur.'?
Indications for Operative Treatment As discussed earlier, the clinical profile of primary hyperparathyroidism has undergone a distinct change over the
Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - - 387
past few decades, particularly with the introduction of automated blood chemistry panels. The 1990 National Institutes of Health Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism was convened to set forth evidence-based diagnosis and management guidelines for this group of patients. The panel recognized surgery as the only definitive treatment for primary hyperparathyroidism and recommended parathyroidectomy for any individual with overt complications and symptoms such as nephrolithiasis, fractures, and neuromuscular syndrome. In addition, surgery was recommended for asymptomatic patients with' (1) serum calcium more than 1 to 1.6 mg/dL (0.25 to 0.4 mM) above the accepted normal reference range; (2) 24-hour urine calcium greater than 400 mg (10 mM); (3) a 30% reduction in creatinine clearance compared with age-matched normal individuals; (4) bone mineral density more than 2 standard deviations (SD) below that of age-, gender-, and race-matched controls; (5) age younger than 50 years; and (6) in whom medical surveillance is not possible or desirable. The vague neurobehavioral axis symptoms (weakness, increased fatigue without overt muscle weakness) were deemed nonspecific and not sufficient in and of themselves to recommend surgery, unless these symptoms were thought to be related to hyperparathyroidism. The panel also recommended that patients not undergoing surgery understand the importance of regular, longterm follow-up and undergo (1) biannual measurements of blood pressure, serum calcium serum creatinine and creatinine clearance and (2) annual abdominal radiography (and/or ultrasonography), 24-hour urine calcium test, and bone mass measurement. Patients were also to be advised on the importance of adequate mobility and seeking prompt medical attention for any intercurrent illness causing dehydration, both of which can worsen existing hypercalcemia. Since the last consensus meeting in 1990, there has been an accumulation of data on the natural history of asymptomatic hyperparathyroidism and the long-term effects of untreated hyperparathyroidism. Moreover, localizing studies are more accurate, readily available, and utilized. Several minimally invasive surgical approaches have also been developed, as have novel medical therapies. Therefore, a follow-up Workshop on Asymptomatic Primary Hyperparathyroidism: A Perspective for the 21st Century was held at the National
Institutes of Health in April 2002 to re-evaluate the recommendations of the previous consensus meeting. The revised recommended indications for surgery along with the reasons for the change are as follows": 1. Serum calcium greater than 1 mg/dL (0.25 mM) above the upper reported normal reference range The range was lowered because the panel believed that even patients with this degree of elevation of serum calcium were at risk for developing symptoms and complications of hyperparathyroidism. 2. 24-hour urine calcium excretion 400 mg/day (unchanged) 3. A 30% decrease in creatinine clearance compared with age-matched control subjects (unchanged) 4. Bone density at the lumbar spine, hip, or distal radius greater than 2.5 SD below peak bone mass (T-score less than -2.5) Hyperparathyroidism classically leads to loss of cortical bone mass. However, a subset of patients with primary hyperparathyroidism have marked bone density loss at sites of cancellous bone such as the spine, and parathyroidectomy has been demonstrated to increase bone mass at these sites. 44•45 T-scores, which represent deviations from an individual's optimal bone mass, seem to be a more reasonable indicator of fracture risk than Z-scores, which compare bone mineral density with that of age- and sex-matched cohorts. Hence, the panel recommended bone mineral density measurement at three sites and a change to T- rather than Z-score measurements. 5. Age younger than 50 years (unchanged) 6. Patients for whom medical surveillance is not possible or desirable (unchanged) The panel also cautioned against the use of neuropsychological abnormalities, cardiovascular disease, gastrointestinal symptoms, menopause, and elevated serum or urine indices of increased bone turnover as sole indications for parathyroidectomy. Rather, these factors should be weighed in the context of the individual patient. Although bisphosphonates and calcimimetics show promise, data are insufficient to recommend medical management in patients with asymptomatic primary hyperparathyroidism and only parathyroidectomy offers curative treatment. The new recommendations for follow-up of patients not undergoing surgery are compared with the previous recommendations in Table 40-4.
388 - - Parathyroid Gland
Rationale for Parathyroidectomy There is good evidence that in about 80% of patients the clinical manifestations improve after successful parathyroidectomy.8,9,10,46,47 Thus, fatigue, exhaustion and weakness, polydipsia, polyuria and nocturia, bone and joint pain, constipation, nausea, and depression improve in some patients.8.10,46,47 This is also true for associated conditions. In these patients, new kidney stones usually stop forming, osteoporosis stabilizes or improves, peptic ulcer disease often resolves, and pancreatitis becomes less likely.46,47 Thus, both neuropsychiatric and somatic problems improve in most, but not all, patients (Figs. 40-1 to 40_4).10,48 Increased fracture risk and weakness also improve after successful parathyroidectomy in most, but certainly not all, patients.Jv" Objective increase in muscular strength has also been documented after successful parathyroidectomy." Patients can also resume a regular diet with or without calcium supplementation and hypercalcemia is not a concern when patients are hospitalized for other medical problems. Several quality of life studies have been performed using standardized tools such as the SF-36 health survey in patients with primary hyperparathyroidism, and demonstrated that patients experience an improvement in health status and quality of life after surgical correction. 14-17,50 Furthermore, this benefit was independent of preoperative calcium levels." Psychological distress, as measured by the General Health Questionnaire, has also been shown to
be ameliorated by parathyroidectomy.-' In contrast to the aforementioned generic quality of life tools, Pasieka and Parsons have developed a patient-based outcome tool specifically for primary hyperparathyroidism.F A multicenter study using this questionnaire indicated that the Parathyroidectomy Assessment of Symptoms is a reliable measure of the symptoms seen in patients with hyperparathyroidism, as shown in Figures 40-5 and 40-6, and that these symptoms improve after parathyroidectomy.P It therefore seems that there are both classic and more subtle clinical manifestations of primary hyperparathyroidism that warrant medical evaluation and, in most patients, parathyroidectomy. This is especially true because parathyroidectomy, when performed by an experienced surgeon, is successful in more than 95% of patients. Furthermore, the operation usually takes less than 2 hours, blood is virtually never required, complications occur in less than 2% of patients, and hospitalization is usually for 24 hours, unless the patient has other serious medical problems or severe osteitis fibrosa cystica with a markedly elevated blood alkaline phosphatase level preoperatively," The latter patient requires treatment with oral and intravenous calcium and 1,25-dihydroxyvitamin D (Rocaltrol, 0.25 to 1 ug orally daily) postoperatively because of hypocalcemia and occasionally hypomagnesemia as a result of "bone hunger." Another and perhaps more important reason for recommending parathyroidectomy is that patients with primary hyperparathyroidism appear to be at risk for premature death primarily because of cardiovascular disease and cancer, as
FIGURE 40-1. Changes in the frequency of symptoms after surgery in parathyroid and thyroid patients. (From Chan AK, Duh QY, Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A case-control study. Ann Surg 1995;222:402.)
Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - -
FIGURE 40-2. Changes in the frequency
of associated conditions after surgery in parathyroid and thyroid patients. (From Chan AK, Duh QY, Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A case-control study. Ann Surg 1995;222:402.)
FIGURE 40-3. Neuromuscular recovery after parathy-
roidectomy in primary hyperparathyroidism with patients having thyroid operations as controls. (From Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995;117:18.)
so = standard deviation, Preop = preoperative
Postop = postoperative 1 week, Late = postoperative 4 weeks P with paired t test
389
390 - - Parathyroid Gland
FIGURE 40-4. Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism with patients having thyroid operations as controls. (From Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995;117:18.)
SD = standard deviation, Preop = preoperative Postop = postoperative 1 week, Late = postoperative 4 weeks P with paired t test
documented in the classic study by Palmer and coworkers>' and confirmed by the studies of Sivula.t' Hedback21,56,57 and their colleagues. Of equal importance, as documented by Hedback and colleagues, is that the increased death rate, even in patients with mild primary hyperparathyroidism, can be
reversed by successful parathyroidectomy. Of interest is the finding that in young patients and in those with the least severe hypercalcemia, the survival curve returns to normal most quickly." Patients between the ages of 55 and 70 years seem to receive the greatest survival benefit,21,56.57
FIGURE 40-5. Comparison of Parathyroidectomy Assessment of Symptoms (PAS) scores between patients with primary hyperparathyroidism (HPT) and those with thyroid cancer at one center. "P < .001; Pre op = preoperative; Post op = postoperative. (From Pasieka J, Parsons L, Demeure M, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942.)
FIGURE 40-6. The Parathyroid Assessment of Symptoms (PAS) scores from three centers over time, "P < .001; Pre op = preoperative; Post op = postoperative. (From Pasieka J, Parsons L, Demeure M, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942,)
Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - - 391
Conclusion In conclusion, the diagnosis of primary hyperparathyroidism can be made with nearly 100% confidence by documenting an increased serum PTH level in a patient with increased ionized or total calcium without hypocalciuria. Making the diagnosis is important, because preoperative vague or classic symptoms or metabolic conditions associated with primary hyperparathyroidism often improve after parathyroidectomy, as does long-term survival.
REFERENCES I. Proceedings of the NIH Consensus Development Conference on diagnosis and management of asymptomatic primary hyperparathyroidism. Bethesda, Maryland, October 29-31, 1990. J Bone Miner Res 1991;6:S 1. 2. Lundgren E, Rastad J, Thrufjell E, et al. Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women. Surgery 1997;121:287. 3. Clark OH, Duh QY. Primary hyperparathyroidism. A surgical perspective. Endocrinol Metab Clin North Am 1989;18:701. 4. Grill V, Martin TJ. Hypercalcemia of malignancy. Rev Endocr Metab Disord 2000;1:253. 5. Grill V, Ho P, Body n, et al. Parathyroid hormone-related protein: Elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab 1991;73:1309. 6. Firkin F, Seymour JF, Watson AM, et al. Parathyroid hormone-related protein in hypercalcaemia associated with haematological malignancy. Br J Haematol 1996;94:486. 7. Kurihashi A, Tamai K, Saotome K, Yamaguchi T. Multifocal Ewing's sarcoma and hypercalcemia. A case report. Clin Orthop 1996;(326):254. 8. Clark OH, Wilkes W, Siperstein AE, Duh QY. Diagnosis and management of asymptomatic hyperparathyroidism: Safety, efficacy, and deficiencies in our knowledge. J Bone Miner Res 1991;6:S135. 9. Solomon BL, SchaafM, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101. 10. Chan AK, Duh QY, Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study. Ann Surg 1995;222:402. 11. Loh KC, Duh QY, Shoback D, et al. Clinical profile of primary hyperparathyroidism in adolescents and young adults. Clin Endocrinol (Oxf) 1998;48:435. 12. Joborn C, Hetta J, Niklasson F, et al. Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the blood-brain barrier function in primary hyperparathyroidism. Psychoneuroendocrinology 1991;16:311. 13. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473. 14. Burney RE, Jones KR, Coon JW, et al. Assessment of patient outcomes after operation for primary hyperparathyroidism. Surgery 1996;120:10 13. 15. Burney RE, Jones KR, Peterson M, et al. Surgical correction of primary hyperparathyroidism improves quality oflife. Surgery 1998;124:987. 16. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608. 17. Talpos GB, Bone HG 3rd, Kleerekoper M, et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: Patient description and effects on the SF-36 health survey. Surgery 2000;128:1013. 18. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513. 19. Kenny AM, MacGillivray DC, Pilbeam CC, et al. Fracture incidence in postmenopausal women with primary hyperparathyroidism. Surgery 1995;118:109. 20. Joborn C, Joborn H, Rastad J, et al. Maximal isokinetic muscle strength in patients with primary hyperparathyroidism before and after parathyroid surgery. Br J Surg 1988;75:77.
21. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990;14:829. 22. Hedback G, Oden A. Increased risk of death from primary hyperparathyroidism-An update. Eur J Clin Invest 1998;28:271. 23. Sugar A. Conjunctival and corneal degenerations. In: Yanoff M, Duker JS (eds), Ophthalmology, 2nd ed. Philadelphia, Mosby, 2004, p 449. 24. Szabo J, Heath B, Hill VM, et al. Hereditary hyperparathyroidism-jaw tumor syndrome: The endocrine tumor gene HRPT2 maps to chromosome Iq21-q31. Am J Hum Genet 1995;56:944. 25. Kebebew E. Parathyroid carcinoma. Curr Treat Options Oncol 2001;2:347. 26. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807. 27. Strewler GJ, Budayr AA, Clark OH, Nissenson RA. Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab 1993;76:1373. 28. Heath H 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723. 29. Gunn IR, Wallace JR. Urine calcium and serum ionized calcium, total calcium and parathyroid hormone concentrations in the diagnosis of primary hyperparathyroidism and familial benign hypercalcaemia. Ann Clin Biochem 1992;29:52. 30. Marx SJ, Attie MF, Stock JL, et al. Maximal urine-concentrating ability: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1981;52:736. 31. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993;75:1297. 32. Chou YR, Brown EM, Levi T, et al. The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nat Genet 1992;1:295. 33. Fujimoto Y, Hazama H, Oku K. Severe primary hyperparathyroidism in a neonate having a parent with hypercalcemia: Treatment by total parathyroidectomy and simultaneous heterotopic autotransplantation. Surgery 1990;108:933. 34. Clark OH. Hyperparathyroidism. In: Oh C (ed), Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985, P 172. 35. Duh QY, Morris RC, Arnaud CD, Clark OH. Decrease in serum uric acid level following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 1986;10:729. 36. Bilezikian JP, Silverberg SJ, Gartenberg F, et al. Clinical presentation of primary hyperparathyroidism. In: Bilezekian JP, Marcus R, Levine MA (eds), The Parathyroids. New York, Raven Press, 1994, p 457. 37. Siperstein AE, Shen W, Chan AK, et al. Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery. Arch Surg 1992;127:1157. 38. Bringhurst FR, Demay MB, Kronenberg HM. Hormones and disorders of mineral metabolism. In: Williams RH, Wilson JD (eds), Williams Textbook of Endocrinology. Philadelphia, WB Saunders, 1998, p 1155. 39. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989;4:283. 40. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:729. 41. Silverberg SJ, Shane E, Jacobs TP, et al. A IO-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249. 42. Arici C, Cheah WK, ltuarte PH, et al. Can localization studies be used to direct focused parathyroid operations? Surgery 2001;129:720. 43. Bilezikian JP, Potts IT Jr, El-Hajj Fuleihan G, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353. 44. Abe Y, Ejima E, Fujiyama K, et al. Parathyroidectomy for primary hyperparathyroidism induces positive uncoupling and increases bone mineral density in cancellous bones. Clin Endocrinol (Oxf) 2000;52:203. 45. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007.
392 - - Parathyroid Gland 46. Uden P, Chan A, Duh QY, et al. Primary hyperparathyroidism in younger and older patients: Symptoms and outcome of surgery. World J Surg 1992;16:79l. 47. Clark OH. "Asymptomatic" primary hyperparathyroidism: Is parathyroidectomy indicated? Surgery 1994;116:947. 48. Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995;117:18. 49. Deutch SR, Jensen MB, Christiansen PM, Hessov I. Muscular performance and fatigue in primary hyperparathyroidism. World J Surg 2000;24:102. 50. Sheldon DG, Lee FT, Neil NJ, Ryan JA Jr. Surgical treatment of hyperparathyroidism improves health-related quality of life. Arch Surg 2002;137:1022. 51. Okamoto T, Kamo T, Obara T. Outcome study of psychological distress and nonspecific symptoms in patients with mild primary hyperparathyroidism. Arch Surg 2002;137:779. 52. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients
53.
54. 55. 56. 57.
with secondary and tertiary hyperparathyroidism. Surgery 2000; 128:531. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942. Palmer M, Adami HO, Bergstrom R, et al. Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up. Lancet 1987;I :59. Sivula A, Ronni-Sivula H. Observations on 334 patients operated on for primary hyperparathyroidism. Ann Chir GynaecoI1985;74:66. Hedback G, Oden A, Tisell LE. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991;15:399. Hedback G, Oden A, Tisell LE. Parathyroid adenoma weight and the risk of death after treatment for primary hyperparathyroidism. Surgery 1995;117:134.
Natural History of Untreated Primary Hyperparathyroidism Goran Akerstrom, MD • Ewa Lundgren, MD
In the early descriptions of patients with primary hyperparathyroidism (HPT), the disease was recognized as a rare disorder and was associated with severe incapacitating bone symptoms, prevalent renal stones, devastating muscular weakness, and often early death from renal failure. Since the introduction in the mid-1970s of automated equipment allowing routine measurements of serum calcium by multiphasic laboratory screening on liberal indications, primary HPT has been diagnosed with increased frequency. I The disease has been revealed to be particularly prevalent in postmenopausal women, and many such patients have had a milder ailment than was common some decades ago. These patients have typically lacked the bone or renal stone complications of HPT and have instead exhibited vague symptoms of fatigue or psychiatric disability or have appeared asymptomatic.P Because general policies of management in primary HPT have been based on studies of symptomatic patients, it has not been obvious that primary HPT detected at a mild and uncomplicated stage requires the same treatment. Accordingly, it has been suggested that subsets of patients with primary HPT may be subjected to surveillance rather than surgery.v' Concomitantly, the diagnosis of HPT has become easier and more precise with the introduction of new methods for measurement of intact serum parathyroid hormone (PTH). HPT can now be diagnosed with assurance, even in cases with no more than borderline elevations of serum calcium.v'
Epidemiology Epidemiologic data on the prevalence of primary HPT are sparse for most countries. An autopsy study of a Swedish population revealed parathyroid adenoma in 2.4% and "subclinical" disease represented by micronodular chief cell hyperplasia in another 7%, with an apparent continuum of abnormality ranging from hyperplastic micronodular lesions to the adenomas." Borderline hypercalcemia could be clinically detected in occasional patients with hyperplastic glands containing larger, predominant nodules or in those
with tiny adenomas, whereas more marked elevation of serum calcium was associated with adenomas of more conspicuous size.? The histologic abnormalities were particularly common in older individuals of both genders and related to histologic signs of nephrosclerosis, even in the absence of clinically detectable renal dysfunction," These findings substantiate the presence of prevalent subclinical and clinical parathyroid disease within the elderly Swedish population. They also mirror problems in clinical management of patients with primary HPT because an increased incidence of micronodular hyperplasia and tiny adenomas has been encountered when patients with borderline hypercalcemia have been liberally submitted to parathyroid exploration."!" Population screening has confirmed the prevalence of parathyroid disease in Sweden, but it has also demonstrated that prevalence data depend on the age of the population studied as well as the level of hypercalcemia that is used to distinguish patients with HPT from normal individuals. I 1·13 Accurate screening for detection of hypercalcemia also requires that repeated serum calcium determinations be used in such surveys. I 1.13 A health screening survey of employees aged 20 to 63 years within Stockholm County in Sweden included repeated measurements of serum calcium and revealed hypercalcemia supposedly resulting from HPT, with an overall prevalence of 0.4% to 0.6%.11 Elevated serum calcium levels were detected in approximately 0.3% of men and 1% of women older than 50 years. This screening used serum calcium levels greater than 2.65 mmol/L (10.6 mg/dL) to define hypercalcemia, and older age groups, in which HPT is in fact most common, were not included. In another health screening survey in Gavle County of Sweden, 16,401 individuals had repeated serum calcium determinations over a 2-year period (1969 and 1971).13 Altogether, 172 individuals were found to have hypercalcemia, with serum calcium levels higher than the normal reference of 2.60 mmol/L on both occasions, without other obvious reasons such as vitamin D or oral calcium medication or malignancy." This corresponded to approximately 1% of the population, 0.3% of men and 1.6% of women.
393
394 - - Parathyroid Gland In women older than 60 years, the prevalence of hypercalcemia was close to 3% (Fig. 41-1),13,14 Female predominance in screening surveys may be partly related to significantly higher normal means of serum calcium in postmenopausal women than in men of the same age, implying that even minimal increases in serum calcium could be more easily detected. 13 This probably does not explain a female overrepresentation in clinically detected HPT, which is also likely to be related to regulatory disturbances within the diseased parathyroid tissue. Although most of the hypercalcemic individuals in this study did not have a parathyroid operation and the diagnosis is not undisputable, it is reasonable to assume that the majority of them had HPT.13,14 In a population screening in which serum calcium levels were determined in conjunction with a mammographic health survey, a comparable prevalence of HPT of 2.2% was found for postmenopausal women with a mean age of 59 years." The majority of hypercalcemia cases were borderline, and most of the individuals were elderly. Similar high prevalence estimates of hypercalcemia and presumable HPT were documented in a more recent health screening survey from Norway.16 Although figures depend on definition criteria, the disease can be expected in at least 2% of postmenopausal women.P:" Reports from the United States and Europe have suggested that the incidence of HPT may be declining, perhaps because of more restricted use of multichannel screening tests for hypercalcemia.lv't-" Comparison of health survey figures and hospital statistics in Sweden and the United States indicates that even if surgery were done for relatively liberal indications, currently only about one tenth of all patients with HPT in the population are subjected to parathyroidectomy.13,19,20 Considering the high prevalence figures of the health surveys, it is reasonable that studies aim to clarify whether surgery for primary HPT is also of benefit for patients with a mild, asymptomatic, and uncomplicated disease or whether such patients may be safely monitored without surgery.
Women (n=149) Number 31
70- Men (n=27) Number 60-69
5
50-59
6
40-49
3
30-39
8
48 OJ
If
41 26 2
2
25-29
3
r,
20
10
10 Per million
20
30
FIGURE 41-1. Prevalence of hypercalcemia in men and women of different age groups in the Gavle County Health Survey. (Adapted from Palmer M, Jakobsson S, Akerstrom G, et al. Prevalence of hypercalcemia in a health survey: A 14-year follow-up of serum calcium levels. Eur J Clin Invest 1988;18:39. Copyright 1988 by Blackwell Science Ltd.)
Follow-up of Health Survey-Detected Hypercalcemia In the Stockholm health survey, 27 randomly selected hypercalcemic patients underwent neck exploration, and all were found to have parathyroid adenoma." Another group of 23 hypercalcemic patients (mean age, 55 years) was monitored with regular checkups and compared with ageand sex-matched normocalcemic control subjects during a to-year period." Their initial mean serum calcium of 2.75 mmollL remained unchanged during the study period, and there was no notable deterioration of kidney function in routine serum analyses. A significant elevation of systolic and diastolic blood pressures in the hypercalcemic individuals compared with control subjects at initiation of the follow-up persisted throughout the 10-year study period. 2l,22 In the Gavle health survey, the mean age of hypercalcemic individuals was 59 years, and their mean serum calcium was 2.72 mmol/L." Eleven patients initially had surgery because of marked hypercalcemia (2.83 to 3.63 mmollL), and another 21 underwent surgery between 1971 and 1983 to 1984 when a follow-up study was performed." The majority of the patients with hypercalcemia were neither informed about their hypercalcemia nor treated. At the follow-up study in 1983 to 1984,57 patients had died and 7 were lost to follow-up. Scrutiny of patients' records did not indicate that any of these individuals had had severe hypercalcemia or renal insufficiency.P'P Of the remaining 95 patients, 47 still had a serum calcium level greater than 2.60 mmollL in 1983 to 1984, and 48 subjects with serum calcium levels slightly below this normal limit had displayed intermittent hypercalcemia in the intervening years. 13 For the majority of hypercalcemic individuals, the serum calcium remained more or less constant throughout the study period, and no patient (including those who subsequently had parathyroid surgery) showed markedly progressive hypercalcemia or an abrupt rise in serum calcium levels.P Serum creatinine levels were above normal in 15 patients at the 1983 to 1984 follow-up, but only 3 patients had a more marked elevation of serum creatinine, and these individuals had either urea nitrogen above normal at the initial screening or obvious nonparathyroid causes of renal impairment.P Using national registration numbers and the causes of death registry, survival was compared between individuals who were hypercalcemic at the 1969 to 1971 survey and matched normocalcemic control subjects." Survival during the l4-year follow-up was significantly lower among the hypercalcemic individuals.P The difference in survival steadily increased and became more marked after 5 years from the initial health survey.F' The hypercalcemic individuals also had significantly higher diastolic and systolic blood pressures as well as serum uric acid and a tendency toward higher glucose and cholesterol levels. Using multivariate analyses, higher levels of serum calcium were associated with increased mortality in patients older than 60 years, but this effect diminished in the oldest age groups. Life table analyses revealed a significant difference in survival between hypercalcemic persons and control subjects at age 70 or younger but not for those older than 70 years (Fig. 41_2),23 The increased mortality in the hypercalcemic
Natural History of Untreated PrimaryHyperparathyroidism - - 395
... ~~ FIGURE 41-2. Survival curves for hypercalcemic subjects and matched control subjects from the Gavle County Health Survey. (From Palmer M, Adami H-O, Bergstrom R. et al. Survival and renal function in persons with untreated hypercalcaemia: A population-based cohort study with 14 years of follow-up. Lancet 1987;1:59. © by the Lancet Ltd., 1987.)
Subjects> 70 years
Subjects s 70 years
All subjects
-
__...._"'"._ / Controls
.....
'"--
····t..·-i
"1
/
/'
/
Hypercalcemics
50
I
5
,
p=0.9
p=0.0025
p=0.0135 ,
,
10
13
5
10
13
5
10
13
Time offollow up (years)
group was not due to any single disease group, but the number of deaths caused by cardiovascular diseases was predominant and distinctly higher than expected. No deaths were caused by hypercalcemic crisis, renal failure, or other conditions that were obviously related to the hypercalcemic state." When examined for symptoms, the hypercalcemic individuals exhibited similar but less significant psychiatric symptoms when compared with patients with clinically detected primary HPT14.24.25 but more symptoms than the normocalcemic control patients. The hypercalcemic individuals were subsequently subjected to a 25-year follow-up, showing a tendency to lowering (or even normalization) of the hypercalcemia but continuing to have increased mortality in comparison with control subjects." The excess mortality was significant among individuals 70 years of age or younger and was valid for cardiovascular disease only." The studies indicate that the risk for progression of hypercalcemia or marked deterioration of renal function is low in borderline hypercalcemic primary HPT. The risk for subclinical renal impairment in HPT and thereby reduced levels of active vitamin D, which could contribute to the increased cardiovascular death rate (and also to lowering or normalization of the hypercalcemia), has been emphasized.'? The raised mortality has, however, not been found in all series28.29 and may depend on the severity and duration of HPT.27 The psychiatric disturbance may be a notable complication in individuals with intellectual occupations and cause states of confusion in elderly people but may not always be impressive in patients with borderline hypercalcemia.P
Conservative Follow-up in Clinically Detected Primary Hyperparathyroidism In 1981, Scholz and Purnell reported a prospective lO-year follow-up study from the Mayo Clinic aiming to evaluate the disease course in patients with asymptomatic primary HPT who were not subjected to surgery.30.31 This study remains
the most important long-term follow-up of conservatively managed primary HPT; it was initiated in 1968 and terminated in 1980.30.31 The intent was to clarify the natural history of the disease and to determine possible risks for progression into a symptomatic or complicated stage that ultimately would require surgery. A further aim was to determine whether such progression could be detected before significant complications developed." Patients included in this study had serum calcium levels of less than 11 mg/dL (2.75 mmollL), normal renal function (evaluated by serum creatinine), absence of roentgenographically demonstrated bone disease (evaluated by roentgenography of the thorax, hands, and skull), and absence of metabolically active or infected renal lithiasis or nephrocalcinosis (investigated by excretory urography). When radioimmunoassays for PTH determination became available during the study, it was also required that the patients have inappropriately elevated PTH to establish the diagnosis definitively. The patients were subjected to a comparatively extensive follow-up. Altogether, 142 patients (Table 41-1) ultimately fulfilled the criteria for participation in the study. During the first 30 months of the study, 21 patients (15%) underwent parathyroid surgery; in the next 30 months, 3 additional patients (2%) underwent surgery; and during the last 7 years before completion of the follow-up, still another 9 patients (6%) were subjected to surgery, that finally 33 (23%) of all patients underwent operation. One of these patients had probable hypercalcemic crisis. Sixteen patients had previous negative parathyroid explorations and were excluded from the final evaluation. Of the unoperated patients, 32 died during the follow-up period, 10 declined follow-up, and 9 could not be traced when the study was terminated. Of the 42 patients remaining in the unoperated group, 12 became spontaneously normocalcemic, and there was some doubt regarding the original diagnosis in these cases; 30 patients with persistently elevated serum calcium were available for follow-up in 1980, and in all of them the diagnosis was supported by elevated PTH levels. Cumulative follow-up data were obtained for 24 of these 30 patients and revealed no progression in 21 patients;
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1 patient had advancing osteoporosis, 1 showed a modest increase in serum calcium, and another experienced a rise in serum creatinine. When deceased and noncompliant patients were excluded, the final compilation of data (including patients undergoing parathyroid surgery) revealed increased serum calcium in 10% of the patients (including one patient with probable hypercalcemic crisis, but a subtle rise in others), decreased renal function in 8%, active renal stone disease in 6%, bone disease in 5%, and psychological problems to the extent that parathyroid surgery was indicated in 5% (Table 41-2). The authors concluded that, for the comparatively few patients in whom adequate data could be collected for the whole study period, marked disease progression was noted only in a minority. Although the authors recommended surgical exploration by an experienced surgeon for the patients with asymptomatic HPf, they also concluded that patients who declined surgery or who had contraindications to operation could be monitored with minimal risk provided that the
patients and their physicians were willing to commit themselves to a rigid follow-up program. However, the authors noted that the conservative follow-up had been time consuming and expensive, and it had been difficult to make the patients comply with this type of follow-up. Several authors have subsequently reported conservative management of patients with primary HPT. Most of these studies have comprised fewer patients, some of whom had persistent hypercalcemia after failed parathyroid operations and others had surgery deferred because of associated illness. Many such patients have had higher serum calcium levels, and some already had symptoms or complications of parathyroid disease before the conservative follow-up. Rohl and colleagues'" thus monitored 30 patients with more severe hypercalcemia for an average of 3 years. Renal lithiasis developed in seven patients and bone disease in one patient; the total incidence of symptoms or complications was 27%. Adams'! described 31 patients with serum calcium levels less than 3.0 mmollL who were managed conservatively for 1 to 12 (mean, 4) years. Before the study, 12 patients had typical clinical features of primary HPT, mainly renal stones. Eighteen patients were considered asymptomatic; many of these were elderly women, often with hypertension. The patients had repeated measurements of serum calcium, creatinine, and alkaline phosphatase levels during follow-up. One of the patients with renal stones experienced deteriorating renal function, poorly controlled hypertension, and a marked rise in serum calcium, for which parathyroid surgery was ultimately required. A large parathyroid tumor was resected, but renal function and hypertension did not improve. In two other patients, a rise in serum calcium was partially attributed to thiazide treatment and thyrotoxicosis, respectively. No patient experienced life-threatening hypercalcemia, and mean serum calcium and creatinine levels did not change significantly during the follow-up. The authors concluded that they had failed to identify any criterion whereby patients who were destined to experience progressive disease could be identified. In this study, minor fluctuations in serum calcium were common and were thought to be mainly methodologic. Some patients, however, displayed more distinct variations, and the serum calcium levels were then typically lower during the winter, apparently related to a fall in vitamin D levels (Fig. 41-3). The author concluded that patients with HPT who avoid sun exposure can experience osteomalacia and lower serum calcium levels. Van't Hoff and coworkers" described 32 patients with primary HPT monitored for a mean of 4 years. Many of these patients had failed operations or were considered unfit to undergo parathyroid operation because of associated diseases, and some patients had refused surgery. Several patients had renal stones, and some had a serum calcium level greater than 3.0 mmollL prior to follow-up. Although the mean serum calcium and mean serum creatinine did not change significantly for the whole group of patients during the conservative management, one patient with a serum calcium level of 3.3 mmollL experienced pancreatitis and impaired renal function, and three patients underwent parathyroid surgery. The frequency of symptomatic renal stones and complications may have indicated a more liberal attitude toward operation.
Natural History of Untreated Primary Hyperparathyroidism - -
2.9
~
E 2.7 E
2.5
1'0]
Phosphate
0.5
1,5]
~ 0.5 S
i i i
WSW
S
I
WSW
FIGURE 41-3. Seasonal variations in the serum concentrations of calcium and parathyroid hormone (iPTH) in a patient with asymptomatic hyperparathyroidism. S = summer; W = winter (arrows). (From Adams PH. Conservative management of primary hyperparathyroidism. J R Coli Physicians Lond 1982;16:184.)
Paterson and colleagues" reported on 14 patients who for various reasons were not operated on and were managed conservatively for 5 to 23 years. One patient had osteitis fibrosa and died with fibrosarcoma, four patients originally presenting with renal calculi experienced further episodes of renal stones, and serum creatinine levels were finally raised in two patients. Three patients experienced progressive hypercalcemia. Corlew and associates" reported a more carefully explored series of 47 patients with primary HPT who either refused surgery or were not offered this option, some of whom were considered poor surgical risks. The diagnosis was accurately established in these patients by measurement of albumin-corrected serum calcium and intact PTH. The patients were classified into three groups on the basis of their levels of serum calcium; one fourth had serum calcium levels higher than 2.78 mmol/L. Sixteen of the 47 patients (34%) either died or suffered from complications that the authors considered to be possibly related to primary HPT, such as peptic ulcer disease (8 patients), with bleeding in some cases; renal failure (5 patients); renal calculus (1 patient); hypercalcemic crisis (1 patient); and ventricular conduction defect (1 patient). With the exception of the patient with hypercalcemic crisis, who initially belonged to the group with the lowest serum calcium levels, the serum calcium levels did not change significantly during the follow-up period. It was, however, impossible for the authors to predict the likelihood of progression or the severity of complications. The authors concluded that they had found nonoperative management inappropriate in good-risk primary HPT patients with reasonable life expectancy, and they suggested that most patients with significant elevation of serum calcium should undergo surgery.
397
Heath and Heath" reviewed 122 personal patients with primary HPT who were managed conservatively. Parathyroidectomy was recommended for patients with complications and definite symptoms of the disease, whereas for asymptomatic patients and those with mild, nonspecific symptoms, surgery was offered only if they were young; the threshold for being young declined during a 10-year period from 60 to 40 years. Diagnosis was based on hypercalcemia associated with elevated or high-normal serum PTH levels. The most common symptom in men was renal stones and in women tiredness and lethargy, and these symptoms were present in 10% of the conservatively monitored group. Ninety-five patients were available for follow-up after a mean of 6 years; in four patients, renal stones developed but serum calcium and creatinine levels did not deteriorate. Fifteen patients died. Although no deaths were attributable to HPT, the group of patients who subsequently died had a rise in serum creatinine levels, but because these patients had several other medical problems, this was not necessarily related to the parathyroid disorder. Thirteen patients were lost to follow-up. Rubinoff and coauthors'" reported a retrospective cursory screening of symptoms and complications in 160 patients who were found to be hypercalcemic on routine multiphasic laboratory examination, and they compared each hypercalcemic person with a matched normocalcemic control subject for a mean follow-up of 8.5 years. Fifteen patients had a parathyroid adenoma removed during the study. Apart from a higher incidence of hypertension and gallstones among the hypercalcemic individuals, the study recorded no differences regarding symptoms or routine estimates of renal function when comparison was made with control subjects. Posen and colleagues'? reported a retrospective survey of 142 patients who underwent successful parathyroid surgery, another 33 patients who had persistent hypercalcemia after a neck exploration, and 90 patients in whom surgery was deferred for various reasons. Although selection bias and variable follow-up (mean, 3 years) might have influenced the outcome in this study, the authors found a similar rate of vertebral crush fractures in all three groups. Forearm osteodensitometry showed higher bone mineral content in the group subjected to successful parathyroid surgery. One patient with persistent HPT experienced progressive, severe osteoporosis during conservative management and died with multiple spontaneous fractures. These studies seem to substantiate the results of the Scholz and Purnell" study in that rapidly progressive disease is relatively rare in patients with primary HPT. A minority of patients experience a marked increase in serum calcium or serum creatinine, but because such progression cannot be predicted in the individual patient, careful and close follow-up is mandatory if parathyroidectomy is not done. The studies indicate that renal damage may be irreversible, and conservative management, therefore, appears inappropriate in patients with more marked elevation of serum calcium or notable signs of renal function deterioration. Evidently, such patients should be offered a chance of amelioration of the parathyroid disease even if this should require a reoperative parathyroid procedure. Rapid progression of hypercalcemia may occur unexpectedly, as emphasized by Corsello and colleagues,"
398 - - Parathyroid Gland who within a 2-year period had five patients who experienced rapidly increasing serum calcium levels and "parathyroid crisis" while being monitored for mild primary HPT. One patient had parathyroid carcinoma, initially presenting with mild hypercalcemia; the others had benign parathyroid lesions. Rao and coworkers" examined the course of untreated mild asymptomatic primary HPT fortuitously discovered by multiphasic biochemical screening. Patients in this study had hypercalcemia persisting at repeated measurements, with serum calcium levels between 2.65 and 3.0 mmollL, and inappropriately high PTH levels or elevated nephrogenous cyclic adenosine monophosphate. The patients lacked symptoms attributable to HPT, showed no evidence of active renal stone disease, had serum creatinine levels less than 133 umol/L, had no radiographic osteitis fibrosa, and had a forearm bone density measurement that was not less than 2.5 standard deviations below the expected level. Of the original 198 patients subjected to conservative follow-up, 80 patients remained with adequate data from repeated measurements of bone density, serum calcium, and creatinine. These patients had a mean age of 61 years and initial mean serum calcium of 2.77 mmollL. They were monitored for 1 to 11 (median, 3.2) years at regular intervals of 6 to 12 months. The mean initial and final levels of serum calcium, serum creatinine, creatinine clearance, PTH (midand C-terminal assay), and forearm bone mineral density at proximal and distal sites of the radius normalized for age, gender, and race were virtually identical. A modest increase in alkaline phosphatase levels was noted in persons with longer follow-up and was apparently related to increased age. No episodes of worsening of hypercalcemia were noted, and there were no changes in renal function or appearance of symptoms of renal lithiasis. The initial mean levels for proximal and distal forearm bone density were significantly reduced, but there was no accelerated bone loss during follow-up apart from that expected with increasing age. The authors suggested that the lack of progression of biochemical parameters or bone loss in primary HPT was compatible with a biphasic disease course. They suggested that an initial short period of disease progression was likely to be followed by a long period of disease stability because they would otherwise have noted derangement of biochemical parameters or accelerated bone loss. The observations were considered to support nonsurgical surveillance in patients with mild asymptomatic and uncomplicated primary HPT, but the authors were unable to obtain adequate follow-up information in more than half of the original group of patients who had been managed conservatively. A subsequent report from the same authors'? included an additional 26 patients who initially had shorter follow-up. This increased the length of the study period to slightly more than 4 years without changing the biochemical parameters or the conclusions of the study. Rudnicki and Transbel'" reported time-limited follow-up in 24 patients with mild primary HPT for an average of nearly 3 years and found that mean ionized serum calcium levels remained stable, whereas levels of intact serum PTH increased significantly. A subgroup of patients whose PTH levels increased by 78% also had a small but significant increase in serum ionized calcium, whereas in the remaining
patients serum PTH levels increased modestly (22%) and ionized calcium levels were unchanged. The serum creatinine concentrations were stable throughout the study. The authors concluded that other studies of mild to moderate primary HPT did not include information on the course of parathyroid function and that primary HPT may progress even when serum calcium levels remain unchanged. They further emphasized that conditions commonly associated with old age, such as poor vitamin D intake and impaired vitamin D synthesis, could be responsible for impairment of intestinal calcium absorption, with a resulting compensatory hypersecretion of PTH. Silverberg and coworkers" reported a lO-year prospective follow-up of 121 HPT patients, 61 of whom were subjected to parathyroidectomy (according to indications established at the National Institutes of Health Consensus Conference Statement, 1991, concerning diagnosis and management of asymptomatic HPT4), whereas 60 patients did not undergo surgery. The majority of nonoperated patients were asymptomatic, but in some patients surgery was not undertaken despite the presence of kidney stone disease. All nonoperated symptomatic patients with kidney stones experienced progressive disease with recurrent stone attacks during follow-up, whereas none of the operated patients had such recurrences. Among nonoperated, asymptomatic patients, 27% had progressive disease with worsened hypercalcemia, increased hypercalciuria, and decrease in bone mineral; the remaining patients had apparently stable disease. The authors concluded that women with HPT seemed to be at risk for disease progression with significant loss of bone mineral, especially at menopause, and should therefore be liberally considered for parathyroidectomy. They also inferred that some asymptomatic patients experience disease progression over time, and all patients not undergoing surgery should therefore have biannual measurements of serum calcium, urinary calcium excretion, and bone mineral density.
Progression of Symptoms The clinical manifestations of HPT tend to be related to the level of hypercalcemia, even if this is not always evident because of slow disease progression, individual susceptibility, and to some extent also gender and age dependence of symptoms." Younger men are particularly likely to experience renal stones, sometimes even with only mild hypercalcemia. For renal stones, the individual susceptibility is more important than the level of hypercalcemia, and the risk for this particular symptom is probably most efficiently revealed by the patient's history. Urinary calcium excretion has been an uncertain predictor of the risk for kidney stones among patients who have previously not had this symptom.f Males excrete 25% to 30% more calcium in the urine than females, and whites also have higher excretion than blacks." In postmenopausal women, renal stones occur infrequently (generally less than 5%) and are often clinically silent. Osteitis fibrosa cystica is now an uncommon finding in patients with primary HPT and is most often seen in patients with severe hypercalcemia. Bone density measurements have, however, demonstrated an average reduction in
Natural History of Untreated Primary Hyperparathyroidism - - 399
cortical bone of nearly 20% among current patients with primary HPT, and the bone loss tends to be most pronounced in postmenopausal women.44-49 Total and trabecular bone mass is often significantly but less markedly reduced.r'r" Bone density measurements are recommended at the distal radius, hip, and lumbar spine because a subset of patients have more apparent reduction in the spine than other sites." The risk for fracture appears to be increased for the vertebra, distal leg, and forearm and returns to normal after parathyroid surgery.SO,SI The bone loss may be most evident at the time of menopause and may constitute an important indication for surgery in female patients." No bone loss has been detected in postmenopausal women with borderline hypercalcemia, but losses were significant when the serum calcium level was higher than 2.74 mmol/L." In postmenopausal women with primary HPT, a neuropsychiatric disability with symptoms of tiredness, lethargy, weakness, and easy fatigue is the most common feature. Although these are not traditional symptoms of HPT, they are typical for the disease, and many patients report improvement after successful parathyrotdectomy." The oldest patients may present with mental confusion, even without profound hypercalcemia, and their mental capacity may recover dramatically after operation.f It is important that these symptoms be recognized as features of the disease and constitute indications for surgery. The psychiatric disability is generally more evident when serum calcium levels are more markedly elevated, but the effects of surgery on the symptoms may sometimes be difficult to predict in individual patients." Clinically evident renal failure is currently an unusual complication of primary HPT. Reductions of creatinine clearance and urinary concentrating capacity, however, occur in more than one third of patients with mild hypercalcemia, indicating that impairment of glomerular as well as tubular function may occur silently.'? Serum creatinine measurements are crude estimates and rise only after creatinine clearance is substantially reduced, and creatinine levels also decrease with declining muscle mass of aging."? Reduction of creatinine clearance is a complication of the disease and an evident indication for surgery." Hypertension is twice as common in patients with primary HPT as in the general population and may be more severe in association with impaired renal function. However, it does not parallel the degree of hypercalcemia and is generally unaffected by parathyroid surgery.47A8,S2 Hypertension and other risk factors for cardiovascular disease may also be of concern with respect to decreased survival in primary HPT,26,27 which is evident also in mild hypercalcemia. 23,26,27,34,53.s4 Hypercalcemia and primary HPT have been associated with increased risk of death in cardiovascular disease in Scandinavian studies but not in two North American series. 26-29 The increased mortality has appeared related to the severity of HPT and renal function impairment." HPT of significant degree or long duration may cause renal impairment that is not always disclosed by creatinine values, and resulting reduced levels of active vitamin D may contribute to development of cardiovascular disease. The increased death risk has appeared reversed if patients with primary HPT have been operated on at an earlier disease stage.
Summary Indications for parathyroidectomy are indisputable in patients with primary HPT who exhibit clear and classic symptoms or marked hypercalcemia. The value of parathyroidectomy in asymptomatic patients with mild to moderate hypercalcemia has, however, been debated. Studies of the natural history of untreated primary HPT document that rapid increases in the serum calcium level, progression of symptoms or complications, or both is uncommon in patients with borderline hypercalcemia. Less clear is our knowledge about the long-term consequences of somewhat more marked hypercalcemia because no study has yet presented adequate follow-up of such patients for a prolonged period of time. It appears as if many patients with moderately elevated serum calcium levels «3.0 mmollL) have symptoms and silent complications of HPT if they are carefully studied. Although rapid progression of hypercalcemia is unusual, serum calcium levels, nevertheless, tend to increase progressively over years of observation in some patients. This advancing hypercalcemia may be obscured by declining levels of active vitamin D, resulting from dietary deficiency, lack of sun exposure, and impairments of renal function. Because these factors lower serum calcium levels, progression of HPT may not be detected. 7,ss.s6 The impact of such relative vitamin D deficiency may be difficult to determine and may simultaneously be part of the pathogenesis of primary HPT in elderly people. The natural course of primary HPT is causally related to the genetic and functional abnormalities within the diseased parathyroid tissue. Variable tumor biology and clinical progression may, therefore, depend on heterogeneity of tumor genetics.V Occasionally, patients' metabolic problems progress rapidly and are then reflected in excessively raised serum calcium values. These patients may have parathyroid tissues that harbor exceptional and critical mutations with oncogene activation or recruitment of growth factors. A PRADl oncogene rearrangement has been described in this context and has been associated with the largest parathyroid adenomas, whereas a menin gene abnormality has also been evident in sporadic, mild HPT.S8 Rare patients with initially mild hypercalcemia but rapidly advancing disease may have parathyroid carcinoma.v' In addition, stepwise "clinical" progression may occur during observation in patients with primary HPT, possibly representing development of secondary mutations that cause accelerated growth of the tumor. Thus, a history of mild primary HPT has been reported in up to one third of patients with hypercalcemic crisis. Because it is not yet possible to predict whether progressive disease will occur in any patient, extended follow-up is crucial if surgery is deferred in primary HPT.S9.6O Younger patients seem to be at greater risk for progressive disease. The absence of marked progression of complications in most patients with mild primary HPT allows medical surveillance in older persons with borderline hypercalcemia (i.e., with increments of serum calcium to less than 2.75 to 2.85 mmol/L, or 11.0 to 11.4 mg/dL) and in those with associated illnesses. Medical surveillance is probably inappropriate in younger patients and in those with more
400 - - Parathyroid Gland
marked hypercalcemia. Nonoperative management in any circumstance requires that the presence of symptoms or complications be carefully excluded and that precise monitoring of symptoms and metabolic function be done." A new consensus statement" has substantiated a risk for disease progression if patients with HPT are monitored without surgery and therefore issued a general recommendation for parathyroidectomy in patients with serum calcium values raised 0.25 mmol/L above the normal reference.
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22. Christensson TAT, Hellstrom K, Wengle B. Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme. Eur J Clin Invest 1977;7:109. 23. Palmer M, Adami H-O, Bergstrom R, et al. Survival and renal function in persons with untreated hypercalcaemia: A population-based cohort study with 14 years of follow-up. Lancet 1987; 1:59. 24. Joborn C, Hetta J, Lind L, et al. Self-rated psychiatric symptoms in patients with primary hyperparathyroidism. Surgery 1989;105:72. 25. Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988;12:476. 26. Lundgren E, Lind L, Palmer M, et al. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery 2001;130:978. 27. Hedback G, Oden A. Death risk factor analysis in primary hyperparathyroidism. Eur J Clin Invest 1998;28: 10II. 28. Soreide JA, van Heerden JA, Grant CS, et al. Survival after surgical treatment for primary hyperparathyroidism. Surgery 1997;122:1117. 29. Wermers RA, Khosla S, Atkinson EJ, et al. Survival after the diagnosis of hyperparathyroidism: A population-based study. Am J Med 1998;104:115. 30. Purnell DC, Smith LH, Scholz DA, et al. Primary hyperparathyroidism: A prospective clinical study. Am J Med 1971;50:670. 31. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism. Mayo Clin Proc 1981;56:473. 32. Rohl PE, Wilkinsson M, Clifton-Blight P, et al. Hyperparathyroidism: Experiences with treated and untreated patients. Med J Aust 1981; I:519. 33. Adams PH. Conservative management of primary hyperparathyroidism. J R Coli Phys Lond 1982; 16:184. 34. Van't Hoff W, Ballardie FW, Bicknell EJ. Primary hyperparathyroidism: The case for medical management. Br Med J (Clin Res Ed) 1983;287:1605. 35. Paterson CR, Bums J, Mowat E. Long-term follow-up of untreated primary hyperparathyroidism. Br Med J (Clin Res Ed) 1984;289: 1261. 36. Corlew DS, Bryda SL. Bradley EL, et al. Observations on the course of untreated primary hyperparathyroidism. Surgery 1985;98: 1064. 37. Heath DA, Heath EM. Conservative management of primary hyperparathyroidism. J Bone Miner Res 1991;6:S117. 38. Rubinoff H, McCarthy N, Hiatt RA. Hypercalcemia: Long-term follow-up with matched controls. J Chronic Dis 1983;36:859. 39. Posen S, Clifton-Bligh P, Reeve TS, et al. Is parathyroidectomy of benefit in primary hyperparathyroidism? Q J Med 1985;215:241. 40. Corsello SM, Folli G, Crucitti F, et al. Acute complications in the course of "mild" hyperparathyroidism. J Endocrinol Invest 1991;14:971. 41. Rao DS, Wilson RJ, Kleerekoper M, et al. Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: Evidence for biphasic disease course. J Clin Endocrinol Metab 1988;67:1294. 42. Parfitt AM, Rao DS, Kleerekoper M. Asymptomatic primary hyperparathyroidism discovered by multichannel biochemical screening: Clinical course and considerations bearing on the need for surgical intervention. J Bone Miner Res 1991;6:S97. 43. Rudnicki M, Transbel 1. Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism. J Intern Med 1992;232:421. 44. Silverberg SJ, Shane E, Jacobs T, et al. A IO-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249. 45. Lafferty FW, Hubay CA. Primary hyperparathyroidism. A review of the long-term surgical and nonsurgical morbidities as a basis for a rational approach to treatment. Arch Intern Med 1989; 149:789. 46. Bilezikian JP, Potts JT Jr, EI-Hajj Fuleihan G, et al. Summary statement from a Workshop on Asymptomatic Primary Hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353. 47. Mitlak BH, Daly M, Potts JT Jr, et al. Asymptomatic primary hyperparathyroidism. J Bone Miner Res 1991;6:SI03. 48. Davies M. Current therapy. Primary hyperparathyroidism: Aggressive or conservative treatment? Clin Endocrinol (Oxf) 1992;36:325. 49. Nagant de Deuxchaisnes C, Devogelaer JP, Huaux JP. Long-term followup of untreated primary hyperparathyroidism. Br Med J (Clin Res Ed) 1985;290:64. 50. Vestergaard P, Mollerup CL, Gedse Frekjer V, et al. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321:598.
Natural History of Untreated Primary Hyperparathyroidism - - 401 51. Vestergaard P, Mosekilde L. Fractures in patients with primary hyperparathyroidism: Nationwide follow-up study of 1201 patients. World J Surg 2003;27:343. 52. Heath H III. Clinical spectrum of primary hyperparathyroidism: Evolution with changes in medical practice and technology. J Bone Miner Res 1991;6:S63. 53. Hedback G, Tisell L-E, Bengtsson B-A, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990;14:829. 54. Hedback G, Oden A, Tisell L-E. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991;15:399. 55. Turner G, Brown RC, Silver A, et al. Renal insufficiency and secondary hyperparathyroidism in elderly patients. Ann Clin Biochem 1991;28:321.
56. Siperstein AE, Shen W, Chan AK, et al. Normocalcemic hyperparathyroidism: Biochemical and symptom profiles before and after surgery. Arch Surg 1992;127:1157. 57. Arnold A. Genetic basis of endocrine disease 5. Molecular genetics of parathyroid gland neoplasia. J Clin Endocrinol Metab 1993;77:1108. 58. Carling T, Correa P, Hessman 0, et aI. Parathyroid MEN] gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab 1998;83:2960. 59. Sarfati E, Desportes L, Gossot D, et al. Acute primary hyperparathyroidism. Br J Surg 1989;76:979. 60. Bondeson A-G, Bondeson L, Thompson NW. Clinicopathological peculiarities in parathyroid disease with hypercalcaemic crisis. Eur J Surg 1993;159:613.
Metabolic Complications of Primary Hyperparathyroidism Gerhard Prager, MD • Claudette Abela, MD • Bruno Niederle, MD
In 1925, the Viennese surgeon Felix Mandl removed for the first time a parathyroid tumor in a patient with symptomatic primary hyperparathyroidism (PHPT).1 The patient was confined to bed and suffered from classic renal and osseous symptoms: recurrent renal calculi, osteitis cystica fibrosa, disabling bone pain, and fatigue. Postoperatively, the patient improved dramatically but unfortunately died 10 years later from the consequences of progressive renal disease.F Since then there has been a dramatic improvement in the outcome of patients with PHPT after parathyroidectomy.' Careful analysis of patients with PHPT reveals that postoperative metabolic complications occur in patients with a long history of PHPT.3,4 For example, the death rate related directly or indirectly to PHPT ranges from 1% to 12%. Death in patients with PHPT is mainly caused by cardiovascular disease (~68%S) and acute or chronic renal failure (~8%3). Over the last 50 years, the clinical picture of PHPT has changed from a "rare" illness characterized by bone disease and renal calculi to a "common" disease characterized by more subtle or no clinical manifestations.f Articles from Scandinavia and North America':" have documented an increasing number of patients with PHPT who are diagnosed because hypercalcemia is detected on undirected routine serum calcium determinations and the diagnosis confirmed by parathyroid immunoassays.f-"!' PHPT is a relatively common, worldwide disorder with a reported incidence ranging from 0.1 % in Central Europe,'? Australia, 12 and South Africa" to as high as 0.52% in Sweden.v?" Heath 14 in England reported that among his patients with PHPT, fewer than 10% have renal calculi and fewer than 10% have bone disease, whereas more than 80% have either vague ill health or are asymptomatic, PHPT patients may be classified as symptomatic, minimally symptomatic, or asymptomatic. Symptomatic patients have renal, skeletal, or gastrointestinal disease or a combination. Osseous disease is defined as osteitis fibrosa, subperiosteal resorption, pathologic bone fractures, and aeroosteolysis. Minimally symptomatic patients have bone pain, diffuse osteopenia, or hypertension and the so-called hypercalcemia syndrome, which includes depression, lethargy, apathy,
402
weakness, loss of memory, confusion, insomnia, headaches, and myopathy with muscular weakness as well as other general manifestations like polyuria and polydypsia, weight loss, vomiting, nausea, or epigastric discomfort without any apparent organic origin.' Asymptomatic patients have neither symptoms nor signs attributable to PHPT (Table 42-1), In this chapter, we describe metabolic manifestations and complications other than the typical well-known, classic manifestations in both treated and untreated patients with PHPT that are described elsewhere in this textbook. Several metabolic complications are not usually attributed to PHPT. Patients with PHPT, for example, may have impaired glucose tolerance and diabetes mellitus. IS,16 Both hyperuricemia-!? and hyperlipidemia's may be increased in patients with PHPT, These conditions may have an adverse effect on hypertension and concomitant cardiovascular disease, and these conditions may contribute to the increased morbidity and mortality in patients with PHPT, even after successful parathyroidectomy. 11,19,20 The severity of the metabolic manifestations that occur in patients with PHPT cannot be predicted by the presence or absence of symptoms. Age, serum calcium level, and renal function are similar in patients with or without symptoms,":" although asymptomatic patients appear to have slightly lower serum calcium levels (Table 42-2). Some symptoms and metabolic changes improve, at least in part, after parathyroidectomye-P On the other hand. about one quarter of asymptomatic patients develop symptoms of PHPT within
1 decade."
Arterial Hypertension In 1958, Hellstrom and associates'? suggested a relationship between hypertension and PHPT; these authors reported that 53% oftheir 95 patients had blood pressures of 1501100 mm Hg or greater. Several series have quoted a prevalence ranging from 21 % to 57% (Table 42_3).28-33 This wide range may be a result of different patient ages as well as different definitions of hypertension. Lafferty!' showed that hypertension
Metabolic Complications of Primary Hyperparathyroidism - - 403
was twice as common among hyperparathyroid patients compared with the general population.W PHPT and hypertension are associated with an increased risk of cardiovascular disease and possibly stroke.r' Bostrom and Alverydr' as well as Palmer and colleagues'" reported a higher mortality rate (61%) mainly because of cardiovascular disease in
patients with hypercalcemia and PHPT. Unfortunately,hypertension failed to improve in 92% after parathyroidectomy." The pathogenesis of hypertension in patients with PHPT has not been completely defined. Studies involving the renin-angiotensin system suggest no direct relationship with the hypertension.v-" Salahudeen and coworkers"
404 - - Parathyroid Gland
found no correlation between blood pressure and total serum calcium in PHPT patients." This is in contrast to the situation with essential hypertension in which a significant positive correlation between blood pressure and total serum calcium has been described.tv" as well as an inverse correlation or no correlation between serum ionized calcium
and hypertension.v-t' Parathyroid hormone (PTH) is said to play a permissive role in the hypertensive action of hypercalcemia.tv" Bernini and associates" compared plasma renin activity in patients with PHPT and essential hypertension and a normotensive control group. They only found a weak relation between PTH and plasma renin activity,
Metabolic Complications of Primary Hyperparathyroidism - - 405
suggesting that hypertension in PHPT is probably of heterogeneous origin. As mentioned, the response of hypertension after successful parathyroidectomy has been variable. Successful cure of hyperparathyroidism only occasionally leads to a lowering of blood pressure to normal. Renal impairment also usually does not improve after successful parathyroidectomy.27.37.39.47.48 Salahudeen and colleagues'? suggested that impaired renal function in PHPT may be the primary event to hypertension.f because the glomerular filtration rate measured by chromium l-edetic acid clearance did not change after parathyroidectomy in their careful study. Declining renal function, in the absence of obstructive renal calculi and nephrocalcinosis, can be related to progressive hypertension.w" The reaction of normotensive PHPT patients to pressor agents has been studied by Rodriguez-Portales and Fardella." Normotensive parathyroid patients had an abnormal response to pressor agents (i.e., norepinephrine and angiotensin II) similar to that found in patients with idiopathic hypertension. This abnormality persisted 6 months after surgical cure even if the blood pressure remained within the normal limits. Lewanczuk and Pang" reported the presence of a parathyroid hypertensive factor (PHF), which is assumed to be secreted by the parathyroid glands. PHF is a circulating hypertensive factor found in a proportion of patients with essential hypertension as well as in spontaneously hypertensive rats. Preoperative values of this factor were raised in hypertensive patients with PHPT. Patients with PHPT and PHF preoperatively had lower blood pressures after successful parathyroidectomy and PHF levels became undetectable. These results suggest that the parathyroid gland can express PHF in humans and that such expression may be responsible for a proportion of the.high incidence of hypertension in PHPT.52 Middeke and Schrader'" showed that hypertensive PHPT patients had a normal circadian blood pressure profile with a normal nocturnal blood pressure fall. The circadian nocturnal blood pressure profile tends to fall by about 15 mm Hg in systolic and diastolic readings and was no different from that seen in normotensive subjects, as opposed to other secondary forms of hypertension (e.g., renal and endocrine forms of hyperthyroidism, primary hyperaldosteronism, and Cushing's syndrome). After successful parathyroidectomy, blood pressure in hypertensive PHPT patients usually remains mainly unchanged4.36.37.39.48,49.54-56 and may increase with time. 27,3o,57 Follow-up studies as long as 22 years after successful parathyroidectomy showed increased hypertension in 9.2% of symptomatic patients and 13.3% of minimal symptomatic patients, whereas asymptomatic patients showed no elevation of blood pressure.t'" The onset of hypertension after parathyroidectomy in PHPT patients who were normotensive occurs in 17% to 33% of patients. 21 On the contrary, reversibility in the form of improvement or normalization of hypertension after parathyroidectomy has also been observed. Improvement in 20% to 50% of patients has been reported.27,58-62 Because hypertension only decreases in a few patients after parathyroidectomy, hypertension is not an indication for surgery in patients with otherwise uncomplicated mild PHPT,37.48.49 However, hypertension is more common after parathyroidectomy in patients who were symptomatic.
Cardiovascular Disease Another interesting finding is the concurrent incidence of cardiovascular disease.l'" Cardiovascular complications are the most common cause of death in patients with successfully treated and untreated PHPT.3,19,20,35 In a follow-up study of 12.3 years, Hedback and colleagues'? showed that, of 896 PHPT patients, 294 had died during follow-up. One hundred-fifty-six patients (53%) died from cardiovascular disease-50 (32%) patients from myocardial infarction, 44 (28%) from stroke, 53 (34%) from heart failure, and 9 (6%) from generalized atherosclerosis. Ronni-Sivula" reported that 23 (68%) of the 34 patients with PHPT who died did so from cardiovascular disease-l 8 (53%) from cardiac disease, 4 (12%) from stroke, and 1 (3%) from vascular disease (thrombosis of the mesenteric artery)]. In this study, there was no difference in the mortality between minimal symptomatic and asymptomatic patients. Bondeson and coworkers's reported that 132 (44%) of 300 patients with PHPT had coronary artery disease preoperatively. Langle and associates-' reported that 11 (23%) of 48 patients with minimal symptomatic and 5 (7%) of 77 of the symptomatic patients suffered from coronary heart disease, whereas 64 (48%) of 132 showed hypertrophy of the left ventricular wall. A study performed on 54 patients with PHPT and 54 age- and sex-matched controls showed a significant incidence of aortic (63%) and mitral valve (49%) calcifications in PHPT patients compared with the 13% found in the normocalcemic controls. Metastatic myocardium calcification was noted in 69% of the patients." The full pattern of cardiac abnormalities, although mild, was exhibited in asymptomatic patients.P These findings suggest that metabolic disorders occur even in patients with asymptomatic PHPT and raise the question whether so-called asymptomatic PHPT actually exists. According to these findings, Smith and colleagues's found an increased arterial stiffness in patients with mild to moderate PHPT. This provides a mechanism for the development of left ventricular hypertrophy in normotensive PHPT patients and is likely to contribute significantly to both cardiovascular morbidity and mortality. In contrast to these studies, Barletta and coworkers's found neither pathologic echocardiographic parameters nor an alteration of the mechanical properties of the brachial and carotid arteries before or after successful parathyroidectomy in 14 patients with mild asymptomatic PHPT. The improved survival after parathyroidectomy raises the question about whether early operation could influence the course of these cardiac manifestations. Regression of left ventricular hypertrophy and a slower progression of cardiac calcifications has been documented postoperatively.W" Some investigators believe that elevation of cytoplasmic calcium increases aortic pressure, elevated wall tension, and adrenergic stimulation'" and results in cardiac hypertrophy. Because all the hypertensive patients in the study by Stefenelli and associates's had antihypertensive therapy and, therefore, had a mean resting blood pressure similar to that of the nonhypertensive patients, the higher incidence of hypertrophy is likely to be a consequence of elevated PTH or calcium concentrations rather than a consequence of raised blood pressure. This finding may explain the reversibility of cardiac hypertrophy after parathyroidectomy.
406 - - Parathyroid Gland Endothelium-independent vasodilation was found to be impaired in PHPT patients without clinical evidence of coronary heart disease compared to normocalcemic control subjects. 68,69 In a follow-up study," the restoration of normocalcemia by parathyroidectomy could not improve the vascular reactivity, but on the other hand, no further progression of vascular disease could be seen. Despite evidence from long-term follow-up, it is still controversial as to whether parathyroidectomy significantly decreases the morbidity and mortality associated with hyperparathyroidism.V" A 15-year follow-up of operated and unoperated PHPT patients showed that mild PHPT is associated with an increase in blood pressure with age. However, this particular study showed aggravation of hypertension after parathyroid surgery.'? Hedback and associates'S" reported an increased risk of premature death in patients after parathyroidectomy in all age groups, with the highest relative risk of death occurring in patients between 55 and 70 years of age. The risk in younger patients and in those with less severe disease returned to a normal survival curve most quickly after successful parathyroidectomy. There was also a shift from an increased risk of death toward a normal risk of death as time passed after surgery, indicating a positive effect of parathyroidectomy on survival. Over the years, there has been a change in trend toward a more rapid normalization of the risk of death (i.e., approximately after 5 years if the patient was operated on in 1980, but not until after 9 years if operated on in 1975). This effect appears to be due to the increased number of mild cases in the more recent series that benefited from early detection and treatment. This study indicated that patients with PHPT of shorter duration have less risk of death. In a further study," the same authors showed an increased risk of death for patients undergoing surgery for mild or moderate PHPT in Sweden between 1987 and 1994. The recent publication of their longterm findings showed "a 50% increased death risk of hypertensive hyperparathyroid patients compared with that of the normotensive patients, but the yearly death risk decrease after surgery for the hypertensive patients was almost doubled as compared with the decrease of the normotensive patients. Cardiovascular disease was directly related to serum calcium level, adenoma weight, osteitis fibrosa, and serum creatinine and inversely related to glomerular filtration rate and urine osmolality'T In another follow-up study of 14 years, the overall survival in 172 untreated hypercalcemic subjects with mild hyperparathyroidism was lower than that of the matched normocalcemic subjects. This trend became obvious within 5 years of presentation." These results support the recommendation for parathyroidectomy for virtually all patients with PHPT.
Psychiatric Symptoms Several authors have documented the common occurrence of nonspecific symptoms such as weakness, fatigue, and mental depression in PHPT.7,24,25 A wide spectrum of psychological symptoms ranging from mild personality changes to severe depression and psychosis has been described. These psychiatric symptoms develop in PHPT patients irrespective of the serum calcium level. Joborn and colleagues" reported that
hypercalcemic patients with asymptomatic PHPT (i.e., no kidney stones or osteitis fibrosa cystica) presented with similar although less pronounced psychiatric disturbances as did patients with symptomatic PHPT, Confusion and delirious states sometimes dominate the clinical picture and occur in about 5% of cases. 75-79 Peterson" correlated the level of hypercalcemia to the severity of the psychiatric symptoms. He also reported the return to the premorbid mental status postoperatively. Personality changes and affective disturbances were associated with plasma calcium levels of 12 to 16 mg/elL (3 to 4 mmol/L). Acute organic brain syndromes with altered levels of consciousness, paranoid ideation, and hallucinations were noted at plasma calcium levels of 16 to 19 mg/elL (4 to 4.5 mmol/L)." However, even slight increases in the serum calcium and PTH levels may produce serious psychiatric symptorns.Y'" Joborn and colleagues" reported that 10 of 13 patients with organic brain syndrome had senile dementia. Twelve of these patients were admitted to a mental hospital. Eight of these patients improved after parathyroidectomy, and 7 of them were able to return to their homes. The postoperative improvement was related to the duration of the mental symptoms. All 8 patients who improved had a clinical history of dementia of fewer than 2 years. Patients with a longer history of mental illness were likely to recover. These studies document that impressive psychological improvement can occur after successful parathyroidectomy in patients with PHPT.81,82 Psychosis involves the disturbance of thought content, thinking processes with perceptual aberrations, paranoid or persecutory ideation, and delusions." Hallucinations and delusions have been reported to occur in about 10% of patients who have psychiatric symptoms,?6,83 Recovery from paranoid states after parathyroidectomy becomes evident after 48 hours." Solomon and coworkers'" showed that all 18 patients suffering from PHPT had clinical multidimensional psychological distress in the individual areas of obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, psychosis, sleep disturbance, and lack of concentration." Depression and lethargy are the most common characteristics experienced by this group of patients.80 An improvement approaching normal was achieved 1 month after surgery. Solomon and coworkers'" found no group differences for somatization and phobic anxiety before and after parathyroidectomy in their 18 patients. Clark and associates.s' however, did document more symptoms in patients with PHPT and resolution of somatic symptoms as well as neuropsychiatric symptoms after parathyroidectomy. No correlation was found between the clinical symptoms and the biochemical constellation.rv" Serious depression is noted in about 10% of patients with PHPT and may be associated with headache (Table 42-4).76 Fatigue normally develops first. Anxiety, depression, and irritability have been noted in up to one third of cases.P The severity of psychiatric symptoms is not linearly related to the degree of hypercalcemia or to PTH values/" The psychological symptoms generally begin to improve within 1 month after successful parathyroidectomy.5,ll,21,24.25,75,80,85,86 Disturbances in monoamine turnover have been documented in patients with PHPT and psychiatric syrnptoms.f-" The cerebrospinal fluid (CSF) concentrations of total and
Metabolic Complications of Primary Hyperparathyroidism - - 407
ionized calcium were higher in 22 unselected PHPT patients. CSF concentrations of PI'H were also higher than in the reference group; monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid were lower. 5-HIAA correlated inversely with CFS ionized calcium. Endogenous depression has been reported to coincide with lowered monoamine metabolites. The central neurotransmitter activity might be influenced by the higher calcium concentrations present in the CSF. Sedation and depression have also been associated with higher CSF calcium concentrations." The precise neurophysiologic reasons for the psychological changes have yet to be clarified, although it has been suggested that excess PI'H enhances the permeability of the blood-brain barrier, raising the CSF concentration of calcium, albumin, and urate. After successful parathyroidectomy, both total and ionized CSF calcium decrease." Postoperative follow-up shows major improvements in anxiety, cognition, depression, fearfulness, and confidence. Preoperative electroencephalograms obtained from seven patients with asymptomatic PHPI' and mild from hypercalcemia were generally abnormal, showing a shift of frequencies toward abnormal slower frequencies «7 Hz; normal range is >9 Hz).89 All seven patients had normal electroencephalograms 3 to 5 months postoperatively. However, this small group of patients showed no consistent postoperative improvement in any of the psychological parameters, although patients with secondary hyperparathyroidism did.89 A biochemical relationship was not found.t" In a recent study, Prager and colleagues?" demonstrated a significant improvement of the patients' cognitive performance (concentration, retentiveness) by parathyroidectomy, applying standardized psychological tests. No correlation between the improvement of concentration/retentiveness and the serum calcium and PI'H levels, age, and gender was found in this study. Pasieka and coworkers?' developed a patient-based surgical outcome tool. They found a significant improvement in the quality of life and self-rated health after parathyroidectomy in patients suffering from PHPI'; these findings were confirmed by Sheldon and coworkers'? using the Short Form Health Survey (SF-36).
Neuromuscular Disease Neuromuscular disease mainly manifests itself as fatigue and weakness, especially in the proximal muscles of the lower extremities.v" Aching muscles, paresthesias, and
unsteadiness of gait have also been reported.V? The incidence of these symptoms varies from 30% to 80%,83,93 probably due to the criteria used, diligence of the respective observers, and patient selection. Muscle weakness and fatigability are subjective symptoms. Both symptoms can be explained by decreased muscle strength on the one hand or lack of mental energy from depression and lethargy on the other hand. Hedman and associates?" studied an unselected series of PHPI' patients to assess the association between these symptoms and muscle strength before and after surgery, A significant increase in the isokinetic strength of knee extension and knee flexion at higher angular velocities was found 3 months after surgery, suggesting that type II (fast twitch) muscle fibers were predominantly affected. The results of this study support the clinical impression that PHPI' surgery is beneficial to patients with muscular symptoms.rv" Joborn and colleagues." however, were unable to find any significant abnormalities of nerve conduction velocity or neuromuscular transmission in unselected PHPI' patients." Joborn and coworkers documented that even patients with mild to moderate HPI' without apparent muscular symptoms had impaired muscle function. Reinvestigation 6 months postoperatively showed improvement in only one patient who had severe preoperative muscular symptomatology.P-" A 1988 study" showed no significant difference in muscle strength between those patients with subjective impairments and the control patients. Seven months postoperatively, the PHPT patients had increased their muscle strength by 8%. These studies demonstrate that patients with PHPI', especially those with neuromuscular symptoms and muscle weakness, improve their muscle strength slightly after parathyroidectomy. Patten and associates'" concluded, on the basis of the clinical, electromyographic, and biopsy evidence, that the neuromuscular abnormality in PHPI' is probably neuropathic in origin." Electromyograms of 12 patients showed short-duration, low-amplitude motor unit potentials in some patients and abnormally high-amplitude, long-duration polyphasic potentials in others. Motor nerve conduction velocities and distal sensory latencies were normal. The major finding on muscle biopsy was atrophy of both type I (slow twitch) and type II muscle fibers, with type II fibers being more extensively involved. With the restoration of normocalcemia, neuromuscular symptoms improved within days to weeks after surgery.88 In contrast, Turken and colleagues" demonstrated that 22 (52%) of 42 patients had neuromuscular symptoms consisting
408 - - Parathyroid Gland either of muscle cramps (45%), paresthesias (45%), or both (18%). No patient showed classic hyperparathyroid neuromuscular disease (muscle weakness, atrophy, hyperreflexia, abnormal gait, or tongue fasciculations). Electromyographic and nerve conduction studies were performed in 9 patients with neurologic abnormalities." None showed myopathy or signs of motor unit denervation. These results differed significantly from those reported earlier," There is clearly a trend toward subtle, earlier neuropathy that also manifests itself among socalled asymptomatic patients. Unfortunately, Turken and colleagues did not report the postoperative results."
Carbohydrate Metabolism It has been frequently reported that PHPT patients have a higher risk of developing impaired glucose tolerance or diabetes mellitus. 3•15,16,18,99 Hyperinsulinemia in patients with PHPT suggested that these patients have a reduced insulin sensitivity and therefore impaired glucose tolerance. lOO- 105 Several studies have shown that up to 8% of patients with PHPT suffer from diabetes mellitus as compared with 2% of normocalcemic patients (Table 42_5).16,18,99,106,107 Whether diabetes mellitus itself is associated with the metabolic abnormalities in PHPT alone or with other known risk factors such as age, obesity, and hypertension is uncertain. Kumar and colleagues 108 showed that PHPT patients have a higher tendency to develop diabetes mellitus in the absence of the earlier mentioned risk factors. Those PHPT patients with impaired glucose tolerance are also likely to have reduced beta cell function. Reduced beta cell function may be a result of the direct effects of PTH and calcium on beta cells, reducing insulin-secretory capacity.'?' Patients lacking adequate beta cell function may therefore acquire overt diabetes because of the reduced capacity of insulin secretion. On the other hand, other studies in nondiabetic hyperparathyroid patients have shown no major change in glucose tolerance in the presence of hyperinsulinemia, suggesting a state of insulin resistance. 101.105.110 A complete understanding of the pathophysiologic mechanisms responsible for the disturbed carbohydrate metabolism in patients with PHPT is not yet known. Downregulation of the insulin receptor has been shown to be present in patients with PHPT. Hyperinsulinemia with mild suppression of endogenous glucose turnover after a glucose load test seems to explain this phenomenon.l' set out to answer the question of just "how asymptomatic is asymptomatic 10 HPT?" In their cohort study of 582 consecutive patients with 10 HPT, 86 patients who were considered asymptomatic preoperatively participated in the follow-up questionnaire given at a median of 72 months postoperatively. The follow-up assessment consisted of the Short Form 36-item (SF-36) quality of life (QOL) instrument and a graded questionnaire that included 19 classic and nonclassic symptoms. They found that in retrospect only 9.3% of the asymptomatic patients were truly asymptomatic. Postoperatively, 81% of the asymptomatic patients reported an improvement in their preoperative state. From this study, it would appear that apparently asymptomatic 10 HPT patients realized symptoms only in retrospect and that these symptoms could not be predicted preoperatively, because they become apparent only after treatment. These studies all suggest that asymptomatic 10 HPT patients might have the same subjective benefit from parathyroidectomy as symptomatic patients. Asymptomatic 10 HPT patients treated conservatively have no frame of reference to validate whether or not they are truly asymptomatic. In an observational study by Silverberg and colleagues of 121 10 HPT patients, they claimed that 101 (83%) were asymptomatic." Patients were randomly assigned. Half (61) underwent parathyroidectomy with a normalization of their biochemical values and an increase in their BMD. The remaining 60 patients underwent observation and, during the 1O-yearfollow-up period, 22 (37%) demonstrated a progression of their disease. Despite these results, they concluded that with clinical follow-up most asymptomatic patients with 10 HPT could be monitored safely without parathyroidectomy. The authors commented that the nonspecific manifestations of 10 HPT were not included in their criteria for symptomatic disease because quantitative measures of these manifestations were not yet available. It is, therefore, likely that the number of patients who were symptomatic in
their observation group and the number of patients who demonstrated progression of their disease were underestimated. Silverberg's study, like many others in the literature, illustrates the need for validated instruments that can measure the impact of intervention on these nonspecific manifestations of HPT.24
Utilization of Outcome Patient-Based Instruments In the past, the vague, nonspecific nature of these nonclassic symptoms in HPT limited the ability of clinicians and investigators to quantitate these symptoms with validated outcome tools. Today, patient-based outcome instruments are utilized to provide a better understanding of the impact of a disease on a patient's well-being and of the effectiveness of intervention on a disease process.P-" Several authors have demonstrated an improvement in the ability to concentrate, in cognitive function, and in some of the psychiatric symptoms such as depression following parathyroidectomy by utilizing generic neuropsychiatric assessment toolS. 19,23,25,26 Others have attempted to illustrate the effect that 10 HPT has on the patient's functional health status and well-being as well as demonstrate the impact of surgical intervention on these parameters utilizing a generic QOL instrument, the SF-36 form.21.32-34 The SF-36 form defines eight domains of health status: general health, physical function, physical and emotional role limitations, social function, mental health, bodily pain, and energy or fatigue. Burney and colleagues were the first to utilize the SF-36 form and demonstrate that 10 HPT patients had a marked impairment in their health status and QOL scoring significantly lower in seven of the eight measured domains compared with population norms before parathyroldectomy.P'" Sustained improvement in six of the eight domains was demonstrated following parathyroidectomy. Talpos and coworkers randomly assigned 53 asymptomatic patients to surgery versus observation alone." The authors demonstrated a statistically significant improvement in two of the eight domains of the SF-36 health survey, those of social functioning and emotional role limitations, in the surgically treated group. These studies give insight into the impact of the nonclassic symptoms of HPT on a patient's well-being and how parathyroidectomy can affect the patient's overall health. Although these observations are important, the generic nature of the SF-36 outcome tool makes it less responsive to clinical changes that may have occurred after parathyroidectomy. 3D A disease-specific outcome measurement tool would be more responsive to the subtle clinical changes that have been observed retrospectively by patients and their surgeons.'? A disease-specific outcome tool for HPT has been validated. This instrument, including both the classic and nonclassic symptoms, has been utilized at the University of Calgary as well as in a multicenter trial studying the impact of parathyroidectomy on patients with HPT.16,17,35 Parathyroidectomy Assessment of Symptoms (PAS) scores were obtained for 13 disease-specific items preoperatively, 7 to 10 days postoperatively, at 3 months, and at 1 year. The higher the PAS score, the higher the patients ranked their
Asymptomatic Primary Hyperparathyroidism - -
experience of the symptom. We found that the 10 HPT patients were more symptomatic preoperatively than the thyroid comparison group. Following surgical intervention, the HPT patients experienced a significant decrease in their PAS scores in the first study period and this decreasing trend continued out to 1 year. 16•17,35 In contrast, the thyroid comparison group demonstrated no change in their PAS scores throughout the study (Fig. 44-1). In a further subset analysis of the University of Calgary's patients, Sywak and coworkers found that 22 of 117 patients with 10 HPT who underwent successful parathyroidectomy had none of the NIH criteria for parathyroidectomy and by definition were free of all classic symptoms." The preoperative PAS scores were equally high in both the 22 patients without NIH criteria for surgery and the 95 patients in whom at least one of the NIH criteria was present. More important, both of these 10 HPT groups were significantly more symptomatic preoperatively than the nontoxic thyroid comparison group. AlII HPT patients reported a significant improvement in their symptom scores after parathyroidectomy (Fig. 44-2). Looking specifically at the nonclassic symptoms of fatigue, depression, irritability, mood swings, and forgetfulness, we found that all of these symptoms improved at l-year follow-up in the 10 HPT patients, in contrast to no change demonstrated in these symptoms in the thyroid comparison group (Fig. 44-A and B). We concluded that the so-called asymptomatic patients were indeed suffering from reversible, nonspecific manifestations of the disease and felt the guidelines for parathyroidectomy should be broadened to include the nonclassical manifestations of 1 HPT. 0
0
Treatment of Asymptomatic Hyperparathyroidism The changing presentation of 10 HPT is a result of the increased recognition of a milder form of the disease. The intention of the NIH consensus guidelines for parathyroidectomy was to
FIGURE 44-1. The Parathyroidectomy Assessment of Symptoms (PAS) scores for primary hyperparathyroidism (HPT).The HPT patients were significantly more symptomatic than the thyroid comparison group preoperatively (P < .05). After surgery, the HPT patients demonstrated a significant decrease in their PAS scores (P < .05). The thyroid comparison group demonstrated no change in their PAS scores throughout the study.
421
FIGURE 44-2. The Parathyroidectomy Assessment of Symptoms (PAS) scores for primary hyperparathyroidism (HPT). Group A had at least one of the National Institutes of Health (NIH) criteria for parathyroidectomy present preoperatively. Group B patients had none of the NIH criteria present and were "asymptomatic." Group C consisted of the thyroid comparison group. Groups A and B were significantly more symptomatic than group C preoperatively (P < .05). After surgery, there was no difference in the PAS scores between any of the three groups.
help guide the clinician to the appropriate treatment for patients with mild 10 HPT.1O Parathyroidectomy remains the only definitive treatment of HPT, reversing the manifestations of the disease and correcting the biochemical abnormalities in over 95% of patients. 9•36,37 There is little debate about the need for parathyroidectomy in overtly symptomatic patients. Other criteria developed at the NIH conference included age younger than 50, marked hypercalcemia (>2.85 mmollL), marked hypercalciuria (>10 mmol/ day), reduction in creatinine clearance, and bone loss more than 2.5 standard deviations compared to healthy controls. These criteria were thought to reflect the physiologic end-organ effects of HPT and thus were likely to identify the patients at risk for developing complications of the disease. Additional criteria for surgery that are utilized by some authors include vertebral bone osteopenia, vitamin D deficiency, recent fracture history, and perimenopausal status for women.F Although rare, there are patients with 10 HPT in whom vertebral osteopenia is more marked than cortical bone loss. Parathyroidectomy has been shown to result in a significant improvement in vertebral bone density and only a modest increase in cortical bone density at lO-year follow-up.P-'? It appears that the patients with significant vertebral osteopenia would benefit the most from parathyroidectomy. Receptors for vitamin D metabolites in the parathyroid glands have been shown to suppress parathyroid hormone (PTH) secretion. It has been postulated that vitamin D deficiency results in even higher PTH levels in patients with HPT. Correcting the vitamin D deficiency may be associated with a worsening hypercalcemia, and thus these patients would benefit from parathyroidectomy before addressing their vitamin D deficiency.P'" Although the increased risk of fracture in HPT is not clearly established in the literature, fractures, particularly cortical fractures, suggest an accelerated course of the disease and therefore
422 - - Parathyroid Gland
FIGURE 44-3. The item-specific Parathyroidectomy Assessment of Symptoms (PAS) scores for the nonspecific symptoms of hyperparathyroidism (HPT). A, PAS scores of the HPT patients, ~emonsr:ating a s~gnifi~ant improvement i~ all five items at I-year follow-up (P < .05). B, PAS scores of the thyroid patients, demonstratmg no difference m their scores for all five Items at I-year follow-up.
have been utilized as an indication for surgery by some authors. 12,41-44 Using the NIH definition of symptomatic disease, approximately 50% of patients with 10 HPT have at least one of the NIH criteria for parathyroidectomy," For the remaining 50% of patients, some authors have suggested conservative management with yearly monitoring of physiologic parameters such as serum calcium, BMD, and renal function. 6,11,13.28,45 In the prospective trial involving 10 HPT patients randomly assigned to surgery versus observation, Silverberg and colleagues found that 37% (22 of 60) of the observation group demonstrated progression of their disease." The majority of these patients were found to have a decrease in their BMD over time, in contrast to the parathyroidectomy group, who demonstrated a significant increase in their BMD. Of the 60 patients in the observation arm, 52 were considered asymptomatic. At 10-year follow-up, 38 of these asymptomatic patients demonstrated no significant progression of their disease. This study illustrated that there is a subgroup of patients with 10 HPT that, when followed closely, demonstrates little progression in the physiologic parameters affected by HPT, such as BMD and renal function. It is, however, likely that the investigators have underestimated the population of symptomatic patients and failed to study the impact of the nonspecific symptoms on the patients overall. There continues to be considerable debate among surgeons and endocrinologists concerning the appropriate treatment of mild, nonprogressive 10 HPT. Outcome studies that assess the impact of parathyroidectomy beyond the physiologic parameters of the disease have clearly demonstrated an improvement in the patients' well-being and general health. These studies, however, have been for the most part surgical studies and, because of the inherent referral basis, still do not clearly resolve the debate. Until a randomized study is performed that includes both classic and nonclassic symptoms and measures not only the impact on the physiologic parameters but also the impact on the patient's healthrelated QOL, the debate over the management of 10 HPT will continue.
Summary The clinical manifestations of 10 HPT have evolved during the past 4 decades. Today, fewer than 20% of patients suffer from the classic symptoms of 10 HPT initially described in the 1920s to 1940s. Many patients today suffer from vague, nonspecific, but nonetheless real manifestations of the disease. It appears from the data achieved with patient-based outcome instruments that very few patients suffering from 10 HPT are truly asymptomatic. More important, many of these nonclassic symptoms improve after parathyroidectomy. It, therefore, becomes important for the primary care clinician not only to assess the physiologic parameters of 1 HPT but also to be aware of the expanding definition of symptoms associated with this disease. With the broadened guidelines for parathyroidectomy, it appears that the majority of patients with 10 HPT require parathyroidectomy and, more important, benefit from such intervention. 0
REFERENCES 1. Welboum RB. The History of Endocrine Surgery. New York, Praeger, 1990. 2. Mandl F. Therapeutischer Veruch bei Osteitis fibrosa generalisata mittels Exstirpation enies Epithelkorperchen tumors. Wien Klin Wochenschr 1925;50:1343. 3. Albright F. A page out of the history of hyperparathyroidism. J Clin Endocrinol 1948;8:637. 4. Sivula A, Ronni-Sivula H. The changing picture of primary hyperparathyroidism in the years 1956-1966. Ann Chir Gynaecol 1984; 73:319. 5. Heath H III, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980;302:189. 6. Silverberg SJ, Bilezikian JP, Bone HG, et aI. Therapeutic controversy therapeutic controversies in primary hyperparathyroidism. J Clin Endocrinol Metab 1999;84:7:2275. 7. Walgenbach S, Hommel G, Junginger T. Outcome after surgery for primary hyperparathyroidism: Ten-year prospective follow-up study. World J Surg 2000;24:564. 8. SoreideJA, van Heerden JA,Grant CS, La CY.Characteristicsof patients surgically treated for primary hyperparathyroidism with and without renal disease. Surgery 1996;120:1033.
Asymptomatic Primary Hyperparathyroidism - - 423 9. Eigelberger MS, Clark OH. Surgical approaches to primary hyperparathyroidism. Endocrinol Metab Clin North Am 2000;29:479. 10. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus development conference statement. Ann Intern Med 1991;114:593. lOa. Bilezikian JP, Potts IT, Fuleihan G, et aI. Summary statement from workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353-5361. II. Rao OS. Parathyroidectomy for asymptomatic primary hyperparathyroidism (PHPT): Is it worth the risk? J Endocrinol Invest 200 I; 24: 131. 12. Bilezikian JP. Primary hyperparathyroidism. When to observe and when to operate. Endocrinol Metab Clin North Am 2000;29:465. 13. Silverberg SJ, Bilezikian JP. Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:2036. 14. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism: Still evolving? J Bone Miner Res 1997;12:856. 15. Hasse C, Sitter H, Bachmann S, et al. How asymptomatic is asymptomatic primary hyperparathyroidism? Exp Clin Endocrinol Diabetes 2000; 108:265. 16. Pasieka JL, Parsons LL, Demeure MJ, et al. A patient-based surgical outcome tool demonstrating improvement of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942. 17. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513. 18. Chan AK, Duh Q, Katz MH, et al. Clinical manifestations of primary hyperthyroidism before and after parathyroidectomy. Ann Surg 1995;222: I. 19. Prager G, Kalaschek A, Kaczirek K, et al. Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism. Surgery 2002; 132:930. 20. Colliander EB, Strigard K, Westblad P, et al. Muscle strength and endurance after surgery for primary hyperparathyroidism. Eur J Surg 1998;164:489. 21. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608. 22. Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery 2002;132:1013. 23. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101. 24. Okamoto T, Gerstein HC, Obara T. Psychiatric symptoms, bone density and non-specific symptoms in patients with mild hypercalcemia due to primary hyperparathyroidism; A systematic overview of the literature. Endocr J 1997;44:367. 25. Ronni-Sivula H, Sivula A. Long-term effect of surgical treatment on the symptoms of primary hyperparathyroidism. Ann Clin Res 1985;17:141. 26. Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988;12:476.
27. Lundgren E, Ljunghall S, Akerstrom G, et al. Case-control study on symptoms and signs of 'asymptomatic' primary hyperparathyroidism. Surgery 1998;124:980. 28. Silverberg SJ, Shane E, Jacobs TP, et al. A IO-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249. 29. Maloney K, Chaiken BP. An overview of outcomes research and measurement. J Healthc Qual 1999;21:4. 30. Lohr KN. Health Outcomes methodology symposium: Summary and recommendations. Med Care 2000;38(9 Suppl):1Il94. 31. Wright JG. Outcomes research: What to measure. World J Surg 1999; 23:1224. 32. Talpos GB, Bone HG III, Kleerekoper M, et aI. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: Patient description and effects on the SF-36 health survey. Surgery 2000;128:1013. 33. Burney RE, Jones KR, Coon JW, et al. Assessment of patient outcomes after operation for primary hyperparathyroidism. Surgery 1996;120:1013. 34. Burney RE, Jones KR, Peterson M, et al. Surgical correction of primary hyperparathyroidism improves quality of life. Surgery 1998;124:987. 35. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients with secondary and tertiary hyperparathyroidism. Surgery 2000; 128:531. 36. Kearns AE, Thompson GB. Medical and surgical management of hyperparathyroidism. Mayo Clin Proc 2002;77:87. 37. Howe JR. Minimally invasive parathyroid surgery. Surg Clin North Am 2000;80:1399. 38. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:729. 39. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia. A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007. 40. Silverberg SJ, Shane E, Dempster Ow. The effects of vitamin 0 insufficiency in patients with primary hyperparathyroidism. Am J Med 1999;107:561. 41. Larsson K, Ljunghall S, Krusemo UB, et al. The risk of hip fractures in patients with primary hyperparathyroidism. J Intern Med 1993;234:585. 42. Kenny AM, MacGillivary DC, Pibeam CC, et al. Fracture incidence in postmenopausal women with primary hyperparathyroidism. Surgery 1995;118: 109. 43. Melton LJ, Atkinson EJ, O'Fallon WM, Heath H. Risk of age related fractures in patients with primary hyperparathyroidism. Arch Intern Med 1992;152:2269. 44. Vestergaard P, Molerup C, Frokjaer V, et al. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321 :598. 45. Davies M, Fraser w.o, Hosking OJ. The management of primary hyperparathyroidism. Clin Endocrinol (Oxf) 2002;57:145.
Normocalcemic Hyperparathyroidism Jack M. Monchik, MD, FACS
Hypercalcemia as manifested by an elevated total serum calcium has traditionally been an important parameter in the diagnosis of primary hyperparathyroidism (PHPT). Initial studies of patients with PHPT stressed the rather constant elevation of the total serum calcium in this entity. Intermittent or no elevation of the total calcium was considered to be rare, if not impossible.l' Subsequent reports have identified patients with PHPT with subtle hypercalcemia defined as intermittent, minimal, or no elevation of the total calcium. For the purpose of this chapter, these patients are considered to have normocalcemic hyperparathyroidism. Most of these patients have renal stone disease and, to a much lesser degree, skeletal abnormalities.f" The introduction of bone densitometry with dual energy x-ray absorptiometry (DEXA) scans for screening for osteoporosis has identified an additional group of patients with normocalcemic hyperparathyroidism. This diagnosis of normocalcemic hyperparathyroidism is a challenge that must be considered in all patients with metabolic complications of PHPT. Solving this diagnostic problem is dependent on an understanding of calcium metabolism.
Distribution of Calcium in the Body Bone accounts for 98% of the calcium content in the body. Calcium in bone is present largely in the form of hydroxyapatite crystals, which are relatively insoluble. One percent of the total body calcium is in a soluble form in extracellular and intracellular fluid compartments, and another 1% is freely exchangeable within extracellular fluid." Calcium in serum is present in three distinct fractions in equilibrium. Figure 45-1 graphically displays the approximate distribution of calcium in serum. The ionized and complexed calcium together make up the ultrafiltrable fraction. Ultrafiltrable calcium represents about 50% of the total serum calcium. Ionized calcium accounts for 90% of the ultrafiltrable calcium and about 45% of the total serum calcium.
424
Complexed calcium is that fraction of the ultrafiltrable component that is ionically bound to citrate, phosphate, and carbonate, which represents approximately 10% of the ultrafiltrable calcium." Protein-bound calcium dependent on pH and temperature represents about 50% of the total serum calcium. Eighty percent of the protein-bound calcium is bound to albumin and 20% is bound to globulin; therefore, hypoalbuminemia can significantly lower the total serum calcium. The total serum calcium is reduced 0.8 to 1.0 mg/dL for each I-g/IOO mL reduction in the serum albumin. to
Calcium Homeostasis Calcium homeostasis is maintained by the complex interrelationship of parathyroid hormone (PTH), vitamin D and its derivatives, and calcitonin. The polypeptide PTH contains 84 amino acids. Once secreted by the parathyroid glands, it undergoes immediate degradation into the amino (N) and carboxyl (C) terminal fragments. The N-terminal fragment is biologically active but is rapidly cleared from the circulation, whereas the C-terminal fragment is biologically inert and is predominantly cleared from the circulation by the kidney. This fragment persists for a longer period in the circulation, particularly in patients with renal failure. 11-13 Intact PTH (iPTH), the 1-84 molecule, is the major circulating form of biologically active PTH. Most of the currently used serum PTH assays measure iPTH.14 The secretion of PTH is regulated by serum ionized calcium acting through a sensitive calcium-sensing receptor that is highly expressed on the surface of the parathyroid cells. Activation of this receptor by a small increase in ionized calcium activates second messengers such as intracellular calcium and inositol through one or more guanine nucleotidebinding (G) proteins to inhibit PTH secretion. Deactivation of this receptor by a small decrease in serum ionized calcium results in stimulation of PTH. Ionized calcium is, therefore, considered to be the physiologically active component of the total serum calcium. IS The parathyroid cells also have a
Normocalcemic Hyperparathyroidism - - 425
PROTEIN BOUND 50%
Bound to Globulin 20%
ULTRAFILTRABLE 50%
IONIZEDCALCIUM 45%
Complexed 10%
FIGURE 45-1. Distribution of calciumin serum.
vitamin D receptor. The binding of calcitriol (l,25-dihydroxyvitamin D) inhibits PTH secretion." Hyperphosphatemia stimulates PTH secretion primarily through induction of hypocalcemia but to a lesser extent through direct stimulation, particularly in patients with advanced renal failure. The major target organs for PTH are the kidneys, skeletal system, and intestine. PTH functions by binding to receptor sites in bone and kidney, resulting in stimulation of production of cyclic adenosine monophosphate (cAMP), which acts to carry out the cellular response of that specific target tissue.'? The predominant response by the kidney to PTH is to increase the tubular resorption of calcium and to decrease the tubular resorption of phosphorus.P:'? The other important function of PTH on the kidney is to increase the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which acts to increase the intestinal absorption of calcium." The action of PTH on the bone to regulate serum calcium is through the remodeling effect of osteoclast and osteoblast activity. The osteoblasts and their precursor cells in bone have a PTH receptor site, and binding to this site results in the production of cAMP. The osteoclasts do not have a PTH receptor site but are stimulated indirectly through the cAMP response in the osteoblasts." Coordinated actions of PTH on bone, kidney, and intestine result in an increase flow of calcium into the extracellular fluid and an increase in the serum calcium. PTH provides the predominant means of immediate regulation of the extracellular calcium. Although physiologically important, vitamin D action affects day to day calcium balance as opposed to the more immediate direct action of PTH.17 Calcitonin has a much smaller role in calcium homeostasis. Calcitonin is secreted by the parafollicular cells of the thyroid and inhibits bone resorption. Extremely high levels of calcitonin found in medullary carcinoma of the thyroid do not result in hypocalcemia.P
Ionized Calcium The measurement of ionized calcium appears to have a major role in the identification of symptomatic patients with PHPT with minimal, intermittent, or no elevation of the total calcium. 6,7,23 Ionized calcium is measured with a calciumselective ion flow-through electrode system.>' This system for measuring ionized calcium was first introduced in 1967 and has since undergone several design changes that have resulted in improved precision. Previous articles and continuing experience indicate that the serum ionized calcium is superior to total calcium in detecting PHPT in patients with intermittent, minimal, or no elevation of the total calcium. Ionized calcium is of no added benefit for diagnostic purposes in patients with elevated total serum calcium. Hypersecretion of PTH increases serum calcium by increasing the tubular resorption of calcium, increasing the net bone resorption and, to a lesser extent, increasing the intestinal absorption of calcium. One can justifiably question why total calcium is not increased in all patients with PHPT, assuming a normal serum albumin and no pancreatitis, increased phosphate intake, or hypomagnesemia, factors known to cause a decrease in the total serum calcium. Some authors have attributed the normal total serum calcium in normocalcemic hyperparathyroidism to an increased ratio of ionized and ultrafiltrable calcium to total calcium compared to normal individuals. Elevated serum PTH has been postulated to decrease the binding of calcium to protein and therefore increases ionized calcium at the expense of the protein-bound fraction. 6,23.25 An alternative explanation postulated for normocalcemia in patients with PHPT is a generalized resistance to the action of PTH on bone and kidney."
Ultrafiltrable Calcium Ultrafiltrable calcium has also been used for identification of normocalcemic PHPT. A comparative study of ultrafiltrable ionized and total calcium in symptomatic patients with intermittent or no elevation of the total calcium showed that ionized calcium was a more sensitive indicator of PHPT in this group of patients.F In this study, ultrafiltrable calcium was a more sensitive indicator of hypercalcemia than total calcium but did not reach statistical significance.
Renal Calculi Most patients with normocalcemic hyperparathyroidism are identified because of renal calculi and many of these patients have hypercalciuria. Most patients with renal calculi and hypercalciuria, however, have idiopathic hypercalciuria, a condition also associated with normocalcemia. Patients with idiopathic hypercalciuria have 24-hour urinary calcium values of 250 mg per 24 hours or higher in females, 300 mg per 24 hours or higher in males, or 4 mg/kg in males or females on a daily intake of 1000 mg of calcium.i" These criteria are useful even when diet is uncontrolled because urine calcium excretion varies only slightly in normal
426 - - Parathyroid Gland
FIGURE 45-2. Concurrent values of ionized and total calcium in a patient with renal calculi and intermittent elevation of the total calcium level. A parathyroidadenomaweighing 200 mg was removed at surgery. (From McLeod MK, Monchik JM, Martin HE The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95:667.)
CONSECUTIVE CONCURRENT VALUES (different days)
individuals when dietary calcium intake is widely altered.P A small fraction of these patients with hypercalciuria have normocalcemic HPTH.3o Figure 45-2 shows concomitant ionized and total calcium values in a patient with nephrolithiasis and intermittent elevation of the total calcium, and Figure 45-3 demonstrates a patient with renal calculi with no elevation of the total calcium. Since the original description of idiopathic hypercalciuria by Albright and associates in 1953, several hypothesis have been advanced to explain this entity." Increased intestinal absorption, diminished tubular resorption of calcium resulting in a renal calcium leak, and a primary phosphate leak have been postulated.P'>' In practice, the classification of idiopathic hypercalciuria stone formers into renal calcium leak, primary intestinal hyperabsorption, or primary phosphate leak is time consuming, expensive, not reproducible, and does not appear to influence the outcome of treatment. The differentiation of hypercalciuric stone formers with normocalcemic hyperparathyroidism from those with one of the subtypes of idiopathic hypercalciuria is of prime importance because of the success of parathyroid surgery in
preventing further stone formation. Failure to accurately separate stone-forming patients with normocalcemic hyperparathyroidism from those with idiopathic hypercalciuria has led to inappropriate neck exploration. Parathyroid surgery in patients with idiopathic hypercalciuria has resulted in finding no abnormal parathyroid tissue and continued stone formation." The renal calcium leak subtype of idiopathic hypercalciuria can have an elevated serum PTH secondary to compensation by the parathyroid glands to increased renal loss of calcium. The serum ionized or total calcium is not elevated in this or other subtypes of idiopathic hypercalciuria." The absence of an elevated serum ionized or total calcium makes further testing necessary to distinguish this entity from normocalcemic hyperparathyroidism. This subtype of idiopathic hypercalciuria can sometimes be separated from normocalcemic hyperparathyroidism by treatment with a thiazide diuretic. The thiazide diuretic reduces the excessive loss of urinary calcium, causing the serum calcium to rise slightly but not above, the normal range, and resulting in a decrease of the serum PTH into the normal range.F-"
TOTAL CALCIUM (mg %)
12.0 11.0 10.0
9.0~ 8.0
FIGURE 45-3. Concurrent values of ionized and
IONIZED CALCIUM (mg %)
PATH.: Adenoma
7.0
6.0
•
•
•
5.0~~R_~_[E2ill~~_R
4.0
3.0..l....--+---+---I----I--~I--~I--~-__+-__+-~
•
• NORMAL RANGE
•
•
•
1 2 3 4 5 6 7 8 CONSECUTIVE CONCURRENT VALUES (different days)
• 9
~
• 10
total calcium levels in a patient with renal calculi and all normal total calcium levels. A parathyroid adenoma weighing 440 mg was removed at surgery. (From McLeod MK, Monchik JM, Martin HE The role of ionized calcium in the diagnosis of subtle hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95:667.)
Normocalcemic Hyperparathyroidism - - 427
I have shown that ionized calcium is more sensitive than total calcium in diagnosing PHPT in patients with nephrolithiasis and minimal or no elevation of the total calcium.i-" We recommend three consecutive days of ionized and total calcium as a screening study for hyperparathyroidism in patients with nephrolithiasis with minimal or no elevation of the serum total calcium. A serum iPTH should be done on at least one day. An elevated iPTH may be the only clue to the diagnosis of normocalcemic hyperparathyroidism.26
Bone Disease Although historically most patients with normocalcemic hyperparathyroidism were identified because of renal calculi, an increasing number of patients have recently been identified by screening patients for osteoporosis with dual-energy x-ray absorptiometry (DEXA) scans. Traditionally, hyperparathyroidism was associated with overt bone disease in a significant number of patients. This traditional bone disease was frequently symptomatic and associated with radiologic findings such as bone cysts, brown tumors of the long bones, subperiosteal resorption of the distal phalanges and clavicles, and "salt and pepper" demineralization of the skull. The increased awareness of the diagnosis of PHPT and multichannel blood screening studies have resulted in an earlier diagnosis of this condition and considerably fewer patients with these classic bone findings. The introduction of screening for osteoporosis with DEXA scans has identified an increasing number of patients with severe osteopenia or osteoporosis." Hyperparathyroidism is considered an important cause of osteoporosis as a consequence of its known catabolic effect promoting osteoclast activity and bone resorption. The human skeleton consists of cortical and trabecular bone. Cortical bone is the compact layer, which predominates in the shafts of the long bones. Trabecular bone is composed of a series of thin plates, which form the interior meshwork of bones, particularly the vertebrae, pelvis, and end of long bones. The major site of bone mineral loss in PHPT appears to be cortical bone; therefore, the DEXA scan of the distal radius is more sensitive than that of the spine or hip in detecting bone loss due to PHPT. 4o The diagnosis of PHPT should be pursued in patients with severe osteopenia or osteoporosis because of the favorable outcome of parathyroid surgery. Correction of PHPT results in stopping the accelerated bone loss attributable to the hyperparathyroidism and a 10% to 12% increase in bone mass in trabecular as well as in cortical bone. This increase lasts at least a decade after successful parathyroid surgery.'" Patients with a low vertebral bone density demonstrated a marked increase in bone density after surgery. This group experienced a 20% increase in vertebral bone density over a 4-year period." This indicates that remineralization after surgical correction of PHPT involves a generalized increase in bone mass, not just cortical bone mass. Minimal, intermittent, or no elevation of the total calcium in patients with PHPT and osteoporosis is not uncommon. A study at Rhode Island Hospital identified 64 patients from
January 1995 to June 1999 with osteoporosis defined by a t score of 2.5 or less who underwent parathyroid surgery. Fifteen (23%) of these patients had 40% of their preoperative total calcium values within the normal range and 6 (9%) of these patients had no preoperative elevated total calcium, These 6 patients had a total of 44 concomitant serum ionized and total calcium measurements; 42 of the ionized calcium values were elevated and 2 were normal. Each of these patients had at least one elevated value for iPTH.43 Patients with severe osteopenia or osteoporosis who do not have an elevated serum total calcium should be screened on 3 consecutive days for serum ionized and total calcium and a serum iPTH on at least 1 day to minimize the risk of missing the diagnosis of normocalcemic hyperparathyroidism.
Diagnostic Studies All patients with recurrent renal calculi and or severe osteopenia or osteoporosis should be screened for PHPT because of the benefits provided by surgical correction. Patients with the combination of an elevated serum ionized calcium and an elevated iPTH have hyperparathyroidism, even in the absence of elevated serum total calcium. An elevated serum iPTH in the absence of elevated ionized or total calcium does not confirm the diagnosis of normocalcemic hyperparathyroidism. The iPTH can be elevated in the absence of an elevated ionized or total calcium in the renal leak form of idiopathic hypercalciuria and vitamin D deficiency.36.44 The iPTH may return to normal with treatment with a thiazide diuretic in the renal leak form of idiopathic hypercalciuria. Patients with vitamin D deficiency have a low 25-hydroxyvitarnin D level, and their serum PTH cannot be corrected by vitamin D replacement. In patients in whom the combination of 3 consecutive days of concomitant serum ionized and total calcium and intact parathyroid hormone screening cannot provide a definitive diagnosis, the oral calcium loading study may be helpful. 26.44 An elevated serum iPTH with no elevation in the ionized or total calcium is not uncommon. In a study of 178 patients with PHPT 27 patients (15%) had no elevation of the total or ionized calcium. The diagnosis in these patients was established by an oral calcium loading study showing the serum ionized calcium increasing to a supranormal value with only a minimal decrease in iPTH. 26 An oral calcium loading study can be accomplished in an office setting. The patient is given an oral dose of 1000 mg of elemental calcium. A baseline serum iPTH is obtained prior to giving the oral calcium load, and subsequent serum iPTH values are obtained at 30, 60, and 120 minutes after giving the oral calcium load. Figure 45-4 illustrates the suppression of iPTH in 18 normal controls, which shows that all but 2 of these patients exhibited suppression to 70% or more of the baseline level of iPTH at 60 minutes after the oral calcium load. Figure 45-5 shows the results of the oral calcium loading study in 6 patients with recurrent renal calculi with normocalcemic or subtle hyperparathyroidism. Five of these 6 patients did not suppress to less than 70% of the baseline iPTH. These results and our continuing
428 - - Parathyroid Gland IRMA PTH (Percent of Baseline)
140 120
100
IRMA PTH (Percent of Baseline) 140120 100
80
80
60
60
40
40
20
20
0-L...--+-------1f------+--------i BASE LINE 30 60 120 TIME (Minutes)
0-4----1-------l.----..+-------j BASE LINE 30 60 120 TIME (Minutes)
FIGURE 45-4. Percentage of change in intact parathyroid hormone values expressed as a percentage of the baseline values during the oral calcium loading test in 18 normal control subjects. IRMA PTH = immunoradiometric assay of parathyroid hormone, (From Monchik JM, Lamberton RP, Roth U. Role of the oral calcium loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103.)
FIGURE 45-5. Percentage of change in intact parathyroid hormone values expressed as a percentage of the baseline values during oral calcium loading in six patients with nonnocalcemic hyperparathyroidism. IRMA PTH = immunoradiometric assay of parathyroid hormone. (FromMonchikJM, LambertonRP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103.)
experience with the oral calcium-loading study emphasize that no single test can be expected to reliably identify all patients with normocalcemic hyperparathyroidism. Subsequent unpublished data from our institution have provided further confirmation that a completely normal suppression of iPTH can occur with oral calcium loading in patients with PHPT.
ionized calcium. All patients with recurrent renal calculi, severe osteopenia, or osteoporosis should be screened for PHPT because of the benefits of surgical correction. We suggest screening these patients with three consecutive days of serum ionized and total calcium and intact parathyroid hormone on one day.
Summary This chapter focuses on the physiology of calcium metabolism and the static and dynamic testing pertinent to the diagnosis of normocalcemic hyperparathyroidism in symptomatic patients with renal calculi or osteoporosis. An important group of patients with PHPT and recurrent renal calculi or severe osteopenia or osteoporosis has minimal, intermittent, or no elevation of the serum total calcium. The ionized calcium has been shown to be a more sensitive indicator of PHPT in this situation than total calcium. Patients with an elevated serum ionized calcium and iPTH have PHPT even in the absence of elevated serum total calcium. Treatment with a thiazide diuretic or correction of vitamin D deficiency may be necessary to separate patients with normocalcemic hyperparathyroidism from those with the renal leak form of idiopathic hypercalciuria or vitamin D deficiency. The oral calcium loading study can be helpful in identifying normocalcemic hyperparathyroidism in patients with normal or no elevation of the total calcium or
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17. 18. 19. 20. 21. 22. 23. 24.
25. 26.
27.
28.
Duncan's Diseases of Metabolism. Philadelphia, WB Saunders, 1974, P 1225. Habener JF, Segre GV, Powell D, et al. Immunoreactive parathyroid hormone in circulation of man. Nature 1972;238: 152. Segre GV, Habener JF, Powell D. et al. Parathyroid hormone in human plasma: Immunochemical characterization and biological implications. J Clin Invest 1972;51:3163. Nussbaum SR, Zabradnik RI, Lavigne JR, et al. Highly sensitive twosite immunoradiometric assay of parathyrine and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 1987;33:1364. Brown EM, Pollak M, Seidman CE, et al. Calcium ion-sensing cellsurface receptors. N Engl J Med 1995;333:234. Neveh-Many T, Friedlaender MM, Mayer H, Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat: Dominant role of 1,25dihydroxyvitarnin D. Endocrinology 1989;125:275. Nordin BEC, Marshall DH, Peacock M, et al. Plasma calcium homeostasis. In: Talmage RV, Owen M, Parsons JA (eds), CalciumRegulating Hormones. New York, Excerpta Medica, 1975, P 239. Spiegel AM, Gierchik P, Levine MA, et al. Clinical implications of guanine nucleotide-binding proteins as receptor-effector couplers. N Engl J Med 1985;312:26. Michelangoli VP, Hung NH, Martin TJ. States of activation of chick kidney adenylate cyclase induced by parathyroid hormone and guanyl nucleotides. J Endocrinol 1977;72:69. Mawer EB, Backhouse J, Hill LF, et al. Vitamin D metabolism and parathyroid function in man. Clin Sci Med 1975;48:349. McSheehy PMJ, Chambers TJ. Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone. Endocrinology 1986;118:824. Friedman J, Raisz LG. Thyrocalcitonin inhibitor of bone resorption in tissue culture. Science 1965;150:1465. Monchik JM, Martin HE Ionized calcium in the diagnosis of primary hyperparathyroidism. Surgery 1980;88: 185. Moore EW. Ionized calcium in normal serum ultrafiltrate and whole blood determined by ion exchange electrodes. J Clin Invest 1976;42:318. Yendt ER, Gange RJA. Detection of primary hyperparathyroidism with special reference to its occurrence in hypercalciuric females with normal or borderline serum calcium. Can Med Assoc J 1968;98:331. Maruani G, Hertig A, Paillard M, Houillier P. Normocalcemic primary hyperparathyroidism: Evidence for a generalized target-tissue resistance to parathyroid hormone. J Clin Endocrinol Metab 2003;88:4641. Forster J, Monchik JM, Martin HE A comparative study of serum ultrafiltrable, ionized, and total calcium in the diagnosis of primary hyperparathyroidism in patients with intermittent or no elevations in total calcium. Surgery 1988;104:1137. Hodgkinson A, Pynah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stones of renal origin. Br J Surg 1958;46:10.
29. Peacock M, Hodgkinson A, Nordin BEC. Importance of dietary calcium in the definition of hypercalciuria. BMJ 1967,3:469. 30. Johansson H, Thoran L, Werner L, et al. Normocalcemic hyperparathyroidism, kidney stones, and idiopathic hypercalcuria. Surgery 1975:77:691. 31. Albright F, Henneman P, Benedict PH, et al. Idiopathic hypercalciuria: A preliminary report. Proc R Soc Med 1953;46:1077. 32. Bordier P, Ryckewart A, Gueris J, et al. On the pathogenesis of so-called idiopathic hypercalcuria. Am J Med 1977;63:398. 33. Broadus AE, Dominquez M, Barter FC. Pathophysiological studies in idiopathic hypercalcuria: Use of an oral calcium tolerance test to characterize distinctive hypercalciuric subgroups. J Clin Endocrinol Metab 1978;47:751. 34. Pak CYC, Kaplan R, Bone H, et al. A simple test for the diagnosis of absorptive, resorptive, and renal hypercalciurias, N Engl J Med 1975;292:497. 35. Poole GV, Albertson DA, Myers RT. Normocalcemic hyperparathyroidism revisited. Am Surg 1983;49:668. 36. Coe FL, Caterbury JM, Firpo JJ, et al. Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 1973; 52:134. 37. Edwards BR, Baer PG, Sutton RAL, et al. Micropuncture study of diuretic effects on sodium and calcium reabsorption in the dog nephron. J Clin Invest 1973;52:2418. 38. Clark OH. Endocrine Surgery of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985, P 202. 39. Silverberg SJ, Bilezikian JP. Clinical presentation of primary hyperparathyroidism in the United States. In: Bilezikian JP, Marcus R, Levine MA (eds), The Parathyroids, 2nd ed. New York, Academic Press, 2001, p 349. 40. Silverberg SJ, Shane E, Jacobs TP, et al. The natural history of treated and untreated asymptomatic primary hyperparathyroidism: A ten-year prospective study. N Engl J Med 1999;341: 1249. 41. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007. 42. Ledger GA, Burritt, MF, Kao PC, et al. Abnormalities of parathyroid hormone secretion in elderly women that are reversible by short term therapy with 1,25-dihydroxyvitamin D 3 • J Clin Endocrinol Metab 1994;79:211. 43. Monchik JM, Gorgun E. Normocalcemic hyperparathyroidism in patients with osteoporosis. Surgery 2004;136:1242. 44. Monchik JM, Lamberton RP, Roth U. Role of the oral calcium-loading test with measurement of intact parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103.
Localization Studies in Persistent or Recurrent Hyperparathyroidism Jose M. Rodriguez, MD • P. Parrilla, MD
The surgical management of patients with hyperparathyroidism (HPT) is successful in more than 90% of cases.l-' Furthermore, in specialized centers, the morbidity rate of parathyroidectomy is lower than 1%.4-8 Patients with persistent HPT (hypercalcemia persists or recurs within 6 months after surgery) or, less commonly, recurrent HPT (hypercalcemia recurs after >6 months of nonnocalcemia) necessitate reoperation. In these cases, the morbidity rate increases up to 10% for permanent recurrent laryngeal nerve injury and to 35% for hypoparathyroidism.tP A successful neck exploration for HPT is primarily dependent on the experience of the surgeon, the anatomic location of the parathyroid glands (normal or ectopic sites), and the presence of a single adenoma as opposed to multiglandular disease or carcinoma.l" The most common causes of recurrent or persistent disease are unlocated parathyroid adenoma (80%),15,16 undiagnosed second adenoma (~9% of cases),'? misdiagnosis of parathyroid hyperplasia as adenomatous disease, and parathyroid carcinoma. 18 Supernumerary glands account for 15% to 25% of failed cases. 19-21 We found ectopic parathyroid tumors in 5% to 11% of failures (thymus, intrathyroid, undescended, in the retroesophageal space and in the carotid sheath).IO,15,22,23 In these cases of persistent or recurrent HPT, surgical intervention is most difficult because of the loss of normal tissue planes (as also occurs after extensive thyroid surgery) and the possibility that the missed parathyroid gland is situated in an ectopic position. Localization studies in these patients reduce operating time, avoid unnecessary dissection, reduce operative morbidity, and improve the success rate. I,24 In cases of persistent or recurrent HPT, one must first confirm the diagnosis of HPT and review previous surgical and pathology reports. With this information, we can usually determine whether the patient has a single adenoma, a double adenoma, parathyroid hyperplasia or, rarely, a carcinoma. Localization studies can be selected according to availability, cost, and experience.P Surgery for persistent or recurrent HPT should be performed only after positive localization studies. Various localization techniques that are 430
no longer used include esophageal fluoroscopy." cineradi-
ography.'? and thermography-" Currently, we classify localization methods as preoperative (invasive or noninvasive) and intraoperative (Table 46-1),
Noninvasive Preoperative Methods Ultrasonography High-resolution ultrasonography (US) (7.5 or 10 MHz) was introduced by Edis and Evans in 1979. 29 It enables exploration of the thyroid, carotid, and jugular areas and the cervical area between the thyroid cartilage and the sternal margin (Fig, 46-1). The advantages are that it is easy to perform, is well tolerated by the patient, does not require the injection of contrast medium, does not emit radiation, and can be done quickly and inexpensively. Unfortunately, the retroesophageal, retrotracheal, retrosternal, and deep cervical glands are difficult to locate by US. However, intrathyroid adenomas can be localized better with US than with other techniques although they can also be confused with a thyroid nodule. 30-32 The sensitivity of US varies according to the ultrasonographer's experience, the frequency of the transducer, the resolution of the image, and the size of the parathyroid gland.P The sensitivity of US reported in the literature varies greatly, from 22% to 82%.1,10,11,13,15,18,34-42 False-positive results are caused by thyroid nodules (6% to 15% of patients with HPT have associated thyroid lesions),3,33 adenopathy, and even esophageal lesions. Metal clips can make interpretation more difficult. The percentage of false-positive results is usually about 15% to 20%.10,15,30,36,37 Only Carlson and associatesf reported 4% false-positive results, but with a sensitivity of only 22%. Endoscopic US has also been used to locate posterior glands adjacent to the esophagus. Henry" diagnosed 52% of parathyroid tumors using endoscopic US, Catargi and colleaguesv reported the sensitivity of endoscopic US was 71 %, In both studies, endoscopic US was better than
Localization Studies in Persistent or Recurrent Hyperparathyroidism - -
431
usually more frequent than with other techniques and may reach up to 50%.1,34,51
Magnetic Resonance Imaging
conventional US. Color Doppler US has been used in an attempt to differentiate thyroid from parathyroid tumors, depending on vascularity (thyroid lesions and large parathyroid tumors are more vascular). However, as Gooding and Clar06 have reported, no clear differentiation can be established by Doppler US alone.
Computed Tomography Computed tomography (CT) is a less sensitive method than magnetic resonance imaging (MRI). It is relatively expensive, exposes the patient to radiation, and requires the administration of contrast material to obtain the best results. It is useful for ectopic parathyroid glands (retrotracheal, retroesophageal, and mediastinal) but is less effective for those in a normal location. Metal clips can also distort the image. Furthermore, peri thyroid lymphadenopathy and even the existence of tortuous or arteriosclerotic vessels may make localizing abnormal parathyroid glands difficult." The sensitivity of CT reported in the literature ranges from 16% to 70%.10,13,15.18.35-37,39-41,48-50 False-positive results are
FIGURE 46-1. Ultrasonogram showing intrathyroidal parathyroid adenoma.
Although CT and MRI both provide excellent anatomic details, MRI is preferable because it does not require the administration of contrast material, there are no artifacts from the clips left in the neck, and shoulder artifact is not a problem. However, MRI is expensive, A parathyroid tumor usually has a low signal intensity in Tl-weighted imaging (similar to muscle or thyroid) and a high signal intensity (more than or the same as fat) in T2-weighted imaging (Fig. 46_2).48 Not all adenomas have the same image characteristics.P MRI is especially useful for identifying ectopic parathyroid glands. Of 121 patients undergoing reoperation for HPT, MRI located 79% of the ectopic glands and only 59% ofthose were situated in a normal position" Superior parathyroid glands are more difficult to localize because they usually lie posterior to the thyroid at the level of the cricoid cartilage. 53 The sensitivity for MRI is greater than for CT scanning, ranging from 50% to 88%.1,13,15,18,34-38,41,49,54,55 Thyroid abnormalities and enlarged lymph nodes are a frequent cause of false-positive results. 55,56 The most common discernible causes for false-negative MRI imaging were adenomas situated closely adjacent to a thyroid goiter and cases of parathyroid hyperplasia. The results obtained for hyperplasia are worse than parathyroid adenomas, probably because of the size of the gland,35,41.53,57 although not all authors agree." Gadolinium can also improve the differential contrast with the adjacent tissues. 59,60
Thallium 201-Technetium Tc 99m Pertechnetate Scanning Thallium uptake by parathyroid adenomas was initially reported by Fukunaga and associates.s' The clinical application was performed using technetium 99m together with thallium 201. 62,63 Subtraction of the two images obtained help locate the abnormal parathyroid gland or glands. The advantages of thallium 20l-technetium 99m pertechnetate (TI-Tc) scanning are its availability, low risk, minimum
FIGURE 46-2. T2-weighted magnetic resonance image with left upper parathyroid adenoma (arrow).
432 - - Parathyroid Gland irradiation, and low operator dependence. Tumors located in perithyroid areas, especially next to the inferior pole, are localized more effectively.'" Conversely, no more than 50% of glands in the mediastinum are localized. False-negative results also depend on the size of the parathyroid glands, because parathyroids weighing less than 0.5 g are usually not detected. The most common cause of false-positive results was patient motion during examination. Also, thyroid lesions such as adenomas, carcinomas, multinodular goiters, or enlarged lymph nodes also cause false-positive results.f Price,66 in a 1993 review of 1432 patients requiring parathyroid reoperation in whom Tl-Tc scanning was used, found an average sensitivity of 55% (range, 45% to 68%); 12% ofresults were false positive. The sensitivity of Tl-Tc was even lower than 25% in the studies by Miller,36 Doherty," and their coworkers. Tl-Tc scintigraphy was a widely used localization study for parathyroid glands until the introduction of sestamibi scanning.
Technetium 99m Sestamibi Scintigraphy In 1988, Coakley and associates'" reported using technetium 99m sestamibi for cardiac function studies. Chiu and colleagues'< demonstrated the incorporation of technetium 99m into the cytoplasm and mitochondria of mouse fibroblasts in response to certain stimuli. Parathyroid cells have a large amount of mitochondria, which enables technetium 99m sestamibi to enter more intensely into the neighboring thyroid tissue.s? O'Doherty and coworkers" compared technetium 99m sestamibi and thallium 201 uptake and observed a greater uptake per gram of sestamibi in the parathyroid tissue. Recent studies relate the sestamibi uptake with the absence of P-glycoprotein in parathyroid adenomas," or even with the cellular proliferation ratio.P There are three different technetium scanning methods. 1. Single-isotope dual-phase scan. The simplest procedure was described by Taillefer and associates as the double-phase study.73 A single radioisotope scan is performed with cervicothoracic planar imaging at 10 to 15 minutes and also at 2 to 3 hours. For the cervical area, a pinhole collimator can be used selectively to improve the resolution. The late phase (2 to 3 hours) is usually preferable for detecting abnormal parathyroid glands because the thyroid clears the uptake faster than the parathyroid adenomas. 2. Dual-isotope subtraction scan. Tc 99m sestamibi is used in conjunction with another radionuclide specific to the thyroid. Iodine 123 or Tc 99m pertechnetate (low cost and quicker) are used for the thyroid subtraction.Y" 3. Three-dimensional studies. The major drawback of anterior planar views (the most frequently used) is the lack of spatial localization of the uptake. A combination of lateral or oblique planar views may help to find abnormal parathyroid glands from adjacent and/or superimposed strucrures.F:" With the help of the computed reconstruction of sagittal or transverse scans or even with three-dimensional images, single-photon emission computed tomography (SPECT) allows better localization of the uptake. 79-81 This is especially useful in case of a mediastinal location. 82
FIGURE 46-3. Tc 99m sestamibi: left lower parathyroid adenoma and thyroid adenoma follicular (false positive).
The sensitivity reported for sestamibi in persistent or recurrent HPT ranges from 57% to 85%,13.15,18.37-43,50,54,55,83 but most of the series are close to 80%, There are not significant differences between the use of the single-isotope dual-phase and the dual-isotope subtraction scan, but SPECT improves the results. 84 The most common cause of false-positive results is the coexistence of benign thyroid disease (adenomas or multinodular goiter) (Fig. 46-3).85 Also, the presence of follicular,86 papillary," and Hurthle cell thyroid carcinomas." primary thyroid lymphomas." and lymph nodes?" account for false-positive sestamibi results (see Fig. 46-3). Falsenegative results, as in our own experience, are related more to the smaller size of the gland. Intrathyroid, mediastinal (Fig. 46-4), or deep cervical parathyroids can be localized using technetium 99m sestamibi (i.e., its accuracy is not
FIGURE 46-4. Tc 99m sestamibi scan demonstrating a mediastinal parathyroid adenoma.
Localization Studies in Persistent or Recurrent Hyperparathyroidism - -
433
FIGURE 46-5. Undescended parathyroid adenoma in a Tc 99m sestamibi scan.
related to location) (Figs 46-5 to 46-8; see also Figs. 46-3 and 46-4). Sestarnibi is inaccurate in patients with multiple adenomas or parathyroid hyperplasia because often only one of the multiple abnormal glands is identified. Tc 99m tetrofosrnin is another isonitrile derivative of pertechnetate. The uptake of tetrofosrnin in parathyroid tissue is similar to sestarnibi, but the thyroid washout rate is slower.90-93 The diagnostic sensitivity of tetrofosrnin is identical to sestamibi using a dual-tracer subtraction method but is markedly lower with the single-tracer method." Tc 99m furifosrnin is also a useful tracer in parathyroid tumors, but the experience reported is limited."
FIGURE 46-7. Intrathyroid adenoma (Tc 99m sestamibi scan).
In some cases, positron emission tomography (PET) (lsF-fluorodeoxyglucose or lie-methionine) has been used because of its increased uptake in neoplastic tissue. 96-98 The results are good; however, there are a limited number of studies published and the cost of PET scanning is high. The characteristics of the most common noninvasive localization methods are shown in Table 46-2.
Invasive Preoperative Methods Invasive localization studies are indicated when the combined results of the noninvasive tests are negative, equivocal, or conflicting.
FIGURE 46-6. Recurrent hyperparathyroidism in hyperfunctioning parathyroid cyst adenoma in a patient with multiple endocrine neoplasia type 1 (Tc 99m sestamibi scan).
FIGURE 46-8. Sestamibi scan with thymic parathyroid adenoma.
434 - - Parathyroid Gland
Fine-Needle Aspiration Fine-needle aspiration (FNA) of the parathyroid tumor performed under sonographic guidance can improve the results obtained with US. FNA enables cytologic examination of parathyroid hormone (PTH) measurement in the aspirate. When the aspiration is positive for PTH, it confirms the diagnosis of a parathyroid tissue." PTH determination is more helpful than cytologic examination for diagnosing parathyroid lesions because cytologists often have difficulty in differentiating between a parathyroid gland and thyroid tissue, and the sample may also be insufficient.l'" Karstrup and associates'?' diagnosed 100% of the cases by bioassay but only 60% by cytologic examination. McFarlane and colleagues 102 also published excellent results for PTH assay (specificity 100% and sensitivity 70%). Some clinicians have recommended injection of 95% ethanol into parathyroid neoplasms to produce necrosis. Unfortunately, the tumor may recur after the ethanol injection, and recurrent laryngeal nerve injury also occurs. Furthermore, parathyroid tissue is also unavailable for histologic examination or for cryopreservation.
Parathyroid Arteriography Proper parathyroid arteriography includes examination of both thyrocervical trunks (to look for parathyroid glands in the superior mediastinum, tracheoesophageal groove, or intrathyroid or juxtathyroid location glands), the internal mammary arteries (glands in the thymus and anterior mediastinum) and carotids (juxtathyroid or undescended glands), and sometimes the selective catheterization of the superior thyroid artery. Parathyroid adenomas appear highly vascularized and oval or round (see Fig. 46-9). The sensitivity obtained with digital subtraction arteriography is around 60% to 65%; it is a difficult and expensive technique. 15,102,103 In selected cases, it is possible to do an angiographic embolization of the localized adenoma (Fig, 46-9),104
because this helps document the exact location of the parathyroid tumor.I'" Nilsson and coworkers.l'" however, published significant results with sampling from large veins such as the jugular vein, innominate vein, and superior cava. A twofold gradient between the intact parathyroid hormone (iPTH) concentration in peripheral blood and that in the selective venous sample (SVS) establishes the site of the venous drainage of the tumor. The problem arises in cases in which this gradient is not attained and localization is uncertain.l'" The sensitivity of the SVS ranges from 63% to 83%.13,15.37,50,53,83.102,108 Jones and coworkers.l'" from the University of California-San Francisco, reported 64 patients with an exact location in 75% of cases, and the SVS was not useful for the surgeon in only 17% of the cases. This technique is the most sensitive and lateralizes about 80% of parathyroid tumors. 37,107.109 Furthermore, it is just as accurate for mediastinal glands as for cervical glands and depends on gland function rather than gland size. It is also helpful when there is more than one abnormal parathyroid gland and can convert an equivocal noninvasive study into a positive one. The reported sensitivity of localizing studies for persistent or recurrent HPT is shown in Table 46-3. In cases of recurrent HPT after total parathyroidectomy with autotransplant in the forearm, the first localizing study to do is the iPTH gradient. PTH assay in the basilic vein of both arms draining the graft, with or without ischemic
Selective Venous Sampling for Parathyroid Hormone Assay Angiography is performed primarily to outline the ve?ous drainage, and it can obtain a sample for PTH assay. It IS an expensive technique and requires an expert radiologist because it is technically difficult. The samples must be taken as selectively as possible from the smallest venous branches
FIGURE 46-9. Ectopic mediastinal adenoma is shown in an internal mammary arteriogram.
Localization Studies in Persistent or Recurrent Hyperparathyroidism - - 435
blockade, is usually diagnostic when there is at least a twofold increase in relation to the other arnl.llO.lll It is recommended to do at least two positive studies before surgery. Sestamibi, CT scan or MRI, and clinical palpation of the arm may also be necessary. 112 In parathyroid carcinoma, CT and MRI are especially useful for detecting mediastinal and thoracic recurrences." US can be used for detecting cervical parathyroid carcinoma recurrence. Sestamibi allows for whole-body scanning and therefore may detect distant metastases.
Intraoperative Localization Methods Intraoperative Ultrasonography High-resolution intraoperative US may be useful once the peak of the learning curve has been reached and operating time can be reduced significantly. Kern and colleagues" found it to be more effective than any other preoperative technique for intrathyroid or perithyroid glands. The benefit of the routine use of intraoperative US in reoperative parathyroid surgery has not been established.
Radio-Guided Parathyroid Surgery Tc 99m sestamibi is the most common localization test in recurrent parathyroid disease. It is possible to use an intraoperative gamma probe to detect abnormal parathyroid tissue. This method permits minimally invasive surgery (including video-assistedparathyroidectomy). Some authors report excellent resultsll3 ·117; however, longer follow-up and more studies are necessary before this procedure can be applied routinely.
The problems of this approach are false-positive results (thyroid disease), cost, and longer operative time.
Intraoperative PTH Determination of intraoperative PTH (IOPTH) may confirm the removal of the hyperfunctioning parathyroid tissue, thus reducing the operative time. 1I8 . 119 If the basal levels of IOPTH drop more than 50% 10 minutes after parathyroid resection, it is indicative of successful surgery. Irvin and coworkers 120.121 reported a sensitivity of 93% with this method. These results have been confirmed by others," but most patients had single adenomas. Perhaps, in persistent parathyroid hyperplasia or double adenomas, the interpretation of the results is more difficult. Occasionally, the IOPTH drop is less than 50%, especially if the initial basal iPTH levels are not very high. For these reasons, this method needs a careful interpretation by the surgeon, considering also the previous sestamibi imaging and the surgical findings. 113 Injection of methylene blue or toluidine blue is of little value and is not used.
Conclusions Positive localization studies are necessary before neck explorations for persistent or recurrent HPT. Noninvasive imaging methods should be used first, and Tc 99m sestamibi is the most accurate localizing study. Localization studies should be used complementarily, such that the results obtained individually improve significantly if the studies are combined or concordant. Sestamibi and US may be useful and inexpensive initial imaging studies. SVS, an excellent invasive method, must be used if the rest of the
436 - - Parathyroid Gland
imaging studies are negative or discordant. IOPTH may be useful in some cases but does not replace good surgical experience and interpretation.
REFERENCES I. Levin KE, Gooding GAW, Okerlund M, et al. Localization studies in patients with a persistent or recurrent hyperparathyroidism. Surgery 1987;102:917. 2. Thompson NW. Localization studies in patients with primary hyperparathyroidism. Br J Surg 1988;75:97. 3. Auguste U, Attie IN, Schanap D. Initial failure of surgical exploration in patients with primary hyperparathyroidism. Am J Surg 1990;160:333. 4. Clark OH, Wilkes W, Siperstein AE, et al. Diagnosis and management of asymptomatic hyperparathyroidism: Safety, efficacy, and deficiencies in our knowledge. J Bone Miner Res 1991;6:25. 5. Lundgren E, Rastad J, Ridefelt P, et al. Long-term effects of parathyroid operation on serum calcium and parathyroid hormone values in sporadic primary hyperparathyroidism. Surgery 1992;112:1123. 6. Uden P, Chan AK, Duh QY, et al. Primary hyperparathyroidism in younger and older patients: Clinical symptoms and outcome of surgery. World J Surg 1992;16:791. 7. Kjellman M, Sandelln K, Famebo 1.0. Primary hyperparathyroidism: Low surgical morbidity supports liberal attitude to operation. Arch Surg 1994;129:237. 8. Sosa JA, Powe NR, Levine MA, et al. Thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: A national survey of endocrine surgeons. J Clin Endocrinol Metab 1998;83:2658. 9. Brennan ME, Norton JA. Reoperation for persistent and recurrent hyperparathyroidism. Ann Surg 1985;120:40. 10. Grant CS, Van Heerden JA, Charboneau EM, et al. Clinical management of persistent and/or recurrent primary hyperparathyroidism. World J Surg 1986;10:555. II. Carty SE, Norton JA. Management of patients with persistent or recurrent primary hyperparathyroidism. World J Surg 1991;15:716. 12. Jarhiilt J, Nordestrom J, Perbeck L. Reoperation for suspected primary hyperparathyroidism. Br J Surg 1993;80:453. 13. Shen W, Duren M, Morita E, et al. Reoperation for persistent and recurrent primary hyperparathyroidism. Arch Surg 1996;131:861. 14. Wells SA, Debenedetti MK, Doherty GM. Recurrent or persistent hyperparathyroidism. J Bone Miner Res 2002;17:158. 15. Jaskowiak N, Norton JA, Alexander HR, et al. A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma. Ann Surg 1996;224:308. 16. Hasse C, Sitter H, Brunne M, et al, Quality of life and patient satisfaction after reoperation for primary hyperparathyroidism: Analysis of long-term results. World J Surg 2002; 13:26. 17. Tezelman S, Shen W, Shaver JK, et al. Double parathyroid adenomas: Clinical and biochemical characteristics before and after parathyroidectomy. Ann Surg 1993;218:300. 18. Kebebew E, Arici C, Duh QD, Clark OH. Localization and reoperations results for persistent and recurrent parathyroid carcinoma. Arch Surg 2001;136:878. 19. Wang C-A. The anatomic basis of parathyroid surgery. Ann Surg 1976;183:271. 20. Liechtty RD. Parathyroid anatomy in hyperplasia. Arch Surg 1992;127:813. 21. Henry JF, Denizot A, Audiffret J, France G. Results of reoperations for persistent or recurrent secondary hyperparathyroidism in hemodialysis patients. World J Surg 1990;14:303. 22. Fraker DL, Doppman JL, Shwaker TH, et al. Undescended parathyroid: An important etiology for failed operations for primary hyperparathyroidism. World J Surg 1990;14:342. 23. Conn lM, Gongalves MA, Mansour KA, McGarity WC. The mediastinal parathyroid. Am Surg 1991;57:62. 24. Patow CA, Norton JA, Bennan ME. Vocal paralysis and reoperative parathyroidectomy: A prospective study. Ann Surg 1986;203:282. 25. Roe SM, Bums P, Graham LD, et al. Cost effectiveness of preoperative localization studies in primary hyperparathyroidism disease. Ann Surg 1994;219:582. 26. Wyman SM, Robbins LL. The roentgen recognition of parathyroid adenoma. AJR Am J Roentgenol1954;71 :777.
27. Stevens AC, Jackson CEo Localization of parathyroid adenoma by oesophageal cineroentgenography. AJR Am J Roentgenol 1967; 99:223. 28. Samuels BJ, Dowdy AH, Lecky Jw. Parathyroid termography. Radiology 1972;104:575. 29. Edis AJ, Evans PC. High-resolution real-time ultrasonography and preoperative localization of parathyroid tumors. N Engl J Med 1979;301:532. 30. Levin K, Clark OH. The reasons of failure in parathyroid surgery. Arch Surg 1989;124:91 I. 31. Liburty SK, Bartlett DL, Jaskowiak NT, et al, The role of the thyroid resection during reoperation for persistent or recurrent hyperparathyroidism. Surgery 1997;122:1183. 32. McIntyre RC, Eisenach JH, Pearlman NW, et al. Intrathyroidal parathyroid glands can be a cause of failed cervical exploration for hyperparathyroidism. Am J Surg 1997;174:750. 33. Gooding GAW. Sonography of the thyroid and parathyroid. Radiol Clin North Am 1993;31:967. 34. Erdman WA, Breslav NA, Weinreb JC, et al. Noninvasive localization of parathyroid adenomas: A comparison of x-ray, computerized tomography, ultrasound, scintigraphy, and MRI. Magn Reson Imaging 1989;102:917. 35. Kurbskack AJ, Wilson SD, Lawson TL, et al, Prospective comparison of radionuclide, computed tomography, sonographic, and magnetic resonance localization of parathyroid tumors. Surgery 1989;106:639. 36. Miller DL, Doppman JL, Shawker TH, et al. Localization of parathyroid adenomas in patients who have undergone surgery: 1. Noninvasive imaging methods. Radiology 1987;162:133. 37. Rodriguez 1M, Tezelman S, Siperstein AE, et al. Localization procedures in patients with persistent or recurrent hyperparathyroidism. Arch Surg 1994;129:870. 38. Numerow LM, Morita ET, Clark OH, et al. Persistent/recurrent hyperparathyroidism: A comparison of sestamibi scintigraphy, MRI and ultrasonography. 1 Magn Res Imaging 1995;5:702. 39. Peeler BB, Martin WH, Sandler MP, Goldstein RE. Sestarnibi parathyroid scanning and preoperative localization studies for patients with recurrent/persistent hyperparathyroidism or significant comorbid conditions: Development of an optimal localization. Am Surg 1997;63:37. 40. Thompson JB, Grant CS, Perrier NO, et al. Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring. Arch Surg 1999;134:699. 41. De Feo ML, Colagrande S, Biagini C, et al. Parathyroid glands: Combination of 99mTc MIBI scintigraphy and US for demonstration of parathyroid glands and nodules. Radiology 2000;214:393. 42. Feingold DL, Alexander HR, Chen CC, et al. Ultrasound and sestamibi scan as the only preoperative imaging test in reoperation for parathyroid adenomas. Surgery 2000; 128: 1103. 43. Carlson GL, Famdon GL, Clayton B, Rose PG. Thallium isotope scintigraphy and ultrasonography: Comparative studies of localization techniques in primary hyperparathyroidism. Br 1 Surg 1990;77:327. 44. Henry JF, Audifret J, Denizot A. Endosonography in the localization of parathyroid tumours: A preliminary study. Surgery 1990;108:1021. 45. Catargi B, Raymond 1M, Lafarge-Gense V, et al, Localization of parathyroid tumours using endoscopic ultrasonography in primary hyperparathyroidism. J. Endocrinol Invest 1999;22:688. 46. Gooding GAW, Clark OH. Use of color Doppler imaging in the distinction between thyroid and parathyroid lesions. Am J Surg 1992;164:51. 47. Kohri K, Ishikawa Y, Mitsumasa K, et al. Comparison of imaging methods for localization of parathyroids tumors. Am J Surg 1992;164:140. 48. Auffermann W, Gooding GAW, Okerlund MD, et al. Diagnosis of recurrent hyperparathyroidism: Comparison of MR imaging and the other techniques. AJR Am J RoentgenoI1988;150:1027. 49. Doherty GM, Doppman JL, Miller DL, et al. Results of a multidisciplinary strategy for management of mediastinal parathyroid adenoma as a cause of persistent hyperparathyroidism. Ann Surg 1992;215: 10 I. 50. Mariette C, Pelliser L, Combemale F, et al. Reoperation for persistent or recurrent primary hyperparathyroidism. Langenbecks Arch Surg 1998;383: 174. 51. Kem KA, Shawker TH, Jones BL. Intraoperative ultrasound on reoperative parathyroid surgery: An initial evaluation. World 1 Surg 1986; 10:631. 52. Aufferman W, Guis M, Tavares NJ, Higgins CB. MR signal intensity of parathyroid adenomas: Correlation with histopathology. AJR Am J Roentgenol 1989;153:873.
Localization Studies in Persistent or Recurrent Hyperparathyroidism - - 437 53. Higgins CB. Role of magnetic resonance imaging in hyperparathyroidism. Radiol Clin North Am 1993;31:1017. 54. Fayet C, Hoeffel C, Fulla Y, et al. Technetium-99m sestamibi scintigraphy, magnetic resonance imaging, and venous sampling in persistent and recurrent hyperparathyroidism. Br 1 Radiol 1998;71:108. 55. Gotway MB, Reddy GP, Webb R, et al. Comparison between MR imaging and 99ffiTc-MIBI scintigraphy in the evaluation of recurrent or persistent hyperparathyroidism. Radiology 2001 ;218:783. 56. Higgins CB, Aufferman W. MRI imaging of thyroid and parathyroid: A review of current status. AJR Am 1 RoentgenoI1988;151:1095. 57. Ishibashi M, Nishida H, Hiromatsu Y, et al. Comparison of technetium99m-MIBI, technetium 99m-tetrofosmin, ultrasound, and MRI for localization of abnormal parathyroid glands. 1 Nucl Med 1998;39:320. 58. McDermott VG, Fernandez RJM, Meaken TJ, et al. Preoperative MR imaging in hyperparathyroidism: Results and factors affecting parathyroid detection. AJR Am 1 RoentgenoI1996;166:705. 59. Seelos KC, De Marco R, Clark OH, Higgins CB. Persistent and recurrent hyperparathyroidism assessment with gadopentetate dimeglumineenhanced MR imaging. Radiology 1990;177:373. 60. Kang YS, Resen K, Clark OH, Higgins CB. Localization of abnormal parathyroid glands of the mediastinum with MR imaging. Radiology 1993;189:137. 61. Fukunaga M, Morita R, Yokenuga Y. Accumulation of 201TI chloride in a parathyroid adenoma. Clin Nucl Med 1979;4:229. 62. Ferlin G, Borsato N, Camerani M, et al. New perspectives in localizing enlarged parathyroids by technetium-thallium subtraction scan. 1 Nucl Med 1983;24:438. 63. Young AE, Gaunt 11, Croft DN, et al. Localization of parathyroid adenomas by thallium 201 and technetium 99m. BMI 1983;286:1384. 64. Chan TY, Serpell lW, Chan 0, et al. Misinterpretation of the upper parathyroid adenoma on thallium-20Iltechnetium-99m subtraction scintigraphy. Br 1 Radiol 1991;64: I. 65. Attie IN, Khan A, Rumanck WM, et al. Preoperative localization of parathyroid adenomas. Am 1 Surg 1988;156:323. 66. Price DC. Radioisotopic evaluation of the thyroid and the parathyroids. Radiol Clin North Am 1993;31:991. 67. Coakley AJ, Kettle AG, Wells CP, et al. 99m-Technetium sestamibi: A new agent for parathyroid imaging. Nucl Med Commun 1989; 10:791. 68. Chiu ML, Kronange JF, Piwnica Worms D. Effect of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile) technetium in cultured mouse fibroblasts. 1 Nucl Med 1990;31:1646. 69. Sandrock D, Merino Ml, Norton lA, et al. Light and electromicroscopic analyses of parathyroid tumours explain results ofTI201 Tc99m parathyroid scintigraphy. Eur 1 Med 1989;15:410. 70. O'Doherty Ml, Kettle AG, Collins REC, Coakley AI. Parathyroid imaging with technetium 99m sestamibi: Preoperative localization and tissue uptake studies. 1 Nucl Med 1992;33:313. 71. Mitchel BK, Cornelius EA, Zoghbi S, et al. Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein. Surgery 1996; 120: 1039. 72. Pinero A, Rodriguez 1M, Martinez-Barba E, et al. Tc-99m sestamibi scintigraphy and cell proliferation in primary hyperparathyroidism: A causal or casual relationship? Surgery 2003; 134:41. 73. Taillefer R, Boucher Y, Potvin C, Lambert R. Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium 99m sestamibi (double-phase study). 1 Nucl Med 1992;33:1801. 74. Wei IP, Burke Gl, Mansberger AR. Prospective evaluation of the efficiency of technetium 99m sestamibi and iodine 123 radionuclide imaging of abnormal parathyroid glands. Surgery 1992; 112: 1111. 75. Wei IP, Burke GJ, Mansberger AD. Prospective imaging of abnormal parathyroid glands in patients with hyperparathyroidism disease using combination Tc99m-pertechnetate and Tc99m sestamibi radionuclide scans. Ann Surg 1994;219:568. 76. Hindie E., Melliere D, Simon D, Perlemuter L, et al. Primary hyperparathyroidism: Is technetium 99m sestamibi/iodine subtraction scanning the best procedure to locate enlarged glands before surgery? 1 Clin Endocrinol Metab 1995;80:302. 77. Chen CC, Skarulis MC, Fraker DL, et al. Technetium-99m sestamibi imaging before reoperation for primary hyperparathyroidism. 1 Nucl Med 1995;36:2186. 78. leanguillaume C, Hindle E, Meignan-Debray S, et al. Tc-99m sestamibi and 1-123 detection of a parathyroid adenoma in the presence of cold thyroid nodule. Clin Nucl Med 1997;22:258.
79. Sfakianakis GN, Irvin GL ill, Foss 1, et al. Efficient parathyroidectomy guided by SPECT-MIBI and hormonal measurements. 1 Nucl Med 1996;88:798. 80. Neumann DR, Esselstyn CB, Kim EY, et al. Primary experience with double-phase SPECT using Tc-99m sestamibi in patients with hyperparathyroidism. Clin Nucl Med 1997;22:217. 81. Chen CC, Holder LE, Scovill WA, et at. Comparison of parathyroid imaging with technetium-99m-pertechnetate/sestamibi subtraction, double-phase technetium-99m sestamibi and technetium-99m sestamibi SPECT. 1 Nucl Med 1997;38:834. 82. Teigen EL, Kilgore EJ, Cowan RJ, et al. Technetium-99m sestamibi SPECT localization of mediastinal parathyroid adenomas. 1 Nucl Med 1996;37:1535. 83. Irvin GL, Molinari AS, Figueroa C, et al. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;229:874. 84. Pattou F, Huglo D, Proye C. Radionuclide scanning in parathyroid diseases. Br 1 Surg 1998;85: 1605. 85. Pinero A, Rodriguez 1M, Ortiz S, et al. Influence of thyroid pathology on the results of parathyroid gammagraphy with Tc99m sestamibi. Clin Endocrinol 2000;53:655. 86. Koss WGM, Brown MR, Balfour JF. A false-positive localization of parathyroid adenoma with technetium Tc99m sestamibi scan secondary to a thyroid follicular carcinoma. Arch Surg 1996; 131:216. 87. Nakahara H, Noguchi S, Murakami N, et al. Technetium-99m sestamibi scintigraphy compared with thallium-201 in evaluation of thyroid tumours. 1 Nucl Med 1996;37:901. 88. Balon HR, Fink-Bennet D, Stoffer SS. Technetium-99m sestamibi uptake by recurrent Hiirthle cell carcinoma of the thyroid. 1 Nucl Med 1992;33: 1393. 89. Scott AM, Kostakoglu L, O'Brien IP, et al. Comparison of technetium-99m-MIBI and thallium-Zul-chloride uptake in primary thyroid lymphoma. 1 Nucl Med 1992;33:1396. 90. Aigner RM, Fueger GF, Nicoletti R. Parathyroid scintigraphy: Comparison of technetium-99m methoxyisobutylisonitrile and technetium-99m-tetrophosmin studies. Eur 1 Nucl Med 1996;23:693. 91. Pattou F, Oudar C, Huglo D, et al. Localization of abnormal parathyroid glands with jugular sampling for parathyroid hormone, and subtraction scanning with sestamibi or tetrophosmin. Aust N Z 1 Surg 1998;68: 108. 92. Ishibashi M, Nishida H, Strauss W, et al. Localization of parathyroid glands using technetium-99m-tetrofosmin imaging. 1 Nucl Med 1997; 38:706. 93. Pattou F, Huglo D, Proye C. Radionuclide scanning in parathyroid disease. Br 1 Surg 1998;85:1605. 94. Giordano A, Meduri G, Rubini G, et al. Italian multicenter study on 99m-Tc-tetrophosmin in parathyroid scintigraphy: Results in 133 subjects. Eur 1 Nucl Med 1998;25:9. 95. Aigner RM, Fueger GF, Wolf G. Parathyroid scintigraphy: First experiences with technetium(ill)-99m-QI2. Eur 1 Nucl Med 1997; 24:326. 96. Arslan N, Rydzewski B. Detection of a recurrent parathyroid carcinoma with FDG positron emission tomography. Clin Nucl Med 2002;27:221. 97. Neumann DR, Esselstyn CB, Macintyre WI, et al. Regional body FOG-PET in postoperative recurrent hyperparathyroidism. 1 Comput Assist Tomogr 1997;21:25. 98. Cook Gl, Wong lC, Smelie WI, et al. [11C]Methionine positron emission tomography for patients with persistent or recurrent hyperparathyroidism after surgery. Eur 1 Endocrinol 1998;139:195. 99. Marcocci C, Mazzeo S, Bruno-Bossio G, et al. Preoperative localization of suspicious parathyroid adenomas by PTU assay in the needle aspiration. Eur 1 Endocrinol 1998;139:72. 100. Tikkakosky T, Stenfors LE, Typpo T, et al. Parathyroid adenomas: Preoperative localization with ultrasound combined with fine-needle biopsy. 1 Laryngol OtoI1989;62:981. 101. Karstrup S, Glenthoj A, Hainau B, et al. Ultrasound-guided, histological, fine-needle biopsy from suspect parathyroid tumours: Success rate and reliability of histological diagnosis. Br 1 Radiol 1989;62:981. 102. McFarlane MP, Fraker DL, Shawker TH, et al. Use of preoperative fine-needle aspiration in patients undergoing reoperation for primary hyperparathyroidism. Surgery 1994; 116:959. 103. Miller DL. Preoperative localization and interventional treatment of parathyroid tumours. When and how? World 1 Surg 1991;15:706.
438 - - Parathyroid Gland 104. McIntyre RC, Kumpe DA, Liechty D. Reexploration and angiographic ablation for hyperparathyroidism. Arch Surg 1994; 129:499. 105. Miller DL. Endocrine angiography and venous sampling. Radiol Clin NorthAm 1993:31:1051. 106. Nilsson BE, Tissell LE, Janson S, et al. Parathyroid localization by catheterization of large cervical and mediastinal veins to determine serum concentrations of intact parathyroid hormone. World Surg 1994;18:605. 107. Sugg SL, Fraker DL, Alexander R, et al. Prospective evaluation of selective venous sampling for parathyroid hormone concentrations in patients undergoing reoperations for primary hyperparathyroidism. Surgery 1993;114:1004. 108. Billingsley KG, Fraker DL, Doppman JL, et al. Localization and operative management of undescended parathyroid adenomas in patients with persistent primary hyperparathyroidism. Surgery 1994; I 16:982. 109. Jones 11, Brunaud L, Dowd CF, et al. Accuracy of selective venous sampling for intact parathyroid hormone in difficult patients with recurrent or persistent hyperparathyroidism. Surgery 2002; 132:944. I 10. Casanova D, Safati E, De Francisco A, et al. Secondary hyperparathyroidism: Diagnosis of site of recurrence. World J Surg 1991;15:546. I I I. Demeter JG, De Jong SA, Lawrence AM, Paloyan E. Recurrent hyperparathyroidism due to parathyroid autografts: Incidence, presentation, and management. Am Surg 1993;59:178. 112. Fong-Fu C, Chiang Hsuan L, Hue-Yon C, et al. Persistent and recurrent hyperparathyroidism after total parathyroidectomy with autotransplantation. Ann Surg 2002;235:99. 113. Alexander HR, Chen CC, Shawker T, et al. Role of preoperative localization manoeuvers including intraoperative PTH assay determination
114.
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for patients with persistent or recurrent hyperparathyroidism. J Bone Miner Res 2002;17: 133. Norman JG, Jaffray CE, Chheda H. The false-positive parathyroid sestamibi: A real or perceived problem and a case for radio-guided parathyroidectomy. Ann Surg 2000;23 I :31. Huang GU, Wu HS, Tsai SC, et al. Recurrent hyperfunctioning parathyroid gland demonstrated radionuclide imaging and an intraoperative gamma probe. Clin Nucl Med 2000;25:348. Geissler B, Grober S, Zugel N, Lindemann F. [Radio-guided parathyroidectomy: Successful intraoperative parathyroid localization diagnosis with 99mTc sestamibi in primary and recurrent hyperparathyroidism.] Chirurg 2001;72:1179. Navarra G, Feggi L, Ascanelli S, et al. Role of radio-guided surgery in recurrent secondary hyperparathyroidism. Nephron 2001;88:36. Proye CA, Goropoulos A, Franz C, et al. Usefulness and limits of quick intraoperative measurements of intact (1-84) parathyroid hormone in the surgical management of hyperparathyroidism: Sequential measurements in patients with multiglandular disease. Surgery 1991;110: 1035. Irvin GL III, Prudhomme BS, Deriso GT, et al. A new approach to parathyroidectomy. Ann Surg 1994;2 I 9:574. Irvin GL III, Dembrow VD, Prudhomme DL. Clinical usefulness of an intraoperative "quick parathyroid hormone" assay. Surgery 1993;114:1019. Irvin GL, Molinari AS, Figueroa C, Carneiro DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;226:874.
Technique of Parathyroidectomy H. Jaap Bonjer, MD, PhD • Hajo A. Bruining, MD, PhD
One of the pioneers of parathyroid surgery, Edward D. Churchill, stated in 1931 that "the success of parathyroid surgery must lie in the ability of the surgeon to know a parathyroid gland when he sees it, to know the distribution of the glands, where they hide, and also to be delicate enough in technique to be able to make use of this knowledge,"! More than half a century later, this statement still describes perfectly the fundamentals of successful parathyroid surgery. Therefore, the embryology and anatomy of parathyroid glands are discussed before the description of the technique of parathyroidectomy.
Embryology of Parathyroid Glands The parathyroid glands develop from the third and fourth pharyngeal pouches.? The upper parathyroid glands originate from the dorsal tips of pharyngeal pouch IV.3 The ventral portion of pharyngeal pouch IV consists of the ultimobranchial body, which is incorporated into the lateral part of the developing thyroid and eventually supplies the parafollicular or C cells. The common embryologic origin of the lateral part of the thyroid and the upper parathyroids accounts for the occasional intrathyroidal location of upper parathyroids, although this is a rare observation." The lower parathyroid glands arise from the dorsal part of pharyngeal pouch III. The thymus, which originates from the ventral part of pharyngeal pouch III, and the lower parathyroid gland descend as a complex in a plane ventrally to pharyngeal pouch IV. Therefore, the lower parathyroids are usually found in a more anterior position than the upper parathyroids. At the caudal descent, the lower parathyroid usually dissociates from the thymus and is ultimately located near the lower pole of the thyroid. The caudal migration of the complex of the lower parathyroid and thymus can vary widely. In the case of absence of migration, the lower parathyroid gland is found cranially to the upper pole of the thyroid, mimicking a superior parathyroid. Thymic tissue surrounding the undescended parathyroid can clarify the
true origin of the ectopic parathyroid gland. The absence of thymic tissue caudally to the thyroid is another indicator of an undescended lower parathyroid. When the lower parathyroid remains attached to the thymus during caudal migration, it becomes positioned in the anterosuperior mediastinum.
Anatomy of Parathyroid Glands Number of Parathyroid Glands The presence of four parathyroid glands is most common in humans. In dissection studies of 428 human subjects by Gilmour, four parathyroid glands were found in 87% of all patients and three parathyroids in 6.3%.5 Akerstrom and colleagues reported comparable rates in an autopsy study of 503 cases." Four parathyroids were found in 84% and three parathyroids in 3% of all patients in this study. The occurrence of supernumerary parathyroid glands is a rare entity that nevertheless has important clinical consequences, particularly in patients with hyperparathyroidism resulting from multiple-gland disease. In a series of 2015 patients who were operated on for primary hyperparathyroidism, a hyperfunctioning supernumerary fifth parathyroid caused hypercalcemia in 15 patients (0.7%).7 Nine of these patients required reoperations to reveal the parathyroid tumor. The majority of these fifth gland tumors were located in the mediastinum, either in the thymus (n = 7) or related to the aortic arch (n = 3). Edis and Levitt" reported a rate of persistent hyperparathyroidism of 10% resulting from an enlarged supernumerary parathyroid in patients with secondary hyperparathyroidism. In a series of 762 patients with primary hyperparathyroidism, Wang and coworkers documented 6 patients with persistent hyperparathyroidism caused by hyperfunctioning supernumerary glands (0.6%), all of which were located in or in close association with the thymus." In a dissection study of 428 cases, Gilmour found supernumerary parathyroid glands in 29 cases (6.7%).5 Five parathyroids were observed in 25 cases (5.8%),6 parathyroids in 2 cases (0.05%),8 parathyroids in 1 case, and 12 parathyroids in another case. Akerstrom and 439
440 - - Parathyroid Gland colleagues concluded in an autopsy study that most supernumerary glands were either rudimentary or divided." When supernumerary parathyroids weighing less than 5 mg were excluded, there were 24 cases of supernumerary glands (5%). These supernumerary parathyroids were most frequently found in the thymus or in relation to the thyrothymic ligament.
Location of Parathyroid Glands The location of parathyroid glands varies widely as a result of differences in degree of migration during embryologic development. Superimposed on the various locations of parathyroid glands are the displacements of parathyroid glands that become enlarged in the process of ensuing hyperparathyroidism. Enlarged parathyroid glands tend to migrate in an areolar plane, which offers little resistance as a result of gravity and perhaps swallowing and lower intrathoracic pressures.!" In some patients, these migrations result in considerable displacement of parathyroid tumors. Awareness of the common "pathways" of migration is invaluable in parathyroid surgery. Eighty percent of the upper parathyroid glands are found at the cricothyroid junction, about 1 em cranial to the intersection of the recurrent laryngeal nerve and the inferior thyroid artery (Fig. 47-1).6 The upper parathyroids, which are tucked posteriorly to the upper pole of the thyroid, are usually covered by a fascial sheath connecting the thyroid to the pharynx. More anteriorly situated upper parathyroids are located on the surface of the thyroid, frequently underneath the capsule of the thyroid. The unique feature of these subcapsular parathyroids is the freedom of movement of the parathyroids within the capsule. This feature distinguishes
FIGURE 47-1. Locations of the upper parathyroid glands. The more common locations are indicated by darker shading. The numbers represent the percentages of glands found at the different locations. (From Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:17.)
parathyroids from thyroid nodules, which cannot move freely. The occurrence of intrathyroidal parathyroids is rare and controversial. A subcapsular parathyroid is easily confused with a true intrathyroidal parathyroid, which is surrounded by thyroid tissue. Akerstrom and colleagues noted true upper intrathyroidal parathyroid glands in three cases (0.2%) among 503 autopsies.f Wang considered the upper parathyroid gland the most likely to be intrathyroidal because of the close embryologic relationship of the primordium of the upper parathyroid gland with the lateral complex of the thyroid. 1I However, Wheeler and coauthors'? reported eight intrathyroidal parathyroid tumors in 7 patients (3.5%) in a series of 200 patients undergoing exploration of the neck for hyperparathyroidism. Seven of these eight intrathyroidal parathyroids were considered to be lower parathyroid glands. The incidence of intrathyroidal parathyroids ranges from 0.5% to 3% in the literature.l':'>" Normal upper parathyroid glands are found in the retroor paraesophageal space in I % of all cases. IS This space is the site where enlarged upper parathyroids descend to the superoposterior mediastinum. The importance of this ectopic location of upper parathyroid glands is illustrated in Figure 47-2. In a series of 104 patients with persistent hyperparathyroidism, 34 parathyroid tumors were found in the superoposterior mediastinum.'?
34 21 19 13 10 5 1 1
SUPERIOR POSTERIOR MEDIASTINUM ANTERIOR MEDIASTINUM BEHIND UPPER POLE OF THYROID BEHIND CLAVICLE WITHIN THYMIC TONGUE BEHIND LOWER POLE OF THYROID BEHIND ESOPHAGUS BEHIND ANGLE OFTHE JAW INTRATHYROIDAL
FIGURE 47-2. Sites of 104 missing parathyroid tumors. (From Wang CA. Parathyroid re-exp1oration: A clinical and pathological study of 112 cases. Ann Surg 1977;186:142.)
Technique of Parathyroidectomy - -
The distribution of locations of the lower parathyroid glands varies more widely (Fig. 47-3). More than half of the lower parathyroids are located around the lower pole of the thyroid. Twenty-eight percent of the lower parathyroids are found in the thyrothymic ligament or within the thymus. A rare location of lower parathyroids is high in the neck at the carotid bifurcation, resulting from absence of embryologic migration. When lower parathyroid glands become enlarged, they tend to migrate into the anterior mediastinum. Figure 47-2 shows that one third of all missed parathyroid tumors were found in the thymus or in the anterior mediastinum.
Gross Features of Parathyroid Glands It is essential in parathyroid surgery to distinguish between normal and hyperfunctioning parathyroid glands. Hyperfunctioning parathyroid glands are enlarged. Therefore, definition of the normal size of a parathyroid gland is crucial. The size of normal parathyroids varies considerably because parathyroids are easily molded as a result of their soft consistency. The shape of the parathyroid gland is dependent on its anatomic position. Parathyroids that are located in loose tissue have an oval, bean, or teardrop shape. When parathyroids lie underneath a capsule, their shape is flat with sharp edges. Although a particular shape of a parathyroid gland is not associated with hyperfunction, a spherical shape often indicates hyperactivity of the parathyroid.P
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Because the shape of parathyroids is diverse, the parenchymal weight of parathyroid glands is the most reliable parameter for parathyroid function.P The weight of parathyroid glands attains its maximum in men in the third decade of life. 22 In women, there is a progressive rise until about the age of 50 years. The weights of parathyroid glands are lower in patients with chronic illnesses, except renal disease, and lower in women than in men.P The weights of the lower parathyroids are greater than those of the upper parathyroids. The normal weight of a parathyroid gland remains uncertain. An upper limit of normal parenchymal weight of 38 mg for a single gland was reported by Gilmour and Martin." Dufour and Wilkerson found an upper normal limit of 49 mg for the parenchymal weight of a single gland.P Akerstrorn and colleagues found a maximal normal glandular weight of 59 mg in an autopsy study of 368 cases without evidence of hyperparathyroidism." Dufour and Wilkerson demonstrated that 95% of the individual glands weighed between 8.2 and 75.0 mg. It should be noted that an overlap of the weights of normal and abnormal parathyroid glands exists. In our series of 1080 patients with hyperparathyroidism, several patients became normocalcemic after removal of abnormal parathyroid glands weighing only 60 mg. Underestimation of the weight of parathyroid glands can easily occur when the parathyroid lies underneath the capsule of the thyroid and only part of the parathyroid can be examined. Therefore, the entire parathyroid should be exposed before assessing its weight. Alternatively, the weights of parathyroid glands, which are surrounded by an abundance of fat, can be overestimated. The color of normal parathyroid glands ranges from yellowish brown to reddish brown. The color depends on the amount of fat, number of oxyphil cells, and degree of vascularity.P Enlarged parathyroid glands display colors varying from dark brown to light yellow. In secondary or tertiary hyperparathyroidism, the enlarged parathyroids sometimes have a typical gray color. Parathyroid carcinomas can also have a grayish white surface.
Blood Supply of Parathyroid Glands Preservation of the blood vessels supplying the parathyroid glands in parathyroid surgery is essential to prevent damage to normal parathyroid glands. Most parathyroid glands have a single artery (80%).26 The length of the parathyroid artery can vary from I to 40 mm. In general, the parathyroid glands derive their arterial branches from the inferior thyroid artery. However, 20% or more of the upper parathyroid glands are vascularized by the superior thyroid artery. Delattre and coworkers" found in an autopsy study that 10% of the lower parathyroid glands were dependent on an anterior branch of the superior thyroid artery. In most of these cases, the inferior thyroid artery was absent, which is not unusual at the left side. Mediastinal parathyroids often have an artery that is a thymic branch of the internal mammary artery." The venous return of parathyroid glands runs almost parallel to the arterial vessels. 0.2 FIGURE 47-3. Locations of the lower parathyroid glands. The more common locations are indicated by darker shading. The numbers represent the percentages of glands found at the different locations. (From Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:17.)
Technique of Parathyroidectomy The diagnosis of hyperparathyroidism should be confirmed by the assessment of an elevated serum parathyroid hormone
442 - - Parathyroid Gland
level using a two-site immunoassay.P" Localization studies of enlarged parathyroid glands are necessary only in patients having exploration of the neck for persistent or recurrent hyperparathyroidism and in patients undergoing parathyroidectomy with local anesthesia.P-" We believe that pre- and postoperative laryngoscopy to assess vocal cord function is mandatory in (para)thyroid surgery.P
Anesthesia Exploration of the neck is performed preferentially under general anesthesia with endotracheal intubation. In patients who are unfit for general anesthesia, an enlarged parathyroid gland can be removed under local anesthesia when localization studies have demonstrated the exact site of the parathyroid tumor. 33 Positioning of the patient on the operating table is of paramount importance. The patient's neck should be extended dorsally to provide optimal access to the neck. Care should be taken not to overextend the neck to prevent postoperative occipital head pain. The arms of the patient should lie alongside the body to allow the surgeon and the assistant to stand on both sides of the neck. Long ventilation tubes facilitate placement of the ventilator at some distance from the operating table, which creates space for the operating team. The ventilation tubes can be fixed on the head of the patient using a sheet or a special Velcro band (Fig. 47-4). The second assistant can stand at the head of the table. Replacement of the endotracheal tube in the case of rupture of the cuff is difficult when the patient's head is covered with drapes. Therefore, we recommend packing of the oropharynx with a gauze strip to prevent gas leakage from any cause.
Exploration of the Neck The use of magnifying glasses (2x) facilitates exploration of the neck. Fine bipolar forceps are a valuable asset to prevent diathermic injury of the recurrent laryngeal nerve. The ligation of small vessels is best done with a fine right-angled dissection clamp. A symmetrical collar incision is made,
FIGURE 47-4. Positioning of the patient on the operating table for (para)thyroid surgery. The neck is hyperextended, and the ventilation tubes are fixed on the head.
preferentially in a natural skin crease, 3 to 4 em cranially to the suprasternal notch. An incision that is located too close to the suprasternal notch is likely to become a hypertrophic scar. The incision should not extend beyond the sternocleidomastoid muscles. After incising the platysma, the cranial skin-platysma flap is dissected upward to the notch of the thyroid cartilage and downward to the suprasternal notch. A self-retaining retractor is used to withdraw the upper and lower skin-platysma flaps. A midline incision is made in the cervical fascia from the cricoid cartilage down to the suprasternal notch. The sternohyoid and sternothyroid muscles are separated from the underlying thyroid and thymus. If present, the middle thyroid vein must be divided to allow the thyroid lobe to be retracted anteriorly and medially. Transection of the strap muscles is unnecessary because they can be retracted sufficiently by a wide blunt retractor, held by the second assistant standing at the head of the operating table, who has the second best view of the operating field, which is important for surgical education. The thyroid lobe can be retracted by an Allis clamp or stitch. It is essential to free the thyroid and thymus from the strap muscles, from the cricoid cartilage to the suprasternal notch, to obtain complete exposure of the lateral aspects of the thyroid and the thymus. Fascial sheaths covering the thyroid should be removed until the surface of the thyroid is shiny; otherwise, subcapsular parathyroid glands can easily be overlooked. The fascia between the common carotid artery and the thyroid should be opened alongside the carotid artery to have access to the retroesophageal space. On the right side, care should be taken to avoid injury to a nonrecurrent laryngeal nerve at this step because this anomaly is more common on the right side.34 Throughout the entire procedure, the surgical field should be kept as bloodless as possible to prevent discoloring the parathyroid glands, which impedes their identification. Parathyroid glands are often (partially) surrounded by fat. Therefore, any lobule of fat at the predilection sites of parathyroids should be inspected. When the thin fascia that covers the fat lobule is carefully opened, the parathyroid gland usually "pops" out. Normal parathyroid glands have a basic light brown color. The color is important to differentiate parathyroid glands from fat, which is more yellow, and from thyroid nodules, which are more red in color. Another important feature of parathyroid glands is their freedom of motion in relation to the thyroid gland. When looking for a parathyroid, it can be helpful to strike along the thyroid with a peanut sponge to find moving structures. A thyroid nodule can mimic a parathyroid gland but is more firmly attached to the thyroid and does not have a distinct vascular stalk. In the thyrothymic ligament or in the thymus, parathyroid glands can easily be confused with lymph nodes. However, the consistency oflymph nodes is firmer than that of parathyroids. Lymph nodes are also grayer than parathyroids. Palpation is another valuable method to detect parathyroid tumors. In particular, enlarged upper parathyroids, which have descended dorsally to the inferior thyroid artery, can often be more readily palpated than seen. On the other hand, a negative palpation does not exclude the presence of a parathyroid tumor because the consistency of parathyroids can be similar to that of the surrounding tissue. A sense of abnormal local "fullness" may indicate the presence of a parathyroid tumor.
Technique of Parathyroidectomy - -
During the dissection of parathyroid glands, the vascular anatomy should be kept in mind. Dissection of the upper parathyroid gland should be started at the dorsal tip of the upper parathyroid to prevent injury to the parathyroid vessels, which usually ascend from the inferior thyroid artery. The dissection of the lower parathyroid gland should start at the caudal end of the parathyroid because the vascular hilus is on the cranial side of the lower parathyroid. When a normal parathyroid gland becomes devitalized during dissection, it should be cut with a razor knife in small fragments of I mm! and replanted in the sternocleidomastoid muscle. The recurrent laryngeal nerve is not exposed routinely because the risk of injury to this nerve is very low when delicate dissection is performed.'? However, the surgeon should realize that the nerve can be embedded in the anterior or medial capsule of an enlarged upper parathyroid gland or in the dorsal capsule of an enlarged lower parathyroid. The parathyroid exploration is usually started by searching for the right upper parathyroid gland. The right upper parathyroid is usually located behind or on the dorsum of the thyroid cranial to the inferior thyroid artery. The posterior aspect of this part of the thyroid can be visualized adequately when the thyroid is retracted medially, the upper part of the strap muscles retracted cranially, and the middle part of the strap muscles retracted laterally. Retraction of the strap muscles is best done by the second assistant with blunt retractors while standing at the head of the operating table. Gentle dissection of the fat lobules and fibrous attachments of the thyroid reveals the majority of the upper parathyroid glands. The dissection should be constantly done under direct vision to prevent injury of the recurrent laryngeal nerve, which runs anteriorly and medially to the upper parathyroid gland. When the upper parathyroid cannot be found in its usual site, the para- and retroesophageal space dorsal to the inferior thyroid artery should be palpated. In the case of a descended upper parathyroid tumor, dissection is facilitated when the assistant pushes the descended parathyroid in a ventrocranial direction. When considerable descent of an upper parathyroid has taken place, the tumor can usually be moved upward by gentle digital teasing. If regular dissection and digital exploration have proved negative, the capsule of the upper pole of the thyroid gland should be opened eventually to inspect for a subcapsular-intrathyroidal parathyroid. After this step, the exploration should proceed to the right lower parathyroid gland. The search for the lower parathyroid gland should start with thorough inspection of the lower pole of the thyroid, the thyrothymic ligament, and the thymus. When the lower parathyroid is not visualized at inspection, the junction of the thyrothymic ligament and the lower pole of the thyroid should be dissected. In many cases, the lower parathyroid hides in the fat between the inferior thyroid veins. Subsequently, the posterior aspect of the lower thyroid lobe should be inspected. If the lower parathyroid has not been identified after these steps, the thin sheath covering the thymus should be incised. Rarely, a parathyroid tumor on the anterior surface of the thyroid gland has been described. After this procedure, the other side of the neck should be explored in a similar fashion.
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Biopsies of Parathyroid Glands The role of biopsies during parathyroid surgery is limited." Some authors rely on the microscopic features of parathyroids to distinguish adenomas from hyperplastic glands.36-39 However, no single criterion has proved irrefutable in making this differentiation.w" In a study of the histology of parathyroid glands in 236 patients with primary hyperparathyroidism, significantly different morphologic features in adenomas and primary hyperplasias could not be demonstrated." Therefore, the surgeon should assess the size and color of the parathyroid glands and determine which parathyroid glands are abnormal. Description of the disease of hyperparathyroidism as "single-glanddisease" or "multiplegland disease" is a consequence of lack of microscopic distinction between adenomas and hyperplasia. The role of the pathologist intraoperatively is limited to the identification of parathyroid tissue." Taking biopsy specimens of parathyroid glands routinely increases the incidence of postoperative transient hypocalcemia/" Kaplan and coworkers'? compared the rates of postoperative transient hypocalcemia in one group of patients with hyperparathyroidism having biopsies of all parathyroids with those of another group having occasional biopsies. The rates of postoperative transient hypocalcemia were 48% and 26%, respectively. In our series of patients with nonfamilial hyperparathyroidism operated on before 1989, I of 156 patients with single-gland disease developed permanent hypoparathyroidism, probably as a result of routine biopsies of all parathyroid glands. An alternative method to differentiate between normal and abnormal parathyroid glands is the density test, as proposed by Wang and Rieder.48 The density test measures the difference in total fat content of two parathyroid glands. A low intercellular fat content indicates hormonal hyperfunction. However, detailed studies of normal parathyroid glands have shown wide variations in the amounts of intercellular fat. Seventy-five percent of normal glands have been shown to have less than 30% intercellular fat and 50% of normal glands less than 10% intercellular fat. With these data, estimations of intercellular fat content have become practically useless as a parameter of normality.f'-" Tibblin and colleagues used the amount of intracellular fat to delineate normal and abnormal parathyroid glands." Normal parathyroid glands contain easily detectable amounts of intracellular fat, whereas in abnormal glands intracellular fat is decreased or absent. However, these are not consistent findings. Approximately 10% of parathyroid adenomas have significant amounts of intracellular fat, and hyperplastic glands can stain for varying amounts of intracellular fat."
Resection of Parathyroid Tissue In patients with nonfamilial hyperparathyroidism and patients with multiple endocrine neoplasia (MEN) type 2 syndromes, only enlarged parathyroid glands with an estimated weight greater than 40 mg should be removed.44 •53,54 In patients with a solitary enlarged parathyroid gland, the vascular stalk of the tumor should be ligated and the tumor removed. At the dissection of the parathyroid tumor, the capsule of the parathyroid should not be opened to prevent
444 - - Parathyroid Gland seeding of parathyroid tissue, which can cause recurrent hyperparathyroidism.v-" The removed parathyroid tumor should be weighed on precise scales before formalin fixation and sent to the pathologist for frozen section confirmation of the presence of parathyroid tissue. The normal-sized parathyroid glands should be marked with a fine nonabsorbable suture to facilitate identification of the parathyroid glands when a reoperation for recurrent hyperparathyroidism is necessary. In the case of enlargement of two or three parathyroid glands, the enlarged glands should be removed. In our series of 179 patients with multiple-gland disease, 120 patients had two enlarged parathyroid glands, 40 had three enlarged glands, 18 had four enlarged glands, and 1 had five enlarged glands. After selective removal of the enlarged glands, irrespective of their microscopic appearances, the rate of recurrent hyperparathyroidism was 1.8% after an average follow-up of 13.5 years.f If all parathyroid glands are enlarged, the left and right thymus should be removed because supernumerary parathyroid glands are frequently located in the thymusf To prevent postoperative hypoparathyroidism, a remnant of approximately 50 mg of parathyroid tissue should be left behind. An easily (re)accessible parathyroid gland with a reliable vascular stalk should be chosen for this purpose. In patients with secondary hyperparathyroidism, familial hyperparathyroidism, or MEN 1 syndrome, all parathyroid glands are involved. The rate of recurrent hyperparathyroidism in these patients ranges from 10% to 50%.58-60 A subtotal parathyroidectomy should be performed, leaving behind a well-vascularized remnant of a lower parathyroid with the dimensions of a normal gland. The thymus should be removed bilaterally because a supernumerary parathyroid gland is located in the thymus in 3% to 5% of all patients."I,62 An alternative for subtotal parathyroidectomy is total parathyroidectomy with autotransplantation of parathyroid tissue into the forearm muscles, combined with cryopreservation of some parathyroid tissue. 63
derivative) should be added to the oral medication. Symptoms of muscular cramps and "tetany" must be promptly countered with administration of intravenous calcium. In some patients, symptoms of tetany may develop while the serum calcium level is normal. This is probably due to a rapid decrease in serum calcium after removal of the parathyroid tumor, causing increased neural excitability, but may also persist after calcium replacement resulting from an accompanying hypomagnesemia.v'
Troubleshooting for a Missing Parathyroid Gland The enlarged parathyroid gland can remain undiscovered after routine exploration of the neck in some patients. Several of such "classic" situations are described next. It is of great importance to identify the normal parathyroid glands during the exploration of the neck because a parathyroid missed at its normal localization can indicate the site of the migrated enlarged parathyroid. Situation 1. Three normal parathyroid glands have been identified but the (right) upper parathyroid gland cannot be localized (Fig. 47-5). In this circumstance, the space dorsal to the thyroid gland and the esophagotracheal groove should be explored. The space between the esophagus and the vertebrae should be opened. Digital palpation for the parathyroid tumor can be helpful. Situation 2. Three normal parathyroids have been identified, but the (right) lower gland is absent at the lower pole of the thyroid and in the thyrothymic ligament (Fig. 47-6). The thymus on the side of the missing lower parathyroid should be exposed. The thymus is lighter in color and smoother than the surrounding fat. The retrosternal part of the thymus can be mobilized by applying light tension on the thyrothymic ligament while freeing the thymus by delicate blunt dissection with a peanut sponge.s" As the extraction of the thymus
Closure of the Neck Incision After completion of the parathyroidectomy, the operative field is thoroughly checked for hemostasis. A low-pressure suction drain can be used. The strap muscles and the platysma muscle are closed with an absorbable suture. The skin is closed intracutaneously.
Postoperative Care A successful parathyroidectomy results in a decrease in the serum calcium level, which usually reaches its nadir 48 hours after the operation. Postoperative hypocalcemia is most frequent in patients with severe skeletal depletion of calcium, resulting in "bone hunger." The manifestations of hypocalcemia include numbness around the mouth, tingling of the fingertips, muscle cramps, carpopedal spasms, anxiety, convulsions, main d'accoucheur (Trousseau's sign), and opisthotonos.f If symptoms appear, calcium should be administered. Patients with hypocalcemia should be given a maximum of 3 g of calcium orally per day. In the event that this treatment is ineffective, alfacalcidol (a vitamin D
FIGURE 47-5. Situation 1. (Modified from Thompson NW, EckhauserE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
Technique of Parathyroidectomy - - 445
FIGURE 47-6. Situation 2. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
FIGURE 47-7. Situation 3. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
proceeds, a small clamp can be moved downward on the thymus to extract the thymus out of the mediastinum. Use of careful blunt dissection prevents injury of the large mediastinal vessels. When the parathyroid tumor has not been found after performing the steps described in situations I and 2, an intrathyroidal parathyroid tumor should be considered. Incision of the thyroid capsule can reveal an intrathyroidal parathyroid. If a parathyroid tumor has not been found at this point, the carotid sheath should be opened from the level of the carotid bifurcation to the base of the neck. When this step has also proved negative, the superior or inferior pole of the thyroid gland should be excised for a missing upper or lower parathyroid gland, respectively. Situation 3. Three normal parathyroids have been localized, but the (left) lower gland is missing (Fig. 47-7). At the level of the superior thyroid artery and anterior to the carotid bulb, an enlarged parathyroid gland with a thymic remnant is encountered. A maldescended fourth pharyngeal pouch is likely, resulting in a cranial position of the upper parathyroid gland. This has been described by Edis and colleagues as an undescended "parathymus,"? Situation 4. Four normal parathyroids have been visualized (Fig. 47-8). Increased levels of parathyroid hormone rule out another cause of hypercalcemia. This situation is not uncommon and can be due to a tumor originating from a supernumerary (fifth) parathyroid gland located in the thymus. Resection of the left and right thymus is indicated. Situation 5. One parathyroid is missing and a contralateral (left lower) gland seems slightly enlarged; the other parathyroids are normal (Fig. 47-9). This is an awkward situation because it is impossible to determine intraoperatively whether this slightly enlarged parathyroid is hyperfunctioning. In the case of moderate hypercalcemia with a mild clinical picture, the slightly enlarged parathyroid can be removed and the procedure completed. In severe disease, the steps in situations I and 2 should be followed. Also, a concomitant
other cause of hypercalcemia may be present (e.g., sarcoidosis or malignancy). Situation 6. On one side, two normal parathyroids are demonstrated; on the other side, a normal parathyroid has been found just below the crossing of the recurrent laryngeal nerve and the inferior thyroid artery (Fig. 47-10). In this situation, it is unclear whether an upper or lower parathyroid is missing; consequently, there is uncertainty about the localization of the parathyroid tumor. In such a case, a virtual coronal plane should be drawn through the recurrent laryngeal nerve.f When the normal parathyroid is located anterior to this plane, the normal parathyroid is the lower parathyroid. If the normal parathyroid is located dorsal to the coronal plane, it is the upper parathyroid.
FIGURE 47-8. Situation 4. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
446 - - Parathyroid Gland
FIGURE 47-9. Situation 5. (Modified from Thompson NW, EckhauserE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
Normal parathyroid glands should never be removed when a parathyroid tumor cannot be found at an exploration of the neck for hyperparathyroidism. Removal of normal parathyroids never decreases hypercalcemia. On the contrary, it can cause permanent hypoparathyroidism when a successful reoperation is performed. A primary sternotomy should be considered only in patients with life-threatening hypercalcemia.
Mediastinotomy A mediastinotomy should be undertaken only after thorough exploration of the neck, including inspection of the para- and retroesophageal space and the left thymus and right thymus.
The anterior mediastinum is exposed through an additional vertical incision from the suprasternal notch to the second or third intercostal space on either the right or left side. A complete sternotomy is done when the posterior mediastinum is explored. Appropriate care should be taken not to injure the internal mammary vessels or the pleura. The left innominate vein can be retracted or divided to inspect the anterior mediastinum. In a series of 400 patients with primary hyperparathyroidism, 84 mediastinal parathyroid tumors were observed/" Only 19 (5%) parathyroid tumors had to be removed through a mediastinotomy. Conn and coworkers reported that only 22% of all mediastinal parathyroid tumors required splitting of the sternum to remove the tumors." In this study, a mediastinal parathyroid tumor was not found when thallium-technetium scanning, computed tomography scanning, magnetic resonance imaging, or angiography of the mediastinum did not detect a parathyroid tumor. In a large series of 2770 patients with primary hyperparathyroidism, only 38 patients (1.4%) had a mediastinotomy to remove an enlarged parathyroid gland." Thoracoscopy has been reported to be a successful minimally invasive technique to remove parathyroid tumors located deep in the mediastinum.F The parathyroid glands that require a mediastinotomy for removal are either ectopic lower parathyroids, which descended into the anterior mediastinum during embryologic development, or supernumerary parathyroids. The blood supply of these mediastinal parathyroids is usually derived from the internal mammary vessels. Approximately 70% of the mediastinal parathyroid glands are found within or attached to the thymus. 69,71 Other locations of mediastinal parathyroids are at the ascending aorta, aortic arch, and its major branches and occasionally on the pericardium.
Lateral Approach for Parathyroid Exploration The lateral approach for parathyroidectomy was first described by Peind." This approach involves dissection between the anterior border of the sternocleidomastoid muscle and the posterior border of the strap muscles." The omohyoid muscle is usually divided. Retraction of the sternocleidomastoid muscle and the carotid sheath laterally and the strap muscles medially exposes the lateral aspect of the thyroid gland, the tracheoesophageal groove, the recurrent laryngeal nerve, and the parathyroid glands. The lateral approach is preferable in parathyroidectomy under local anesthesia because the limited dissection and moderate retraction of the neck muscles are well tolerated by patients.s" Another indication for the lateral approach is parathyroidectomy after previous neck surgery. The lateral approach in these patients provides a dissection plane more likely to be devoid of scar tissue from the previous operation."
Summary FIGURE 47-10. Situation 6. (Modified from Thompson NW, Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
An understanding of the embryology of the parathyroid glands and the ability to distinguish between a normal and an abnormal parathyroid gland are essential for successful
Technique of Parathyroidectomy - - 447
parathyroid surgery. A systematic approach knowing the routine and unusual locations for parathyroid glands results in successful parathyroidectomy in more than 95% of patients with primary hyperparathyroidism. Normal parathyroid glands should not be removed, and biopsy should be done selectively. Routine biopsy of normal parathyroid glands results in more hypoparathyroidism.
REFERENCES I. Cope O. The story of hyperparathyroidism at the Massachusetts General Hospital. N Engl 1 Med 1966;274: 1174. 2. Boyd JD. Development of the thyroid and parathyroid glands and the thymus. Ann R Coli Surg Engl 1950;7:455. 3. Mansberger AR, Wei JP. Surgical embryology and anatomy of the thyroid and parathyroid glands. Surg Clin North Am 1993;73:727. 4. Wang CA. Surgical management of primary hyperparathyroidism. Curr Probl Surg 1985;12:1. 5. Gilmour lR. The gross anatomy of the parathyroid glands. 1 Pathol 1938;46: 133. 6. Akerstrom G, Malmaeus 1, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95:14. 7. Russell CF, Grant CS, van Heerden lA. Hyperfunctioning supernumerary parathyroid glands. Mayo Clin Proc 1982;57:121. 8. Edis AJ, Levitt MD. Supernumerary parathyroid glands: Implications for the surgical treatment of secondary hyperparathyroidism. World 1 Surg 1987;11:398. 9. Wang CA, Mahaffey JE, Axelrod L, Perlman lA. Hyperfunctioning supernumerary parathyroid glands. Surg Gynecol Obstet 1979;148:711. 10. Cope O. Surgery of hyperparathyroidism: The occurrence of parathyroids in the anterior mediastinum and the division of the operation into two stages. Ann Surg 1941;114:706. II. Wang CA. Hyperfunctioning intrathyroid parathyroid gland: A potential cause of failure in parathyroid surgery. 1 R Soc Med 1981;74:49. 12. Wheeler MH, WIlliams ED, Path FRC, Wade lSH. The hyperfunctioning intrathyroidal parathyroid gland: A potential pitfall in parathyroid surgery. World 1 Surg 1987;11:110. 13. Black EM, Zimmer lE Hyperparathyroidism, with particular reference to treatment. Arch Surg 1956;72:830. 14. Hellstrom 1, Ivemark BI. Primary hyperparathyroidism: Clinical and structural findings in 138 cases. Acta Chir Scand 1962;294S:1. 15. Coffey RJ, Potter IF, Canary 11. Diagnosis and surgical control of hyperparathyroidism. Ann Surg 1965;161:732. 16. Katz AD, Hopp D. Parathyroidectomy: Review of 338 consecutive cases for histology, location and reoperation. Am 1 Surg 1982; 144:411. 17. Thompson NW. The techniques of initial parathyroid exploration and reoperative parathyroidectomy. In: Thompson NW, Vinik AI (eds), Endocrine Surgery Update. New York, Grune & Stratton, 1983, p 365. 18. Wang CA. The anatomic basis of parathyroid surgery. Ann Surg 1975;183:271. 19. Wang CA. Parathyroid re-exploration: A clinical and pathological study of 112 cases. Ann Surg 1977;186:140. 20. Bruining HA. Operative strategy in primary hyperparathyroidism. In: Kaplan EL (ed), Surgery of the Thyroid and Parathyroid Glands. Assen, The Netherlands, Van Gorcum, 1983, p 158. 21. Grimelius L, Johansson H, Ljunghall S, et al. Controversies in the treatment of hyperparathyroidism. Acta Chir Scand 1979;145:355. 22. Gilmour JR, Martin Wl. The weight of the parathyroid glands. 1 Pathol Bacteriol 1937;44:431. 23. Dufour R, Wilkerson SY. Factors related to parathyroid weight in normal persons. Arch Pathol Lab Med 1983;107:167. 24. Akerstrom G, Grimelius L, Johansson H, et al. The parenchymal cell mass in normal human parathyroid glands. Acta Pathol Microbiol Scand 1981;89:367. 25. Castleman B, Roth SI. Tumors of the Parathyroid Glands (Atlas of Tumor Pathology, 2nd series). Washington, DC, Armed Forces Institute of Pathology, 1978, p 14. 26. Delattre JF, Flament JB, Palot lP, Pluot M. Les variations des parathyroides. Nombre 2, situation et vascularisation arterielle. Etude anatomique et applications chirurgicales. 1 Chir (Paris) 1982;1l9:633.
27. Hackeng WHL, Lips P, Netelenbos rc, Lips C1M. Clinical implications of estimation of intact parathyroid hormone (PTH) versus total immunoreactive PTH in normal subjects and hyperparathyroid patients. 1 Clin Endocrinol Metab 1986;63:447. 28. Blind E, Schmidt-Gayk H, Armbruster FP, Stadler A. Measurement of intact human parathyrin by an extracting two-site immunoradiometric assay. Clin Chern 1987;33:1376. 29. Frolich M, Walma ST, Paulson C, Papapoulos SE. Immunoradiometric assay for intact parathyroid hormone: Characteristics, clinical application and comparison with a radio-immunoassay. Ann Clin Biochem 1990;27:69. 30. Brennan MF, Doppman Jl., Kurdy AG, et al. Assessment of techniques for preoperative parathyroid gland localization in patients undergoing reoperation for hyperparathyroidism. Surgery 1981;91:6. 31. Edis AJ, Sheedy PF II, Beahrs OH, van Heerden lA. Results of reoperation for hyperparathyroidism, with evaluation of preoperative localization studies. Surgery 1978;84:384. 32. Patow CA, Norton lA, Brennan ME Vocal cord paralysis and reoperative parathyroidectomy. Ann Surg 1986;203:282. 33. Pyrtek U, Belkin M, Bartus S, Schweizer R. Parathyroid gland exploration with local anaesthesia in elderly and high-risk patients. Arch Surg 1988;123:614. 34. Lore 1M. An Atlas of Head and Neck Surgery. Philadelphia, WB Saunders, 1988, p 729. 35. Bruining HA. Surgical Treatment of Hyperparathyroidism. Springfield, Ill, Charles C Thomas, 1971, p 44. 36. Cooke TJC, Boey JH, Sweeney EC, et al. Parathyroidectomy: Extent of resection and late results. Br 1 Surg 1977;64:153. 37. Paloyan E, Lawrence AM, Baker WH, et al. Near total parathyroidectomy. Surg Clin North Am 1969;43:49. 38. Rudberg C, Akerstrorn G, Palmer M, et al. Late results of operation for primary hyperparathyroidism in 441 patients. Surgery 1986;99:643. 39. Haff RC, Armstrong RG. Trends in the current management of primary hyperparathyroidism. Surgery 1974;75:715. 40. Badder EM, Graham WP III, Harrison TS. Functional insignificance of microscopic parathyroid hyperplasia. Surg Gynecol Obstet 1977; 145:863. 41. Lawrence DAS. A histological comparison of adenomatous and hyperplastic parathyroid glands. 1 Clin Pathol 1978;31 :626. 42. Nishiyama RH. Pathology of parathyroid tumors. In: Thawley SE, Panje WR (eds), Comprehensive Management of Head and Neck Tumors. Philadelphia, WB Saunders, 1987, p 1650. 43. Bonjer H1. Single and Multiple Gland Disease in Primary Hyperparathyroidism [thesis]. Rotterdam, The Netherlands, Erasmus University, 1992, p 57. 44. Bonjer HJ, Bruining HA, Birkenhager lC, et al. Single and multigland disease in primary hyperparathyroidism: Clinical follow-up, histopathology, and flow cytometric DNA analysis. World 1 Surg 1992;16:737. 45. Nishiyama RH. The intraoperative diagnosis of parathyroid lesions. Acta Chir Aust 1994;112:8. 46. Edis AJ, Beahrs OH, van Heerden lA, Akwari OE. "Conservative" versus "liberal" approach to parathyroid neck exploration. Surgery 1977;82:466. 47. Kaplan EL, Bartlett S, Sugimoto 1, Frediand A. Relation of postoperative hypocalcemia to operative techniques: Deleterious effect of excessive use of parathyroid biopsy. Surgery 1982;92:827. 48. Wang CA, Rieder SV. A density test for the intraoperative differentiation of parathyroid hyperplasia from neoplasia. Ann Surg 1978;187:63. 49. Dekker A, Dunsford HA, Geyer Sl, The normal parathyroid gland at autopsy. The significance of stromal fat in adult patients. 1 Pathol 1979;128:127. 50. Dufour DR, Wilkerson SY. The normal parathyroid revisited: Percentage of stromal fat. Hum PathoI1982;13:717. 51. Tibblin S, Bondeson AG, Ljungberg O. Unilateral parathyroidectomy in hyperparathyroidism due to single adenoma. Ann Surg 1982;195:245. 52. Bondeson AG, Bondeson L, Ljungberg 0, Tibblin S. Fat staining in parathyroid disease. Diagnostic value and impact on surgical strategy: Clinicopathologic analysis of 191 cases. Hum PathoI1986;17:1255. 53. Thompson NW, Sandelin K. Technical considerations in the surgical management of primary hyperparathyroidism caused by multiple gland disease (hyperplasia). Acta Chir Aust 1994;112S:16. 54. Wells SA, Leight GS, Hensley M, Dilley WG. Hyperparathyroidism associated with the enlargement of two or three parathyroid glands. Ann Surg 1985;202:533.
448 - - Parathyroid Gland 55. Akerstrorn G, Rudberg C, Grimelius L, Rastad 1. Recurrent hyperparathyroidism due to parathyroid tissue. Acta Coo Scand 1988;154:549. 56. Rattner DW, Marrone GC, Kasdon E, Silen W. Recurrent hyperparathyroidism due to implantation of parathyroid tissue. Am 1 Surg 1985;149:745. 57. Bonjer HI, Bruining HA, Bagwell CB, et al. Primary hyperparathyroidism: Pathology, flow cytometric DNA analysis, and surgical treatment. Crit Rev Clin Lab Sci 1992;29:1. 58. Lamers CBHW, Froeling PGAM. Clinical significance of hyperparathyroidism in familial multiple endocrine adenomatosis type 1 (MEA I). Am 1 Med 1979;66:422. 59. Clark OH, Way LW, Kunt TK. Recurrent hyperparathyroidism. Ann Surg 1976;184:391. 60. Marsden P, Day JL. Hyperparathyroidism: The risk of recurrence. Clin Endocrinol (Oxf) 1973;2:9. 61. Palmer JA, Sutton FR. Importance of a fifth parathyroid gland in the surgical treatment of hyperparathyroidism. Can J Surg 1978;21 :350. 62. Goretzki PE, Dotzenrath C, Rocher 00. Management of primary hyperparathyroidism caused by multiple gland disease. World J Surg 1991;15:693. 63. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: A randomized study. World J Surg 1991;15:745. 64. Clark OH, Siperstein AE. The hypercalcemic syndrome: Hyperparathyroidism. In: Friesen SR, Thompson NW (eds), Surgical Endocrinology: Clinical Syndromes, 2nd ed. Philadelphia, JB Lippincott, 1990, p 311.
65. Granberg PO, Cederrnark B, Farnebo LO, et al. Parathyroid tumors. Curr Probl Cancer 1985;9:32. 66. Ahlers J, Rothmund M. Die cervicale Thymektomie als erweitertes Operationsverfahren beim prirnaren und sekundaren Hyperparathyroidismus. Chirurg 1980;51:629. 67. Edis AJ, Purnell DB, van Heerden lA. The undescended "parathymus": An occasional cause of failed neck exploration for hyperparathyroidism. Ann Surg 1979:190:64. 68. Pyrtek U, Painter RL. An anatomic study of the relationship of the parathyroid glands to the recurrent laryngeal nerve. Surg Gynecol Obstet 1964;9:509. 69. Nathaniels EK, Nathaniels AM, Wang CA. Mediastinal parathyroid tumors: A clinical and pathological study of 84 cases. Ann Surg 1970;171:165. 70. Conn JM, Goncalves MA, Mansour KA, McGarity WC. The mediastinal parathyroid. Am Surg 1991;57:62. 71. Russel CF, Edis AI, Scholz DA, et al. Mediastinal parathyroid tumors: Experience with 38 tumors requiring mediastinotomy for removal. Ann Surg 1981;193:805. 72. Prinz RA, Lonchyna V, Camaille B, et al. Thoracoscopic excision of enlarged mediastinal parathyroid glands. Surgery 1994;116:999. 73. Feind CR. Re-exploration for parathyroid adenoma. Am J Surg 1964; 108:543. 74. Stevens JC. Lateral approach for exploration of the parathyroid gland. Surg Gynecol Obstet 1979;148:431. 75. Kadowski MH, Fulton N, Shark C, et al. Difficulties of parathyroidectomy after previous thyroidectomy. Surgery 1989; I06: 1018.
Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) Quan-Yang Duh, MD
Surgery offers the only definitive treatment for patients with primary hyperparathyroidism. I The success of parathyroidectomy depends on the skill and judgment of the surgeon. The best surgical approach should give the highest rate of cure with the lowest rate of complications. In this chapter, issues that influence surgical strategy are discussed. A strong case is made for surgeons to have a good understanding of the embryologic development of the parathyroid glands and to have experience in exploring thoroughly both sides of the neck during the initial operation for primary hyperparathyroidism. Advances in localization studies and intraoperative parathyroid hormone (PTH) monitoring allow the surgeon to limit the extent of exploration in some patients. Bilateral exploration of all four parathyroid glands, however, remains the "gold standard," against which the results of other approaches are evaluated. Bilateral exploration is necessary in patients who are at high risk for having multiple-gland disease, such as those with familial syndromes and those with negative localization studies. When in doubt, bilateral exploration, identifying all four parathyroid glands, is most likely to result in the highest success rate.
Indications for Parathyroidectomy Primary hyperparathyroidism is a common disease in nontropical areas of the world. It is found in 1 in 2000 men and in 1 in 500 women after menopause and is more common in elderly people. Because hypercalcemia is frequently detected by routine laboratory studies and because of the availability of specific, sensitive, and accurate assays for intact PTH, most patients are diagnosed now at an early stage. Thus, it is uncommon to see patients with severe
primary hyperparathyroidism with osteitis fibrosa cystica or nephrolithiasis with renal dysfunction.
Etiology of Primary Hyperparathyroidism About 80% of patients with primary hyperparathyroidism have a single adenoma, 15% have hyperplasia of all four glands, and 5% have double adenomas.? The cause of parathyroid adenoma or hyperplasia is not known. Head and neck irradiation increases the risk of primary hyperparathyroidism by 11% per centigray.v' Ten percent of parathyroid adenomas have a PRAD-I oncogene (cyclin D gene activated by PTH promoter). Mutations in the calcium sensor protein appear not to be an important cause of primary hyperparathyroidism.' although decreased calcium receptor has been described in parathyroid adenomas and in hyperplastic parathyroid glands in patients with chronic renal failure. Retinoblastoma tumor suppressor gene is found to be frequently mutated in parathyroid cancers," whereas p53 mutations are rare.' Two thirds of apparently sporadic parathyroid cancers have mutations in the HRPT2 gene, the gene responsible for the hyperparathyroidism-jaw tumor syndrome.! Patients with multiple endocrine neoplasia (MEN) types 1 and 2A are more likely to have hyperparathyroidism, as are family members of patients with familial hyperparathyroidism. In the mouse, deletion of the MEN 1 tumor suppressor gene in the parathyroid gland results in parathyroid neoplasia and hypercalcemic hyperparathyroidism." Patients with Cowden's disease'? (breast cancer, thyroid neoplasm, and gastrointestinal polyps) and McCune-Albright syndrome!' (caused by activating mutations of the stimulating guanosine triphosphate-binding protein) are also at higher risk for developing primary hyperparathyroidism.
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450 - - Parathyroid Gland
Diagnosis of Primary Hyperparathyroidism The biochemical diagnosis of primary hyperparathyroidism is made by documenting an elevated serum PTH in a patient with hypercalcemia (serum calcium> to.5 mg/dL) without hypocalciuria. Patients with benign familial hypocalciuric hypercalcemia (BFHH) are also hypercalcemic and have an inappropriately high PTH. Virtually all patients with other causes of hypercalcemia have a suppressed serum PTH level. Patients with BFHH have elevated levels of PTH in the presence of hypercalcemia because of mutations in the gene encoding the extracellular calcium sensor protein, making the parathyroid cells less sensitive to hypercalcemia.P BFHH can be suspected on the basis of a family history and identified by low urinary calcium excretion (calcium clearance less than 1% of creatinine clearance). Cancer is the other most common cause of hypercalcemia." Patients with hypercalcemia of malignancy can be diagnosed by a thorough history and physical examination. Many solid tumors associated with hypercalcemia secrete parathyroid hormone-related protein (PTHrP); others cause hypercalcemia through cytokines or by direct bone destruction. With the exception of some very rare renal cell carcinomas and ovarian carcinomas that secrete PTH, none of these patients have elevated serum PTH levels. Other laboratory findings consistent with primary hyperparathyroidism include a low serum phosphorus level «2.5 mg/dL), elevated serum chloride level (> 107 mmol!L), and elevated serum chloride-to-phosphate ratio (>33). Some patients have elevated serum levels of alkaline phosphatase and uric acid. Subperiosteal resorption can be demonstrated in hand radiographs of patients with elevated alkaline phosphatase levels. It is rare in other patients with primary hyperparathyroidism.
Mild Primary Hyperparathyroidism The symptoms and signs of mild primary hyperparathyroidism can be more subtle and less specific, such as fatigue, weakness, lethargy, depression, memory loss, personality changes, constipation, and decreased bone density. It is controversial whether to operate on patients with few or no symptoms or metabolic problems and minimal hypercalcemia. A prospective study of patients with primary hyperparathyroidism showed, however, that truly asymptomatic patients are uncommon: less than 5% of patients." Many patients with these nonspecific symptoms improved after a successful parathyroid operation compared with a control group of patients who underwent thyroidectomy. Ninety-five percent had improvement of one or more symptoms after parathyroidectomy, and 55% felt better overall (compared with 30% after thyroidectomyj.P The severity of hypercalcemia did not correlate with the presence of these symptoms before parathyroidectomy; neither did it correlate with the improvement in symptoms after successful surgery.l-!"
Benefits of Parathyroidectomy in Patients with Primary Hyperparathyroidism Patients with untreated primary hyperparathyroidism have an increased risk of death from cardiovascular disease and cancers. This increased risk of death is similar in magnitude to that associated with smoking, and the risk appeared to correlate with parathyroid tumor size and the peak calcium level. 17,18 Parathyroidectomy benefits most patients with primary hyperparathyroidism. Muscle strength and fine motor function'? as well as psychiatric symptoms'" improve within 1 month after parathyroidectomy. The incidence of renal colic decreases from 66% to 2% per year 1 year after parathyroidectomy." Left ventricular hypertrophy also improves within 1year after parathyroidectomy.P Bone mineral density improves after parathyroidectomy in patients with asymptomatic primary hyperparathyroidism, and the improvement is sustained for at least 4 years after parathyroidectomy.-' Quality of life measurement also improves after parathyroidectomy.t'
Surgical Strategy in Patients with Primary Hyperparathyroidism The primary goal of parathyroidectomy for patients with primary hyperparathyroidism is to cure the primary hyperparathyroidism and to achieve normocalcemia. The best surgical strategy should achieve this goal with minimal complications, such as persistent hyperparathyroidism, recurrent hyperparathyroidism, postoperative hypoparathyroidism, and recurrent laryngeal nerve injury, and with efficient use of operating time and resources. The most important variable that influences the success of parathyroidectomy is the experience of the surgeon. The success rate for parathyroidectomy reported by most endocrine surgery centers is 95% or better. The rate of persistent hyperparathyroidism can be as high as 30% in less experienced hands." Persistent hyperparathyroidism is usually caused by missing an ectopic tumor or missing one of the multiple abnormal glands." Recurrent hyperparathyroidism usually occurs in patients with familial disease, such as those with familial hyperparathyroidism and MEN 1.26 It is more cost-effective to have a higher success rate in the initial operation than to rely on reoperation when the initial operation fails. Although reoperation for hyperparathyroidism can be successful 90% of the time.i? it costs twice as much because of the need for preoperative localization studies.l" and the risk of recurrent nerve injury is higher. The general principles that my colleagues and I follow for surgical exploration in patients with primary hyperparathyroidism are listed in Table 48-1.
Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - -
451
Double adenomas are more common in older patients; the incidence is about 9% for patients older than 60 years." Finding only a minimally enlarged parathyroid gland in a patient who has severe hypercalcemia should also raise the suspicion that another larger parathyroid tumor is present and should be found and resected. When frozen section reveals an oxyphil adenoma, one should also identify at least four parathyroid glands because some oxyphil adenomas are nonfunctional. Interestingly, double adenomas are not distributed randomly; it is much more likely to have bilateral upper gland double adenomas than would be predicted by random distribution.P
Initial Operation No routine localization study is necessary before the initial neck exploration for patients with primary hyperparathyroidism.29.30 A small, low cervical incision along the skin crease is made. The strap muscles are dissected and separated but are not divided. The surgical plane of dissection is different for parathyroidectomy and thyroidectomy. For thyroidectomy, I dissect as close to the thyroid gland as possible, taking individual branches of the thyroid vessels on the thyroid gland and leaving the parathyroid glands lateroposteriorly in the surrounding tissue to preserve vascularity when the thyroid gland is removed. For parathyroidectomy, I dissect more laterally along the carotid sheath, leaving the parathyroids on the posterior surface of the thyroid gland, thus making them easier to find. Both sides of the neck are explored, and all four glands are tentatively identified before any gland is resected. I rarely perform mediastinotomy during initial operation unless the patient is severely hypercalcemic (serum calcium> 14 mg/dL after optimal medical treatment) because many of these can be removed by thoracoscopy or mediastinoscopy."
Single Adenoma When a single large parathyroid tumor is found, the remaining three parathyroid glands are identified. The large tumor is then excised and confirmed by frozen section. If there is doubt about the nature of the normal-appearing parathyroid glands, a biopsy of one of them can be performed by placing a titanium clip at the tip of the gland away from the hilum to avoid devascularizing the gland. The risk of postoperative hypoparathyroidism is increased if biopsies of all normal parathyroid glands are performed routinely, so routine biopsy of all normal parathyroid glands should be discouraged.l? An experienced surgeon can accurately identify 95% of normal parathyroid glands, even without frozen section.
Double Adenomas When two enlarged parathyroid glands are found, the remaining two normal glands should also be identified. One or both of the normal-appearing glands should be biopsied, marked with a titanium clip, and confirmed by frozen section. This avoids leaving two hyperplastic glands should the patient have parathyroid hyperplasia and asymmetrically enlarged glands. The two tumors should then be excised and confirmed by frozen section.
Hyperplasia When all the glands are enlarged (>7 mm in largest dimension), the patient has hyperplasia. A subtotal parathyroidectomy is indicated. My routine procedure is to identify all four glands and then perform a biopsy on the one that appears the least abnormal and is away from the recurrent laryngeal nerve, leaving a 50-mg remnant marked by a titanium clip. After the parathyroid tissue is confirmed by frozen section and the remnant appears to be well vascularized and viable, the remaining three abnormal glands can be excised and confirmed by frozen section. If the remnant appears dusky and its viability is questionable, with a high risk of postoperative hypoparathyroidism, it is completely excised, and a second gland should be chosen for subtotal resection, and so on. Performing the subtotal resection first before removing the rest of the abnormal glands gives four chances to leave a perfect remnant. Bilateral cervical thymectomy should be a routine part of the operation in patients with hyperplasia because supernumerary glands occur in 20% of patients and are usually situated in the thymus or perithymic fat. Some parathyroid tissue, preferably that from the least abnormal hyperplastic parathyroid gland, should be cryopreserved. If the patient becomes hypoparathyroid later, the tissue can then be autotransplanted. Total parathyroidectomy with autotransplantation to the forearm is an alternative that I do not usually use. It has a lower risk of recurrence but a higher risk of hypoparathyroidism than subtotal parathyroidectomy for parathyroid hyperplasia. Total parathyroidectomy is indicated in children with severe neonatal hypercalcemia because of the high risk of persistent hyperparathyroidism after a subtotal parathyroidectomy. Parathyroid tissue should also be cryopreserved. Parathyroid hyperplasia occurs in 15% to 20% of cases in various published series. When hyperplasia is found, one should be suspicious of familial hyperparathyroidism or MEN. Patients with a family history of hyperparathyroidism tend to have a more severe presentation clinically, are more likely to have multiple gland disease, and are at higher risk for persistent or recurrent hyperparathyroidism after parathyroidectomy. Thyroid anomalies may also be associated with parathyroid hyperplasia. 34 If thyroid hemiagenesis or agenesis of the isthmus is found in a patient with primary hyperparathyroidism, parathyroid hyperplasia should be suspected.
452 - - Parathyroid Gland
Multiple Endocrine Neoplasia and Familial Hyperparathyroidism Patients with MEN 1 and familial hyperparathyroidism without other endocrine disorders usually, but not inevitably, have hyperplasia; the gland size can vary significantly. When all glands are enlarged, a subtotal parathyroidectomy or a total parathyroidectomy with autotransplantation as well as bilateral thymectomy is indicated; some parathyroid tissue should be cryopreserved. In patients with MEN 1 who have one or two enlarged parathyroid glands, resection of only these glands with biopsy of the normal-appearing glands is an adequate operation with a higher risk of recurrent hyperparathyroidism over the patient's lifetime.P One alternative is a unilateral clearance of all parathyroid tissues from the affected side of the neck, including a unilateral cervical thymectomy, so that if hyperparathyroidism recurs in the remaining glands, the reoperation will be needed only on the contralateral side." Patients with MEN 2A can also have hyperparathyroidism. All of these patients warrant total thyroidectomy and possible central neck node dissection to treat or prevent medullary thyroid cancer. In contrast to patients with MEN I, those with MEN 2A are likely to develop hypoparathyroidism after a subtotal parathyroidectomy. One should, therefore, resect only the enlarged glands and biopsy and mark the normal-appearing glands. Patients with MEN 2A are much less likely to develop recurrent hyperparathyroidism than those with MEN I or familial hyperparathyroidism without MEN.35 Total parathyroidectomy with autotransplantation is more aggressive than necessary for these patients.
Location of Parathyroid Glands An ectopically situated parathyroid tumor is a common cause of persistent hyperparathyroidism (Fig. 48-1). This is one reason why an experienced surgeon achieves a 95% success rate for the initial parathyroid operation, by knowing where the parathyroid glands are commonly found, whereas an inexperienced surgeon has only about a 70% success rate.25 The inferior parathyroid glands and the thymus develop embryologicallyfrom the third branchial pouch. They descend from the upper neck down to the anterior mediastinum. Ectopic lower parathyroid glands can, therefore, be found anywhere along this long path of descent. The lower parathyroid glands are usually on the surface of the lower pole of the thyroid gland or in the thyrothymic ligament. They are frequently found within or adjacent to the thymus in the upper anterior mediastinum and are rarely found in the carotid sheath. The most common position of the inferior parathyroid gland is anteroinferior to the junction of the inferior thyroid artery and the recurrent laryngeal nerve. The superior parathyroid glands develop from the fourth branchial pouch. They descend less than the third branchial pouch and, therefore, become the superior glands. The superior glands vary less in position than the inferior glands. The most common location for the superior gland is just superoposterior to the junction of the inferior thyroid artery and the recurrent laryngeal nerve at the level of the cricoid cartilage. The superior parathyroid gland is frequently found in the
FIGURE 48-1. Locations of parathyroid tumors found at reoperation after a failed initial operation. Most of these parathyroid tumors can be excised through a neck incision, and most would have been found at the initial operation if the common ectopic locations were thoroughly explored in both sides of the neck. (From Shen W, Duren M, Morita E, et aI. Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 1996;131:861. © 1996, American Medical Association.)
tracheoesophageal groove posteriorly and may descend along the esophagus into the posterior mediastinum. Intrathyroidal parathyroid glands occur in about I % of patients and may originate from a superior or an inferior parathyroid gland. Intrathyroidal parathyroid glands account for about 12% of failed initial operations. Ultrasonography helps identify these tumors."
Focused or Unilateral Neck Exploration Versus Bilateral Neck Exploration for Primary Hyperparathyroidism Rationale for Focused or Unilateral Exploration Currently, there are three different approaches to parathyroidectomy; they differ in the extent of exploration. For the bilateral approach, the surgeon explores and identifies all four parathyroid glands. For the unilateral approach, the surgeon identifies two glands on the same side of the neck. For the focused approach, only one gland (the presumed single adenoma) is identified. There are potential advantages of a focused or unilateral approach for parathyroidectomy. In theory at least, not having to find all the other parathyroid glands when a parathyroid adenoma is already identified can shorten the operating time and lower the risk of injury to the recurrent laryngeal nerve and other normal parathyroid glands. A focused approach
Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - - 453
requires localization studies to pinpoint the most likely location of the adenoma. In the past, my colleagues and I used the focused approach routinely only in patients undergoing reoperations to avoid unnecessary dissection in scarred tissue; this is possible with the aid of multiple localization studies.'? With the widespread use of preoperative localization studies in patients undergoing the initial operation, the focused approach has gained popularity. Several techniques have been described; many are called "minimally invasive parathyroidectomy," including small lateral incision, local anesthesia, gamma probe guidance, and video-assisted techniques. In general, for a successful focused approach to parathyroidectomy, the surgeon needs to know where to start the operation (localization studies) and when to stop (intraoperative PTH monitoring or by calculation of probabilityl.P'-" If bilateral exploration is planned for the initial operation, no localization studies or intraoperative monitoring of PTH is necessary because 95% of the abnormal glands can be found by the surgeon without these studies. There is controversy regarding whether routine use of localization studies for initial parathyroid surgery is economically justifiable or necessary. If a focused or unilateral approach is planned, a localization study is necessary to help the surgeon decide where to start the exploration. In the traditional unilateral approach, the surgeon chooses the side of initial exploration randomly and does not use localization studies or PTH monitoring.t" One side of the neck is chosen randomly for the initial exploration. If a localization study has been done and it is positive, the side of the neck where the adenoma is expected is explored. If an abnormal gland and a normal gland are found and confirmed by frozen section, the abnormal gland is presumed to be the only adenoma that is causing the patient's primary hyperparathyroidism. The contralateral side is not explored. If the initial side shows two normal parathyroid glands, the contralateral side is then explored to look for the adenoma. If two abnormal glands are found on the initial side, hyperplasia is presumed, and the contralateral side is explored to perform a subtotal parathyroidectomy. If only one gland is found on the initial side, the contralateral side is also explored/? For focused exploration, localization studies are used to direct where the exploration should be started. Intraoperative PTH is used to monitor the drop in PTH; a greater than 50% drop from either the baseline or preexploration level (whichever is higher) 10 minutes after excising the adenoma predicts a successful operation." Once the adenoma is found and the intraoperative PTH confirms that there are no more pathologic parathyroid glands remaining, which occurs in almost all cases of patients with a single adenoma, the operation is concluded. There is controversy, however, regarding the accuracy of intraoperative PTH monitoring to predict the presence of a second adenoma or hyperplasia." It has been shown that double adenomas are found in fewer patients when focused exploration is used than when bilateral exploration is used. The discrepancy is caused by some large glands that are either "nonsecreting large parathyroid glands" or "latent adenomas." Long-term follow-up is needed to distinguish between the two possibilities. There is an alternative way to perform a focused parathyroidectomy without using intraoperative PTH monitoring. Both sestamibi scanning and ultrasonography are performed.
In two thirds of patients, both studies show a single adenoma and are concordant in location. Focused exploration in this subgroup of patient is successful in 96% without using intraoperative PTH monitoring.F Although it may seem obvious that complications should occur less with a focused or unilateral approach compared with a bilateral approach, it remains to be proved. Studies comparing the results of a focused or unilateral approach with those of a bilateral approach have not compared them by intent." Series of bilateral explorations routinely include complicated cases of multiple adenomas and hyperplasia, whereas series of focused or unilateral approaches have selected the patients who are likely to have a single adenoma and thus less likely to have failure or complications. Operating time perhaps should be shorter for the more limited approaches, but it is mostly surgeon dependent." Some proponents of bilateral exploration argue that exploring the remaining normal glands should not take longer than the time spent waiting for the results of intraoperative PTH. There are no prospective randomized studies comparing these approaches.
Incidence of Multiple-Gland Disease and the Accuracy of Localization Studies and Intraoperative PTH Monitoring Determine the Success of the Focused or the Unilateral Approach The most serious potential problem of the focused or unilateral exploration is failure to identify a second adenoma or hyperplasia. This risk depends on the percentage of patients with multiglandular disease, the accuracy of localization studies to identify multiglandular disease, and the accuracy of intraoperative PTH monitoring to identify a residual pathologic parathyroid gland.r' The long-held belief that 15% to 20% of patients have multiglandular disease is being challenged by some series with excellent short-term results after a focused approach aided by preoperative sestarnibi scanning and intraoperative PTH monitoring showing that only 5% of patients have multiglandular disease.f Most studies have shown that localization studies are much less accurate for multiple-gland disease than for a single adenoma. The sensitivity of most studies is greater than 80% for a single adenoma but much lower for multiglandular disease. 46,47 A rule of thumb is that one third of patients with multiglandular disease would have a negative scan, one third would have a scan consistent with a single adenoma, and one third would have a scan showing more than one abnormal gland.f The accuracy of intraoperative PTH monitoring for multiglandular disease also remains controversial."
Difficulty in Determining Whether a Parathyroid Tumor is an Adenoma or Hyperplasia Inherent in the strategy of focused or unilateral exploration is the assumption that one can identify an abnormal parathyroid gland as an adenoma or as part of generalized hyperplasia. Most endocrine surgeons and experienced endocrine pathologists believe that one cannot make a definitive diagnosis of adenoma versus hyperplasia by examining only the
454 - - Parathyroid Gland abnormal gland. Characteristics other than size of the gland can help distinguish between an adenoma or a hyperplastic parathyroid gland and a normal gland. Abnormal or hypercellular parathyroid tissue is darker, firmer, and more vascular; sinks in saline; and has a low fat content and high cellularity. A compressed rim of normal parathyroid tissue is suggestive of an adenoma, but there are many exceptions. Data from physiologic and molecular studies support the existence of double adenomas. Intraoperative PTH monitoring shows that in some patients the PTH level does not become normal until a second adenoma is excised. 48,49 Many parathyroid tumors that are considered hyperplastic histologically can be shown to be monoclonal tumors. 50
Conclusion Primary hyperparathyroidism can be definitively diagnosed on the basis of an elevated serum PTH in hypercalcemic patients without hypocalciuria. Asymptomatic patients with minimal hypercalcemia appear to benefit from successful parathyroidectomy, and 95% of patients can be cured when treated by an experienced endocrine surgeon. Focused exploration and unilateral neck exploration are acceptable when the probability of multiglandular disease is low; the success rate is high if two preoperative localization studies show concordance or a successful localization study is combined with intraoperative PTH monitoring. Bilateral neck exploration, however, remains a safe approach with an excellent success rate. Whether the focused or unilateral exploration is superior to the bilateral approach in success rate, complication rate, or cost-effectiveness remains to be proved by a prospective randomized study.
REFERENCES 1. NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus development conference statement. Ann Intern Med 1991;114:593. 2. Bartsch D, Nies C, Hasse C, et al. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. BrJ Surg 1995;82:926. 3. Schneider AB, Gierlowski TC, Shore-Freedman E, et aI. Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995;80:254. 4. Tezelman S, Rodriguez JM, Shen W, et aI. Primary hyperparathyroidism in patients who have received radiation therapy and in patients who have not received radiation therapy. J Am Coil Surg 1995;180:81. 5. Hosokawa Y, Pollak MR, Brown EM, Arnold A. Mutational analysis of the extracellular Ca 2+-sensing receptor gene in human parathyroid tumors. J Clin Endocrinol Metab 1995;80:3107' 6. Cryns VL, Thor A, Xu HJ, et al. Loss of the retinoblastoma tumorsuppressor gene in parathyroid carcinoma. N Engl J Med 1994; 330:757. 7. Hakim JP, Levine MA. Absence of p53 point mutations in parathyroid adenoma and carcinoma. J Clin Endocrinol Metab 1994;78:103. 8. Shattuck TM, Valimaki S, Obara T, et aI. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003;349: 1722. 9. Libutti SK, Crabtree JS, Lorang D, et aI. Parathyroid gland-specific deletion of the mouse Menl gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism. Cancer Res 2003;63:8022. 10. Hamby LS, Lee EY, Schwartz RW. Parathyroid adenoma and gastric carcinoma as manifestations of Cowden's disease. Surgery 1995; 118:115. II. Cavanah SF, Dons RF. McCune-Albright syndrome: How many endocrinopathies can one patient have? South Med J 1993;86:364.
12. Pearce SH. Clinical disorders of extracellular calcium-sensing and the molecular biology of the calcium-sensing receptor. Ann Med 2002;34:201. 13. Deftos LJ. Hypercalcemia in malignant and inflammatory diseases. Endocrinol Metab Clin North Am 2002;31:141. 14. Eigelberger MS, Cheah WK, Ituarte PH, et al. The NIH criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism: Are they too limited? Ann Surg 2004;239:528. 15. Chan AK, Duh QY, Katz MH, et aI. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A casecontrol study. Ann Surg 1995;222:402. 16. Siperstein AB, Shen W, Chan AK, et aI. Normocalcemic hyperparathyroidism: Biochemical and symptom profiles before and after surgery. Arch Surg 1992;127:1157. 17. Hedback G, aden A, Tisell LE. Parathyroid adenoma weight and the risk of death after treatment for primary hyperparathyroidism. Surgery 1995;117:134. 18. Ogard CG, Engholm G, Almdal TP, Vestergaard H. Increased mortality in patients hospitalized with primary hyperparathyroidism during the period 1977-1993 in Denmark. World J Surg 2004;28:108. 19. Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995; 117:18. 20. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101. 21. Jabbour N, Corvilain J, Fuss M, et aI. The natural history of renal stone disease after parathyroidectomy for primary hyperparathyroidism. Surg Gynecol Obstet 1991;172:25. 22. Stefenelli T, Mayr H, Bergler-Klein J, et al. Primary hyperparathyroidism: Incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am J Med 1993;95: 197. 23. Silverberg SJ, Gartenberg F, Jacobs TP, et aI. Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:729. 24. Pasieka JL, Parsons LL, Demeure MJ, et aI. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942. 25. Malmaeus J, Granberg PO, Halvorsen J, et aI. Parathyroid surgery in Scandinavia. Acta Chir Scand 1988;154:409. 26. Shen W, Duren M, Morita E, et aI. Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 1996;131:861; discussion 867. 27. Weber CJ, Sewell CW, McGarity We. Persistent and recurrent sporadic primary hyperparathyroidism: Histopathology, complications, and results of reo peration. Surgery 1994;116:991. 28. Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for primary hyperparathyroidism. Surgery 1994;116:954. 29. Oertli D, Richter M, Kraenzlin M, et al. Parathyroidectomy in primary hyperparathyroidism: Preoperative localization and routine biopsy of unaltered glands are not necessary. Surgery 1995;117:392. 30. Roe SM, Bums RP, Graham LD, et al. Cost-effectiveness of preoperative localization studies in primary hyperparathyroid disease. Ann Surg 1994;219:582. 31. Prinz RA, Lonchyna V, Camaille B, et al. Thoracoscopic excision of enlarged mediastinal parathyroid glands. Surgery 1994;116:999. 32. Uden P, Chan A, Duh QY, et al. Primary hyperparathyroidism in younger and older patients: Symptoms and outcome of surgery. World J Surg 1992; 16:791. 33. Milas M, Wagner K, Easley KA, et al. Double adenomas revisited: Nonuniform distribution favors enlarged superior parathyroids (fourth pouch disease). Surgery 2003;134:995; discussion 1003. 34. Duh QY, Ciulla TA, Clark OH. Primary parathyroid hyperplasia associated with thyroid hemiagenesis and agenesis of the isthmus. Surgery 1994;115:257. 35. Kraimps JL, Duh QY, Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery 1992;112:1080. 36. Feliciano DY. Parathyroid pathology in an intrathyroidal position. Am J Surg 1992; 164:496. 37. Rodriguez 1M, Tezelman S, Siperstein AE, et aI. Localization procedures in patients with persistent or recurrent hyperparathyroidism. Arch Surg 1994;129:870. 38. Carty SE, Worsey J, Vnji MA, et aI. Concise parathyroidectomy: The impact of preoperative SPECT 99mTc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997; 122: 1107; discussion 1114.
Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - - 455 39. Irvin GL 3rd, Dembrow VD, Prudhomme DL. Clinical usefulness of an intraoperative "quick parathyroid hormone" assay. Surgery 1993;114: 1019; discussion 1022. 40. Wang CA. Unilateral neck exploration for primary hyperparathyroidism. Arch Surg 1990;125:985. 41. Haciyanli M, Lal G. Morita E, et al. Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma. JAm Coll Surg 2003;197:739. 42. Arici C, Cheah WK, Ituarte PH, et aI. Can localization studies be used to direct focused parathyroid operations? Surgery 2001;129:720. 43. Wei JP, Burke OJ. Analysis of savings in operative time for primary hyperparathyroidism using localization with technetium 99m sestamibi scan. Am J Surg 1995;170:488. 44. Proye CA, Carnaille B, Bizard JP, et al. Multiglandular disease in seemingly sporadic primary hyperparathyroidism revisited: Where are we in the early 1990s? A plea against unilateral parathyroid exploration. Surgery 1992;112:1118.
45. Carneiro DM, Irvin GL 3rd. Late parathyroid function after successful parathyroidectomy guided by intraoperative hormone assay (QPTH) compared with the standard bilateral neck exploration. Surgery 2000;128:925;discussion 935. 46. Heller KS, Attie IN, Dubner S. Parathyroid localization: Inability to predict multiple gland involvement. Am J Surg 1993;166:357. 47. Thompson GB, Mullan BP, Grant CS, et aI. Parathyroid iinaging with technetium-99m-sestarnibi: An initial institutional experience. Surgery 1994; 116:966. 48. Weber CJ, Ritchie JC. Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration. Surgery 1999;126:1139; discussion 1143. 49. Kao PC, van Heerden JA, Taylor RL. Intraoperative monitoring of parathyroid procedures by a 15-minute parathyroid hormone immunochemiluminometric assay. Mayo Clin Proc 1994;69:532. 50. Arnold A, Brown MF, Urena P, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 1995;95:2047.
Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) Anders O. J. Bergenfelz, MD, PhD • Sten A. G. Tibblin, MD, PhD
Historical Background The purpose of surgical treatment in primary hyperparathyroidism (PHPT) is to remove enough abnormal parathyroid tissue to make and keep the patient normocalcemic. Patients with PHPT caused by a solitary parathyroid adenoma are almost always cured by removal of this adenoma. To accomplish unilateral neck exploration, the side on which the adenoma is located has to be known preoperatively, and this should be a true solitary adenoma rather than hyperplasia or multiple adenomas. When Felix Mandl operated on his first patient for PHPT, the general belief was that enlarged parathyroid glands were the result of bone disease and deficiency of parathyroid activity; his patient, Albert, initially received a parathyroid homograft from a deceased patient. When the treatment failed to improve Albert's condition, Mandl had the knowledge, confidence, and courage to re-explore the patient and remove the pathologic parathyroid gland with at least temporary cure of the patient. I In the early days of parathyroid surgery,removal of the enlarged gland was usually successful. However, with the recognition of primary parathyroid hyperplasia as a distinct histopathologic entity, it became obvious that more parathyroid tissue had to be removed.' To be sure not to miss multiglandular disease, a bilateral neck exploration was advocated. Some surgeons even recommended incisional biopsy of the three normal-appearing parathyroid glands when a solitary parathyroid tumor was identified. Later, Paloyan and associates" suggested that all patients with PHPT had hyperplasia and should, therefore, be treated by subtotal parathyroidectomy. During the 1970s, when the number of patients diagnosed with PHPT rapidly increased, it became obvious that bilateral neck exploration with biopsy of all glands had its price because some patients experienced postoperative hypocalcemia. In a Scandinavian survey, including more than 600 parathyroid operations performed during 1 year, hypocalcemia occurred postoperatively in about 15% of patients." Hypocalcemia occurred
456
less often in patients undergoing only excision of the adenoma rather than biopsy and removal of more than one gland." A unilateral approach in patients with PHPT had been originally advocated in the 1970s by C. A. Wang.s He used intraoperative oil red 0 staining and the saline float test to help determine whether a parathyroid gland was normal or abnormal. Unilateral parathyroidectomy was introduced in our department in 1977, and the initial 5-year results were presented in 1982.6 The principle for the unilateral approach is to restrict the neck exploration to the side on which the solitary adenoma is located. Originally, we did not use any localization studies; consequently, about half of our patients had unilateral approaches because 50% of the solitary adenomas were found on the left side and 50% on the right side. When a parathyroid adenoma was localized intraoperatively, the ipsilateral normal-appearing parathyroid and the adenoma were both removed, thus eliminating presumably all parathyroid tissue on this side. If the wrong side happened to be explored first, the two normal parathyroids were left intact and a contralateral exploration was performed. Again, both the adenoma and the normal parathyroid glands were removed on the second side. Intraoperative frozen section histopathologic examination was used to confirm the diagnosis of a solitary adenoma and a normal-sized parathyroid gland.
Histopathologic Varieties of PHPT
A variety of pathologic conditions cause PHPT (Fig. 49-1). The most common cause of PHPT (85% to 90%) is a solitary benign parathyroid adenoma. Malignant tumors of the parathyroid gland are extremely unusual, occurring in less than 1% of cases; parathyroid cancers are sometimes difficult to distinguish from atypical adenomas. Parathyroid tumor metastases are certainly a sign of malignancy. Chief cell
Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - -
457
HYPERPARATHYROIDISM
FIGURE 49-1. Various forms of hyperparathyroidism encountered in the surgical practice. MEN = multiple endocrine neoplasia.
hyperplasia (four-gland parathyroid hyperplasia) constitutes about 10% to 15% of all cases of PHPT. It affects all glands, but the hyperplasias may vary considerably in size, color, and configuration. Findings of microscopic areas of nodular hyperplasia have been described by Harrison and colleagues," and their biologic significance seems to be minimal. Hyperplasia is identified as primary when there is no obvious reason for it to occur. Secondary hyperparathyroidism (HPT) is usually caused by end-stage renal disease. Secondary HPT usually resolves after successful kidney transplantation. Sporadic multiple adenomas can occur synchronously or metachronously. Multiple adenomas occur much more frequently in patients with multiple endocrine neoplasia (MEN) 1 or 2 and in patients with familial HPT without other endocrinopathies. Oil red 0 staining of parathyroid tissue, as introduced by Roth and Gallagher"and modified by Ljungberg and Tibblin,9 has helped pathologists distinguish between normal and abnormal parathyroid tissue and between solitary adenoma and hyperplasia. True solitary adenomas often have a compressed rim of normal parathyroid tissue. Characteristically, the red stain is taken up by the suppressed chief cells, whereas the hyperactive adenomatous cells do not take up this fat stain. In the normal parathyroid, there is a homogeneous picture of chief cells stained red by the oil red 0 as an expression of the suppression. These criteria help differentiate between a solitary adenoma and a hyperplastic gland, although some pathologists believe that it is impossible to differentiate between a hyperplastic gland and an adenomatous gland without histologic evidence of another normal
gland. The advantageof giving the pathologista whole normalappearing parathyroid gland is to eliminate the possibility of four-gland parathyroid hyperplasia as a cause of PHPT. The cooperation of an experienced pathologist is essential. It is a great advantage for the pathologist if the suppressed rim of normal parathyroid cells can be identified. The surgeon can help the pathologist by tying a suture around the vascular pedicle of the gland because the vessels often first enter the normal compressed tissue of the adenoma. Intraoperative oil red 0 staining is performed as a complement to the conventional hematoxylin-eosin method. Although this technique improves the diagnostic accuracy and microscopic interpretation in some cases, it is still difficult to be completely sure of this diagnosis. Thus, among 165 consecutive patients with PHPT, all of whom had their parathyroid stained by hematoxylin-eosin and oil red 0 intraoperatively, 8% were judged equivocal."
Results of Unilateral Parathyroidectomy (Original Approach) When patients are considered for unilateral parathyroidectomy, it is important to exclude familial HPT because these patients usually have multiple abnormal parathyroid glands. Patients who had previous operations in their neck for either parathyroid disease or thyroid disease are not candidates for unilateral parathyroidectomy because the functional parathyroid reserve cannot be evaluated.
458 - - Parathyroid Gland Identification of a normal parathyroid gland is easy in most instances, but occasionally it is difficult or even impossible. Extensive exploration to identify normal parathyroid glands should be avoided because it might result in ischemia of the normal glands. When original exploratory principles were followed in 102 patients in which the side of the parathyroid neoplasm was unknown preoperatively, the intended operation could be performed in 88 patients (i.e., unilateral parathyroidectomy either with or without bilateral exploration). In 14 patients, various examples of atypical exploration of normal parathyroid glands were applied. I I Most commonly, one or two of the normal glands were missing.'! In a multicenter study, including five departments of surgery, unilateral neck exploration was compared to bilateral neck exploration in regard to long-term effects on the serum calcium level.P In each department, the prevailing exploratory principles were strictly defined. All patients from a 5-year period fulfilling these definitions and other inclusion criteria were analyzed postoperatively and after 8 to 9 years with regard to calcium status. Two percent of the patients who underwent unilateral operations had hypercalcemia after 8.7 years, whereas 5% of those patients who had a bilateral neck exploration had hypercalcemia after an average follow-up time of 8.0 years. Permanent hypocalcemia occurred in 2% and in 6% of those patients who had a unilateral and bilateral neck exploration, respectively. Nonnocalcemia was observed in 96% of patients who had unilateral neck exploration. In patients who had bilateral neck exploration, 89% were normocalcemic.P Also, the frequency of early postoperative hypocalcemia was significantly lower in the patients who had unilateral neck exploration as compared to patients who had bilateral neck exploration. None of the patients who had a unilateral approach had a postoperative serum calcium below 2.00 mmollL, whereas among patients who had a bilateral approach 19% had serum calcium levels below 2.00 mmollL.
Preoperative Localization Without preoperative localization, the chance of exploring the correct side in which the parathyroid adenoma is located is 50%. 6 If the adenoma is not found on the initial side, the contralateral side has to be explored, which increases operative time and possibly morbidity. The accuracy of available imaging studies for parathyroid localization depends on the size and position of the adenoma, the degree of parathyroid hyperfunction, and other unknown factors. In patients with mild PHPT and a small parathyroid adenoma, localization studies are less successful. This is one reason that preoperative localization procedures are generally considered unnecessary and costly" by most surgeons who routinely perform bilateral neck exploration. An experienced surgeon is able to find the abnormal parathyroid gland or glands in 92% to 98% of patients. 14 Ultrasonography of the neck gives good results when the adenoma is large, when it is situated in the neck, and when there is a normal thyroid gland." The accuracy of ultrasonography for localizing parathyroid neoplasm is operator and equipment dependent. When ultrasonography is combined with fine-needle aspiration biopsy and parathyroid hormone (PTH) sampling of the suspected lesion, the accuracy of the method when positive approaches 100%.16
Isotope methods for parathyroid localization studies have been used extensively during the past 20 years. Thalliumtechnetium subtraction scintigraphy was initially used but has been replaced by sestamibi scintigraphy, which has high sensitivity and positive predicted value for solitary parathyroid adenomas." By adding delayed sestamibi scans'? and single photon-emission computer tomography" or oblique views with a higher dose of Tc 99m sestamibi," an even higher accuracy might be possible. Although sensitive for localizing a solitary parathyroid adenoma, sestamibi scintigraphy is less accurate for identifying multiglandular disease. 2o-22 Furthermore, small parathyroid adenomas are localized less accurately.22,23 We have used selective venous sampling and intact PTH assay in two variations. First, we have used it preoperatively to help identify the region of the elusive parathyroid tumor.>' We have also directly punctured the jugular veins and obtained blood for PTH sampling after induction of anesthesia. For the latter studies, we used a rapid method for the analysis of intact PTH levels. A high degree of specificity (92%) could be reached with this method; the sensitivity was 64%.25 This test is more reliable when the parathyroid adenoma is the superior gland and drains directly into the jugular vein. When the parathyroid adenoma is in the lower gland position, the accuracy is lower. Hence, the ideal localization procedure has yet to be developed. Currently, we advocate the use of preoperative localization procedures in the following clinical situations: (1) in patients with previous thyroid or parathyroid surgery and (2) in patients in whom a focused parathyroid exploration is planned.
Intraoperative Monitoring ofPTH Intraoperative measurement of intact PTH concentration during parathyroidectomy was first described by Nussbaum and associates.i" A highly sensitive intact PTH assay was modified, enabling the incubation time to be shortened to about 15 minutes. After removal of a parathyroid adenoma, there is a sharp decrease in the PTH level if the PHPT was due to a solitary parathyroid adenoma (Fig. 49-2). Several groups-"!' have subsequently reported similar findings. An even shorter turnaround time is possible when the analytic equipment, including proper laboratory personnel, is situated in the operating room." When a macroscopic diagnosis is strongly suggestive of a solitary adenoma, the wound may be closed but the patient is kept under anesthesia. When the PTH level fails to drop after removal of the suspected adenoma, the removed gland either is not of parathyroid origin or is a normal parathyroid gland (Fig. 49-3). When the removed lesion is of parathyroid origin and the PTH level decreases less than 60% at 15 minutes after gland removal, parathyroid hyperplasia or double parathyroid adenoma should be suspected and a comprehensive bilateral neck exploration performed (Fig. 49-4).29 The quick intact PTH assay offers the advantage of a functional evaluation of the surgical procedure and therefore renders intraoperative histologic examination unnecessary. Some surgeons have proposed that when the same solitary parathyroid tumor is identified by both sestamibi scintigraphy
Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - -
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and ultrasonography, a focused parathyroid exploration can be done with a 95% success rate." Other surgeons suggest that from a cost-effective standpoint, same-day PTH testing for minimal invasive parathyroidectomy is superior to intraoperative PTH monitoring.>' Clearly, these issues can only be definitively resolved by a multicenter, prospective, randomized trial.
125
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FIGURE 49-4. Decline of intact parathyroid hormone (PTH) in four patients with primary parathyroid hyperplasia at 15 minutes after removal of one enlarged gland compared with 43 patients with primary hyperparathyroidism due to solitary parathyroid adenomas. Individual values are shown for the patients with hyperplasia, whereas for those with parathyroid adenoma the mean is shown (±2 SD).
Surgical Treatment of PHPT under Local Anesthesia Some patients with PHPT have coexisting severe cardiovascular disease and respiratory insufficiency.Pv" Surgical removal of parathyroid adenomas under local anesthesia'r' ! was initially proposed as an attractive alternative to longterm medical treatmenr'v" or percutaneous biochemical ablatiorr'" for high-risk patients. Focused parathyroidectomy under local or regional anesthesia has been proposed as an alternative to operation under general anesthesia for most patients with PHPT.45-48 Parathyroid exploration under local anesthesia is well tolerated by patients, and heart rate and blood pressure fluctuate less than in patients having neck exploration under general anesthesia.t" For patients who have a focused parathyroidectomy under local anesthesia, accurate localization studies are of paramount importance. If noninvasive localization studies are performed, we recommend that the results of at least two tests should agree for definite localization because of a high incidence of false-positive results." As an alternative, ultrasonography combined with fine-needle aspiration for PTH sampling of the suspected lesion may be used."
10 15
Time (min after gland excision)
FIGURE 49-3. In a 45-year-old woman with primary hyperparathyroidism, two parathyroid glands were interpreted as being macroscopically enlarged and excised. Frozen section showed normal parathyroid tissue. The parathyroid hormone (PTH) level did not decrease until a 0.38-g parathyroid adenoma was removed. Data are shown as a percentage of baseline value.
Minimal Invasive Parathyroidectomy Owing to the advancement in preoperative localization procedures, as well as intraoperative PTH monitoring and refinement of surgical technique, endoscopic and video-assisted
460 - - Parathyroid Gland
parathyroidectomyhave recently been introduced and are proposed to improve cosmesis and reduce postoperative pain.50-55 Conversionto standard bilateral neck exploration occurs in 8% to 15% of the patients,52,56 which is close to the 7% reported with a conventional minimal invasive parathyroidectomy."
Advantages of Unilateral Parathyroidectomy Good results have been claimed by the proponents of the unilateral approach, with a decreased risk of hypocalcemia I 1,12.58,59 and vocal cord injury.58 Furthermore, focused parathyroidectomy has been suggested to lower costs, shorten hospital stay, and enhance recovery time.6°-63 In agreement with these studies, a systematic review comparing unilateral with bilateral neck exploration indicated a tendency to favor the unilateral procedure.v' Recently, the first prospective, randomized, controlled trial comparing unilateral and bilateral neck exploration for PHPT was reported.P Cure rate and costs did not differ between the two groups. However, the patients in the bilateral group had a higher incidence of early symptomatic hypocalcemia and lower serum calcium values on postoperative days I to 4 compared with patients in the unilateral group. In addition, in patients with PHPT due to a solitary parathyroid adenoma, unilateral neck exploration was associated with a shorter operative time. Complications occurred mainly in the bilateral group.P
Conclusion and Future Aspects High-quality preoperative localization procedures such as sestarnibi scintigraphy and ultrasonography as well as the introduction of intraoperative monitoring for intact PTH serum levels have facilitated the treatment of patients with solitary parathyroid adenoma. Minimal invasive parathyroidectomy is the ideal surgical treatment for patients with PHPT due to a single parathyroid adenoma. In a survey of the members of the International Association of Endocrine Surgeons, more than half of them indicated that they current!y perform minimal invasive parathyroidectomy and use the technique for an average of 44% of the patients with PHPT.65 Several questions need to be addressed in the future, such as the role of video-assisted parathyroidectomy compared to a focused conventional approach, and the precise role for parathyroidectomy under local anesthesia. Furthermore, although a 5-year follow-up has shown that measurement of intraoperative PTH can predict long-term operative success.t" long-term data from prospective, randomized trials are necessary to provide the answer to a possible difference in long-term normocalcemia between the different surgical strategies.
REFERENCES I. Mandl F. Therapeutischer Versuch bei Ostitis Fibrosa generalisata Mittels Exstirpation eines Epitehelkorperchen Tumors. Wien Clin Wochenschr 1925;50:1343. 2. Bloch MA, Frame B, Jackson CE, et al. The extent of operation for primary hyperparathyroidism. Arch Surg 1974;109:798.
3. Paloyan K, Lawrence AM, Oslapas R, et al. Subtotal parathyroidectomy for primary hyperparathyroidism: Long-term results in 292 patients. Arch Surg 1983;118:425. 4. Johansson H, Granberg PO, Tibblin S, et al. Scandinavian study of the parathyroid surgical activity in 1975. Acta Chir Scand Suppl 1979;493:66. 5. Wang CA. Surgical management of primary hyperparathyroidism. Curr Probl Surg 1985;22: I. 6. Tibblin S, Bondeson A-G, Ljungberg O. Unilateral parathyroidectomy in hyperparathyroidism due to single adenoma. Ann Surg 1982; 195:245. 7. Harrison ST, Duarte B, Reitz RE, et al. Primary hyperparathyroidism four- to eight-year postoperative follow-up demonstrating persistent functional insignificance of microscopic parathyroid hyperplasia and decreased autonomy of parathyroid hormone release. Ann Surg 1981; 194:429. 8. Roth SI, Gallagher MJ. The rapid identification of "normal" parathyroid glands by the presence of intracellular fat. Am J Pathol 1976;84:521. 9. Ljungberg 0, Tibblin S. Perioperative fat staining in frozen sections in primary hyperparathyroidism. Am J PathoI1979;95:633. 10. Bondeson A-G, Bondeson L, Ljungberg 0, Tibblin S. Fat staining in parathyroid disease: Diagnostic value and impact on surgical strategy-Clinicopathologic analyses of 191 cases. Hum Pathol 1985;16:1255. II. Tibblin S, Bondeson A-G, Bondeson L, Ljungberg O. Surgical strategy in hyperparathyroidism due to solitary adenoma. Ann Surg 1984; 200:776. 12. Tibblin S, Bizard JP, Bondeson A-G, et al. Primary hyperparathyroidism due to solitary adenoma: A comparative multicenter study of early and long-term results of different surgical regimens. Eur J Surg 1991;157:511. 13. Thompson NW. Localization studies in patients with primary hyperparathyroidism. Br J Surg 1988;75:97. 14. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:814. 15. Uden P, Aspelin P, Berglund J, et al. Preoperative localization in unilateral parathyroid surgery. Acta Chir Scand 1990;156:29. 16. Bergenfelz A, Forsberg L, Hederstrom E, Ahren B. Preoperative localization of enlarged parathyroid glands with ultrasonic-guided fine-needle aspiration for parathyroid hormone assay. Acta Radiol 1991; 32:403. 17. Billotey C, Aurengo A, Najean Y, et al. Identifying abnormal parathyroid glands in the thyroid uptake area using technetium-99m sestamibi and factor analysis of dynamic structures. J Nuel Med 1994; 35:1631. 18. Taillefer R. 99mTc sestamibi parathyroid scintigraphy. In: Freeman EM (ed), Nuelear Medicine Annual, 1995. New York, Raven Press, 1995, p 51. 19. Norman J, Chheda H, Farrell C. Minimally invasive parathyroidectomy for primary hyperparathyroidism: Decreasing operative time and potential complications while improving cosmetic results. Am Surg 1998;64:391. 20. Bergenfelz A, Tennvall J, Valdemarsson S, et al. Sestamibi versus thallium subtraction scintigraphy in parathyroid localization: A prospective comparative study in patients with predominantly mild primary hyperparathyroidism. Surgery 1997;121:601. 21. McBiles M, Lambert AT, Cote MG, et al. Sestamibi parathyroid imaging. Semin Nuel Med 1995;25:221. 22. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: A prospective randomized controlled trial. Ann Surg 2002;236:543. 23. Lee VS, Wilkinsson RH, Leight GS Jr, et al. Hyperparathyroidism in high-risk surgical patients: Evaluation with double-phase technetium99m sestamibi imaging. Radiology 1995;197:627. 24. Bergenfelz A, Lundstedt C, Stridbeck H, Ahren B. Large vein sampling for intact parathyroid hormone in the preoperative localization of enlarged parathyroid glands. Acta Radiol 1992;33:528. 25. Bergenfelz A, Algotsson L, Roth B, et al. Side localization of parathyroid adenomas by simplified intraoperative venous sampling for parathyroid hormone. World J Surg 1996;20:358. 26. Nussbaum SR, Thompson AR, Hutcheson KA, et al. Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery 1988;104:1121.
Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - - 461 27. Irvin GL, Dembrow VD, Prudhomme DL, et aI. A new approach to parathyroidectomy. Ann Surg 1994;219:574. 28. Bergenfelz A, Norden NE, Ahren B. Intraoperative fall in plasma levels of intact parathyroid hormone after removal of one enlarged gland in hyperparathyroid patients. Eur J Surg 1991;147:109. 29. Bergenfelz A, Isaksson A, Ahren B. Intraoperative monitoring of the intact PTH during surgery for primary hyperparathyroidism. Langenbecks Arch Chir 1994;379:50. 30. Ryan MF, Jones SR, Barnes AD. Modification to a commercial immunoradiometric assay permitting intraoperative monitoring of parathyroid hormone levels. Ann Clin Biochem 1990;27:65. 31. Irvin GL, Dembrow VD, Prudhomme DL. Operative monitoring of parathyroid gland hyperfunction. Am J Surg 1991;162:299. 32. Carneiro DM, Irvin GL III. New point-of-care intraoperative parathyroid hormone assay for intraoperative guidance in parathyroidectomy. World J Surg 2002;26:1074. 33. Miura D, Wada N, Arici C, et aI. Does intraoperative quick parathyroid hormone assay improve the results of parathyroidectomy? World J Surg 2002;26:926. 34. Agarwal G, Barakate MS, Robinson B, et aI. Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy-A cost-effectiveness study. Surgery 200 I; 130:963. 35. Palmer M, Bergstrom R, Akerstrom G, et aI. Survival and renal function in untreated hypercalcemia. Lancet 1987;1:59. 36. Palmer M, Adami HO, Bergstrom R, et aI. Mortality after surgery for primary hyperparathyroidism: A follow-up of 441 patients operated on from 1956-1979. Surgery 1987;102:1. 37. Ronni-Svivula H. Causes of death in patients previously operated on for primary hyperparathyroidism. Ann Chir GynaecoI1985;74:13. 38. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990; 14:829. 39. Pyrtek LJ, Belkin M, Bartus S, Schweizer R. Parathyroid gland exploration with local anesthesia in elderly and high-risk patients. Arch Surg 1988;123:614. 40. Bergenfelz A, Algotsson L, Ahren B. Surgery for primary hyperparathyroidism performed under local anaesthesia. Br J Surg 1992;79:931. 41. Chapuis Y, Icard PH, Fulla Y, et aI. Parathyroid adenomectomy under local anaesthesia with intraoperative monitoring of UcAMP and/or 1-84 PTH. World J Surg 1992;16:570. 42. Lafferty FW, Hubay CA. Primary hyperparathyroidism: A review of the long-term surgical and nonsurgical morbidities as a basis for rational approach to treatment. Arch Intern Med 1989;149:789. 43. Jansson S, Tisell LE, Linstedt G, Lundberg PA. Disodium pamidronate in the preoperative treatment of hypercalcemia in patients with primary hyperparathyroidism. Surgery 1991;110:480. 44. Karstrup S, Transbol I, Holm HH, et aI. Ultrasound-guided chemical parathyroidectomy in patients with primary hyperparathyroidism: A prospective study. Br J RadioI1989;62:1037. 45. Chapuis Y, Fulla Y, Bonnichon P, et aI. Values of ultrasonography sestamibi scintigraphy and intraoperative measurement of 1-84 PTH for unilateral neck exploration of primary hyperparathyroidism. World J Surg 1996;20:835. 46. Inabnet WB, Fulla Y, Richard B, et aI. Unilateral neck exploration under local anesthesia: The procedure of choice for asymptomatic primary hyperparathyroidism. Surgery 1999;126:1004.
47. Chen H, Sokoll LJ, Udelsman R Outpatient minimally invasive parathyroidectomy: A combination of sestamibi-SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016. 48. Ditkoff BA, Chabot J, Feind C, et aI. Parathyroid surgery using monitored anesthesia care as an alternative to general anesthesia. Am J Surg 1996; 172:698. 49. Harness JK, Ramsberg SR, Nishiama RH, et aI. Multiple adenomas of the parathyroids: Do they exist? Arch Surg 1979;114:468. 50. Henry JF. Defechereux T, Gramatic L, et aI. Minimally invasive videoscopic parathyroidectomy by lateral approach. Langenbecks Arch Surg 1999;384:298. 51. Gauger PG, Reeve TS, Delbridge LW. Endoscopically assisted minimally invasive parathyroidectomy. Br J Surg 1999;86:1563. 52. Miccoli P, Berti P, Conte M, et aI. Minimally invasive video-assisted parathyroidectomy: Lesson learned from 137 cases. JAm Coll Surg 2000;191:613. 53. Dralle H, Lorenz K, Nguyen-Thanh P. Minimally invasive videoassisted parathyroidectomy-selective approach to localized single gland adenoma. Langenbecks Arch Surg 1999;384:556. 54. Miccoli P, Bendinelli C, Berti P, et aI. Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: A prospective randomized study. Surgery 2000;128:121. 55. Henry JF, Raffaelli M, Iacobone M, Volot F. Video-assisted parathyroidectomy via the lateral approach vs conventional surgery in the treatment of sporadic primary hyperparathyroidism: Results of a casecontrol study. Surg Endosc 2001;15: 1116. 56. Henry JF, Iacobone M, Mirallie E, et aI. Indications and results of video-assisted parathyroidectomy by a lateral approach in patients with primary hyperparathyroidism. Surgery 2001;130:999. 57. Agarwal G, Barraclough BH, Robinson BG, et al. Minimally invasive parathyroidectomy using the "focused" lateral approach: 1. Results of the first 100 consecutive cases. Aust N Z J Surg 2002;72: 100. 58. Worsey MJ, Carty SE, Watson CG. Success of unilateral neck exploration for sporadic primary hyperparathyroidism. Surgery 1993;114:1024. 59. Westerdal J, Lindbom P, Valdemarsson S, et aI. Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism. Arch Surg 2000;135:142. 60. Irvin GL III, Sfakianakis G, Yeung L, et aI. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996; 131:1074. 61. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665. 62. Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000;232:331. 63. Udelsman R. Is unilateral neck exploration for parathyroid adenoma appropriate? Adv Surg 2000;34:319. 64. Reeve TS, Babidge WJ, Parkyn RF, et aI. Minimally invasive surgery for primary hyperparathyroidism: Systematic review. Arch Surg 2000; 135:481. 65. Sackett WR, Barraclough B, Reeve TS, Delbridge LW. World-wide trends in the surgical treatment of primary hyperparathyroidism in the era of minimally invasive parathyroidectomy. Arch Surg 2002; 137:1055. 66. Westerdahl J, Lindblom P, Bergenfelz A. Measurement of intraoperative parathyroid hormone predicts long-term operative success. Arch Surg 2002;137:186.
Minimally Invasive Parathyroid Surgery Paolo Miccoli, MD • Piero Berti, MD
Minimally invasive procedures proposed for the treatment of primary hyperparathyroidism (PHPT) have become widespread after the first operation performed by Michel Gagner in 1996.1 This term, however, can be misleading if one assumes that the simple shortening of the surgical scar is enough to define a surgical procedure as minimally invasive. In fact, if one uses the guidelines of the 1990 National Institutes of Health Consensus Conference as the starting point, all operations other than bilateral exploration with possible biopsy of suspected enlarged parathyroid glands constitute less invasive surgery; however, less invasive does not mean minimally invasive. The concept of invasiveness cannot be limited only to the length of the skin incision but must be extended to other structures, and above all this reduction in invasiveness must not decrease the operative field of vision. For this reason, an endoscope is usually (although not always) used in minimally invasive procedures. This chapter examines mainly endoscopic procedures. These can be performed either with gas flow insufflation and trocars or with external retraction instead of gas insufflation.
Techniques Although several approaches have been proposed as endoscopic parathyroidectomy, the most commonly used are the (1) endoscopic parathyroidectomy (Gagner, 1997),2 (2) video-assisted parathyroidectomy with external retraction (Miccoli, 1997),3·4 and (3) videoscopic parathyroidectomy by a lateral approach (Henry, 1998).5
Endoscopic Parathyroidectomy Endoscopic parathyroidectomy was the first technique described for endoscopic parathyroidectomy. It uses steady gas flow, not exceeding 8 mm Hg pressure." A 5-mm endoscope (0 degrees when starting and 30 degrees once the subplatysmal plane is reached) is inserted through a central neck trocar and two or three additional trocars are used for the instruments (Fig. 50-1). Needlescopic instruments are used.
462
The subplatysmal plane is dissected to obtain a good working space. The space anterior to the sternocleidomastoid muscle is then opened and the strap muscles are retracted medially to expose the thyroid lobes. The parathyroid glands are explored after the thyroid is dissected from the investing fascia. Once the parathyroid adenoma is completely mobilized, the vascular pedicle is dissected and divided between two 5-mm clips. The gland is then extracted in a small sac made from a fingertip from a surgical glove. A quick parathyroid hormone assay (qPTHa) is performed 10 and 20 minutes after resection. A bilateral exploration is possible with this technique.
Video-Assisted Parathyroidectomy Video-assisted parathyroidectomy is a technique that requires no trocars or gas insufflation. The patient's neck is not hyperextended so as to allow a sufficient operative space under the strap muscles. A 15-mm transverse incision is made 2 em above the sternal notch; even minimum bleeding should be avoided since gasless procedures cannot take advantage of the hemostatic effect of gas pressure. The strap muscles are then separated in the midline longitudinally for not more than 3 em. One retractor laterally retracts the strap muscles on the side of the suspected adenoma gently to include the carotid artery while the other one retracts medially to include the thyroid lobe. The thyrotracheal groove is then exposed after cutting the middle thyroid vein between the clips. The lobe is mobilized from the strap muscles using only small spatulas under direct vision. A 30-degree endoscope, 5 mm in diameter, is then introduced through the incision, and from this point on the entire procedure is performed endoscopically using small reusable surgical instruments (spatulas, forceps, scissors, and vascular clips) (Fig. 50-2). Three surgeons are generally involved in this video-assisted procedure: (1) the operator, (2) the first assistant (holding the endoscope and a spatula-aspirator), and (3) a second assistant holding the retractors, one more than during the endoscopic procedures. Usually, only one side of the neck is explored, but the opposite side can be explored through the same incision if necessary. Once the
Minimally Invasive Parathyroid Surgery - - 463
FIGURE 50-1. Endoscopic approach (Gagner procedure).
adenoma is located it is dissected without disrupting the which ~s capsule using spatuias. The pedicle. of t~e gl~d, well visualized under optical magnification (FIg. 50-3), IS then clipped. The adenoma is then retrieved.throug~ the skin incision. The incision is generally closed WIth a skin sealant while the surgeon is waiting for the result of the qPTHa.
Lateral Approach Parathyroidectomy The lateral approach parathyroidectomy, as described by Henry and associates,' uses a 12-mm. skin incision on ~e medial border of the sternocleidomastoid muscle on the SIde of the lesion. A lO-mm trocar is inserted, through which a a-degree lO-mm endoscope is inserted with low-~ressure (8 mm Hg) insufflation. Two small trocars (3 mm) are Inserted below and above the first trocar along the medial margin of the sternocleidomastoid muscle for instruments (Fig. 50-4). The adenoma is gently dissected by the surgeon, who needs only one assistant to hold the camera. Once completely
FIGURE 50-2. Video-assisted parathyroidectomy procedure).
FIGURE 50-3. Video-assisted parathyroidectomy-intraoperative view. PA = parathyroid adenoma.
isolated, the gland is partly extracted and its pedicle is ligated externally using a conventional forceps; qPTHa is also used. A bilateral exploration is not possible with this technique, which is a lateral approach.
Other Approaches In addition to endoscopic operations, other "minimally invasive" approaches to parathyroid surgery have been proposed, some based on the use of intraoperative nuclear mapping first described by Norman and Chheda,' and all characterized by small skin incisions (3 to 4 ern) directly over the supposed adenoma.f A clearly positive preoperative scintigraphic localization study is mandatory for these focused procedures. Some single, well-defined parathyroid adenomas can be visthey repr~ible by ultrasonography but not by scintigrap~y; sent 10% of patients undergoing an endoscopic procedure In our experience. They are excellent candidates for any of the endoscopic or video-assisted parathyroidectomies but not for a radio-guided parathyroidectomy.
(Miccoli FIGURE 50-4. Lateral approach (Henry procedure).
464 - - Parathyroid Gland
Indications Generally, the ideal patient for minimally invasive parathyroidectomy is one with sporadic PHPT and a single, welllocalized adenoma in a virgin neck. There is debate about the percentage of patients who are eligible for minimally invasive parathyroidectomy-this depends on the selection criteria used by the surgeon. In our experience, these criteria were modified by the experience acquired during the development of our technique and the continuing improvement of surgical instrumentation. Contraindications may be absolute or relative. Absolute contraindications include the following: • Large goiters • Recurrent disease • Extensive previous neck surgery • Multiple endocrine neoplasia and familial PHPT • Parathyroid carcinoma Relative contraindications include the following: • Adenomas larger than 3 em (depending on their shape, even larger adenomas can be removed) • Lack of preoperative localization (a bilateral exploration can be performed through a central incision) • Neck surgery on the opposite side of the suspected adenoma (a lateral access can be used) • Previous neck irradiation or small thyroid nodules (concurrent thyroidectomy is possible) Careful selection of the patient is most important to achieve an excellent outcome and to keep the conversion rate low. Although these criteria are presumably shared by most surgeons performing minimally invasive parathyroidectomy, the percentage of patients eligible for this surgery has varied greatly, from as little as 25%9 to as much as 66%.10
Conversion: When, Why? As in many other fields of endoscopic surgery, converting to open surgery is sometimes necessary. In minimally invasive parathyroid surgery, it is due to both technical difficulty of the procedure and drawbacks that are peculiar to parathyroid surgery. Thyroid abnormalities can cause bleeding or difficult dissection. Suspicion of malignancy, intrathyroidal parathyroid adenoma, and prolonged exploration time are also reasons for conversion. Although most minimally invasive procedures are targeted parathyroidectomies (identifying only the adenoma) that have been validated by qPTHa2,4 or postoperative scintigraphy,"!' we prefer a unilateral exploration (identifying both an adenoma and a normal gland), which is almost always possible when using the endoscope. Before elective conversion, at least one side of the neck should have been explored thoroughly. Then, if a lateral approach was used, one should convert to open operation; however, if a central approach was used, contralateral exploration is still possible by the endoscopic technique. We explore the contralateral side endoscopically only if the procedure has not taken too long (l to 1.5 hours) and if preoperative localization studies were not definitive. In our experience, an open operation does not guarantee that the adenoma will be easily found. In three cases out of nine conversions in our series, the
adenoma was still not found even after an extensive open exploration (see "Results").
Complications To define a new procedure as safe and effective, we need to demonstrate that both its complication rate and its success rate are comparable or better than those obtained by traditional surgery. This is particularly difficult when comparing endoscopic parathyroidectomy to traditional parathyroidectomy, which has a success rate of 95%12 with a negligible complication rate. These complications include recurrent nerve palsy and hypoparathyroidism. Hypoparathyroidism is particularly rare, probably due to minimal manipulation required by endoscopic surgery and improved visualization. This is in contrast to the traditional approach of extensive bilateral neck exploration and sometimes frequent biopsy. Thus, the incidence of postoperative hypocalcemia, either transient or permanent, is significantly less after minimally invasive parathyroidectomy.P This rate is similar to that of open unilateral exploration. The use of qPTHa also avoids the unnecessary removal of enlarged glands with normal function and minimizes postoperative hypoparathyroidism. 14 Recurrent nerve palsy is rare in all the series with rate of I % or lower both in traditional operations15 and in endoscopic approaches. !1.I6 There is no evidence of an increased rate of persistent disease after the adoption of minimally invasive parathyroidectomies. Our persistence rate is lower than 2% in almost 300 cases; other published rates of persistent disease also do not exceed 4% to 5%,5.10.11.16-18 which is similar to the results obtained by traditional surgery. 12.15 Nevertheless, it should be noted that patients undergoing minimally invasive parathyroidectomies are a selected group and this could bias the results.
Advantages and Disadvantages It is difficult to assess the advantages offered by minimally invasive parathyroid surgery because of the many different techniques considered minimally invasive. Similarly, "conventional parathyroidectomy" includes both bilateral and unilateral explorations. Furthermore, early sporadic reports of minimally invasive parathyroidectomy included only few cases that had inadequate follow-up and were not prospective studies. Possible advantages include cosmetic outcome and postoperative distress. There are two prospective papers comparing a minimally invasive to a conventional approach, both based on less than 50 patients, concluding that patients have less discomfort postoperatively after minimally invasive operations using a radio-guided'? or video-assisted approach.'? The advantage of the cosmetic outcome is generally considered obvious because a scar of I to 2 em tends to be better accepted than a 4- to 6-cm scar in the same region. Patients' satisfaction evaluated in a prospective study by means of a visual analog scale score proved to be significantly better in a minimally invasive video-assisted parathyroidectomy versus a conventional procedure. 19
Minimally Invasive Parathyroid Surgery - - 465 The duration of hospitalization cannot constitute a further advantage because parathyroid surgery is now frequently performed on an outpatient basis, even under locoregional anesthesia, whether the patient is undergoing a minimally invasive" or a conventional parathyroidectorny.P Endoscopic procedures are generally more expensive and thus a disadvantage. The expenses are due to surgical instrumentation and the technical support needed to set up a new procedure, as well as the longer duration of the procedure. The additional costs of preoperative imaging studies are also widely accepted by surgeons using the conventional approaches? I so this is not an issue. Furthermore, for minimally invasive surgery using a central approach, bilateral exploration is possible. thus making preoperative localization theoretically superfluous. 1I Similarly, qPl'Ha is used in both conventional and endoscopic operations, and its cost has sharply decreased lately, matching that of frozen section. Many surgeons consider it technically demanding, but the surgical equipment required does not differ much from that needed for other laparoscopic procedures.P Finally, the higher cost due to longer procedure duration occurs at the beginning of the surgeon's experience. The learning curve (Fig. 50-5), however, clearly shows that a reasonable operating time can be reached after the first 30 operations and it rivals that of conventional surgery. A significant disadvantage for the endoscopic procedures is the need for general anesthesia, whereas in conventional surgery locoregional anesthesia might be used." This issue is less relevant in Europe, where the problem of surgery on an outpatient basis is not considered of paramount importance. In our center, patients undergoing video-assisted parathyroidectomy are discharged within 24 hours (overnight stay).
Results Our experience consists of 282 patients who underwent minimally invasive video-assisted parathyroidectomy (MIVAP) from February 1997 to April 2002. They represented 76% of a total of 370 referred to our department in the same period for PHPl'. Correct preoperative localization
70
65.4
60
lil Q) 50 "5 c
I
Q)
~
40 30
ci. 20 0
27.5
24.4
25
10 0 1997 1998 1999 2000 2001 2002 FIGURE So-S. Learning curve associated with minimally invasive video-assisted parathyroidectomy. Op. = operating.
of the lesion was considered mandatory before performing MIVAP.This consisted of either an ultrasound examination or a double-phase Tc 99m sestamibi scan. In many cases, both imaging studies had already been performed before referral. The mean age of the patients was 56 ± 13 years (range, 20 to 87 years); there were 224 women (79.5%) and 58 men (20.5%). The mean operative time of the procedure was 39 ± 22 minutes (range, 10 to 180 minutes). Fifteen patients had a concurrent video-assisted thyroid resection for associated diseases (microfollicular nodule, small papillary cancer), including 11 thyroid lobectomies (8 ipsilateral and 3 contralateral) and 4 total thyroidectomies. Conversion to traditional cervicotomy was required in 20 patients (7%) (Table 50-1). The reasons for conversion were multiglandular disease in 4 (double adenoma); intrathyroid adenoma in 3; difficult dissection in 2; negative exploration in 9 (in 3 cases the adenoma was not found even after conversion); intraoperative suspicion of parathyroid carcinoma in 1 (confirmed by frozen section and thus treated with synchronous thyroid lobectomy); and inadequate intraoperative PTH assay in 1. The conversions for double adenoma and intrathyroid lesions occurred at the beginning of our experience, when we were concerned about the prolonging the operation. More recently, when a further adenoma (even contralateral) or intrathyroid adenoma was suspected, we always continued with the video-assisted technique to perform a bilateral exploration or even a thyroid lobectomy (if necessary). The mean size of the removed adenoma was 1.8 em in its largest diameter. The lesion was superior right in 20.5% of cases, superior left in 23.1 %, inferior right in 23.8%. and inferior left in 32.6%. Patients are usually discharged after careful evaluation overnight for clinical symptoms of hypocalcemia and for serum calcium measurement. There were two permanent laryngeal nerve palsies (0.7%) (6 months after surgery). There was one case of postoperative bleeding (0.3%) from a displaced clip on a middle thyroid vein, which required a reoperation 2 hours after surgery. Transient hypocalcemia occurred in 10 patients (3.5%) (Table 50-2). Five (1.7%) patients had persistent hyperparathyroidism. In three patients, the adenoma was not found at exploration even after conversion. These patients are being re-evaluated. In two patients, the persistence was due to a false-positive qPTHa. A second exploration revealed a second adenoma missed at the time of the first operation. Both missed second
466 - - Parathyroid Gland
adenomas were at the opposite side of the first operation, and they were successfully treated again by the MIVAP approach. In this series, six patients had previously undergone thyroid surgery and two patients had undergone a prior exploration for PHPT. We successfully used a lateral approach in these patients so as to avoid adhesions in the midline.
Conclusions Fewer patients now undergo classic open bilateral neck exploration for PHPT because of the desire for smaller scars, shorter postoperative stay, and less postoperative distress. Better preoperative localization studies now allow for patient selection for targeted parathyroidectomies with low rates of persistent disease.P Endoscopic parathyroidectomy offers thorough exploration of the neck, unilaterally-' or even bilaterally.l'P' The use of qPTHa reduces the possibility of missing a second adenoma or a hyperplasia. In our experience, qPTHa has helped avoid conversion to open surgery in 2% of our patients. Endoscopic parathyroidectomy is an excellent option. In contrast, radio-guided parathyroidectomy is logistically demanding, requiring nuclear mappings and coordination among the nuclear medicine physician, the operating room staff, and the surgical team." Endoscopic parathyroidectomy allows for neck exploration of two glands and, with a central incision, even bilateral exploration of four glands. This is not possible by the lateral approach.
REFERENCES I. Gagner M. Endoscopic parathyroidectomy [Letter]. Br J Surg 1996;83:875. 2. Gagner M. Endoscopic parathyroidectomy and thyroidectomy. Semin Laparosc Surg 1997;4:235. 3. Miccoli P, Cecchini G, Conte M, et al. Minimally invasive videoassisted parathyroid surgery for primary hyperparathyroidism. J Endocrinol Invest 1997;20:429.
4. Miccoli P. Minimally invasive surgery for thyroid and parathyroid diseases. Surg Endosc 2002;16:3. 5. Henry JF, Defechereux T, Gramatica L, de Boissezon C. Minimally invasive videoscopic parathyroidectomy by lateral approach. Langenbecks Arch Surg 1999;384:298. 6. Rubino F, Pamoukian VN, Zhu JF, et al. Endoscopic endocrine neck surgery with carbon dioxide insufflation: The intracranial pressure in a large animal model. Surgery 2000;128:1035. 7. Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping. Surgery 1997;122:998. 8. Chen H, Sokoll LJ, Udelsman R. Outpatient minimally invasive parathyroidectomy: A combination of sestamibi-SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016. 9. Gauger PG, Reeve TS, Delbridge LW Endoscopically assisted, minimally invasive parathyroidectomy. Br J Surg 1999;86:1563. 10. Miccoli P, Berti P, Conte M, et al. Minimally invasive video-assisted parathyroidectomy: Lesson learned from 137 cases. J Am Coli Surg 2000;191:613. II. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665. 12. Duh QY, Uden P, Clark OH: Unilateral neck exploration for primary hyperparathyroidism: Analysis of a controversy using a mathematical model World J Surg 1992;16:654. 13. Lorenz K, Nguyen-Thanh P, Dralle H. Unilateral open and minimally invasive procedures for primary hyperparathyroidism: A review of selective approaches. Langenbecks Arch Surg 2000;385:106. 14. Irvin GL III, Sfakianakis G, Yeung L, et al. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131:1074. 15. Kaplan EL. Endocrine surgery. J Am Coli Surg 1999;188:118. 16. Lorenz K, Miccoli P, Monchick lM, et al. Minimally invasive videoassisted parathyroidectomy: Multi-institutional study. World J Surg 2001;25:704. 17. Goldstein RE, Blewins L, Delbeke D, Martin WH. Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism. Ann Surg 2000;231 :732. 18. Monchick JM, Barellini L, Langer P, Kahya A. Minimally invasive parathyroid surgery in 103 patients with local/regional anesthesia, without exclusion criteria. Surgery 2002; 131:502. 19. Miccoli P, Bendinelli C, Berti P, et al. Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: A prospective randomized study. Surgery 1999;126:1117. 20. Lo Gerfo P. Bilateral neck exploration for parathyroidectomy using local anesthesia: A viable technique in patients with co-existing thyroid disease with or without sestamibi scanning. Surgery 1999;126:1011. 21. Sosa JA, Powe NR, Levine MA, et al. Cost implications of different surgical management strategies for primary hyperparathyroidism. Surgery 1998;124:1028. 22. Miccoli P, Monchick 1M. Minimally invasive parathyroid surgery: A review. Surg Endosc 2000;14:987. 23. Inabnet WB III, Dakin GF, Haber RS, et al. Targeted parathyroidectomy in the era of intraoperative parathormone monitoring. World J Surg 2002;26:921. 24. Gagner M, Rubino F. Endoscopic parathyroidectomy. In: Gagner M, Inabnet WB (eds), Minimally Invasive Endocrine Surgery. Philadelphia, Lippincott Williams & Wilkins, 2002, p 110. 25. Moley JF. Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of stay, and costs in the management of primary hyperparathyroidism [Comment]. Ann Surg 2000;231 :741.
Endoscopic Parathyroidectomy Jean Francois Henry, MD • Frederic Sebag, MD
Since the first successful parathyroidectomy performed in 1925 by Felix Mandl of Vienna, I bilateral exploration and four-gland exploration has been considered the traditional approach in patients with primary hyperparathyroidism (pHPT). Performed by an experienced surgeon, this procedure is certainly one of the most gratifying of all operations. The success rate is reported to be of more than 96% with a concomitantly negligible operative mortality and morbidity rate? Nevertheless, today the surgical management of PHPT is in transition. The development and improvement of pre- and intraoperative localization methods, the introduction of intraoperative quick parathormone (QPTH) assessment, and the minimally invasive surgery revolution are the main reasons that have pushed surgeons at least to investigate the feasibility of other parathyroid procedures. Several new minimally invasive techniques for parathyroidectomy have been developed: the unilateral approach.r" radioguided surgery.'t? mini-open invasive techniques (miniincision with or without local anesthesiaj.v!" and video-assisted or fully endoscopic techniques. I 1-21 These techniques have two common threads: they all have a limited incision compared with the classic open transverse cervical incision, and the surgery is targeted to one specific parathyroid gland. In most cases, the exploration of other glands is not performed or is limited. Minimally invasive techniques are particularly suitable for parathyroid surgery for several reasons: they are only ablative procedures that do not require any elaborate surgical reconstruction, most parathyroid tumors are small and benign, and reduction in the length of the scar to about 10 to 15 mm is appealing to many patients. It has been demonstrated that endoscopic parathyroidectomy is a feasible surgical procedure. Curiously, the first endoscopic removal of enlarged parathyroid glands was not from the neck but from a major ectopic location in the mediastinum." The first case of an endoscopic parathyroidectomy in the neck was reported by Gagner in 1996. 11 Since then, the application of endoscopic techniques for parathyroid surgery has become more and more widely reported.
endoscopic when endoscopic equipment is used during the procedure. Techniques such as video-assisted parathyroidectomies that require the endoscope during one step but not necessarily during the whole operation should also be considered endoscopic procedures. The three endoscopic neck procedures in most widespread use are described in the following. Other techniques that have been proposed but are less commonly used are the axillary approach-" and the anterior chest approach.'?
Surgical Technique
Minimally Invasive Video-Assisted Parathyroidectomy
The term endoscopic parathyroidectomy must be clearly defined: a parathyroidectomy can be considered to be
Minimally invasive video-assisted parathyroidectomy (MIVAP) was described by Miccoli and colleagues."
Pure Endoscopic Parathyroidectomy This technique, first described by Gagner, II is carried out entirely under a steady gas flow. The patient is placed supine with the neck less hyperextended than for open operation to allow room for insufflation. Under general anesthesia, the neck area is prepared and draped in the fashion typical for conventional surgery. A 5-mm skin incision is made just above the sternal notch in the lower midline of the neck and a 5-mm trocar is inserted. Then, a 5-mm scope is introduced and a larger subplatysmal space is created by blunt dissection with the tip of the scope. Carbon dioxide insufflation is started at 12 to 15 mm Hg but can be decreased to 8 to 10 mm Hg. When enough space has been created, the midline is opened and the strap muscles retracted in order to expose the thyroid lobes. Two or three additional trocars are used: one 2-mm trocar is placed laterally above the clavicle on the side of exploration; another 2-mm trocar is placed at the midline just below the thyroid cartilage. An optional second 5-mm trocar is placed at the anterior border of the sternocleidomastoid muscle (SCM) below the angle of the mandible. Needlescopic instruments are used. A bilateral parathyroid exploration is possible with this technique. When the tumor is discovered and freed, it is placed in a bag, made from the tip of the finger of a rubber glove, and removed through the 5-mm port site. Subcuticular sutures and Steri-Strips or glue are used to close the skin incisions.
467
468 - - Parathyroid Gland The patient is placed in the supine position with the neck in slight extension. A 15-mm skin incision is made at the suprasternal notch. The cervical midline is opened, and complete dissection of the thyroid lobe is achieved by blunt dissection with small instruments under endoscopic vision using a 30-degree 5-mrn endoscope. Small conventional retractors maintain the operative space. Small instruments, 2 mrn in diameter, are used for the dissection. The harmonic scalpel is very useful, particularly during the dissection of the superior thyroid pedicle. The procedure is carried out only through the initial midline incision. There is no need for an additional trocar or for gas insufflation. This technique also permits bilateral exploration. The surgeon must be aided by two assistants.
Endoscopic Parathyroidectomy by Lateral Approach24 In both techniques described previously,access to the parathyroid is achieved through the midline. The midline approach is suitable for superficially located parathyroids, which in most cases means the inferior glands located at the lower pole of the thyroid lobe or in the thyrothymic tracts. However, for superior adenomas that tend to migrate posteriorly,the midline approach requires complete exposure and medial retraction of the thyroid lobe. This is sometimes difficult, particularly in patients with a short wide neck or with large thyroid glands. Conversely, the lateral approach or back door approach, already described by Feind in open surgery for parathyroid re-exploration," allows direct access to the lateral and posterior aspects of the thyroid lobe and therefore to the posteriorly located parathyroids. The patient is placed in the supine position but without extension of the neck. Under general anesthesia, a l2-mrn transverse skin incision is made on the anterior border of the SCM, 3 to 4 em above the sternal notch. Through this incision, the fascia connecting the posterior portion of the strap muscles to the carotid sheath is gently divided with scissors, far enough to visualize the prevertebral fascia. When enough space has been created, two 2- to 3-mrn trocars are inserted on the line of the anterior border of the SCM, 3 to 4 em above and below the first skin incision. A lO-mrn trocar is inserted through the l2-mrn skin incision (Fig. 51-1). The working space is easily created with minimal dissection and maintained with low CO2 pressure at 8 mrn Hg. At this low pressure, there is no risk of subcutaneous emphysema or pneumomediastinum. Unilateral video-assisted parathyroid exploration is then carried out using a lO-mrn O-degree endoscopic camera. The dissection is performed using 2- or 3-mrn instruments: graspers, scissors, and cautery hook. The anatomic structures, posterior aspect of the thyroid lobe, esophagus, trunk and branches of the inferior thyroid artery, inferior laryngeal nerve, and thyrothymic tract, can be explored. During the exploration, one can identify both the adenoma and the ipsilateral parathyroid gland but contralateral exploration is not possible. When the adenoma has been completely dissected, the vascular branches of its pedicle are coagulated with the cautery hook. Then, small adenomas are grasped and directly extracted through the 10-mm trocar; large adenomas that cannot be introduced into the 10-mrntrocar are extracted directly through the trocar site,
FIGURE 51-1. Endoscopic parathyroidectomy by a lateral approach: trocar positions.
with the thyroid lobe being retracted medially and anteriorly with a small conventional retractor. There is no need to place the gland into a sterile plastic bag. Draining is not necessary. The lateral approach is a rapid, direct, and bloodless approach. In our opinion, it is the procedure of choice in most cases because it provides the best access to the posterior aspect of the thyroid lobe. It is therefore applicable in all cases in which the parathyroid lesions are located posteriorly, meaning superior parathyroid glands, because their enlargement pushes them to migrate posteriorly and slide along the prevertebral plane next to the lateral esophageal border. The lateral approach is also ideal for inferior parathyroid glands located posterior to the inferior poles of the thyroid lobe. It is in these cases that they become intimate with the recurrent laryngeal nerve. The lateral view permits easy identification of the nerve abutting the adenoma and therefore allows a secure dissection. However, the lateral approach is not suitable for superficially located parathyroids, which means the inferior glands located at the lower pole of the thyroid lobe or in the thyrothymic tracts. These glands can easily be reached through a l5-mrn skin incision at the suprasternal notch. The procedure is carried out between the strap muscles with the assistance of a 5-mrn endoscope (0 or 30 degrees). All maneuvers are therefore performed openly without gas insufflation. All instruments are introduced through the midline incision. There is no need for an additional trocar. Because of their anterior locations, the dissection of these glands remains anterior to the trachea and does not require the previous identification of the recurrent laryngeal nerve, which runs more posteriorly. Parathyroid glands deeply located in the thymus can also be removed endoscopically using this midline access.
Contraindications Not all patients presenting with PHPT are candidates for this surgery. Contraindications are mainly due to a larger goiter,
Endoscopic Parathyroidectomy - -
previous surgery in the parathyroid vicuuty, suspicious multiglandular disease, and equivocal preoperative localization studies. Depending upon the operator's experience and according to the specific technique utilized, these contraindications can become relative. The central approach appears to be the best one for cases in which a bilateral exploration is anticipated or localization is uncertain. Occasionally, endoscopic parathyroidectomy by the lateral approach can be performed in patients who have previously undergone contralateral neck operation or tracheotomy. According to certain authors, more than 60% of patients with PTHP are candidates for video-assisted parathyroidectomy." The endoscopic dissection of large adenomas (>3 ern) can be difficult because the working area remains limited. With limited experience, some surgeons can encounter major difficulties that may lead to capsular rupture and local seeding of parathyroid adenomatous cells. When this happens, a conversion is recommended. Nevertheless, some large but elongated adenomas, especially if situated in the posterosuperior mediastinum, can be removed endoscopically. The pedicle can be easily dissected at the level of the inferior thyroid artery, and their shape is amenable to expeditious extraction. Patients with suggested multiglandular disease are not eligible for these procedures. Endoscopic parathyroid procedures should be reserved for patients with sporadic PHPT. All endoscopic parathyroid surgeons consider that the adenoma should be clearly localized before the operation. Therefore, the surgeon is highly dependent upon the quality of preoperative imaging to make a judicious choice for an endoscopic approach. Once contraindications have been eliminated, all patients with sporadic primary PHPT are considered candidates for this procedure. The choice between approaches is dependent on the quality and adequate interpretation of preoperative imaging studies. If the cervical ultrasonography and the nuclear scan do not correlate with a unique lesion at the same site, a traditional open cervical transverse incision is preferable. However, if the lesion is unique and confirmed by both studies, an endoscopic approach can be proposed. Depending on a posterior or anterior location, one can choose a central or lateral approach (Fig. 51-2). Absolute contraindications remain the presence of a carcinomatous parathyroid gland, voluminous goiter, or both, no matter the experience of the surgeon or type of endoscopic technique employed. Finally, endoscopic thyroidectomy and parathyroidectomy can be performed at the same time through the midline, but these procedures are indicated for small suspicious thyroid nodules less than 2.5 em in diameter associated with PHPT.
Results In cases of removal of mediastinal parathyroid adenomas by thoracoscopy, the advantages to the patient are irrefutable. However, taking into account the excellent results of the traditional bilateral cervical exploration, the same advantages are more difficult to demonstrate for all cervical approaches. Two studies comparing conventional parathyroid surgery with endoscopic techniques have clearly shown a diminution of postoperative pain and better cosmetic results with
.:
469
Sestamibi scan + Ultrasonography
15 mg/dL), and 31% presented in hypercalcemic crisis, requiring emergency hospitalization. As seen in Table 55-2, 45% of 51 patients in the literature presented with a serum calcium of 15 mg/dL or greater and 67% with a serum calcium of 13.5 mg/dL or greater. Thus, unlike the non-MEN familial medullary thyroid cancer that is less aggressive than sporadic medullary thyroid cancer or MEN 2B, NMFH appears to be more aggressive than other forms of the disease. One third to one half of the patients with NMFH experience nephrolithiasis. One fifth of the patients have severe osteoporosis, and osteitis fibrosa cystica with brown tumors is more common. Other nonspecific symptoms or signs that occur more frequently in the patients with primary HPT, including hypertension, fatigue, weakness, pancreatitis, or peptic ulcer, may also be common in patients with NMFH, but currently there is insufficient information to know with certainty. Four patients in the UCSF series were asymptomatic initially, but two of these initially asymptomatic patients experienced hypercalcemic crises when the disease persisted after the initial parathyroidectomy at another medical center. The mean age of the patients with NMFH at initial diagnosis was 43.5 years (range, 12 to 86 years) in the UCSF 493
494 - - Parathyroid Gland
series, which is older than that of patients in other reports (mean, 32.3 years; range, 12 to 68 years) but is similar in that of patients with MEN 157-68 and younger than that of patients with sporadic primary HPT.69 Both genders are affected, Some patients experience NMFH as children but rarely, if ever, before 10 years of age. The mechanism of inheritance of NMFH is unknown. In contrast to the autosomal dominant inheritance characteristic of MEN, Law and colleagues reported on an autosomal recessive inheritance of NMFH in three siblings.'? The inheritance of NMFH may therefore vary and be more complex. Restriction fragment length polymorphism linkage analysis showed the presence of HPT to be linked to a locus on chromosome llq13 (near or identical to the MEN 1 gene) in members of a family with NMFH, and genetic mapping found few families with NMFH that have incomplete expression or a subset of MEN 1.70-76 No distinctive genetic abnormalities, except NMFH with tumors of jawbones, have been found to date with NMFH.33,77
Associated Diseases Coexistent thyroid disease occurred in 62% of patients with NMFH in the UCSF patients, and 19% of the patients had coexistent papillary thyroid cancer. Because thyroid abnormalities are common in patients with other types of primary HPT,78-82 this apparent increase in frequency of benign and malignant thyroid neoplasms may not be statistically significant. Fibroosseous tumors of the mandible or maxilla (i.e. tumors of the lower and upper jawbones) or so-called NMFH-JT or FlH-JT, rather than brown tumors caused by osteitis fibrosa cystica, have been associated with patients with NMFH in 28 families in the literature, and genetic studies have revealed that this disorder is autosomal dominant and linked to chromosome lq25_q31.19,2J.23-33.38,77,83 In addition, 16 of these 28 families have family members with parathyroid cancer, Other associations such as colon cancer, diabetes mellitus, breast cancer, neurilemoma, and sarcoidosis are also occasionally described.
Familial Hyperparathyroidism - -
Initial Impression
Initial Operation
Final Pathology
~
Cure 4
~
~
9--remove one adenoma
~
4--remove two adenomas
495
Recurrent 3
-E
4
34 Y r ~
1
10 yr ~
1
8yr~1
Persistent 2
~
c u re 2
~2
Persistent 2 ~
2
1
~1 8§] 3 --subtotal--Cure 3 ------8§] 3 parathyroidectomy
Persistent or Recurrent Hyperparathyroidism Multiple abnormal parathyroid glands (two or more) were present in 75% of patients treated at UeSF and in 45% of patientsreported in the literature with NMFH (see Table 55-2). Persistent or recurrent (normocalcemia for at least 6 months after parathyroidectomy) HPT occurred in 44% of patients treated at UeSF and in 20% of patients reported in the literature (see Table 55-2).A shorter duration of follow-up probably accounts for the lower incidence of recurrence reported in the literature. As with MEN 1,84 supernumeraryglands were found in 19% of patients treated at UeSF with NMFH, which is similar to the rate reported in patients with MEN and contributed to the high incidence of persistent or recurrent disease. Because three of our patients experienced recurrent HPT after 8, 10, and 34 years of normocalcemia, respectively (Fig. 55-1), postoperative normocalcemia does not preclude subsequent recurrence of the disease. Long-term follow-up of these patients, as well as screening of family members, is essential.
Surgical Treatment The more aggressive biologic behavior of the parathyroid disease in patients with NMFH, as well as the high incidence of multiple abnormal glands and supernumerary glands and high recurrence rate, warrants a somewhat more aggressive surgical approach. Failure in these patients, as in others with primary HPT, was usually due to failure to identify and remove parathyroid glands in their usual location as well as failure to identify and remove supernumerary parathyroid glands. Because parathyroid rests or supernumerary glands are often present in the thymus or perithymic tissue, we advocate bilateral cervical thymectomy with removal of all perithymic fat.
FIGURE 55-1. UCSF patients' data on persistent or recurrent hyperparathyroidism and pathology. ITQ]N = one abnorm~and, no. of cases; ~N = two abnormal~nds, no. of cases; l1QjN = three abnorm~lands, no. of cases;~N =four abnormal glands, no. of cases; ~ N = five abnormal glands, no. of cases.
If all glands appear to be abnormally enlarged, we recommend subtotal parathyroidectomy, leaving about 50 mg of the most normal parathyroid glands with bilateral thymectomy. Although total parathyroidectomy with autotransplantation has been recommended for patients with hyperplasia and familial disease, we believe this results in an increased frequency of hypoparathyroidism and thus prefer subtotal resection. For patients with recurrent or persistent disease, we recommend total parathyroidectomy with autotransplantation to the forearm and cryopreservation. Although cryopreserved parathyroid tissue functions adequately in only about 60% of patients, it is still useful in these patients for preventing permanent hypoparathyroidism. Postoperatively, it is often difficult to know whether a patient has bone hunger or permanent hypoparathyroidism. The intact parathyroid hormone (PTH) assay helps to differentiate between these two conditions. When a solitary adenoma is found and the three other parathyroid glands appear normal, we recommend removal of the adenoma, ipsilateral thymectomy, and removal of the normal-appearing gland on the same side to confirm that it is not hyperplastic. If there is recurrence, this side of the neck usually does not have to be reexplored. When double adenomas are found, a similar surgical approach to patients with a solitary adenoma can be applied: the pathologic glands should be removed, and one of the normal-appearing parathyroid glands is excised or undergoes biopsy, preferably leaving parathyroid tissue on only one side of the neck.
Key Points for Differential Diagnosis Defined NMFH is diagnosed by excluding other cases of familial hypercalcemia with HPT. The three following
496 - - Parathyroid Gland disorders should be considered. First, BFHH is known as an autosomal dominant, symptomless, nonprogressive, lifelong hypercalcemic disorder with 100% penetration. Individuals with BFHH show abnormal parathyroid and renal responsiveness to changes in extracellular calcium levels.t' Linkage studies have demonstrated that the disease locus in most BFHH patients is located on chromosome 3q13.3q2l68,-69, and the defect has proven to be the calciumsensing receptor (CASR) gene. 86-91 Rare kindreds are linked to a defect on chromosome 19p13.3 or 19q13.86,92 Patients with BFHH are heterozygous for this mutation, whereas patients with neonatal HPT tend to be homozygous for the mutation,93,94 Patients with BFHH are hypercalcemic before age 10 years. The serum calcium level is usually moderate (the values were 10.9 ± 0.1 mg/dL in a study of 21 BFHH families?') and never greater than 14 mg/dL.85-88,95-102 The symptoms and signs are usually vague or mild, Although the incidence of gallstone, diabetes mellitus, relapsing pancreatitis, and myocardial infarction is slightly increased, the incidence of nephrolithiasis is normal. Occasionally, fatigue, mental problems, headaches, arthralgia, and polydipsia may be noted. 97,101 These patients do not appear to benefit from parathyroidectomy.P'v'P However, patients with neonatal HPT need to be treated by total parathyroidectomy with parathyroid autotransplantation and cryopreservation.w''" In 20% of BFHH patients, the serum PTH is usually normal'" or mildly elevated.f-"? The normal or mildly elevated PTH values in the presence of hypercalcemia imply or represent a set-point error of parathyroid function and parathyroid cells insensitive to serum calcium because of functional loss of the CASR. 89,98 The parathyroid glands are normal grossly and histologically demonstrate mild hyperplastic changes.l'" Hypocalciuria is another important feature because the capacity of renal tubular reabsorption of calcium increases in patients with BFHH. Because magnesium is handled similarly to calcium by the kidney in these patients, about half of the patients with BFHH have an elevated serum magnesium concentration.f The urinary calcium level of less than 0.01 for the urinary calcium-to-creatinine clearance ratio (Cca/Ccr) is the most reliable diagnostic criterion for BFHH to distinguish it from primary HPT.85 Genetic mapping is another powerful diagnostic tool for differentiating BFHH from primary HPT. Medical or surgical therapy is unnecessary and uniformly ineffective. 101. 102 Hypercalcemia usually persists after partial parathyroidectomy and permanent hypocalcemia after total parathyroidectomy. Second, MEN 1 is a genetic autosomal dominant disorder characterized by multiple neoplasms of the parathyroid, neuroendocrine tumors of the pancreas, and neoplasms of the anterior pituitary gland. Multiple lipomas and carcinoid tumors are also more common in patients with MEN 1, The predisposing genetic defect has been assigned to chromosome region llqll-q13 by linkage analysis. 57.58 Germline mutations have been identified in about 90% of MEN 1 families. The mutations included nonsense, missense, splice, frameshift, and in-frame deletions. 104 - 106 The clinical features of MEN 1 depend on the number and combinations of endocrine glands that are hyperfunctioning.
Although Majewski and coworkers suggested an "all or none" phenomenon in which the affected members invariably have pathologic changes if tissue from these three glands are examined.t" there is considerable variation of the endocrine glands of patients with MEN 1. Not only do the features of MEN 1 vary among members within the same family, but also some families with MEN 1 may have different degrees of penetration. In addition, the age at which the clinical manifestations of MEN 1 develop can differ considerably from one family member to another, which is also true for NMFH. Most often, the first sign of MEN 1 is HPT. HPT usually antedates other manifestations of MEN L60 Virtually all individuals who inherit the trait experience hypercalcemia by the age of 40 years. 61,62 Periodic testing should begin at about 12 years of age and be repeated yearly; a normocalcemic person older than 50 years is unlikely to have inherited the MEN 1 gene. The incidence of clinically detectable islet cell lesions increases as patients grow older. Because some islet cell tumors fail to elaborate functioning hormone, the absence of any clinical syndrome does not rule out the presence of a pancreatic islet cell tumor, A secretin provocative test for gastrin helps to make the diagnosis in patients with a "silent" gastrinoma, Pituitary tumors are common in MEN 1 patients. About one third of patients with MEN 1 experience pituitary tumors and clinical symptoms. Autopsy studies demonstrate that pituitary microadenomas occur even more often. 63 Although DNA genetic techniques are being developed to diagnose patients with MEN 1 and familial HPT,57 a detailed family history concerning the presence of ulcer disease, renal stones, or recognized parathyroid, pancreatic, or pituitary tumor is essential. Patients with MEN 1 also often have multiple lipomas and angiomas. The following three points are crucial for excluding the possibility of MEN 1 from patients with familial HPT: 1. Autopsy data of family members with isolated familial HPT showing that no pancreatic or pituitary tumors are present. 2. Repeated laboratory tests for gastrin, prolactin, insulin, glucagon, pancreatic peptide, corticotropin, and growth hormone for family members yielding normal results. 3. Genetic mapping of chromosome 11 to detect MEN 1 gene mutations or the possibility of incomplete phenotype expression of MEN 1. The hypercalcemia in most patients with MEN 1 is usually mild (serum calcium level less than 11 mg/dL), and most of these patients are relatively asymptomatic, The mean serum calcium level is usually less than 12 mg/dL and rarely greater than 14 mg/dL,60,64.65,67 although one patient has been reported with a calcium level of 16 mg/dL. 64 Patients with MEN 1 and HPT usually have multiple abnormal parathyroid glands with a high incidence of supernumerary glands." Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation is recommended by most authorities in this field. Among our patients with primary HPT and MEN, we have identified two populations of patients: one population has solitary or double adenomas and recurrence is uncommon, whereas the other group has diffuse hyperplasia and persistent or recurrent disease
Familial Hyperparathyroidism - -
is common.v' We recommend a similar operative strategy for treating patients with HPT and MEN 1 and for patients with NMFH.64 Both groups are susceptible to recurrent HPT. Third, MEN 2 is known to be an autosomal dominant cancer syndrome characterized by medullary thyroid cancer, pheochromocytoma (usually bilateral), and HPT. The genes responsible for MEN 2 have been mapped to genetic intervals within lOql1.2 107,108 and a mutation in either exon 10 or 11. A point mutation of the ret protooncogene has been found in more than 95% of the patients with MEN 2A.109,11O MEN 2B is also an autosomal dominant disease, attributable to a site-specific point mutation on codon 918 of the ret protooncogene.l'" characterized by medullary thyroid cancer, pheochromocytoma, and the presence of mucosal neuromas, ganglioneuromatosis, or marfanoid habitus, producing a distinct clinical phenotype. HPT is a very rare component of MEN 2B. Medullary thyroid cancer or C-ce1l hyperplasia is the dominant feature and usually is first seen in all the affected members, III but the penetrance of pheochromocytoma or HPT is variable. The prevalence of HPT varies from 0% to 70% (median about 20%), and the prevalence of pheochromocytoma ranges from 5% to 95%.112-114 HPT is the least common feature of MEN 2 and tends to develop later than medullary thyroid cancer or C-ce1l hyperplasia, usually after the third decade of life. lIS A normal serum calcitonin level excludes the possibility of MEN 2 in patients without previous total thyroidectomy. The reason for the different penetrance of HPT in MEN 2 is unknown. The increased calcitonin levels in patients with medullary thyroid cancer do not account for the HPT because patients with sporadic medullary thyroid cancer or those with MEN 2B do not have parathyroid tumors. Of interest, primary HPT rarely develops in individuals who undergo total thyroidectomy at a young age.!" Removed parathyroid glands from patients with MEN 2A usually demonstrate chief cell hyperplasia.U':'!? Even in patients with normocalcemic MEN 2A, enlarged parathyroid glands or normal-appearing parathyroid glands are often microscopically hyperplastic when removed at total thyroidectomy.U? The parathyroid glands are often asymmetrically involved. I 18 We recommend a conservative selective approach to the parathyroid glands in these patients because postoperative hypocalcemia is more common than persistent or recurrent hypercalcemia. Only about 30% of patients with HPT and MEN 2A have symptoms, and most of these patients have only slightly elevated serum calcium levels.!" The most common clinical manifestations reveal colic and nephrolithiasis. Hypercalcemic crisis or significant bone disease rarely occurs. 67,l17 At the Mayo Clinic, for patients with MEN 2A and HPT, the serum calcium level ranged from 10.2 to 13.5 mg/dL (mean, 10.7 mg/dL). As mentioned, because an unacceptable consequence of subtotal parathyroidectomy or total parathyroidectomy with autotransplantation in patients with MEN 2 and HPT is hypoparathyroidism, we and others''? recommend excision of only grossly enlarged parathyroid glands, and at least one or two normal-sized glands should be left intact and marked with a metal clip or suture to facilitate their identification if reoperation becomes necessary. This recommendation is
497
based on the findings that selective parathyroid excision has cured most patients with MEN 2 and HPT and recurrent HPT is rare in these patients.
Non-MEN Familial Hyperparathyroidism and Parathyroid Cancer Both parathyroid cancer and NMFH are rare parathyroid disorders. The association of these rare conditions suggests a common cause. Until 2002, 29 patients with NMFH and parathyroid cancer in 22 families were reported. 16,21,23,27-33,35,43 Sixteen of these families have NMFH-JT or FIR-JT, and about one fourth of reported NMFH families have one or two affected members suffering from parathyroid cancer. Endocrinologists and surgeons should be aware of this association for proper management of these patients.
Clinical Features Reviews of 15 cases of NMFH and cancer were reported before 1993. The mean age of the patients with NMFH and parathyroid cancer at initial diagnosis was 30 years (range, 14 to 43 years), which is considerably younger than that of other patients with parathyroid cancer (50 years) (Table 55_3).41 Seven males and eight females were affected. The clinical manifestations among these patients were similar to those of other patients with parathyroid cancer. The mean serum calcium level was 16.1 mg/dL, and one third presented in hypercalcemic crisis. Sixty-one percent of these patients had severe osteitis fibrosa cystica and 30% had nephrolithiasis. Twenty-three percent presented with a palpable neck mass.
Pathogenesis In some patients with NMFH and parathyroid cancer, one or more of the other parathyroid glands were also abnorma1.21,35,43 This occurrence raises the possibility of the transformation of benign parathyroid neoplasms to parathyroid cancer similar to the transformation of C-ce1l hyperplasia to medullary thyroid carcinoma. In most studies, however, there is no evidence of transformation proceeding from hyperplastic glands to parathyroid cancer because 60% of these patients have only parathyroid cancer. 36.37,39-42
498 - - Parathyroid Gland NMFH-JT or FIH-JT is known to be linked to chromosome Iq25-q31 abnormalities. NMFH and parathyroid cancer arising without tumors of the upper and lower jawbones have never, to our knowledge, been identified with a specific genetic mutation.P although three somatic chromosome abnormalities (reciprocal translocation between chromosomes 3 and 4, trisomy 7, and a pericentric inversion in chromosome 9) were also noted in cultured parathyroid cells from one patient with NMFH and parathyroid cancer." At operation, when one encounters a parathyroid tumor that is hard, grayish white, lobulated, or invasive, parathyroid cancer must be suspected. An en bloc excision of the parathyroid neoplasm and ipsilateral thyroid lobe or other adherent tissues is recommended (especially for patients with profound hypercalcemia). For such patients with recurrent or metastatic disease, an aggressive surgical approach, even when palliative, is recommended to palliate symptoms of HP'f'I1 and to decrease the metabolic problems. Persistent or recurrent hypercalcemia occurred in about 40% of the patients with NMFH and parathyroid cancer, a rate similar to that reported for patients with sporadic parathyroid carcinoma.
Familial Neonatal Hyperparathyroidism Neonatal HPT is a rare disorder. It is usually associated with severe hypercalcemia, requiring urgent treatment. More than 50 cases of neonatal HPT have been reported in the literature. 44-56,89,119-126 They may be sporadic or familial. Hillman and colleagues first drew attention to the familial occurrence of neonatal HPT.119 About half of the patients with neonatal HPT have a documented familial inheritance.44-56,120,121 Two types of inheritance-autosomal dominant and autosomal recessive-have been reported in neonatal HPT. The documentation of seven cases from three families suggests an autosomal recessive transmission.'!"!" Other cases of neonatal HPT are associated with BFHH. Patients with BFHH appear to have a benign course with normal survival. In contrast, children with neonatal HPT often have a poor clinical course. Pollak and associates'? demonstrated that a single defective allele causes BFHH, whereas two defective alleles cause severe neonatal HPT, and the genetic defect maps to the CASR gene on chromosome 3q13.3-21. Genetic studies also showed that a de novo CASR gene mutation resulted in sporadic neonatal HPT,127,128 and infants with a homozygous CASR gene mutation or infants with a heterozygous mutation,89,93,94 delivered by a normal mother, develop neonatal HPT.89,127 At birth, newborns are usually normal in terms of size and weight. Both genders are affected. The clinical manifestations usually become evident during the first week of life but may not be recognized until 3 or 4 months of age or later. Severe hypotonia is almost always present in children with profound hypercalcemia. Failure to thrive is common and is usually combined with digestive disorders, including constipation, anorexia, difficult feeding, vomiting, and ileus. Some infants present with dehydration, and renal stones have been reported in three infants. Advanced demineralization is present in most children, and limb and thoracic cage deformities or pathologic fractures have been reported.
At neck exploration, the parathyroid glands are diffusely enlarged and chief cell hyperplasia is evident histologically.123 Medical management, including vigorous hydration, should be instituted in all patients and may be successful in milder cases,46,51,52 although urgent parathyroidectomy is recommended for most patients with severe urgent conditions. Because of the high recurrence rate after subtotal parathyroidectomy, total parathyroidectomy with immediate autotransplantation or with late autotransplantation of cryopreserved parathyroid tissue is recommended. After total parathyroidectomy and parathyroid autotransplantation, some infants have modest hypercalcemia, a normal serum PTH level, hypermagnesemia, and relative hypocalciuria, similar to patients with BFHH. 49 All newborns from families with BFHH must have a serum calcium determination.
Summary NMFH is a distinct clinical entity. The definite diagnosis can be made either by complete clinical work-up or by genetic study to exclude the possibility of MEN 1, MEN 2, or BFHH. These patients are younger and more susceptible to the development of profound hypercalcemia or hypercalcemic crisis than are patients with sporadic HPT or those with HPT and MEN. Patients with NMFH also appear to have a higher incidence of parathyroid cancer and perhaps thyroid neoplasms. Patients with NMFH-JT have unique genetic mutations that are often associated with an extraordinarily high incidence of parathyroid cancer. Patients with NMFH, like those with MEN 1, frequently have multiple abnormal parathyroid glands, either synchronously or metachronously, and, therefore, are at risk for persistent or recurrent disease. NMFH is a unique disease that warrants appropriate recognition, screening of family members, aggressive treatment, and long-term follow-up. Patients with neonatal HPT differ from those with NMFH, although both often present with profound hypercalcemia. Neonatal HPT is associated with BFHH. Determination of the serum calcium level at birth is most important in patients with BFHH to detect this condition early and treat it appropriately.
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Metabolic Complications of Secondary Hyperparathyroidism Juan J. Sancho, MD • Antonio Sitges-Serra, MD
The term secondary hyperparathyroidism (SHPT) means that external factors stimulate the parathyroid glands to increase the production of parathyroid hormone (PTH) and eventually to develop hyperplastic or adenomatous overgrowth, or both. The most common condition causing the parathyroid glands to grow is chronic renal failure (CRF). The often used term renal hyperparathyroidism reflects this fact. SHPT may develop, however, in a variety of conditions such as idiopathic hypercalciuria,' hypennagnesuria, osteomalacia, rickets, malnutrition, or osteoporosis' with low serum levels of 1,25-dihydroxyvitamin D3 (1,25-[OHhD 3, calcitriol).' Hyperparathyroidism in psychiatric patients receiving longterm treatment with lithium is also associated with parathyroid hyperplasia.' In this chapter, the pathogenesis of SHPT related to CRF, its metabolic complications, and its relationship with the clinical manifestations of CRF are reviewed.
Pathogenesis of Secondary Hyperparathyroidism Stimulated by the description of enlarged parathyroid glands in uremic patients by Albright and colleagues,' the Viennese pathologists Pappenheimer and Wilens6 were the first to attribute parathyroid hyperplasia to CRE Since then, researchers have attempted to link decreased kidney functions with the biochemical, morphologic, and clinical manifestations of SHPT. The task has proved to be difficult because both the excretory and endocrine functions of the kidney are impaired in CRE In addition, the treatment of CRF and its complications contribute to the pathogenesis of SHPT, complicating the complete explanation of the pathophysiology of SHPT. The past 30 years have witnessed a dramatic improvement in our understanding of the factors involved in the pathogenesis of renal SHPT. The first landmarks were the
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development of the radioimmunoassay" for PTH fragments and later an immunoradiometric assay for intact PTH(l-84). Understanding some factors in the pathogenesis of SHPT, such as hypocalcemia, hyperphosphatemia, decreased 1,25(OHhD 3 levels, altered PTH metabolism, skeletal resistance to PTH, and the changed set-point in PTH production, provided the initial body of knowledge to help rationally treat these patients. The other advances took place at the biomolecular and genetic levels. They include the discovery of receptors for calcium and calcitriol in the parathyroid cells, their regulation, and the implications of polymorphism; the identification of the PTH gene; and the demonstration of monoclonality in some parathyroid hyperplasia nodules. Increased PTH levels cause, besides the classic skeletal disorders, many clinical manifestations of SHPT. A PTHmediated elevation of cytosolic ionized free calcium (Ca 2+;) is responsible for much of the generalized organ dysfunction in CRF.7 It also has to be taken into account that the assay used for the dosage of "intact PTH" has also been found to detect "7-84" fragments, with a potentially inhibitory effect on the action of the whole hormone, Intact PTH assays also react with non-(l-84)PTH, large carboxyltenninal (C) fragments with a partially preserved aminotenninal (N) structure. They account for up to 50% of intact PTH in renal failure and may be implicated in PTH resistance." The following are the main pathogenic factors linking CRF and SHPT.
Before Kidney Transplantation HYPOCALCEMIA
Hypocalcemia is not a primary event in CRF but a consequence of hyperphosphatemia, bone resistance to PTH, and low circulating calcitriol, each playing a dominant role in different stages of SHPT. The fact that serum calcium is normal in more that 50% of patients with CRp9 is explained
Metabolic Complications of Secondary Hyperparathyroidism - -
by the gradually increasing PTH secretion to maintain serum calcium levels. PTH raises the serum calcium level through its effects on bone and kidney; calcitriol produces similar effects by working in concert with PTH on bone and by enhancing calcium absorption in the gastrointestinal tract. High serum concentrations of calcium inhibit the synthesis of preproPTH messenger RNA (mRNA) and secretion of PTHlO by the parathyroid cells. PTH stimulates the synthesis of calcitriol by enhancing renal Iu-hydroxylase activity, whereas calcitriol inhibits the synthesis and secretion of PTH by impairing PTH gene expression. I I Parathyroid gland becomes hyperplastic in response to prolonged hypocalcemia. 12 Hypocalcemia is a potent stimulator of PTH mRNA synthesis. This stimulation, however, is independent of the cytosolic calcium concentration of the parathyroid cell. Although little is known about the regulation of parathyroid cell proliferation, constant stimulation of PTH mRNA synthesis is associated with the development of parathyroid hyperplasia.P:'" DIMINISHED SYNTHESIS OF CALCITRIOL
The kidney produces calcitriol," the most active metabolite of vitamin D. The synthesis of calcitriol from 25-(OH)D3by the renal enzyme Iu-hydroxylase is stimulated by PTH, by hypocalcemia per se, and by hypophosphatemia. Calcitriol exerts its actions on mineral metabolism through the bone, the gut, the parathyroid glands, and the kidney. On the bone, calcitriol works in concert with PTH to mobilize calcium by enhancing osteoclastic activity and recruiting stem cells to differentiate into osteoclasts. It also has an indirect action in ossification, probably by recruiting cells into osteoblasts, which in tum are responsible for bone mineralization." Calcitriol promotes the intestinal absorption of calcium by enhancing the expression of the calciumbinding protein (calbindin)." On the parathyroid glands, calcitriol inhibits PTH synthesis and secretion by increasing the sensitivity of the parathyroid cell to calcium.'? inhibiting PTH gene expression.V'P and inhibiting parathyroid cell proliferation." Calcitriol also appears to upregulate its own receptor in the parathyroid gland." In addition, the hypercalcemic effect of calcitriol indirectly inhibits PTH synthesis and secretion. On the kidney, calcitriol promotes phosphorus excretion." There is considerable evidence that patients with advanced renal failure, despite elevated serum PTH levels, have reduced or even undetectable levels of calcitriol.Pv" although in mild uremia calcitriol levels are only slightly reduced or even normal. 25.26 The reduction of renal mass and the hyperphosphatemia are the main reasons for calcitriol deficiency. A relative resistance of lre-hydroxylase to the effect of PTH has also been advocated." Extrarenal production of calcitriol from macrophages, keratinocytes, and aortic endothelial cells might compensate for the decrease in renal production." but this occurs only after high doses of 25-(OH)D 3. Although the metabolic clearance rate of calcitriol is also decreased in CRF, it does not compensate for the low calcitriol production.r" The decreasing ability of the failing kidney to hydroxylate 25-hydroxyvitamin D causes an absolute or relative
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deficiency of calcitriol that plays a key role in the genesis of SHPT. 23.24 Low calcitriol levels impair the mobilization of calcium from the bone and the absorption of calcium by the intestine. Its suppressive effect on PTH secretion is lifted." and the renal reabsorption of phosphate is enhanced. In addition, low levels of calcitriol may lower the response of the parathyroid glands to serum ionized calcium.P Calcitriol receptors are diminished in the parathyroid glands of CRF patients, rendering the glands less responsive to the inhibitory action of 1,25-(OH)zD3, and therefore contribute to the development of SHPT.3' PHOSPHATE RETENTION
First proposed by Neil Bricker32.33 as the clue for the "tradeoff' hypothesis, the role of phosphate retention as a major factor in the pathogenesis of hypocalcemia and SHPT was emphasized by Slatopolsky and coworkers.Y''? An imbalance between dietary intake of phosphate and the decreased renal excretory capacity leading to phosphate retention and directly to SHPT is not likely to be the initial pathogenic event-" because hyperphosphatemia is not demonstrable in early CRF during fasting or after an oral phosphate load." The origin of hyperphosphatemia in the CRF patient is doubled. The dietary intake of phosphate, greatly increased in the patient taking phosphate, adds to the effect of reduced excretion of phosphate by an insufficient kidney subject to the stimulus of increasing levels of PTH. The original observation that reducing the phosphate intake in proportion to the decrease of glomerular filtration prevented the progression of SHPT led to the theory that hyperphosphatemia caused SHPT by directly lowering ionized calcium. Upon revision, it has been shown that in patients with a moderate degree of CRF, phosphate restriction suppresses PTH secretion by increasing serum calcitriol through a direct effect on the kidney." However, studies in patients and dogs with advanced renal insufficiency have demonstrated that phosphate per se, independent of the levels of calcitriol or ionized calcium, can stimulate the secretion of PTH.20 Phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol and by a post-transcriptional mechanism increases PTH synthesis and secretion.P On the other hand, intracellular phosphate retention, which may develop as renal insufficiency ensues, may interfere with the action and production of calcitriol," adding the effect of phosphate retention to that of diminished calcitriol production. RESISTANCE OF BONE TO PARATHYROID HORMONE EFFECT
PTH exerts one of its main actions by inducing bone remodeling and liberating calcium to the extracellular compartment. The osteoblast has PTH receptors and binding of PTH activates osteoclasts, probably in concert with calcitriol. In the presence of an increased concentration of PTH, infusion of PTH did not cause as much increase in serum calcium. 4o-42 The mechanisms responsible for this blunted calcemic response include (1) low levels of calcitriol,43.44 which prevent activation of osteoclasts; (2) phosphate retention," either through a direct effect or by diminishing calcitriol production; and (3) downregulation of PTH bone receptors by high levels ofPTH.45 The latter is increasingly recognized
504 - - Parathyroid Gland to play a major role in the decreased response to PTH in renal failure." The progressive bone resistance to the calcemic effect of PTH sets up an endless loop of increased need for PTH to maintain serum calcium levels, causing parathyroid hyperplasia and resulting in a progressively demineralized bone matrix.
transplant recipients may continue to have persistent HPT and hypercalcemia. 12 The following are some of the factors that may prevent the involution of the hyperplastic parathyroid gland even after the primary stimulus (i.e., kidney failure) has been removed.
PARATHYROID HORMONE SET-POINT CHANGES
Renal function rarely returns completely to normal" and it is possible that the mild degree of renal insufficiency slows or prevents the involution of parathyroid glands. In some series, an inverse correlation between serum PTH levels and creatinine clearance suggests that impaired renal function is responsible for post-transplantation SHPT.55.56
The PTH set-point is defined as the serum calcium concentration that decreases the maximal PTH level by 50%.46 In early CRF, there is a shift in the PTH set-point rendering the parathyroid relatively insensitive to the suppressive effects of calcium.P''? In advanced CRF and in patients having maintenance hemodialysis, changes in the set-point appear to be dependent on the particular form of their bone disease and calcitriol status.'? Changes in the set-point may be a function of changes in the parathyroid cell calcium receptor" mediated by low levels of calcitriol.20 Specifically, it has been suggested that a calcium-sensing receptor gene polymorphism (codon G990R) influences the responsiveness of the parathyroid gland to changes of extracellular ionic calcium in uremic patients. The glands of patients with the GG genotype of the calcium-sensing receptor gene may be more sensitive to extracellular ionic calcium changes." The vitamin D parathyroid receptors are also diminished. The parathyroid cell becomes more resistant to the suppressive effects of calcium and of calcitriol, and therefore excessive PTH is secreted at a given serum calcium concentration.
IMPAIRED GRAFT FUNCTION
PARATHYROID AUTONOMY
Initially, some authors have postulated autonomous parathyroid activity, when PTH production could no longer be regulated by serum calcium (or the set-point was altered so that hypercalcemia was considered "normal" by the parathyroid glands). NONSUPPRESSIBLE PARATHYROID HORMONE SECRETION
Kidney transplantation is the best treatment for SHPT.48 The hyperfunction of the parathyroid glands, however, may continue or even become apparent after kidney transplantation.
The recognition that the PTH secretion could not be totally suppressed by calcium infusion in these patients led to the concept of nonsuppressible PTH secretion. In this theory, the parathyroid cells are not autonomous but instead diminish their PTH production to a minimum after transplantation. The increased PTH level is then the result of an increased number of parathyroid cells, each secreting a minimum amount of PTH that cannot be suppressed even when the serum calcium level is elevated." This nonsuppres sible PTH secretion then also increases calcitriol production by the transplanted kidney, leading to hypercalcemia.57
PREVALENCE
SLOWINVOLUTION OF PARATHYROID GLANDS
The prevalence of persistent SHPT after kidney transplantation has been reported to be 8% to 50%,49-52 depending on when hypercalcemia is assessed and how SHPT is treated before and after kidney transplantation. Absence of hypercalcemia does not mean normal parathyroid function. Elevated intact PTH and abnormal bone biopsy persist in 50% to 70% of recipients with a longterm graft.50,53 Hypercalcemia of more than 1 year is found in one third of the transplant recipients. The hypercalcemia resolves in 50% of the patients in the first month after kidney transplantation, 85% on the first 6 months, and 95% after 6 months. The hypercalcemia is not dependent on age, postoperative medication, preoperative serum calcium, or alkaline phosphatase levels/" Hypercalcemia after transplantation is due to the continuous hyperfunction of hyperplastic parathyroid glands. In patients with a well-functioning kidney transplant, factors such as calcitriol deficiency, hyperphosphatemia, and skeletal resistance of PTH action are no longer present. Although the prevalence of hypercalcemia in patients after kidney transplantation has decreased because of better control of SHPT before transplantation, some renal
The nonsuppressible PTH secretion theory depends on an increased parathyroid mass that involutes slowly. In a detailed review, Parfitt" outlined possible reasons for this slow involution, including the low rate of parathyroid cell turnover inherent in the parathyroid gland, the inefficiency of cell deletion mechanisms, and the slow rate at which parathyroid glands become smaller in response to hypercalcemia.
After Kidney Transplantation
INSUFFICIENT CALCITRIOL SECRETION
Vitamin D metabolism is usually normal within I week after transplantation, irrespective of the onset of diuresis or the dose of cyclosporine A,52 However, vitamin D metabolism may remain impaired in 20% of kidney transplant recipients/" perpetuating after kidney transplantation the most important pathogenic factor of SPTH. PARATHYROID HORMONE SET-POINT
There is insufficient information about the PTH set-point in patients after transplantation with or without hypercalcemia, but it is likely that a PTH set-point is restored slowly after transplantation. Many patients are found to have high intact PTH for calcium levels after kidney transplantation.
Metabolic Complications of Secondary Hyperparathyroidism - -
Clinical Manifestations of Secondary Hyperparathyroidism Replacement of the kidney's excretory function by dialysis has prolonged life, but it has also revealed the extent and importance of its endocrine functions." Patients with CRF have considerable morbidity and mortality. Classic clinical manifestations of SHPT come from bones (pain, deformities, fractures), from metastatic calcifications, and from skin (pruritus, calciphylaxis). Patients with CRF also suffer from a wide range of organ dysfunctions that were attributed to a "uremic toxin." As we begin to understand the physiopathology of CRF, we recognize that many organ derangements are the consequences of the effects of high PTH levels on cellular metabolism.
Bone Disease Musculoskeletal problems remain among the main limitations of the quality of life of patients with renal failure, in particular those treated with long-term maintenance dialysis. The mechanical problems caused by uremic bone disease include fractures of long bones, crush vertebral fractures, and rib fractures. Bone pain is a common manifestation, insidious in appearance and more frequent in the lower back, hips, and legs. In children, growth retardation is common and may be worsened by other factors such as chronic acidosis, malnutrition, and low levels of somatomedin.w" Skeletal deformities are common in uremic children because of the intense remodeling. In adults, deformities arise mainly from vertebral fractures producing kyphosis and lumbar scoliosis. TYPES OF BONE DISEASE
Histologic skeletal abnormalities develop early in patients with chronic renal disease. Bone resorption, the most common abnormality, occurs in several locations (subperiosteal, subchondral, trabecular, endosteal, and subligamentous), whereas brown tumors and periosteal reaction are less common. Osteosclerosis primarily affects the axial skeleton, and associated osteoporosis and osteomalacia cause generalized osteopenia. Bone biopsies reveal increased PTH activity on bone in half of the patients whose glomerular filtration rate has fallen to 50% of normal or less. In the early stages, mild hyperparathyroid bone disease is seen. When the glomerular filtration rate falls to between 20 and 40 mL/min, bone biopsies show a mineralization defect." Youth, female gender, tubulointerstitial types of nephropathy, and a long duration of uremia appear to be independent risk factors for the development of bone disease." Bone disorders in renal failure have a wide spectrum of histologic types, including the classic osteitis fibrosa, osteomalacia, a mixed form (with features of both osteitis fibrosa and osteomalacia), aluminum osteodystrophy, and adynamic bone disease. The form and severity of the bone disease depend on the gender and age of the patient; the severity and duration of the CRF; the metabolic acidosis; the characteristics of the dialysis; the calcitriol and PTH levels; the dietary calcium, phosphate, and aluminum load; additional medications (specially steroids); and the associated endocrine
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diseases (frequently diabetes mellitus). In addition, parathyroidectomy and renal transplantation can suddenly modify the precarious adaptation of the long-deranged mineral metabolism. In addition to the defects in bone formation and mineralization, patients receiving long-term hemodialysis may have bone deposits of ~2-microglobulin, which per se cause bone disease and increase the risk of fractures.f High-Turnover Hyperparathyroid Bone Disease. Osteitis fibrosa cystica (although no inflammatory process was ever identified) is the result of long-standing hyperparathyroidism. Seen in 5% to 30% of dialyzed patients, it rarely arises before initiation of dialysis.v' It is characterized by an increase in the osteoblast surface, an increased number of osteoclasts and osteoblasts, and accelerated bone resorption and bone formation. Woven osteoid is increased, with a random arrangement of collagen instead of the normal lamellar pattern and deposition of amorphous calcium phosphate instead of hydroxyapatite.f In advanced cases, collagen deposition produces fibrosis and cysts (hence fibrosa cystica) replacing the bone marrow. The resulting structure, even with an increased bone mass, consists mainly of frail woven bone prone to fractures. Low-TurnoverBoneDisease. The other end of the spectrum is associated with a relative PTH deficiency, a decrease in the osteoblast surface, and paucity of bone cells, with a profound decrease in the number of active remodeling sites. Aluminum overload contributes significantly to low-turnover bone disease, and it occurs in 30% to 85% of these patients.v' Patients with low-turnover bone disease tend to become hypercalcemic, have aging of bone caused by stunted bone remodeling and microfractures, and are at higher risk for fractures.P The term low-turnover aluminum-associated bone disease (LTAABD) has been used to describe this histologic lesion.P Other factors that reduce bone turnover, such as parathyroidectomy, diabetes." and medication, can account for a significant proportion of low-turnover bone disease. Patients with high-turnover hyperparathyroid bone disease and LTAABD present with similar clinical and laboratory features; therefore, differentiating these two bone abnormalities is often difficult. An erroneous diagnosis of osteitis fibrosa cystica may lead to parathyroidectomy that exacerbates aluminum deposition and low-turnover bone disease." Within this group, two subgroups can be identified. When reduced mineralization is coupled with a parallel decrease in bone formation, the end result is "adynamic uremic bone disease." When reduced mineralization precedes or is more pronounced than the decreased collagen deposition, "lowturnover osteomalacia" is the consequence. 12 The use of peritoneal dialysis with a supraphysiologic level of calcium in the dialysate, use of calcium-based phosphate binders, and diabetes appear to be independent pathogenic factors for the development of adynamic uremic bone disease." Most patients with uremic bone disease, however, have a mixed form (mixed uremic osteodystrophy) with or without aluminum deposition. DIAGNOSIS OF UREMIC OSTEODYSTROPHY
No serum biochemical or other noninvasive test can diagnose unequivocally renal osteodystrophy or can distinguish different forms of the disorder with reasonable sensitivity
506 - - Parathyroid Gland and specificity. Bone biopsies remain the surest and most rational approach." Hypercalcemia, for example, may be present in patients with either low-turnover osteomalacia or hyperparathyroid bone disease. Although the desferrioxamine test was once advocated for the diagnosis of aluminum overload/'? it has proved useful in only a small fraction of those who have low serum PTH levels and gives false-negative results in many patients.l? Also, the radiographic findings are not specific and the radiographic signs of oxalosis can mimic those of hyperparathyroid bone disease." Positron emission tomography (PET) scanning of bone using fluoride has been advocated to differentiate low-turnover from highturnover renal osteodystrophy and to provide quantitative estimates of bone cell activity that correlate with histomorphometric data. 10
Extraskeletal Calcification There are three kinds of extraskeletal calcification: visceral, periarticular, and vascular. Visceral calcifications may involve the lungs (causing restrictive lung disease), myocardium.TP mitral valve," kidneys, skeletal muscle, breast." and stomach. Penile calcification may produce impotence, and its prevalence is probably underestimated.P Patients with visceral calcifications have hyperphosphatemia, an elevated calcium-phosphorus product, and high levels of PTH.43 Periarticular calcification produces calcific periarthritis and small-joint effusions, and radiography usually shows the calcification around the joint. Vascular calcification, in both large and small vessels, occurs in 20% of patients with endstage CRF76 and may cause falsely elevated blood pressure readings.f Calcium deposits on the conjunctiva can cause a red eye syndrome. Parathyroidectomy rarely affects vascular calcification but usually diminishes nonvascular calcium deposits."
Pruritus Pruritus affects up to 85% of patients receiving hemodialysis, and it may be a major and distressing symptom. Although dramatic improvement of pruritus has been repeatedly observed after parathyroidectomy.P''" PTH does not seem to be directly involved in its patbogenesis.v-f Serum phosphate, calcium, and magnesium and especially their ionic products may cause pruritus or are markers of an as yet unknown prurogen.v-"
Calciphylaxis Calciphylaxis, an uncommon syndrome of disseminated calcification, is a severe complication of SHPT. It results in soft tissue calcification and vascular medial calcinosis leading to ischemic tissue necrosis. Patients present with painful, violaceous, mottled lesions that progress to skin and subcutaneous tissue necrosis, nonhealing ulcers, and gangrene. Lesions are characteristically located in the hands and fingers, lower extremities, and sometimes lower abdomen. Gangrene of fingers and toes frequently requires amputation, produces nonhealing wounds, and can lead to sepsis and death." Patients usually have a high Ca-P product but not necessarily extremely high PTH levels. It has been
described after kidney transplantation and also after recurrent SHPT.62 The prognosis for patients with calciphylaxis is dismal, with mortality approaching 50%. When signs and symptoms of calciphylaxis are recognized, the patient should be treated with phosphate binders and timely parathyroidectomy'v" A mathematical expression involving the Ca-P product and the alkaline phosphatase and PTH levels has been developed to help identify high-risk patients.t"
Anemia Normochromic, normocytic anemia is a prominent complication of CRF. In addition to decreased erythropoietin production, iron deficiency, systemic infections, aluminum toxicity, and increased hemolysis are contributing factors in some patients. Increased PTH levels may cause anemia by inhibition of erythropoiesis." shortening red blood cell survival, and inducing bone marrow fibrosis." Parathyroidectomy improves the hematocrit in many patients with SHPT.89-91 Recombinant human erythropoietin is used to treat anemia in CRF patients. The dose of erythropoietin required to achieve an adequate hematocrit response may depend on the severity of SHPT and the extent of bone marrow fibrosis.f? Hypertension is its most serious side effect.
Insulin Resistance Treatment of SHPT by correcting phosphate retention improves glucose intolerance with increased insulin secretion." Diabetic patients with CRF have lower serum calcium and intact PTH levels than nondiabetic patients. Osteitis fibrosa is noted radiologically in a third of nondiabetic patients but in none of the diabetic patients. Because of the lower PTH level, low-turnover bone disease is a special problem for the diabetic patient receiving dialysis." Insulin secretion may be impaired in CRF related to SHPT.95 The impaired insulin secretion in association with peripheral resistance to the action of insulin causes glucose intolerance in CRF. The impaired insulin secretion induced by excess PTH may be related to the effect of PTH on the pancreatic islets to increase intracellular calcium. A calcium channel blocker prevents calcium accumulation in the islet cells, antagonizes the effect of PTH, reverses the abnormalities in insulin release, and normalizes glucose tolerance in animals with CRF.96 Calcitriol modulates secretion of insulin by the beta cell. The regulation of insulin secretion in uremia is affected directly by the low calcitriollevel and indirectly by the low PTH level, both independently of serum calcium."?
Hypertension Arterial hypertension is a cause and also a consequence of CRF. Cytosolic calcium metabolism is altered in the saltdependent type of essential hypertension and also in CRF patients. Patients with CRF and overt SHPT have more severe hypertension'" and a higher intracellular calcium content?' than uremic patients without bone resorption and SHPT. Parathyroidectomy lowers blood pressure in a significant proportion of patients with SHPT.l00 Calcitriol causes
Metabolic Complications of Secondary Hyperparathyroidism - - 507
hypertension,'?' whereas PTH is a vasodilator and calcium has a hypotensive effect. An identified parathyroid hypertensive factor,102,103 a 3000-d protein-lipophospholipid.Pv'P' may be the cause of hypertension in genetically hypertensive rats, 106 salt-sensitive low-renin essential hypertension in humans, 107 and hypertension associated with primary hyperparathyroidism. 107.108 This parathyroid hypertensive factor is secreted by the parathyroid gland!'? and its secretion is inhibited by calcium. 110 The role of parathyroid hypertensive factor in SHPT, however, has not been studied.
Hyperlipemia Hyperlipidemia is common in CRF, but the underlying mechanisms are not clearly defined. Experimental and clinical data have shown that SHPT may be the cause of hypertriglyceridemia. Excess PTH reduces postheparin lipoprotein lipase activity in plasma, impairing lipid removal from the circulation.I? There is a significant positive correlation between serum levels of alkaline phosphatase and triglycerides in patients with SHPT. Serum triglycerides may become normal after parathyroidectomy in some patients with hypertriglyceridemia.'!' Both hyperlipemia and hyperphosphatemia promote atherosclerosis and may explain the high prevalence of coronary heart disease in CRF patients.U?
Impaired Phagocytosis Polymorphonuclear leukocytes in patients with CRF have elevated basal levels of cytosolic calcium, reduced ATP content, and impaired phagocytosis. Excess PTH seems to cause these abnormalities and may be prevented by either reducing the levels of PTH or blocking its action with verapamil. 113
Clinical Manifestations of Secondary Hyperparathyroidism after Kidney Transplantation Although post-transplantation SHPT most often follows an asymptomatic course, it can cause significant morbidity and give rise to serious complications.F' Symptoms resemble those of primary hyperparathyroidism such as increased bone resorption, nephrolithiasis, and pancreatitis. Increased bone resorption may persist'!" and osteopenia may be present for as long as 96 months after transplantation because of preexisting osteodystrophy, SHPT, and steroids given to control graft rejection.57. I 15 Steroid-induced osteopenia is more intense in the spine than in cortical bone.P Avascular necrosis of the hip joint, highly prevalent among transplant recipients, correlates more with steroid therapy than with the degree of SHPT. Nephrolithiasis occurs in 5% to 10% of transplanted kidneys and may appear years after transplantation. It may arise as an asymptomatic radiologic finding, as painless hematuria because the grafted kidney is denervated, or as painless ureteral obstruction causing oliguria and hydronephrosis.V!" Although it can be precipitated by other factors, SHPT is the main cause of nephrolithiasis in transplanted kidneys. Hypercalciuria, common in hypercalcemic transplant recipients, also predisposes to stone formation.P
Pancreatitis occurs in 2% to 6% of kidney transplant recipients. Among those with hypercalcemia, acute pancreatitis has a prevalence of 11%.117 Hypercalcemia is a more important cause of acute pancreatitis than immunosuppressive therapy, gallstones, alcoholism, or steroids in these
patients.V!"
Summary SHPT after chronic kidney disease can lead to clinically significant bone disease. Additional consequences include soft tissue and vascular calcification, cardiovascular disease, and arteriole calcification, and it may contribute to the increased risk of cardiovascular morbidity and mortality among uremic patients. The pathogenesis of SHPT comprises decreased 1,25-(OHhD3 levels, hyperphosphatemia, altered PTH metabolism, skeletal resistance to PTH, and possibly gene-mediated changes in the sensitivity of the parathyroid cell to the effects of calcium and calcitriol. The treatment of CRF and its complications may also contribute to the pathogenesis of SHPT. After kidney transplantation, impaired graft function, some level of parathyroid autonomy, nonsuppressible PTH secretion, and a slow involution of parathyroid glands may cause persistent parathyroid overgrowth.
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43. Salusky I, Coburn 1. The renal osteodystrophies. In: DeGroot LJ (ed), Endocrinology, 2nd ed. Philadelphia, WB Saunders, 1989, p 1032. 44. Rodriguez M, Felsenfeld AI, Llach F. Calcemic response to parathyroid hormone in renal failure: Role of calcitriol and the effect of parathyroidectomy. Kidney Int 1991;40:1063. 45. Rosenblatt M, Kronenberg H, Potts 1. Parathyroid hormone. Physiology, chemistry, biosynthesis, secretion, metabolism, and mode of action. In: DeGroot LJ (ed), Endocrinology, 2nd ed. Philadelphia, WB Saunders, 1989, p 848. 46. Felsenfeld AI, Rodriguez M, Dunlay R, Llach F. A comparison of parathyroid-gland function in haemodialysis patients with different forms of renal osteodystrophy. Nephrol Dial Transplant 1991;6:244. 47. Yokoyama K, Shigematsu T, Tsukada T, et al. Calcium-sensing receptor gene polymorphism affects the parathyroid response to moderate hypercalcemic suppression in patients with end-stage renal disease. Clin NephroI2002;57:131. 48. Alfrey AC, lenkins D, Groth CG, et al. Resolution of hyperparathyroidism, renal osteodystrophy and metastatic calcification after renal homotransplantation. N Engl 1 Med 1968;279:1349. 49. Lins LE. Renal function in hypercalcemia after renal transplantation. Scand 1 Urol Nephrol SuppI1977;(42):159. 50. Sitges-Serra A, Esteller E, Ricart Ml, Caralps A. Indications and late results of subtotal parathyroidectomy for hyperparathyroidism after renal transplantation. World 1 Surg 1984;8:534. 51. Pletka PG, Strom TB, Hampers CL, et al. Secondary hyperparathyroidism in human kidney transplant recipients. Nephron 1976;17:371. 52. Saha HH, Salmela KT, Ahonen PI, et al. Sequential changes in vitamin D and calcium metabolism after successful renal transplantation. Scand 1 Urol NephroI1994;28:21. 53. Straffen AM, Carmichael Dl, Fairney A, et al. Calcium metabolism following renal transplantation. Ann Clin Biochem 1994;31:125. 54. David DS, Sakai S, Brennan BL, et al. Hypercalcemia after renal transplantation. Long-term follow-up data. N Engl 1 Med 1973;289:398. 55. Christensen MS, Nielsen HE. The clinical significance of hyperparathyroidism after renal transplantation. Scand 1 Urol Nephrol Suppl 1977;(42):130. 56. Garvin PI, Castaneda M, Linderer R, Dickhans M. Management of hypercalcemic hyperparathyroidism after renal transplantation. Arch Surg 1985;120:578. 57. Sitges-Serra A, Caralps-Riera A. Hyperparathyroidism associated with renal disease. Pathogenesis, natural history, and surgical treatment. Surg Clin North Am 1987;67:359. 58. Parfitt AM. Hypercalcemic hyperparathyroidism following renal transplantation: Differential diagnosis, management, and implications for cell population control in the parathyroid gland. Miner Electrolyte Metab 1982;8:92. 59. Malluche HH, Faugere Me. Renal osteodystrophy. N Engl 1 Med 1989;321:317. 60. Salusky IB, Goodman WG. Renal osteodystrophy in dialyzed children. Miner Electrolyte Metab 1991;17:273. 61. Cundy T, Hand Dl, Oliver DO, et al. Who gets renal bone disease before beginning dialysis? Br Med 1 (Clin Res Ed) 1985;290:271. 62. Onishi S, Andress DL, Maloney NA, et al. Beta 2-microglobulin deposition in bone in chronic renal failure. Kidney Int 1991;39:990. 63. Malluche H, Faugere MC. Renal bone disease 1990: An unmet challenge for the nephrologist. Kidney Int 1990;38:193. 64. Chazan lA, Libbey NP, London MR, et al. The clinical spectrum of renal osteodystrophy in 57 chronic hemodialysis patients: A correlation between biochemical parameters and bone pathology findings. Clin Nephrol 1991;35:78. 65. Malluche HH, Monier-Faugere Me. Risk of adynamic bone disease in dialyzed patients. Kidney Int Suppl 1992;38:S62. 66. Pei Y, Hercz G, Greenwood C, et al. Renal osteodystrophy in diabetic patients. Kidney Int 1993;44:159. 67. Sherrard Dl. The role of aluminum in renal osteodystrophy. Mayo Clin Proc 1993;68:510. 68. Hercz G, Pei Y, Greenwood C, et al. Aplastic osteodystrophy without aluminum: The role of "suppressed" parathyroid function. Kidney Int 1993;44:860. 69. Milliner DS, Nebeker HG, Ott SM, et al. Use of the deferoxamine infusion test in the diagnosis of aluminum-related osteodystrophy. Ann Intern Med 1984;101:775. 70. lulian BA, Faugere MC, Malluche RH. Oxalosis in bone causing a radiographical mimicry of renal osteodystrophy. Am J Kidney Dis 1987;9:436.
Metabolic Complications of Secondary Hyperparathyroidism - - 509 71. Mako J, Lengyel M, Szucs J. Intracardiac calcification in patients under chronic haemodialysis. Int Urol Nephrol 1987;19:441. 72. Rostand SG, Sanders PC, Rutsky EA. Cardiac calcification in uremia. Contrib NephroI1994;106:26. 73. Forman MB, Virmani R, Robertson RM, Stone WJ. Mitral anular calcification in chronic renal failure. Chest 1984;85:367. 74. Sommer G, Kopsa H, Zazgornik J, Salomonowitz E. Breast calcifications in renal hyperparathyroidism. AJR Am J Roentgenol 1987;148:855. 75. Dalal S, Gandhi VC, Yu AW, et al. Penile calcification in maintenance hemodialysis patients. Urology 1992;40:422. 76. Cassidy MJ, Owen JP, Ellis HA, et al. Renal osteodystrophy and metastatic calcification in long-term continuous ambulatory peritoneal dialysis. Q J Med 1985;54:29. 77. De Francisco AM, Cassidy MJ, Owen JP, et al. Ectopic calcification. The role of parathyroid hormone. Proc Eur Dial Transplant Assoc Eur RenAssoc 1985;21:888. 78. Massry SG, Popovtzer MM, Coburn JW, et al. Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia. Disappearance of itching after subtotal parathyroidectomy. N Engl J Med 1968;279:697. 79. Albertucci M, Zielinski CM, Rothberg M, et al. Surgical treatment of the parathyroid gland in patients with end-stage renal disease. Surg GynecolObstet 1988;167:49. 80. Demeure MJ, McGee DC, Wilkes W, et al. Results of surgical treatment for hyperparathyroidism associated with renal disease. Am J Surg 1990;160:337. 81. Carmichael AJ, McHugh MM, Martin AM, Farrow M. Serological markers of renal itch in patients receiving long term haemodialysis, Br Med J (Clin Res Ed) 1988;296:1575. 82. Stahle-Backdahl M, Hagermark 0, Lins LE, et al. Experimental and immunohistochemical studies on the possible role of parathyroid hormone in uraemic pruritus. J Intern Med 1989;225:411. 83. Chou FF, Ho JC, Huang SC, Sheen-Chen SM. A study on pruritus after parathyroidectomy for secondary hyperparathyroidism. J Am Coli Surg 2000;190:65. 84. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary hyperparathyroidism. Diagnosis and parathyroidectomy. Arch Surg 1991;126:1213; discussion, 1218. 85. Roe SM, Graham LD, Brock WB, Barker DE. Calciphylaxis: Early recognition and management. Am Surg 1994;60:81. 86. Levin A, Mehta RL, Goldstein MB. Mathematical formulation to help identify the patient at risk of ischemic tissue necrosis-A potentially lethal complication of chronic renal failure. Am J Nephrol 1993; 13:448. 87. McGonigle RJ, Wallin JD, Husserl F, et al. Potential role of parathyroid hormone as an inhibitor of erythropoiesis in the anemia of renal failure. J Lab Clin Med 1984;104:1016. 88. Massry SG. Pathogenesis of the anemia of uremia: Role of secondary hyperparathyroidism. Kidney Int SuppI1983;16:S204. 89. Grutzmacher P, Radtke HW, Fassbinder W, et aI. Effect of secondary hyperparathyroidism on the anaemia of end-stage renal failure: In vivo and in vitro studies. Proc Eur Dial Transplant Assoc 1983; 20:739. 90. Urena P, Eckardt KU, Sarfati E, et al. Serum erythropoietin and erythropoiesis in primary and secondary hyperparathyroidism: Effect of parathyroidectomy. Nephron 1991;59:384. 91. Zingraff J, Drueke T, Marie P, et al. Anemia and secondary hyperparathyroidism. Arch Intern Med 1978; 138: 1650. 92. Rao DS, Shih MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993;328:171. 93. Mak RH, Turner C, Haycock GB, Chantler C. Secondary hyperparathyroidism and glucose intolerance in children with uremia. Kidney Int SuppI1983;16:S128. 94. Vincenti F, Arnaud SB, Recker R, et al. Parathyroid and bone response of the diabetic patient to uremia. Kidney Int 1984;25:677.
95. Fadda GZ, Akmal M, Premdas FH, et al. Insulin release from pancreatic islets: Effects ofCRF and excess PTH. Kidney Int 1988;33:1066. 96. Fadda GZ, Akmal M, Soliman AR, et al. Correction of glucose intolerance and the impaired insulin release of chronic renal failure by verapamil. Kidney Int 1989;36:773. 97. Quesada JM, Martin-Malo A, Santiago J, et aI. Effect of calcitriol on insulin secretion in uraemia. Nephrol Dial Transplant 1990;5:1013. 98. London GM, De Vernejoul MC, Fabiani F, et al. Secondary hyperparathyroidism and cardiac hypertrophy in hemodialysis patients. Kidney Int 1987;32:900. 99. Raine AE, Bedford L, Simpson AW, et al. Hyperparathyroidism, platelet intracellular free calcium and hypertension in chronic renal failure. Kidney Int 1993;43:700. 100. Pizzarelli F, Fabrizi F, Postorino M, et al. Parathyroidectomy and blood pressure in hemodialysis patients. Nephron 1993;63:384. 101. Bukoski RD, Kremer D. Calcium-regulating hormones in hypertension: Vascular actions. Am J Clin Nutr 1991 ;54:220S. 102. Pang PK, Lewanczuk RZ. Parathyroid origin of a new circulating hypertensive factor in spontaneously hypertensive rats. Am J Hypertens 1989;2:898. 103. Pang PK, Lewanczuk RZ, Benishin CG. Parathyroid hypertensive factor. J Hypertens Suppl 1990;8:S155. 104. Benishin CG, Lewanczuk RZ, Pang PK. Purification of parathyroid hypertensive factor from plasma of spontaneously hypertensive rats. Proc Nat! Acad Sci USA 1991;88:6372. 105. Benishin CG, Lewanczuk RZ, Shan J, Pang PK. Purification and structural characterization of parathyroid hypertensive factor. J Cardiovasc Pharmacol 1994;23(Suppl 2):S9. 106. Pang PK, Benishin CG, Lewanczuk RZ. Parathyroid hypertensive factor, a circulating factor in animal and human hypertension. Am J Hypertens 1991;4:472. 107. Lewanczuk RZ, Benishin CG, Shan J, Pang PK. Clinical aspects of parathyroid hypertensive factor. J Cardiovasc Pharmacol 1994; 23(Suppl 2):S23. 108. Lewanczuk RZ, Pang PK. Expression of parathyroid hypertensive factor in hypertensive primary hyperparathyroid patients. Blood Press 1993;2:22. 109. Pang PK, Benishin CG, Shan J, Lewanczuk RZ. PHF: The new parathyroid hypertensive factor. Blood Press 1994;3: 148. 110. Lin CM, Saito K, Tsujino T, Yokoyama M. Calcium supplementation inhibits the expression of parathyroid hypertensive factor in DOCAsalt hypertensive rats. Am J Hypertens 1994;7:201. III. Nishizawa Y, Miki T, Okui Y, et al. Deranged metabolism of lipids in patients with chronic renal failure: Possible role of secondary hyperparathyroidism. Jpn J Med 1986;25:40. 112. Ritz E, Deppisch R, Stier E, Hansch G. Atherogenesis and cardiac death: Are they related to dialysis procedure and biocompatibility? Nephrol Dial Transplant I994;9(Suppl 2):165. 113. Chervu I, Kiersztejn M, Alexiewicz JM, et al. Impaired phagocytosis in chronic renal failure is mediated by secondary hyperparathyroidism. Kidney IntI992;41:1501. 114. Pietschmann P, Vychytil A, Woloszczuk W, Kovarik J. Bone metabolism in patients with functioning kidney grafts: Increased serum levels of osteocalcin and parathyroid hormone despite normalisation of kidney function. Nephron 1991;59:533. 115. Almond MK, Kwan JT, Evans K, Cunningham 1. Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 1994;66:52. 116. Guest G, Tete MI, Beurton D, Broyer M. [Urinary lithiasis after kidney transplantation. Experience at a pediatric center.] Arch Fr Pediatr 1993;50: 15. 117. Frick TW, Fryd DS, Sutherland DE, et al. Hypercalcemia associated with pancreatitis and hyperamylasemia in renal transplant recipients. Data from the Minnesota randomized trial of cyc1osporine versus antilymphoblast azathioprine. Am J Surg 1987;154:487. 118. Sitges-Serra A, Alonso M, de Lecea C, et al. Pancreatitis and hyperparathyroidism. Br J Surg 1988;75: 158.
Surgical Approach to Secondary Hyperparathyroidism Juan J. Sancho, MD, PhD • Antonio Sitges-Serra, MD, PhD
Indications for Surgery Pretransplantation Parathyroidectomy (PIX) is indicated when medical treatment fails to control progressive secondary renal hyperparathyroidism (SHPT) (Table 57_1).1-3 Clinical manifestations include persistence or worsening of skeletal symptoms, pruritus, and extraskeletal calcifications." Because high parathormone (PTH) levels may worsen many disorders associated with chronic renal failure (CRF), other potential indications include hypertension, anemia, deranged myocardial function, and peripheral neuropathy.' High intact PTH (iPTH) (1-84) levels and a proven highturnover bone disease are prerequisites for considering a CRF patient with SHPT for surgery>" Calciphylaxis is an absolute indication for immediate PTX.5.9
Post-Transplantation PTX is indicated in some patients after kidney transplantation because of clinical manifestations similar to those of primary hyperparathyroidism: hypercalcemia plus nephrolithiasis, acute pancreatitis, changes in mental status (lethargy, irritability, confusion), or overt bone disease.'? Mild hypercalcemia alone does not appear to be a serious threat to the patient with a transplanted kidney, but impaired renal function in the presence of high PTH and hypercalcemia should be an indication for PTX, 11.12 as is the association of kidney stones and long-standing hypercalcemia.13,14 Whether asymptomatic hypercalcemia alone is an indication for PTX in renal transplant recipients is controversial. Post-transplantation hypercalcemia can arise with four different patterns: (1) subacute severe hypercalcemia, (2) transient hypercalcemia, (3) persistent hypercalcemia, and (4) hypercalcemia appearing after a period of normocalcemia.v'> The indications for surgery are summarized in Table 57-2.
510
SUBACUTE SEVERE HYPERCALCEMIA
Now an exceptional occurrence, severe hypercalcemia (serum calcium greater than 13 mg/dL) usually arises shortly after renal transplantation. It requires prompt PTX, especially if it threatens graft function. J 5-18 TRANSIENT HYPERCALCEMIA
Hypercalcemia after kidney transplantation resolves spontaneously in two thirds of the patients; 85% of them become normocalcemic during the first year. lO,17 In addition to overt post-transplantation SHPT, hypercalcemia can be caused by hypophosphatemia.l'' and the latter is exacerbated by the normally functioning kidney and high levels of PTH from a still hyperplastic parathyroid glands.'? Resorption of calcium phosphate salts may explain hypercalcemia and hyperphosphatemia in some patients. 15,16 Moreover, a preexisting vitamin D intoxication can be unmasked by the transplanted kidney. For the aforementioned reasons, the mild hypercalcemia present during the first 6 to 12 months after kidney transplantation is not an indication for surgery. PERSISTENT HYPERCALCEMIA
Whether the state of hypercalcemia is considered permanent depends on the investigators; the criteria range from 6 months to 6 years after transplantation. The old liberal approach of PTX for patients with more than 6 months of hypercalcemia-P has progressively been replaced by a more conservative approach in which the clinical status and the kidney function are closely monitored' and PTX is not even considered for 2 years if the graft is functioning. In any case, the longer the duration of hypercalcemia, the less likely it is to resolve spontaneously. Only 25% of cases of hypercalcemia persisting more than 12 months after transplantation resolve spontaneously." Two groups of patients may be considered for surgery for asymptomatic persistent hypercalcemia: those with
Surgical Approach to Secondary Hyperparathyroidism - -
511
and acute pancreatitis, or graft failure. I? When a previously normocalcemic transplant recipient develops hypercalcemia, graft failure should be ruled out. If graft failure is not the cause of hypercalcemia, PTX should be considered to prevent the development of complications of hyperparathyroidism or graft failure.
Preoperative Care
hypercalcemia that is not likely to resolve spontaneously and those with hypercalcemia lasting more than 2 years. A serum calcium level of 12 mg/dl," and borderline hyperphosphatemia 10 are good predictors of hypercalcemia that will not resolve spontaneously. The tolerable limits of serum calcium in persistent hypercalcemia vary among authors and are between 11.0 and 13.0 mg/dL. 3,1O,15,16,18 Elevated serum alkaline phosphatase levels have also been advocated as an independent predictor of persistent hypercalcemia. 3,1O,15,16,18 A declining alkaline phosphatase level after transplantation may, however, be due to inhibition of osteoblasts by steroids and thus would be an unreliable marker of bone resorption after transplantation." Some authors did not find elevated serum alkaline phosphatase predictive of persistent hypercalcemia.'? There may be a sound set of reasons for withholding PTX in those patients (fear of precipitating an adynamic bone disease or a high surgical risk), but expecting its spontaneous resolution is certainly not one of them." Prophylactic PTX in asymptomatic patients with persistent hypercalcemia may reduce the incidence of subsequent nephrolithiasis, acute pancreatitis, and vascular calcifications that are potentially graft and life threatening. I? RELAPSING HYPERCALCEMIA
Relapsing hypercalcemia is a rare condition. The few cases reported have associated complications, such as nephrolithiasis
Preoperative preparation of dialysis patients includes control of hyperkalemia, hypomagnesemia, and hypervolemia and careful evaluation and treatment of hypertension and cardiovascular disease.P Patients should receive oral calcitriol (1 ug) before surgery to avoid severe postoperative hypocalcemia. Patient should be dialyzed no longer than 1 day before PTX and then again no later than 2 days after the operation. When PTX is performed after kidney transplantation, immunosuppressive medication does not have to be interrupted in the perioperative period. Replacement steroid doses should be administered."
Localization Localization studies of the parathyroid glands are discussed in detail elsewhere in this book. Some issues, however, are unique to SHPT. Because image-based localizing tests depend on gland size and patients with SHPT tend to have large glands, the specificity and positive predictive value of computed tomography (CT) scanning, ultrasonography, and thallium-technetium (Tl-Tc) scintigraphy are much higher for SHPT than for primary hyperplasia." Ultrasonography has found to be useful for screening and follow-up of SHPT.26,2? It has a reported sensitivity of 45% to 70%.28,29 When large glands are not found by ultrasonography in patients with severe SHPT, they are usually situated in the superior mediastinum, behind the trachea or esophagus, or deep within the neck. 29 CT scanning and magnetic resonance imaging should then be the studies of choice.
512 - - Parathyroid Gland Although Tl-Tc scintigraphy also has greater success in finding the parathyroids in patients with SHPT than in those with primary hyperplasia." its sensitivity is only 30% to 55%.25.31,32 CT scanning has a sensitivity of only 50% in SHPT,25.28.31.32 but it is better than ultrasonography in localizing glands in the mediastinum.P Finally, 99mTc sestamibi-P'T subtraction scanning is positive in 88% of cases but has an overall sensitivity of only 67% for the localization of all hyperplasic glands, in relation to the functional status of the glands and not their weight'"; it is sometimes extremely useful in identifying an ectopic or supernumerary gland, or both.P
Surgical Management The critical factor for successful PTX is a highly skilled surgeon experienced in parathyroid surgery. The second most important factor is the localization of all parathyroid tissue," and that is closely linked to the former. All efforts should be made to locate all parathyroid glands, knowing that in 15% of these patients a fifth'" or even a sixth gland may be hidden in an ectopic situation. The patient is placed in a semi seated Kocher position. A standard collar incision is made and meticulous hemostasis is maintained throughout the procedure. Some authors routinely divide the strap muscles to obtain better exposure." but it is usually not necessary. The thyroid gland is widely exposed, the middle thyroid vein is ligated and transected, and the thyroid lobe is retracted medially and the carotid sheath laterally. The recurrent laryngeal nerve is exposed. The search for the parathyroid glands is then started, first in their normal location. The principle of "not removing anything before seeing everything" certainly applies here. All four, or more, parathyroid glands should be exposed and a confirmatory frozen section of each one obtained. Approximately 80% of the superior parathyroid glands are located within a circumscribed area of 1 inch above the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. The glands are frequently secluded in the connective tissue that binds the posterior edge of the thyroid lobe to the larynx. The posterior thyroid capsule should be incised and the superior pole vessels divided if the upper glands are not found. To find the lower glands, the inferior poles of the thyroid should be cleared from fat and all tissue within I inch from the inferior pole of the thyroid dissected free and removed. Approximately 15% of lower glands are found in the thoracic inlet within the thymus. Regardless of the glands found, the thymus is routinely resected to ensure removal of possible supernumerary glands, an ectopic fourth or fifth gland (10% of the cases"), or rudimentary parathyroid tissue. The prethymic fascia extending from the middle cervical fascia is incised to identify the thymus. The thymus is then mobilized upward, using a small gauze swab to gently dissect the surrounding soft tissues from it. Veins draining the thymus into the innominate vein should be carefully ligated to avoid bleeding." When a gland is not found in its orthotopic location or within the thymus, the relatively avascular paraesophageal, paralaryngeal, retroesophageal, and retropharyngeal regions
should be carefully dissected." Next, the carotid sheath should be incised from its emergence from the mediastinum to the bifurcation. Finally, if a gland is still missing, a thyroid lobectomy is considered. Although true intrathyroidal parathyroid glands occur in only 2%, some parathyroid glands are so closely attached to the thyroid capsule that thyroid lobectomy may be required to identify them." Once all the parathyroid glands have been exposed, the subsequent steps depend on the procedure chosen. If subtotal PTX is planned, the smallest parathyroid is selected. The nonvascular pole of the gland is excised, leaving in place a 40- to 60-mg remnant. If there are doubts about the viability of the remnant, the gland is completely excised and the next best gland is selected in tum. All the remaining glands must be left in place until a viable, properly sized, well-colored remnant has been obtained. Only then are the remaining glands resected. We usually try to leave the remnant from a superior gland. The upper glands commonly have good vascular attachments to the thyroid capsule, and blood supply to lower glands may be interrupted during thymectomy. Lower gland remnants can also descend into the mediastinum, making an eventual reoperation more difficult.f The remnant is marked with nonreabsorbable material (ideally a titanium clip and a long silk thread). If only three parathyroid glands are found after exhaustive search, all three are removed. Thirty percent of the patients can be expected to have persistent hyperparathyroidism if this contingency arises.!? If total PTX and autotransplantation are planned, all four glands are resected and the most suitable gland is selected to obtain the autograft." Using glands with nodularity for the graft carries a high risk of graft-dependent recurrence.v" A 40- to 60-mg portion of the gland is sliced into l-mm fragments and 10 to 20 fragments are placed into several separate intramuscular pockets in the nondominant forearm, as far as possible from present and planned arteriovenous fistula location. The muscle pockets are closed with nonreabsorbable material to facilitate localization in case reoperation for recurrence is needed. Although exceptional, parathyromatosis is a potential cause of unexpected recurrence.f Care should be taken, therefore, to avoid breaking the parathyroid gland capsule and spilling parathyroid cells on the operative field. Intraoperative measurement of iPTH 15 or 30 minutes after removing all parathyroid tissue using a quick assay is found to be valuable where available, signaling either the end of the procedure or an overlooked fifth gland. 44.45 Cryopreservation should be routine in case permanent hypoparathyroidism develops. The technique and results obtained with cryopreserved parathyroid tissue are discussed elsewhere in this book.
Type Of Surgical Procedure The two accepted surgical procedures for the management of SHPT are subtotal parathyroidectomy (sPTX) and total PTX with parathyroid autotransplantation (PTX + AT). Total PTX46.47 is still supported by some groups on the basis of lower recurrences, but in these patients the bone does not mineralize in the absence of PTH and the patient must
Surgical Approach to Secondary Hyperparathyroidism - - 513
undergo life-long treatment with vitamin D and oral calcium.' The rationale for choosing a procedure to treat parathyroid hyperplasia and the relative merits and risks of each approach are discussed in detail in a separate chapter.
Subtotal Versus Autotransplantation Trials There are many reports supporting one procedure versus the other, but trials dealing specifically with SHPT are scarce. In a prospective randomized trial, Rothmund and coworkers'" found that PTX + AT was superior to sPTX in a group of 40 patients. During a mean follow-up of nearly 4 years, four patients in the sPTX group developed recurrence. Bone pain was alleviated in a significantly higher proportion of patients with PTX + AT. The other clinical responses were similar in both groups. One criticism of the study is that they left a larger remnant (60 to 80 mg) than the size recommended by other authors (40 to 60 mg). When evaluating this trial, one should keep in mind that the author's team was well known for their previous excellent results in a large series of PTX + AT. 49 There are several reports comparing both techniques'v-' in a retrospective sequential design. They found both techniques to have similar results, but the authors recommended one procedure over the other on the basis of theoretical merits. Proye and coworkers considered the technique less important than the accuracy of indication for operation and the complete
localization of all parathyroid tissue'" because one third to one half of the recurrences arise from an overlooked gland (ectopic or supernumerary, or both) in the neck. Different ways to report results make comparison among the reports of a single technique inappropriate (Table 57-3). In assessing the merit of each technique, one should keep in mind that most authorities find the technique they routinely use and have more experience with to be most appropriate.
Subtotal Parathyroidectomy The success of sPTX depends mainly on the size and viability of the remnant. Remnants that are nodular are more likely to grow and cause recurrent disease. sPTX has the theoretical advantage of inducing less postoperative hypocalcemia because the remnant continues to function. If persistent or recurrent hyperparathyroidism occurs, the gland is in the neck or, exceptionally, in the mediastinum. The main disadvantage is that reoperations are tedious and carry an increased risk of recurrent laryngeal nerve injury. The overall results from large series showed that 10% to 16% had postoperative hypercalcemia, 8% required reoperation because of remnant growth, and 4% to 25 % had hypocalcemia longer than 12 months after operation. Compared with PTX + AT, successful sPTX provided less immediate relief of bone pain but carried less risk of postoperative low-turnover bone disease. ss-s8
514 - - Parathyroid Gland
Total Parathyroidectomy and Autotransplantation AS THE TECHNIQUE OF CHOICE
Success of total PTX and autotransplantation depends mainly on the absence of nodularity of the gland from which the graft is obtained and the number and weight of the fragments implanted. Graft-dependent recurrence is three times higher when implanting a nodular gland instead of a diffusely hyperplastic one.59 Most published series did not consider this as a source of variability and therefore may have had higher recurrence rates than are theoretically possible. The advantage of autotransplantation is that if hyperparathyroidism recurs, the graft can be partially resected under local anesthesia. Nevertheless, reresection may be necessary and sometimes a tumor-like growth develops in the implant, making it difficult to remove. The Casanova test requires total ischemic blockade of the arm bearing the parathyroid graft and measuring PTH levels proximally and distally to the blockade. It is used to assess graft function after PTX + AT or to determine the site of recurrence/" Published series show a 5% to 38% rate of postoperative hypercalcemia, 2% to 6% rate of recurrence requiring graft resection, and 5% to 30% rate of hypocalcemia lasting more than 12 months. 21,49,61-65 AS AN ALTERNATIVE TECHNIQUE
Even surgeons who routinely perform sPTX for SHPT use PTX + AT in some selected cases: when thyroidectomy is necessary because of thyroid disease, when the viability of the remnant is in doubt in sPTX, or when the remnant overgrows and causes recurrence.e'>'
Complications of Parathyroidectomy The mortality after PTX for SHPT is less than 1%.4 Hyperkalemia is the single most preventable cause of death. Infection, cardiac complications not related to hyperkalemia, acute hypocalcemia, pancreatitis, and respiratory complications are other miscellaneous causes of mortality. TRANSIENT HYPOCALCEMIA
Hypocalcemia occurs in 20% to 85% of patients after PTX for SHPT. These patients usually develop the classic symptoms of numbness, paresthesias, and tetany cramps the day after PTX if hypocalcemia is not prevented. The causes of hypocalcemia include increased deposition of calcium in bone ("hungry bone" syndrome), uncoupling of bone formation and resorption." hypoparathyroidism resulting from failure of the parathyroid remnant or autograft, and hypomagnesemia.?" Hypocalcemia is more common in patients with more severe preoperative bone disease and can be anticipated in those with elevated serum levels of alkaline phosphatase." Serum potassium, calcium, phosphate, and magnesium should be carefully monitored. Intravenous calcium gluconate in 10% solution or diluted in 5% dextrose may be needed if the serum calcium falls below 7.5 mg/dL. Once the acute episode is controlled or if the hypocalcemia is mild, oral calcium is given in doses of up to 6 g of elemental calcium per day.24 Phosphate binders should be adjusted to maintain serum phosphate concentration between
3.5 and 5.0 mg/dL. Oral calcitriol (0.5 to 4Ilg/day) should be given in addition to calcium to control hypocalcemia.s? When postoperative hypocalcemia is likely, prophylactic calcium and calcitriol administration can be started before or immediately after surgery. Calcitriol (2 ug) given during dialysis has been used for 5 days before the operation to prevent postoperative hypocalcemia.' Patients receiving peritoneal dialysis can be given intraperitoneal calcium therapy to control hypocalcemia.v Supplementation with elemental magnesium at 1 mEq/kg per day should be started if the serum magnesium concentration drops below 1.5 mg/dL. 24 If not properly treated, hypocalcemia can lead to tetany and convulsions, especially during the later hours of hemodialysis. Hypocalcemic seizures can cause multiple fractures.' PERMANENT HYPOPARATHYROIDISM
The prevalence of permanent hypoparathyroidism varied greatly from 0%48 to 73%2 in early series but is most commonly between 4% and 12%. Parathyroid autotransplants can fail and cause hypocalcemia up to 2 years after surgery.'? It is difficult to assess the exact percentage of hypoparathyroidism because of retrospective analysis and reporting heterogeneity (see Table 57-3). Patients with hypoparathyroidism need vitamin D and calcium supplementation for life. The hypocalcemic symptoms can be exaggerated after a kidney transplantation reversing the acidemia. Hypercalcemia can also occur because of vitamin D intoxication. PERSISTENCE AND RECURRENCE
The prevalence of persistent or recurrent hyperparathyroidism is between 2% and 12%. In one third to one half of the cases, the recurrence is due to an incomplete first operation: less than four glands were found, cervical thymectomy was not performed, or there were supernumerary glands in the neck or mediastinum.P These patients have hypercalcemia, elevated iPTH levels, and persistence or worsening of clinical manifestations. If sPTX was the initial operation, reexploration of the neck and PTX + AT are indicated. If PTX + AT was the initial operation, the Casanova test should be performed. Graft resection or re-exploration of the neck is then indicated, depending on the site of recurrence. In all cases of repeated neck operations, imaging studies should be done to localize the recurrent disease. Reoperations for hyperparathyroidism are treated in detail in another chapter of this book. Some authors suggest that the recurrent tumor can be injected with ethanol under ultrasonographic guidance, but recurrent nerve injury has been reported. 64•69-71
Clinical Course after Successful Parathyroidectomy Clinical Manifestations The overall clinical result is considered good in 70% to 85% of the patients. Bone pain improves in few days in 60% to 80% of patients, joint pain in 85%, and malaise in 75%.4Abdominal pain and irritated eyes are less likely to improve." Muscle weakness is relieved in one third of the patients and radiologic
Surgical Approach to Secondary Hyperparathyroidism - -
signs improve in 95%.48 Itching decreases overnight in almost all patients and disappears in 60% to 80%.4,48 Successful PTX improves nonvisceral calcification in 50% to 60% but does not change arterial calcification despite reduction in the Ca-P product and PTH. Small peripheral arterial calcification may even develop or progress in as many as 56% of the patients after PTX.65
Bone Disease A rapid decrease in serum parathyroid hormone level after PTX appears to suppress bone resorption as well as cause a transient marked increase in bone formation and an increase in normal lamellar osteoid seams." PTX decreases resorption surfaces and osteoclast number as well as bone formation rate." A much debated issue is the development of aluminumrelated osteomalacia after PTX. Some reports showed that PTX did not enhance accumulation of bone aluminum or increase the prevalence of clinical bone disease during dialysis.I" whereas other reports clearly demonstrated aluminum accumulation in bone after PTX.75 If aluminum is available to bone (through ingestion of phosphate binders or through the dialysate) or if there was an aluminum-related bone disease before surgery, it deposits in the low-turnover post-PTX bone. If, however, vitamin D levels are maintained and calcium is available, no low-turnover aluminum-related bone disease should arise. Symptomatic osteomalacia after PTX usually indicates that surgery was unnecessary and that the hypercalcemia was due to aluminum toxicity. The bone mass density of the lumbar spine can be significantly increased with postoperative supplementation with vitamin D and calcium."
Calcium Metabolism Immediately after PTX, serum PTH and calcium concentrations decline abruptly. Serum alkaline phosphatase, usually elevated before surgery, increases in the immediate postoperative period and then declines with time." A strong correlation has been noted between the degree of hypocalcemia after the operation and the level of serum alkaline phosphatase before the operation.?" Circulating levels of calcitriol also decrease after PTX, further contributing to hypocalcemia."
Anemia Anemia improves in CRF patients after PTX.80 PTX increases serum erythropoietin and blood reticulocytes in 50% of the patients. 81,82 Normalizing levels of PTH, extraor intracellular calcium and phosphorus, and increased tissue sensitivity to erythropoietin after PTX could all be responsible." ,83,84
Summary Before kidney transplantation, PTX is indicated when medical treatment fails to control progressive hyperparathyroidism. High PTH levels and high-turnover bone disease
515
are prerequisites for surgically treating this condition. Calciphylaxis is an absolute indication. The main posttransplantation indication is a persistent or symptomatic hypercalcemia. The keys to a successful surgery are to locate all parathyroid glands and leave 40 to 60 mg of viable tissue as a remnant in the neck or as an autotransplant in the forearm. In any case, minute details of the surgical technique influence the outcome. The most frequent postoperative sequel is persistent or recurrent hyperparathyroidism.
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47. Ockert S, Willeke F, Richter A, et al. Total parathyroidectomy without autotransplantation as a standard procedure in the treatment of secondary hyperparathyroidism. Langenbecks Arch Surg 2002;387:204. 48. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: A randomized trial. World J Surg 1991;15:745. 49. Rothmund M, Wagner PK. Total parathyroidectomy and autotransplantation of parathyroid tissue for renal hyperparathyroidism. A one- to six-year follow-up. Ann Surg 1983;197:7. 50. Gasparri G, Camandona M, Abbona GC, et al. Secondary and tertiary hyperparathyroidism: Causes of recurrent disease after 446 parathyroidectomies. Ann Surg 2001;233:65. 51. Takagi H, Tominaga Y, Uchida K, et al. Subtotal versus total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure. Ann Surg 1984;200:18. 52. Welsh CL, Taylor GW, Cattell WR, Baker LR. Parathyroid surgery in chronic renal failure: Subtotal parathyroidectomy or autotransplantation? Br J Surg 1984;71:591. 53. Malmaeus J, Akerstrom G, Johansson H, et al. Parathyroid surgery in chronic renal insufficiency. Subtotal parathyroidectomy versus total parathyroidectomy with autotransplantation to the forearm. Acta Chir Scand 1982;148:229. 54. Proye C, Carnaille B, Sautier M. Hyperparathyroidism in patients with chronic renal failure: Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation? Experience with 121 cases. J Chir (Paris) 1990;127:136. 55. Delmonico FL, Wang CA, Rubin NT, et al. Parathyroid surgery in patients with renal failure. Ann Surg 1984;200:644. 56. Decker PA, Cohen EP, Doffek KM, et al. Subtotal parathyroidectomy in renal failure: Still needed after all these years. World J Surg 2001;25:708. 57. Yu I, DeVita MV, Komisar A. Long-term follow-up after subtotal parathyroidectomy in patients with renal failure. Laryngoscope 1998; 108:1824. 58. Kim HC, Cheigh JS, David DS, et al. Long term results of subtotal parathyroidectomy in patients with end-stage renal disease. Am Surg 1994;60:641. 59. Tominaga Y, Uchida K, Haba T, et al. More than 1,000 cases of total parathyroidectomy with forearm autograft for renal hyperparathyroidism. Am J Kidney Dis 2001;38(4 Suppll):SI68. 60. Casanova D, Sarfati E, De Francisco A, et al. Secondary hyperparathyroidism: Diagnosis of site of recurrence. World J Surg 1991;15:546; discussion 549. 61. Albertucci M, Zielinski CM, Rothberg M, et al. Surgical treatment of the parathyroid gland in patients with end-stage renal disease. Surg Gynecol Obstet 1988;167:49. 62. Benz RL, Schleifer CR, Teehan BP, et al. Successful treatment of postparathyroidectomy hypocalcemia using continuous ambulatory intraperitoneal calcium (CAlC) therapy. Perit Dial Int 1989;9:285. 63. Mozes MF, Soper WD, Jonasson 0, Lang GR. Total parathyroidectomy and autotransplantation in secondary hyperparathyroidism. Arch Surg 1980;115:378. 64. Page B, Zingraff J, Souberbielle JC, et al. Correction of severe secondary hyperparathyroidism in two dialysis patients: Surgical removal versus percutaneous ethanol injection. Am J Kidney Dis 1992;19:378. 65. de Francisco AM, Ellis HA, Owen JP, et al. Parathyroidectomy in chronic renal failure. Q J Med 1985;55:289. 66. Coen G, Mazzaferro S, De Antoni E, et al. Procollagen type I C-terminal extension peptide serum levels following parathyroidectomy in hyperparathyroid patients. Am J Nephrol 1994;14:106. 67. Clair F, Leenhardt L, Bourdeau A, et al. Effect of calcitriol in the control of plasma calcium after parathyroidectomy. A placebo-controlled, double-blind study in chronic hemodialysis patients. Nephron 1987; 46:18. 68. Cattan P, Halimi B, Aidan K, et al. Reoperation for secondary uremic hyperparathyroidism: Are technical difficulties influenced by initial surgical procedure? Surgery 2000;127:562. 69. Giangrande A, Castiglioni A, Solbiati L, Allaria P. Ultrasound-guided percutaneous fine-needle ethanol injection into parathyroid glands in secondary hyperparathyroidism. Nephrol Dial Transplant 1992;7:412. 70. Giangrande A, Castiglioni A, Solbiati L, et al. Chemical parathyroidectomy for recurrence of secondary hyperparathyroidism. Am J Kidney Dis 1994;24:421. 71. Solbiati L, Giangrande A, De Pra L, et al. Percutaneous ethanol injection of parathyroid tumors under US guidance: Treatment for secondary hyperparathyroidism. Radiology 1985;155:607.
Surgical Approach to Secondary Hyperparathyroidism - - 517 72. Yajima A, Ogawa Y, Takahashi HE, et aJ. Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism. Am J Kidney Dis 2003;42:729. 73. Charhon SA, Berland YF, Olmer MJ, et al. Effects of parathyroidectomy on bone formation and mineralization in hemodialyzed patients. Kidney Int 1985;27:426. 74. Dahl E, Nordal KP, Halse J, Flatrnark A. Pretransplant parathyroidectomy in renal failure: Effects on bone histology and aluminum deposits during dialysis and after kidney transplantation. Scand J Urol Nephrol 1992;26:283. 75. Felsenfeld AJ, Harrelson lM, Gutman RA, et aI. Osteomalacia after parathyroidectomy in patients with uremia. Ann Intern Med 1982;96:34. 76. Yano S, Sugimoto T, Tsukamoto T, et aJ. Effect of parathyroidectomy on bone mineral density in hemodialysis patients with secondary hyperparathyroidism: Possible usefulness of preoperative determination of parathyroid hormone level for prediction of bone regain. Horm Metab Res 2003;35:259. 77. Urena P, Basile C, Grateau G, et aI. Short-term effects of parathyroidectomy on plasma biochemistry in chronic uremia. Kidney Int 1989;36:120.
78. Chandran PK, Ulahannan TJ, Skiles M. Biochemical changes following parathyroidectomy. Int J Artif Organs 1993;16:700. 79. Fanti P, Smith AJ, Price PA, et aJ. Effects of parathyroidectomy on circulating levels of I alpha, 25-dihydroxyvitarnin D and bone Gla protein in dialyzed patients. J Clin Endocrinol Metab 1986;62:869. 80. Zingraff J, Drueke T, Marie P, et aJ. Anemia and secondary hyperparathyroidism, Arch Intern Med 1978;138:1650. 81. Urena P, Eckardt KU, Sarfati E, et aJ. Serum erythropoietin and erythropoiesis in primary and secondary hyperparathyroidism: Effect of parathyroidectomy. Nephron 1991;59:384. 82. Barbour GL. Effect of parathyroidectomy on anemia in chronic renal failure. Arch Intern Med 1979;139:889. 83. Yasunaga C, Matsuo K, Yanagida T, et aJ. Early effects of parathyroidectomy on erythropoietin production in secondary hyperparathyroidism. Am J Surg 2002;183:199. 84. Washio M, Iseki K, Onoyama K, et aJ. Elevation of serum erythropoietin after subtotal parathyroidectomy in chronic haemodialysis patients. Nephrol Dial Transplant 1992;7:121.
Parathyroid Reoperations Chung Yau Lo, MB, BS(HK), MS(HK), FRCS(Edin), FACS • Jon A. van Heerden, MB, ChB, MS(Surg)[Minn], FRCS(C), FACS
The prospect of an imminent, initial, cervical exploration for biochemically proven hyperparathyroidism (HPT) invariably results in a release of endogenous endorphins in the experienced endocrine surgeon. In stark contrast, the prospect of cervical re-exploration for the same disease, by the same endocrine surgeon, invariably results in an increase in the secretion of fractionated urinary catecholamines. What is the reason for these opposite reactions when operating for the same disease entity in the same anatomic region of the body? In the first instance, the surgeon can accurately predict that the operation will usually be a technically easy one, that the cure rate (return to a normocalcemic state) will be high (>98%) both short and long term, and that the operative procedure will be accompanied by a negligible operative mortality and morbidity.' We have, at times, jokingly stated that the surgical team should in fact reimburse the patient for being allowed to perform the operation. In direct contrast, the surgeon can accurately predict that in a sizable percentage of patients undergoing reoperation, the surgical procedure will be a technically demanding one (a "no-fun case"), that the success rate will be 10% to 15% lower than in the primary procedure, and that the operative and postoperative complications will be considerably higher. It is fairly obvious that there would be no need for reoperative surgical procedures for HPT if the initial exploration was uniformly successful. This is unfortunately not the case, and it behooves all of us to re-examine the causes for initial failed cervical exploration and the overall approach to this challenging group of patients.
Causes of Failed Initial Exploration for Hyperparathyroidism HPT following a prior cervical or mediastinal exploration for hypercalcemia can be divided arbitrarily into persistent (defined as hypercalcemia recurring within 6 months after initial operation) or recurrent (hypercalcemia recurring after 6 months of normocalcemia following initial operationj.i-'
518
The former denotes missed pathology and the latter refers to newly developed pathology. The distinction of these two categories has been loosely applied since it is possible that a physiologically insignificant amount of hyperfunctioning tissue that was present at the first operation could proliferate and produce a biochemical recurrence several years later? It has been estimated that 2% to 10% of surgical failures may be attributed to an incorrect diagnosis." However, this is much less of a problem today with the advent of a reliable radioimmunoassay for intact parathyroid hormone (PTH). In patients with renal disease, PTH clearance is compromised by impaired renal clearance and may lead to spurious elevations of PTH levels if the hormone is measured by assays that fail to detect intact PTH molecular structures. In such circumstances, the measurement of PTH using doubleantibody methods will help resolve this issue. Another, albeit rare, diagnostic pitfall are patients with benign familial hypocalciuric hypercalcemia (BFHH). This disorder is associated with moderate hypercalcemia and normal or slightly elevated blood PTH levels. BFHH can be diagnosed by a positive family history of hypercalcemia at times associated with unsuccessful parathyroid surgery, a 24-hour urinary calcium excretion of less than 100 mg, and the calculated value of calcium-to-creatinine clearance ratio of less than 0.01. 4 Other causes of hypercalcemia (intake of thiazide diuretics or lithium, vitamin D intoxication, sarcoidosis, multiple myeloma, malignancy, and paraneoplastic syndromes) rarely cause confusion today in the diagnosis of primary HPT. This is largely due to the accuracy and sensitivity of the currently available intact PTH assays. In contrast to the incorrect diagnosis of primary HPT, inexperience on the part of the surgeon is a major cause of surgical failure because of the lack of knowledge regarding parathyroid embryology and knowing the usual "hiding places" of the parathyroid glands; the inability to recognize and excise an abnormal gland; failure to recognize and adequately treat multiple gland disease; failure to locate an ectopic gland; the presence of supernumerary glands; errors on frozen section examination; incomplete excision of invasive parathyroid carcinoma; or parathyromatosis (i.e., multiple nodules of hyperfunctioning parathyroid tissue scattered
Parathyroid Reoperations - -
through the neck and mediastinum) due most often to spillage of diseased tissue during removal or rarely due to abnormal embryologic development. The anatomy and embryologic descent of the parathyroid glands are variable in 20% of patients.' Inability to recognize an anomalous location of an abnormal gland or the inability to perform a bloodless, thorough dissection of the neck is a common cause for failed cervical exploration by the inexperienced endocrine surgeon, Although multiple-gland disease accounts for 5% to 15% of patients undergoing initial exploration, up to 37% of patients who come to reoperation have multiple-gland disease rather than a single adenoma. 2,3,6,7 This heterogeneous group of patients includes patients with familial HPT and multiple endocrine neoplasia (MEN) types I and 2. The logistic difficulty in diagnosing some of these rare conditions can be attributed to a negative family history and the disparity of size of the enlarged glands, although all are hypercellular (unequal or asymmetrical hyperplasia). In general, the location and excision of an adenoma, visual identification of all parathyroid glands, and biopsy of a second suspicious gland constitute a safe and effective strategy for most patients with primary HPT undergoing initial operation. In multiple-gland hyperplasia, it is vitally important to adequately reduce the amount of functioning parathyroid tissue to prevent recurrence without being overly aggressive and creating an aparathyroid state with the need for chronic calcium and vitamin D supplementationa regimen that is unpleasant for the patients and that has a poor rate of patient compliance. Subtotal parathyroidectomy (3.5-g1and resection: leaving ±50 mg viable parathyroid tissue) or total parathyroidectomy with immediate forearm reimplantation is considered the treatment of choice for patients with familial HPT.8,9 The incidence of supernumerary ("fifth") glands in 1% to 6% of patients with MEN 1 adds further surgical difficulty. Routine transcervical thymectomy for the possible removal of a supernumerary fifth gland is indicated in all patients with MEN 1. Undoubtedly, failure to identify multiple-gland disease and to remove adequate functioning parathyroid tissue, the presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction invariably lead to persistent or recurrent hypercalcemia." Despite the success of this approach, there is a steady push toward a more limited, or focused, cervical exploration, often under local anesthesia and increasingly on an outpatient basis.' Considerable interest has been focused on the adoption of minimally invasive approaches including endoscopic, video-assisted, and radio-guided parathyroidectomy for primary HPT.IO,II Application of these techniques depends on an accurate preoperative sestamibi scanning or the use of intraoperative gamma probe technology to locate the adenoma as well as the increasing availability of the intraoperative "quick" PTH assay to confirm surgical success, However, the fact that there are numerous types of minimally invasive parathyroidectomy, and that no firmly established method has been accepted as the standard technique, makes evaluation and comparison with the open approach difficult. 10 These new approaches should be evaluated carefully and compared objectively with the excellent results obtained when surgical expertise alone is used. 1 In addition,
519
these techniques can be applied only to selected patients'' it can be difficult to distinguish a lymph node with metastatic thyroid cancer from a parathyroid gland.
Multiple-Gland Disease: Initial Surgery Multiple-gland disease can be anticipated in patients with multiple endocrine neoplasias, familial disease, and secondary hyperparathyroidism. Two surgical strategies are widely used: (1) subtotal (3.5-gland excision) parathyroidectomy leaving tissue attached to its native blood supply and (2) total parathyroidectomy and autotransplantation to forearm muscles or subcutaneously. Regardless of the strategy selected, cryopreservation of resected parathyroid tissue as a backup is warranted. Autotransplantation with fresh tissue is not uniformly successful, as reflected by an incidence of postoperative hypoparathyroidism of approximately 10% in patients undergoing total parathyroidectomy with immediate autotransplantation.' Autotransplantation with biopsy-proven cryopreserved tissue offers the patient a second chance to be free from calcium supplements.
Reoperative Parathyroid Surgery An important part of planning reoperative parathyroid surgery is the review of operative and pathology notes by the surgeon and the review of resected tissue by a pathologist. Should it be determined that the patient's only functioning parathyroid tissue is a single remaining adenoma, resection with immediate transplantation of a portion of the adenoma and
534 - - Parathyroid Gland
cryopreservation of the remaining tissue are preferred over angiographic ablation. Another situation that may be anticipated by a review of operative documents and histologic slides is that of reoperation for multiple-gland disease. Saxe and Brennan" reported a 54% incidence of spontaneous normocalcemia and a 12% incidence of persistent hypercalcemia in 26 such patients who underwent attempted total parathyroidectomy without immediate autotransplantation. Of particular interest were 13 patients who had histologically documented four-gland resections. Fully 69% of those patients remained normocalcemic (seven patients) or hypercalcemic (two patients) without calcium supplementation or autotransplantation. This indicates that in this setting even patients undergoing intentional removal of all parathyroid tissue may (unpredictably) have residual tissue. The seven normocalcemic patients might well have become hypercalcemic had they received immediate autotransplants. The authors concluded that for patients undergoing intentional "total parathyroidectomy" at reoperation for multiple-gland disease, a prediction of inevitable hypocalcemia is unwarranted and immediate autotransplantation with fresh tissue is unwise. They recommended restricting autotransplantation (with cryopreserved tissue) to patients with documented hypoparathyroidism.
Research Cryopreservation of parathyroid tissue has utility beyond autotransplantation for treatment of hypoparathyroidism. Research using parathyroid tissue can be facilitated by harvesting tissue on the day of resection for use at a time convenient to the investigator. Access to a "bank" of cryopreserved tissue frees the investigator from the vagaries of the operating room schedule and permits accumulation of masses of tissue sufficient to perform complex experiments. It also permits comparison of several patients' tissues in a single experiment as well as the same patient's tissue in several experiments. Cryopreserved tissue has been used in the investigation of several aspects of physiology: comparison of hormone release in adenoma versus hyperplasia," effect of lithium on thymidine incorporation," parathyroid immunology.Pr" effect of cimetidine on hormone secretion.i? effect of phorbol ester on hormone secretion," mitochondrial incorporation
of sestamibi.!? and generation of microcapsules of parathyroid tissue.'? In general, cryopreservation appears to preserve parathyroid function, although there does appear to be a difference in preservation of estrogen receptors in fresh versus cryopreserved human parathyroid tissue (Table 60-4),31 For in vitro experiments, we have used the following protocol for preparation of cell suspensions. Thawed tissue is placed in 10 mL of a 0.5-mg/mL collagenase (Boehringer Mannheim, Indianapolis, IN) in RPMI-I640 solution. The culture tube containing the tissue is placed in a 37°C shaking water bath and agitated gently (92/min) for 30 to 60 minutes. Because the viability of cryopreserved cells is variable, we have used an additional step to remove necrotic cells and enrich the proportion of viable cells. A stock solution of isotonic Percoll (Pharmacia, Uppsala, Sweden) is made by mixing Percoll with lOx phosphate-buffered saline (PBS). Working solutions of 25% and 75% stock solutions are made by dilution in PBS. In a 12- x 75-mm culture tube, 1.5-mL portions of the 25% and 75% stock solutions are added below the parathyroid cell suspension using a spinal needle, and the tube is centrifuged at 450 g for 15 minutes. The superficial 0.5 mL containing debris and necrotic cells is discarded. Of the remaining Percoll gradient, 1.5 mL is aspirated, diluted with 3.5 mL of culture medium, recentrifuged, and resuspended in whatever solution is to be used for the experiment.
Conclusion In conclusion, techniques for preparing and transplanting cryopreserved parathyroid tissue have been presented. Surgeons who perform parathyroid surgery should be familiar with these techniques. The success rate of using this technique is about 70% (see Table 60-2) versus better than 90% with autotransplantation of fresh parathyroid autografts.
REFERENCES I. Blumenthal HT, Walsh LB. Survival of guinea pig thyroid and parathyroid autotransplants previously subjected to extremely low temperatures. Proc Soc Exp BioI Med 1950;73:62. 2. Russel PS, Wood ML, Gittes RF. Preservation of living tissue in the frozen state: A study using parathyroid tissue. J Surg Res 1961; I:23. 3. Huggins CE, Abo S. Preservation of rat parathyroid glands by freezing. In: Norman JC (ed), Organ Perfusion and Preservation. New York, Appleton-Century-Crofts, 1968, p 739.
Cryopreservation of Parathyroid Tissue - 4. Wells SA, Christiansen C. The transplanted parathyroid gland: Evaluation of cryopreservation and other environmental factors which affect its function. Surgery 1974;75:49. 5. Saxe A. Parathyroid transplantation: A review. Surgery 1984;95:507. 6. Niederle B, Roka R, Brennan ME The transplantation of parathyroid tissue in man: Development, indications, technique, and results. Endocr Rev 1982;3:245. 7. SaxeAW, Gibson GW. Kay S. Characterization of a simplified method of cryopreserving human parathyroid tissue. Surgery 1990;108:1033. 8. Wagner PK, Seesko HG, Rothmund M. Replantation of cryopreserved human parathyroid tissue. World J Surg 1991;15:751. 9. Basile C, Drueke T, Lacour B, et al. Total parathyroidectomy and delayed autotransplantation using a simplified cryopreservation technique: Human and animal studies. Am J Kidney Dis 1984;3:366. 10. Kapur MM, Mehta SN, Moulik BK, et al. Parathyroid preservation and transplantation. Indian J Med Res 1976;64: 1793. II. Herrera MF, Grant CS, van Heerden JA, et al. The effect of cryopreservation on cell viability and hormone secretion in human parathyroid tissue. Surgery 1992;112:1096. 12. Wagner PK, Rumpelt HI, Krause U, et al. The effect of cryopreservation on hormone secretion in vitro and morphology of human parathyroid tissue. Surgery 1986;99:257. 13. Saxe AW. The effect of phorbol ester on in vitro release of parathyroid hormone from abnormal human parathyroid cell. Surgery 1987;102:932. 14. Brennan MF, Brown EM. Prediction of in vivo function of human parathyroid tissue autografts by in vitro testing. World J Surg 1980;4:747. 15. McHenry CR, Stenger DB, Calandro NK. The effect of cryopreservation on parathyroid cell viability and function. Am J Surg 1997;174:481. 16. Saxe AW, Gibson G. Lithium increases tritiated thymidine uptake by abnormal human parathyroid tissue. Surgery 1991;110:1067. 17. Hetrakul N, CivelekAC, Stagg CA, Udelsman R. In vitro accumulation of technetium 99m-sestamibi in human parathyroid mitochondria. Surgery 200 I; 130:10II. 18. Goudet P, Cougard P, Zeller V, et al. Transplantation of human cryopreserved adenomatous and hyperplastic parathyroid tissue to the hypocalcemic nude mouse. World J Surg 1993;17:628. 19. Brennan MF, Brown EM, Spiegel AM, et al. Autotransplantation of cryopreserved parathyroid tissue in man. Ann Surg 1979;189:139. 20. Rothmund M, Wagner PK. Assessment of parathyroid graft function after autotransplantation of fresh and cryopreserved tissue. World J Surg 1984;8:527. 21. Saxe AW, Spiegel AM, Marx SJ, et al. Deferred parathyroid autografts with cryopreserved tissue after reoperative parathyroid surgery.Arch Surg 1982;117:538. 22. Smeds S, Trulsson L, Garovoy M, et al. Survival of human parathyroid tissue xenotransplanted in nude mice after 9 to 55 months' cryopreservation. APMIS 1999;107:445. 23. Tanaka Y, Fuahashi H, Imai T, et al. Functional and morphometric study of cryopreserved human parathyroid tissue transplanted into nude mice. World J Surg 1996;20:692. 24. Lahey PH, The transplantation of parathyroids in partial thyroidectomy. Surg Gynecol Obstet 1926;42:508. 25. Saxe AW, Brennan MF. Reoperative parathyroid surgery for primary hyperparathyroidism caused by multiple-gland disease: Total
26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.
43. 44.
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parathyroidectomy and autotransplantation with cryopreserved tissue. Surgery 1982;91:616. Brown EM, Gardner DG, Brennan MF, et al. Calcium-regulated parathyroid hormone release in primary hyperparathyroidism: Studies in vitro with dispersed parathyroid cells. Am J Med 1979;66:923. Saxe A, Gibson G, Elfont E. In vitro assessment of parathyroid immunogenicity: The effect of cryopreservation. Surgery 1990; I08:56. Martin L, Viennet G, Racadot E, et al. Antigenicite des adenomes parthyroidiens humains frais, cryopreserves et conserves en milieu liquide. Pathol BioI (Paris) 1998;46:315. Saxe AW, Chen SL, Marx SJ, et al. In vitro studies of parathyroid hormone release: Effect of cimetidine. Surgery 1982;92:793. Kobayashi S, Amano J, Minoru F, et al. Microcapsulated parathyroid tissue in vitro. Biomed Pharmacother 2000;54(Suppl 1):66. Saxe AW, Gibson GW, Russo IH, et al. Measurement of estrogen and progesterone receptors in abnormal human parathyroid tissue. Calcif Tissue Int 1992;51:344. Walgenbach S, Rosniatowski R, Bittinger F,et al. Modified cryopreservation and xenotransplantation of human parathyroid tissue. Langenbecks Arch Surg 1999;384:277. Brennan MF, Brown EM, Sears HF, et al. Human parathyroid cryopreservation: In vitro testing of function by parathyroid hormone release. Ann Surg 1978;187:87. Ulrich F, Steinmuller T, Rayes N, et al. Cryopreserved human parathyroid tissue: Cell cultures for in vitro testing of function. Transplant Proc 2001;33:666. Leight GS, Parker GA, Sears HF, et al. Experimental cryopreservation and autotransplantation of parathyroid glands: Technique and demonstration of function. Ann Surg 1978;188:16. Sonoda T, Ohkawa T, Takeuchi M, et al. Successful parathyroid preservation: Experimental study. Surgery 1968;64:791. Caccitolo JA, Farley DR, van Heerden JA, et al. The current role of parathyroid cryopreservation and autotransplantation in parathyroid surgery: An institutional experience. Surgery 1997;122:1062. Carty SE, Norton JA. Management of patients with persistent or recurrent primary hyperparathyroidism. World J Surg 1991;15:716. Higgins RM, Richardson AJ, Ratcliffe PJ, et al. Total parathyroidectomy alone or with autograft for renal hyperparathyroidism? Q J Med 1991;79:323. Mozes MF, Soper WD, Jonasson 0, et al. Total parathyroidectomy and autotransplantation in secondary hyperparathyroidism. Arch Surg 1980;115:378. Tolloczko T, Wozniewic B, Sawicki A, et al. Cultured parathyroid cell transplantation without immunosuppression in the treatment of surgical hypoparathyroidism. Transplant Proc 1994;26: 190I. Walgenbach S, Junginger T, Kohler H, Wandel E. Diagnostik von Dysfunktionen replantierten Nebenschilddrugenwebes durch seitengetrennte analyse des intakten parathomons im kubitalvenenblut. Med Klin (Munich) 1995;90:8. Wells SA, Gunnells JC, Gutman RA, et al. The successful transplantation of frozen parathyroid tissue in man. Surgery 1977;81:86. Wells SA, Farndon JR, Dale JK, et al. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980;192:451.
Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein Gordon J. Strewler, MD
Hypercalcemia is a relatively common complication of malignant tumors, occurring in 5% to 10% of all cancers. The incidence of hypercalcemia in malignancy is 15 cases per 100,000 person-years, about one half the incidence of primary hyperparathyroidism, 1 and it is the most common cause of hypercalcemia in hospitalized patients.? In 1924, Zondek and colleagues' first described hypercalcemia as a complication of cancer, and in 1941 Albright! proposed that hypercalcemia may be caused by humoral factors rather than direct resorption of bone by metastatic tumor. Our understanding of the causation and treatment of the syndrome of hypercalcemia in malignancy has burgeoned rapidly since 1980.5.6
Clinical Syndrome of Hypercalcemia in Malignancy The onset of hypercalcemia in malignancy is usually rapid, and hypercalcemia is often manifested as confusion, stupor, nausea, vomiting, or dehydration. The offending neoplasm is almost always evident clinically, even when hypercalcemia is its initial manifestation. Thus, physical examination, a chest radiograph, complete blood count, and urinalysis disclose the underlying tumor in about 98% of patients. Given these characteristics, it is not surprising that malignancy is the most common cause of hypercalcemia in hospitalized patients but is a rare cause of hypercalcemia in an office practice, which is dominated by patients with primary hyperparathyroidism and other forms of chronic, minimally symptomatic hypercalcemia. Because hypercalcemia usually occurs in advanced malignancy, the prognosis is poor, with a median survival of only 4 to 8 weeks after the discovery of hypercalcemia.' Exceptions to this rule are breast carcinoma and multiple myeloma. In both these disorders, successful therapy for the underlying malignancy may provide long survival in the hypercalcemic patient.
536
Tumors Causing Hypercalcemia Table 61-1 shows the frequency of individual tumors in collected series of patients with hypercalcemia. The most common single cause of hypercalcemia is lung carcinoma. Lung carcinomas with squamous or large-cell histology produce hypercalcemia frequently, but small-cell carcinoma almost never does." About two thirds of lung cancer patients have bone metastasis when hypercalcemia develops. In the remainder, hypercalcemia clearly has a humoral basis, usually humoral secretion of the parathyroid hormone-related protein (PTHrP), as discussed later. Together, lung carcinoma, breast carcinoma, and multiple myeloma account for more than 50% of all cases of malignancy-associated hypercalcemia. Among other solid tumors, the most common are squamous carcinomas of the esophagus and female reproductive tract and renal carcinoma. Gastrointestinal tumors and prostate carcinoma are less common causes of hypercalcemia. Among hematologic malignancies, hypercalcemia is common in multiple myeloma but distinctly uncommon in lymphomas and leukemia.
Pathogenesis of Hypercalcemia Parathyroid Hormone-Related Protein By far the most common cause of hypercalcemia in cancer is secretion of a protein similar to parathyroid hormone (PTH).5,6 The PTHrP is a distinct gene product with sequence homology to PTH only in a limited domain at the aminoterminal end of the molecule, where 8 of the first 13 amino acids in the two proteins are identical (Fig. 61-1). Although tightly circumscribed, this region of homology is critical, for the aminoterminal domain is the region required for activation of the receptor shared by the two proteins, the PTH-PTHrP receptor. Overall, PTHrP is 139 to 173 amino acids long compared with the 84-amino acid PTH molecule.
Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein - - 537
The two are cousins not only structurally but also in ancestry; shared features of gene structure and chromosomal location indicate that their genes arose from a common ancestral gene," Because PTH and PTHrP share a receptor, it can be anticipated that their biologic actions and the clinical syndrome they produce will be similar.'? Both produce humoral hypercalcemia by increasing resorption of bone throughout the skeleton and by increasing the renal resorption of calcium, and both produce relative hypophosphatemia through a phosphaturic effect at the kidney," Most tumors that produce PTHrP, such as squamous and renal carcinomas (see Table 61-1), cause hypercalcemia without bone metastasis in a large fraction of cases (Table 61-2). Even in squamous and renal carcinoma patients who do have bone metastasis, the primary cause of hypercalcemia is probably humoral secretion of PTHrP because the serum level of PTHrP is better correlated with the serum calcium and phosphorus than is the number or size of bone metastases. Overall, about 80% of hypercalcemic cancer patients have increased serum levels of PTHrP, which can be measured in two-site, aminoterrninal, or midregion assays (Fig. 61_2).11-15 This group includes most solid tumor patients but only a few
FIGURE 61-1. Primary structures of the aminoterminal part of parathyroid hormonerelated protein (PTHrP) and of parathyroid hormone. The human sequences I to 34 are compared. Identical amino acids are highlighted.
patients with multiple myeloma, lymphoma, or leukemia. However, one leukemia, the adult T-cell leukemia syndrome, produces hypercalcemia in an extraordinarily high percentage of cases (about 60%) by direct secretion of PTHrP from malignant T Iymphocytes.ls" This is of particular interest because the adult T-cell leukemia syndrome, which is rare in the United States but endemic in Japan and the Caribbean basin, is caused by infection with a retrovirus, human T-cell leukemia-lymphoma virus (HTLV) type 1. It appears that a protein encoded in the genome ofHTLV-1 can directly activate transcription of the PTHrP gene in T cells. 19 It is likely that, in addition to humoral hypercalcemia, PTHrP can produce local osteolytic hypercalcemia by direct activation of osteoclasts in the vicinity of bone metastases. The best example is breast carcinoma. Unlike most other solid tumors, breast carcinoma produces hypercalcemia mainly in patients with extensive bone metastases (see Table 61-2). About 50% of these patients have elevated serum levels of PTHrP,11-15 presumably indicative of humoral hypercalcemia. However, metastases to bone are immunohistochemically positive for PTHrP in 92% of cases compared with 17% of nonosseous metastases." This suggests either that tumor cells that secrete PTHrP have an advantage in bone (perhaps because they induce local resorption) or that the bone environment induces the expression of PTHrP. In either case, PTHrP could act locally to produce osteolysis. Transfection of the PTHrP gene into breast carcinoma cells increases the number of bone metastases, and animals with such metastases are hypercalcemic but do not have increased levels of circulating PTHrp.21 On the basis of this evidence, it seems likely that PTHrP can act as either a humoral factor or a local osteolytic factor in breast carcinoma. Secretion of PTHrP also causes hypercalcemia in a few benign conditions. The best example is pheochromocytoma. 22,23 Hypercalcemia can also be a part of the watery diarrhea with hypokalemic alkalosis syndrome produced by tumors that secrete vasoactive intestinal peptide. Because these are closely related to pheochromocytomas in their histology and origin, it is likely that PTHrP will be incriminated as the cause of hypercalcemia in these tumors as well, but this has yet to be confirmed, PTHrP is produced by the mammary gland and appears to be associated with hypercalcemia in two benign conditions of the breast: hypercalcemia complicating Iactation" and massive mammary hypertrophy and hypercalcemia."
538 - - Parathyroid Gland unlike PTH, the humoral regulator of calcium homeostasis, PTHrP is a local regulator of growth and differentiation." Its best established role is to stimulate the proliferation of chondrocytes in the growth plate and retard the mineralization of hypertrophic cartilage. Targeted ablation of the PTHrP gene in the mouse produced an embryonic lethal disorder characterized by short-limbed dwarfism and premature mineralization of cartilage." In postnatal life, PTHrP appears to regulate the differentiation of skin and skin appendages" (its expression in keratinocytes probably explains the high incidence of hypercalcemia in squamous carcinomas that originate from this cell type). In addition, PTHrP is involved in regulation of the mammary gland" and is secreted into milk at levels 1O,OOO-fold higher than serum levels." As a product of a variety of smooth muscle beds (vascular,31 gastrointestinal, bladder.P uterine") that is released in response to stretch 32,33 and functions as a smooth muscle relaxant,34-36 PTHrP is a candidate for short-loop, local regulation of smooth muscle tone.
1,25-Dihydroxyvitamin D
Although PTHrP was not identified until 1983 and was not purified and cloned until 1987, there is now little doubt about its primary role in the causation of hypercalcemia in solid tumor patients. Less certain, but of intense interest, is the role of this protein in normal physiology. It appears that,
Probably the most important cause of hypercalcemia in lymphoma is production of the active vitamin D metabolite 1,25-dihydroxyvitamin D(l,25-(OH)z-D) in lymphoma tissue.'? About half of lymphoma patients who present with hypercalcemia have inappropriately high serum 1,25-(OH)z-D levels. 38.39 In a few cases, lymph node tissue from such patients has been shown to produce 1,25-(OH)z-D
FIGURE 61-2. Plasma concentrations of parathyroid hormone-related protein (PTHrP) in patients with hyperparathyroidism (HPT), normocalcemic patients with malignancy (Normocalc), and patients with hypercalcemia of malignancy resulting from a solid tumor (Solid) or a hematologic malignancy (Hematol). Radioimmunoassay (RIA) was used for arninoterminal PTHrP(1-34) (left), an immunoradiometric assay for PTHrP(1-74) (middle), and an RIA for midregion PTHrP(53-84) (right). The hatched area represents the normal ranges, and the dotted line represents the limits of detection; the numbers attached to each group indicate the number of patients. In the PTHrP(1-74) assay, the group Solid includes five patients classified as having the local osteolytic type of hypercalcemia (delta) and two patients with lymphoma. Note the different scales of the y axes. (Modified from Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807; Burtis WJ, Brady TJ, Orloff 11, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N EngI J Med 1990;322: 1106; and Blind E, Raue F, Gotzmann J, et al, Circulating levels of midregional parathyroid hormone-related protein in hypercalcemia of malignancy. CUn Endocrinol [Oxf] 1992;37:290.)
Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein - - 539
in vitro from 25-0HD.40 Challenge of normocalcemic lymphoma patients with the precursor sterol 25-0HD resulted in increased serum 1,25-(OH)z-D levels, increased serum calcium levels, and suppression of PTH.40 In contrast, healthy individuals regulate the conversion of substrate to 1,25-(OH)z-D so precisely that virtually no abnormality of calcium homeostasis is induced by the administration of vitamin D. The abnormal responsiveness of normocalcemic lymphoma patients to vitamin D indicates that the fundamental abnormality in lymphoma, unregulated extrarenal production of 1,25-(OH)z-D, is actually more common than hypercalcemia. As would be expected from this interpretation, hypercalciuria is more common than hypercalcemia in lymphoma patients'? and presumably provides a compensatory mechanism to deal with the inappropriate synthesis of 1,25(OH)z-D. In all regards, this syndrome resembles the hypercalcemia of sarcoidosis, the first proven instance of extrarenal production of 1,25-(OH)z-D in hypercalcemia.t'v? As in sarcoidosis, hypercalcemia in lymphoma is frequently responsive to administration of corticosteroids.
Parathyroid Hormone Ectopic secretion of genuine PTH from extraparathyroid tumors, once thought to be common, is now recognized as extremely rare. Only a few authenticated cases have been reported,43.44 including a single case that fulfills the most rigorous criterion for proof of ectopic hormone production: demonstration of an arteriovenous (AV) gradient for PTH across the tumor." Most of the tumors reported to secrete PTH ectopically have had small-cell histology. The diagnosis should be considered in patients with malignant tumors (particularly small-cell tumors), hypercalcemia, and elevated PTH levels. However, most cases meeting this definition prove to have a malignant tumor with coincident primary hyperparathyroidism because this coincidence is more likely than the truly rare syndrome of ectopic PTH secretion. Thus, exploration of the parathyroid glands is indicated in patients with a malignant nonparathyroid tumor who require treatment for hypercalcemia, unless the malignant neoplasm can be shown to produce PTH by immunohistochemistry or, better, by demonstration of an AV gradient for PTH across the tumor. The diagnosis of ectopic hyperparathyroidism has been made to date by exclusion in patients with normal parathyroid glands.
Prostaglandins Once thought to be the dominant mechanism by which nonparathyroid tumors produce hypercalcemia, the production of prostaglandins is now thought to be a rare cause of hypercalcemia. It is not possible to give a precise incidence or to describe a unique clinical syndrome. Nonetheless, a few well-documented cases in which prostaglandins were high and hypercalcemia was reversed by inhibition of prostaglandin synthesis seem authentic."
Local Osteolytic Hypercalcemia Local osteolysis around osseous tumors can produce hypercalcemia. The predominant mechanism involves the activation of
osteoclasts by secretion of bone-resorbing cytokines. The list of cytokines with osteoclast-activating activity includes interleukin-I, tumor necrosis factor o, interleukin-6, and transforming growth factor c, as well as PTHrp.47 As discussed, there is accumulating evidence that PTHrP is the local osteolytic factor that produces hypercalcemia in breast carcinoma. The other classic example of local osteolytic hypercalcemia is multiple myeloma. Although this is a very common syndrome, with at least one third of myeloma patients experiencing hypercalcemia at some time during their disease, the offending cytokine has not been identified with certainty. Cultured human myeloma cell lines produce bone-resorbing factors that can be neutralized with antisera to interleukin-Ijr" or tumor necrosis factor ~ (lymphotoxin)." However, it is not clear whether either of these, or a third factor, is responsible for the syndrome observed in patients.
Differential Diagnosis The most important consideration in the differential diagnosis of hypercalcemia in a patient with a malignant neoplasm is intercurrent primary hyperparathyroidism. One clue to this possibility is the presence of chronic hypercalcemia, especially hypercalcemia that predates discovery of the malignant tumor. It is important to measure the PTH level in all patients with cancer and hypercalcemia, using a two-site assay for intact PTH (immunoradiometric or immunochemoluminescent). In such assays, the level of PTH is consistently suppressed below 20 ng/L (2 nmollL) in patients with malignancyassociated hypercalcemia. I 1,50 (Older midregion and aminoterminal assays were not able to detect suppression of PTH in patients with nonparathyroid hypercalcemia and should not be used in this setting.) The finding of a high-normal or increased level of intact PTH suggests the presence of primary hyperparathyroidism. In a 1994 study of 123 consecutive hypercalcemic patients, 6 (5%) had biochemical evidence of primary hyperparathyroidism together with a malignant neoplasm." As mentioned, true ectopic secretion of PTH is rare, which should be considered in patients with inappropriately increased PTH levels in the presence of a malignant neoplasm in whom a thorough exploration of the parathyroid glands was negative. It is probably unnecessary to measure PTHrP or 1,25(OH)z-D in all patients with malignancy-associated hypercalcemia. In the typical patient with a diffusely metastatic solid tumor and a suppressed level of PTH, determination of PTHrP is unlikely to change either the diagnosis or the management. Some studies have suggested that high PTHrP levels predict a poor response to antiresorptive therapy of hypercalcemia, but as discussed later (under "Treatment of Hypercalcemia"), it is not clear whether this effect is robust enough to mandate additional laboratory testing. However, in lymphoma patients, a determination of 1,25-(OH)z-D may guide the subsequent treatment of hypercalcemia with corticosteroids. Assays ofPTHrP and 1,25-(OH)z-D are also indicated in hypercalcemic patients with suppressed PTH levels but without an obvious malignancy. The serum or plasma level of PTHrP can be determined in aminoterminal.l-!" midregion," or carboxyterminal radioirnrnunoassays (RIAs) or in two-site immunoradiometric
540 - - Parathyroid Gland
assays (lRMAs).52.53 Both aminoterminal RIAs and IRMA assays for PTHrP are currently available commercially in the United States. Although the absolute level of PTHrP is considerably higher in midregion RIAs than in aminoterminal assays or IRMAs, all classes of assays perform similarly in the setting of malignancy-associated hypercalcemia (see Fig. 61-2). IRMA assays for PTHrP are highly sensitive and specific. However, they require collection of blood in special tubes containing protease inhibitors because proteases present in serum are capable of cleaving the PTHrP molecule at a site that disrupts the two-site assay.
Treatment of Hypercalcemia There are two points of attack on hypercalcemia.t'Y One is to inhibit osteoclastic bone resorption, thus reducing the flux of calcium into the extracellular fluid. The other is to increase the urinary excretion of calcium, potentiating the only homeostatic mechanism to clear an excess calcium load. The urinary clearance of calcium is often impaired in patients with malignancy-associated hypercalcemia. The glomerular filtration rate is reduced both by direct effects of hypercalcemia and by the dehydration and prerenal azotemia that result from impaired urinary concentrating ability. In patients with PTHrP-induced hypercalcemia, the renal tubular reabsorption of calcium is also increased. Thus, the first line of attack on hypercalcemia is usually to correct dehydration and increase the urinary clearance of calcium by inducing a saline diuresis. If necessary, the urinary clearance of calcium can be greatly enhanced with the use of loop diuretics such as furosemide together with saline infusions to induce a massive natriuresis and calciuresis. However, close monitoring of central pressures, serum potassium, and serum magnesium and replacement of urinary losses of fluids and electrolytes are necessary to carry out this mode of therapy safely. Several potent and effective inhibitors of bone resorption are available for acute treatment of hypercalcemia. The bisphosphonate agent parnidronate disodium is administered in a single intravenous infusion of 60 to 90 mg over 6 to 24 hourS.56. 57 Normocalcemia results in 80% to 90% of patients, although the nadir of the serum calcium concentration is not reached until about 5 days after administration. The efficacy and safety of pamidronate make it the agent of first choice. The mean duration of the response is I to 2 weeks, and patients can be retreated on relapse. Pamidronate is considerably more potent and more effective than the older bisphosphonate etidronate disodium, but several other new bisphosphonates will prove equally effective. Among these, alendronate disodium and clodronate have had extensive trials, but neither is yet approved. Synthetic salmon calcitonin in large doses of 200 to 800 U/day reduces the serum calcium level rapidly and is a useful adjunct to pamidronate, whose action has a delayed onset. However, refractoriness to calcitonin ensues within 2 to 4 days. In patients who are refractory to pamidronate and calcitonin, the cytotoxic antibiotic plicamycin (mithramycin) is useful. Although effective, plicamycin is no longer considered the drug of first choice because of its hepatic, renal, and bone marrow toxicity after repeated administration.
PTHrP has the same hypocalciuric effect on the kidney as PTH. For this reason, it was anticipated that patients with high levels of PTHrP might be relatively refractory to agents targeted to osteoclastic bone resorption. Several studies have shown that nonresponders to pamidronate treatment have higher serum PTHrP levels than responders. 5l ,5S,59 However, this relationship is a weak one that has not been observed consistently'"; most patients with PTHrP-induced hypercalcemia respond to pamidronate treatment. Thus, the finding of a high PTHrP level should not influence the choice of therapy. In PTHrP-induced hypercalcemia, however, it is doubly important that aggressive measures to increase the urinary calcium clearance be instituted. Definitive treatment of the underlying neoplasm is also indicated. The treatment is rarely surgical because the cancer is usually advanced and diffuse by the time hypercalcemia supervenes. Chemotherapy of breast carcinoma, multiple myeloma, lymphoma, and leukemia is usually successful in hypercalcemic patients. In solid tumors other than breast carcinoma, chemotherapy is less valuable: chemotherapy has failed in many patients before the appearance of hypercalcemia.
Summary Hypercalcemia is a common end-stage problem in patients with malignant neoplasms. Malignancy is the most common cause of hypercalcemia in hospitalized patients, whereas primary hyperparathyroidism is the most common cause of hypercalcemia in nonhospitalized patients. PTHrP is the most common cause of hypercalcemia in patients with cancer. There are now PTHrP assays to quantitate PTHrP levels. Unfortunately, there are no good means of treating patients with malignant tumors and high PTHrP levels, and most patients die within 8 weeks.
REFERENCES I. Mundy GR, Cove DH, Fisken R. Primary hyperparathyroidism: Changes in the pattern of clinical presentation. Lancet 1980;I: 1317. 2. Fisken RA, Heath DA, Bold AM. Hypercalcaemia-A hospital survey. Q J Med 1980;49:405. 3. Zondek H, Petow H, Siebert W. Die bedeutung der calciumbestirnmung im blute fur die diagnose der niereninsuffizientz. Z Klin Med 1924; 99:129. 4. Case records of the Massachusetts General Hospital. Case 27461. N Engl J Med 1941;225:789. 5. Broadus AE, Mangin M, Ikeda K, et al. Humoral hypercalcemia of cancer: Identification of a novel parathyroid hormone-like peptide. N Engl J Med 1988;319:556. 6. Strewler GJ, Nissenson RA. Hypercalcemia in malignancy. West J Med 1990;153:635. 7. Ralston SH, Gallacher SJ, Patel U, et al. Cancer-associated hypercalcemia: Morbidity and mortality. Ann Intern Med 1990;112:499. 8. Bender RA, Hansen H. Hypercalcemia in bronchogenic carcinoma. Ann Intern Med 1974;80:205. 9. Broadus A, Stewart A. Parathyroid hormone-related protein: Structure, processing, and physiological actions. In: Bilezikian J, Levine M, Marcus R (eds), The Parathyroids. New York,Raven Press, 1994, p 259. 10. Orloff JJ, Reddy D, de Papp AE, et al. Parathyroid hormone-related protein as a prohormone: Posttranslational processing and receptor interactions. Endocr Rev 1994;15:40. 11. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807.
Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein - - 541 12. Burtis WJ, Brady TG, Orloff JJ, et a1. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 1990;322: 1106. 13. Grill V, Ho P, Body JJ, et a1. Parathyroid hormone-related protein: Elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab 1991;73:1309. 14. Ratcliffe WA, Norbury S, Stott RA, et a1. Immunoreactivity of plasma parathyrin-related peptide: Three region-specific radioimmunoassays and a two-site immunoradiometric assay compared. Clin Chern 1991;37:1781. 15. Blind E, Raue F, Gotzmann J, et a1. Circulating levels of midregional parathyroid hormone-related protein in hypercalcaemia of malignancy. Clin Endocrinol (Oxf) 1992;37 :290. 16. Fukumoto S, Matsumoto T, Ikeda K, et a1. Clinical evaluation of calcium metabolism in adult T-cellieukemiallymphoma. Arch Intern Med 1988; 148:921. 17. Watanabe T, Yamaguchi K, Takatsuki K, et a1.Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-I) carriers and adult T cell leukemia patients that can be transactivated by HTLV-l tax gene. J Exp Med 1990;172:759. 18. Ikeda K, Ohno H, Hane M, et a1. Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: Evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma. J Clin Endocrinol Metab 1994;79: 1322. 19. Dittmer J, Gitlin SD, Reid RL, et a1.Transactivation of the P2 promoter of parathyroid hormone-related protein by human T-celllymphotropic virus type I Tax 1: Evidence for the involvement of transcription factor Etsl.J Virol 1993;67:6087. 20. Powell GJ, Southby J, Danks JA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: Increased incidence in bone compared with other sites. Cancer Res 1991;51:3059. 21. Guise TA, Taylor SD, Yoneda T, et a1. Parathyroid hormone-related protein (PTHrP) expression by breast cancer cells enhanced osteolytic bone metastases in vivo [Abstract]. J Bone Miner Res 1994;9:S128. 22. Kimura S, Nishimura Y, Yamaguchi K, et a1.A case of pheochromocytoma producing parathyroid hormone-related protein and presenting with hypercalcemia. J Clin Endocrinol Metab 1990;70:1559. 23. Mune T, Katakami H, Kato Y, et al. Production and secretion of parathyroid hormone-related protein in pheochromocytoma: Participation of an alpha-adrenergic mechanism. J Clin Endocrinol Metab 1993;76:757. 24. Lepre F, Grill V, Ho PW, et a1. Hypercalcemia in pregnancy and lactation associated with parathyroid hormone-related protein [Letter]. N Engl J Med 1993;328:666. 25. Braude S, Graham A, Mitchell D: Lymphoedemalhypercalcaemia syndrome mediated by parathyroid-hormone-related protein. Lancet 1991;337:140. 26. Strewler GJ, Nissenson RA. The parathyroid hormone-related protein as a regulator of normal tissue functions. In: Kohler PO (ed), Current Opinion in Endocrinology and Diabetes. Philadelphia, Current Science, 1994, p 286. 27. Karaplis AC, Luz A, Glowacki J, et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 1994;8:277. 28. Wysolmerski JJ, Broadus AE, Zhou J, et al. Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci USA 1994;91: 1133. 29. Wysolmerski JJ, McCaughern-Carucci JF, Daifotis AG, et at. Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development. Development 1995;121:3539. 30. Budayr AA, Halloran BP, King JC, et a1. High levels of a parathyroid hormone-like protein in milk. Proc Natl Acad Sci USA 1989; 86:7183. 31. Hongo T, Kupfer J, Enomoto H, et a1.Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation. J Clin Invest 1991;88:1841. 32. Yamamoto M, Harm SC, Grasser WA, et al. Parathyroid hormonerelated protein in the rat urinary bladder: A smooth muscle relaxant produced locally in response to mechanical stretch. Proc Nat! Acad Sci USA 1992;89:5326.
33. Thiede MA, Daifotis AG, Weir EC, et al. Intrauterine occupancy controls expression of the parathyroid hormone-related peptide. Proc Natl Acad Sci USA 1990;87:6969. 34. Winquist RJ, Baskin EP, Vlasuk GP. Synthetic tumor-derived human hypercalcemic factor exhibits parathyroid hormone-like vasorelaxation in renal arteries. Biochem Biophys Res Commun 1987; 149:227. 35. Nickols GA, Nickols MA, Helwig JJ. Binding of parathyroid hormone and parathyroid hormone-related protein to vascular smooth muscle of rabbit renal microvessels. Endocrinology 1990;126:721. 36. Mok LL, Cooper CW, Thompson Je. Parathyroid hormone and parathyroid hormone-related protein inhibit phasic contraction of pig duodenal smooth muscle. Proc Soc Exp BioI Med 1989;191 :337. 37. Seymour JF, Gagel RF. Calcitriol: The major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993;82: 1383. 38. Adams JS, Fernandez M, Gacad MA, et al. Vitamin D metabolitemediated hypercalcemia and hypercalciuria patients with AIDS and non-AIDS-associated lymphoma. Blood 1989;73:235. 39. Seymour JF, Gagel RF, Hagemeister FB, et al. Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma. Ann Intern Med 1994;121:633. 40. Davies M, Hayes ME, Yin JA, et a1. Abnormal synthesis of 1,25dihydroxyvitamin D in patients with malignant lymphoma. J Clin Endocrinol Metab 1994;78:1202. 41. Barbour GL, Coburn JW, Slatopolsky E, et a1. Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1,25-dihydroxyvitarnin D. N Engl J Med 1981;305:440. 42. Stern PH, De Olazabal J, Bell NH. Evidence for abnormal regulation of circulating 1 alpha, 25-dihydroxyvitamin D in patients with sarcoidosis and normal calcium metabolism. J Clin Invest 1980;66:852. 43. Strewler GJ, Budayr AA, Clark OH, et a1. Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab 1993;76: 1373. 44. Yoshimoto K, Yamasaki R, Sakai H, et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 1989;68:976. 45. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma. N Engl J Med 1990;323: 1324. 46. Brereton HD, Halushka PV, Alexander RW, et a1. Indomethacinresponsive hypercalcemia in a patient with renal-cell adenocarcinoma. N Engl J Med 1974;291:83. 47. Mundy G. Hypercalcemic factors other than parathyroid hormonerelated protein. Endocrinol Metab Clin North Am 1989;18:795. 48. Kawano M, Yamamoto I, Iwato K, et at. Interleukin-l beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma. Blood 1989;73:1646. 49. Garrett IR, Durie BGM, Nedwin GE, et a1.Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma. N Engl J Med 1987;317:526. 50. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. Highly sensitive twosite immunoradiometric assay of parathyrin and its clinical utility in evaluating patients with hypercalcemia. Clin Chern 1987;33:1364. 51. Wimalawansa SJ. Significance of plasma PTHrP in patients with hypercalcemia of malignancy treated with bisphosphonate, Cancer 1994;73:2223. 52. Burtis WJ, Brady TG, Orloff JJ, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 1990;322: 1106. 53. Fraser WD, Robinson J, Lawton R, et a1. Clinical and laboratory studies of a new immunoradiometric assay of parathyroid hormone-related protein. Clin Chern 1993;39:414. 54. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med 1992;326: 1196. 55. Nussbaum SR. Pathophysiology and management of severe hypercalcemia. Endocrinol Metab Clin North Am 1993;22:343. 56. Gucalp R, Ritch P, Wiernik PH, et a1. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 1992; 10: 134. 57. Nussbaum SR, Younger J, VandePol CJ, et a1. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-,60-, and 90-mg dosages. Am J Med 1993; 95:297.
542 - - Parathyroid Gland 58. Dodwell OJ, Abbas SK, Morton AR, et al. Parathyroid hormonerelated protein (50-69) and response to pamidronate therapy for tumour-inducedhypercalcaemia. Eur I Cancer 1991;27:1629. 59. Body 11, Dumon IC, Thirion M, et al. Circulating PTHrP concentrations in tumor-induced hypercalcemia: Influence on the response to
bisphosphonate and changes after therapy. I Bone Miner Res 1993;8:701. 60. Budayr AA, Zysset E, Jenzer A, et al. Effects of treatment of malignancy-associated hypercalcemia on serum parathyroid hormone-related protein. I Bone Miner Res 1994;9:521.
Hypercalcemic Crisis Hiroshi Takami, MD
The most generally accepted criteria for the diagnosis of hypercalcemic crisis include a statement about the severity of the hypercalcemia (usually Ca >14.5 mg/dl.)! and that it is associated with acute symptoms and signs that can be reversed by correcting the hypercalcemia. I Primary hyperparathyroidism (PHPT) and malignancy are the main causes of hypercalcemic crisis. Hypercalcemic crisis secondary to PHPT has been referred to in the literature as acute HPT, parathyroid crisis, parathyroid poisoning, parathyroid intoxication, parathyrotoxicosis, and parathyroid storm.r'' The manifestations include weakness, nausea and vomiting, drowsiness, stupor, coma, constipation, and tachycardia.Y Severe lifethreatening symptoms and signs of hypercalcemia constitute a "crisis," and rapid diagnosis and treatment are essential to avoid significant morbidity or mortality? The emergency treatment of hypercalcemic crisis is the same regardless of the cause, and an emergency diagnostic algorithm must be followed to demonstrate or rule out PHPT. Serum calcium should be lowered during the etiologic work-up for hypercalcemia. Earlier fluid replenishment and optimized strategies for the intensive care of critically ill hypercalcemic patients have made hypercalcemic crisis a rare event. to
Incidence and Etiology of Hypercalcemic Crisis The incidence of hypercalcemic crisis has never been determined. Bondeson and colleagues 11 reported a 10% incidence of hypercalcemic crisis as a complication in 514 cases of PHPT presenting between 1961 and 1988. Hypercalcemic crisis secondary to PHPT is commonly caused by a large parathyroid mass but may also be caused by carcinoma or hyperplasia.>' Bondeson and colleagues, II however, reported that the distribution of parathyroid pathology (adenoma, hyperplasia, and carcinoma) causing hypercalcemic crisis was the same as that of PHPT not complicated by hypercalcemic crisis. Parathyroid carcinoma is usually associated with much higher parathyroid hormone (PTH) and calcium levels than nonmalignant PHPT, and the incidence of hypercalcemic crisis complicating it may be as high as 14%.12 Maselly and coworkers" reported that 10 of 325 consecutive PHPT patients went on to develop hypercalcemic crisis and that 9 of
the 10 patients had a single adenoma. The risk of developing hypercalcemic crisis in untreated PHPT is low. Only 1 of a group of 47 patients observed over a 5-year interval developed hypercalcemic crisis,'? and only 1 of 142 patients, or 0.7%, of the patients in a prospective series at the Mayo Clinic observed for 10 years developed hypercalcemic crisis related to PHPT. 15 Fitzpatrick- reported that age at the time of clinical presentation of hypercalcemic crisis is the same as or lightly lower than the average age of PHPT patients at the time of presentation.v'v-" Other authors have reported a wide age distribution but that most cases develop in the sixth decade of life. 2,4 The male/female ratio (1.0:1.1) was found to be similar to the distribution of parathyroid carcinoma"?" but markedly different from the gender ratios in series of PHPT. 16 •17 The principal causes of hypercalcemia in inpatient and outpatient settings differ? The two most common causes of hypercalcemia, malignancy and PHPT, are also the most common causes of hypercalcemic crisis in hospitalized and ambulatory patients, respectively, accounting for more than 90% of patients (Table 62-1). However, there are many other causes of hypercalcemic crisis. In granulomatous diseases, macrophages activated by the granuloma can metabolize 25-hydroxyvitarnin D (25-0H vitamin D, calcidiol) to the more active 1,25-dihydroxyvitarnin D 3 (l,25(OHh vitamin D, calcitriol) and produce endogenous hypervitaminosis D, and on rare occasions the resultant increase in intestinal calcium absorption leads to hypercalcemic crisis," Less commonly, some lymphomas have been associated with excess endogenous 1,25(OHh vitamin D production and sometimes cause hypercalcemic crisis." The mechanism of the hypercalcemia in hyperthyroidism is a direct stimulatory effect of thyroxine on osteoclastic bone resorption,' and hypercalcemia caused by this mechanism may occur when young patients with hyperthyroidism are immobilized. Hypercalcemia may mask the usual hypermetabolic signs of thyrotoxicosis and make the hyperthyroidism more difficult to diagnose. The most common cause of hypercalcemia in inpatient settings is malignancy.P There are three separate syndromes in which malignant tumors can result in life-threatening hypercalcemic crisis: a syndrome of humoral hypercalcemia caused by endocrine and paracrine mediators, a syndrome of
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hypercalcemia associated with localized osteolytic disease, and a syndrome of hypercalcemia associated with multiple myeloma and related hematologic malignancies. Humoral hypercalcemia of malignancy (HHM) results from elaboration of a bone-resorbing substance by the tumor, most often PTHrelated polypeptide (PTHrP). This 146-amino acid polypeptide is homologous to PTH in 8 of its first 13 aminoterminal residues, and it binds to the PTH receptor and produces the same hypercalcemic effects as PTH on end-organs: bone, gut, and kidney." Because PTHrP is secreted by solid malignancies in a manner that is not subject to the feedback regulation by serum calcium that occurs with PHPT, PTHrP secretion may cause an unrelenting hypercalcemic state. Humoral mediators of hypercalcemia in malignancy lead to increases in bone resorption by increasing osteolytic activity, and they probably also lead to complex disturbances in calcium homeostasis in the kidney and gut. Solid tumors of the lung, head, neck, kidney, pancreas, and ovary are often associated with humorally mediated hypercalcemia and produce factors, including PTHrP, that are potent activators of osteoclastic bone resorption and cause hypercalcemia in vivo.? Hematologic malignancies, most notably multiple myeloma, secrete a number of cytokines, which act locally in the bone marrow to stimulate osteoclastic bone resorption.'
Clinical Features of Hypercalcemic Crisis A serum calcium level of 14.5 mg/dL or higher must generally be considered a medical emergency, and most patients are symptomatic." Nevertheless, because relatively asymptomatic patients with a serum calcium of 20 mg/dL, and
even patients with levels below 14.5 mg/dL, have presented in hypercalcemic crisis," the serum calcium level should not be the sole marker used to define hypercalcemic crisis. 1 The severity of the hypercalcemia is usually proportional to the increase in PTH level. 9 The serum PTH level of patients in hypercalcemic crisis is almost always at least twice the normal level, and as many as 40% to 50% have a palpable mass on physical exarnination.s-" Mild to moderate hypercalcemia may be manifested only by anorexia, malaise, weakness, osteoporosis, and kidney stones. When these manifestations develop slowly, as they do in many mildly hyperparathyroid patients, their presence may be recognized only retrospectively, after parathyroidectomy,?·26 Hypercalcemia causes anorexia, polyuria, nausea, and vomiting, and the resultant dehydration may be profound." Isolated components of the syndrome are often nonspecific and observed in many other diseases,'? but the simultaneous presence of several of these components strongly suggests hypercalcemia. The renal symptoms of hypercalcemic crisis are polyuria and polydipsia. The neurologic symptoms are less characteristic and include depression, anxiety, and psychosis. Gastrointestinal symptoms are nausea, vomiting, constipation, peptic ulcer, and pancreatitis. Gastric acid secretion and pancreatic enzyme secretion are increased.!" Cardiac symptoms also are nonspecific. A shortened QT interval and tachycardias may be observed. The mechanism of hypertension attributable to PHPT is unclear,'? Hypercalcemic crisis is a constellation of the preceding signs and symptoms, including psychological disturbances (ranging from drowsiness to stupor to coma), renal insufficiency, and cardiac dysrhythmias (bradyarrhythmias, bundle branch blocks, complete heart blocks, and cardiac arrest)." (The preceding signs and symptoms are mild and usual, but the signs with italic letters are severe and not common.) Hypercalcemia of malignancy must be considered in cases with a history of, for example, breast cancer, in women, and lung cancer or myeloma, in both sexes.'?
Diagnosis A complete history and physical examination and a review of the medical records are the most important elements in the emergency diagnosis of hypercalcemic crisis." Patients with PHPT rarely experience hypercalcemic crisis, and those who do usually have a long-standing history of progressive symptoms of hypercalcemia. Most patients presenting with hypercalcemia secondary to malignancy have an antecedent diagnosis of malignancy, and many are already hospitalized when severe hypercalcemia develops. A serum calcium assay should be performed in all patients who present with psychological disturbances, renal insufficiency, cardiac dysrhythmias, and neurologic abnormalities," The most accurate and useful laboratory test for ruling out hypercalcemia is the ionized calcium assay," but most hospitals measure total serum calcium (ionized plus proteinbound calcium) unless the ionized calcium level is requested. If an ionized calcium assay is not available, total serum calcium may be measured and the value corrected for the measured albumin level.
Hypercalcemic Crisis - -
The most specific laboratory test in the differential diagnosis of hypercalcemia is the serum intact PTH assay?" An increased intact PTH level and calcium level are almost pathognomonic of HPT. Before the radioimmunoassay for intact PTH became available, the PTH assays in common use measured the PTH C-terminal or midregional fragment." Although detection of an elevated intact PTH level is a useful means of diagnosing PHT, the test usually takes a few days to complete and is of no immediate use in the management of hypercalcemic crisis. The quick intact PTH assay developed by Irvin and colleagues," however, has allowed rapid differential diagnosis of hypercalcemic crisis. It is an immunochemiluminometric assay and has a turnaround time of only 10 minutes." Conditions besides PHPT in which the intact PTH level is increased include hypocalcemia, secondary HPT (with low to low-normal serum calcium), and tertiary HPT (with normal to increased serum calcium) after a history of long-standing renal insufficiency? The intact PTH levels in patients with secondary HPT are characteristic of the patientto-patient variability of the half-life of intact PTH and its molecular heterogeneity and biphasic metabolism.P-" Hypercalcemia secondary to malignancy occurs in patients whose diagnosis of malignancy is already established.' Most patients who present with nonparathyroid hypercalcemia have malignant disease. It is important to establish whether the patient has HHM or skeletal metastases. Hypercalcemia develops before death from the malignancy in 30% of patients with carcinoma of the breast, 10% of patients with squamous cell carcinoma of the lung, and smaller percentages of patients with carcinoma of the esophagus, skin, kidney, pancreas, liver, colon, and ovary.v'" Reliable assays for PTHrP are now available, but it takes several days to obtain the results, and they cannot be relied on as an adjunct to the emergency management of hypercalcemia.? If the PTHrP levels are low, other osteolytic factors may be produced by the tumor, and other cases are associated with the production of interleukin-l, -6, or -11; transforming growth factor a or ~; interferon; or granulocyte-macrophage colony-stimulating factor. 10 Paraneoplastic production of ectopic PTH is extremely rare.32 If familial hypocalciuric hypercalcemia (FHH) is suspected, an above-normal 24-hour urine calcium or a calcium clearance-to-creatinine ratio greater than 0.01 in patients who have never been documented to be normocalcemic rules out FHH. I The serum 25-0H vitamin D level may be checked if excessive vitamin D intake is suspected. The serum 1,25(OHh vitamin D level is high normal or mildly elevated in patients with PHPT. A cost-effective and accurate diagnosis of HPT can be made by documenting increased calcium and intact PTH levels in patients who are not hypocalciuric.
545
Maternal PTH levels increase to enhance gastrointestinal absorption of calcium during pregnancy," thereby facilitating placental transport of calcium to the fetus. The degree of hypercalcemia, however, may be blunted by the physiologic hypoalbuminemia of pregnancy. Some of the criteria used to make the diagnosis of hyperparathyroidism in nonpregnant patients should be adjusted (i.e., lower calcium and higher PTH levels should be used) because of the physiologic increase in maternal PTH levels associated with pregnancy and the normally depressed maternal calcium levels. The maternal hypercalcemia accompanying maternal HPT depresses fetal parathyroid function." After birth, the neonate no longer has access to maternal serum calcium and is unable to mobilize calcium adequately from bone because of depressed parathyroid function, resulting in a risk of neonatal tetany. The pregnant woman, in tum, is at risk for hypercalcemic crisis. Placental delivery of calcium to the fetus is greatest during the third trimester and is protective for the mother.P:" Because this protection is lost with the delivery of the child, the neonate is at greatest risk for tetany several hours after delivery, and the mother is at greatest risk for hypercalcemic crisis during the same period.F'" The incidence of fetal complications has been reported to be 53% for treated mothers 35 ,40 and 80% for untreated mothers.f 27% to 31% of whose infants die in the neonatal period. 35,40 Other complications include intrauterine growth restriction, low birth weight, preterm delivery, and intrauterine fetal demise. 33•35,40-42 Postpartum neonatal hypocalcemic tetany has been reported to occur in 50% of infants born to untreated mothers," The diagnosis of HPT in pregnant patients is most commonly made postpartum when the infant develops neonatal tetany.'? If hypercalcemia is not controlled medically, parathyroidectomy by an experienced surgeon should be recommended despite advanced gestation.'? Urgent parathyroidectomy using improved technology is the best option, even in late gestation. Developments in surgical technology have greatly improved the safety of parathyroidectomy.P'P Innovations such as the intraoperative quick PTH assay," sestamibi scintigraphy/ 10 em), or when there are preoperative indications that the tumor has invaded surrounding anatomic structures. Because of the progress in preoperative diagnosis and localization, the use of the anterior approach is decreasing. A long, curved transverse incision ("reversed smile") is used, with the center point situated halfway between the umbilicus and the xiphisternum. A vertical (midline or paramedian) incision has also been advocated. The anatomic stratification in the incision line is outlined in Table 64-2.
Left Adrenalectomy. There are three ways of accessing the adrenal region." 1. Incision of the posterior parietal peritoneum lateral to the left colon, continued upward, dividing the splenorenalligament (important relations are with the spleen, the splenic vessels, and the pancreas, which are enveloped by the splenorenal ligament, and caution should be used to avoid injury) 2. Opening of the lesser sac through the gastrocolic omentum (incision should be longitudinal, outside of the gastroepiploic arcade) 3. Through the left mesocolon, with the problem of maintaining the main branches of the middle and left colic arteries forming the vascular arcade and yet allowing enough space. Anterior access to the adrenal gland allows easy recognition of the hilum and isolation of the adrenal vein from the elements of the renal pedicle. Right Adrenalectomy. After mobilization of the hepatic flexure of the colon, the liver is carefully retracted upward; to provide maximum exposure of the adrenal gland, the falciform and the right triangular ligaments are carefully divided. The duodenum is mobilized in its second portion (Kocher's maneuver) by incision on its lateral aspect (the avascular peritoneal
SurgicalEmbryology and Anatomy of the Adrenal Glands - - 569 reflection), allowing exposure of the vena cava, the right adrenal gland, and the upper pole of the right kidney. In this area, there are important relations to remember with the common bile duct and the gastroduodenal artery. The critical step is the clamping of the right adrenal vein because it is short, leaves the gland on its anterior aspect, and enters the vena cava on its posterior surface. Early control and ligation of the adrenal vein in surgery for pheochromocytomas have been advocated in an attempt to control the amount of catecholamines released in circulation during tumor handling. Whichever technique of adrenalectomy is chosen, however, it is clear to any operator that this ideal is not easily achieved, and in some approaches the adrenal vein might be the last connection to be divided, allowing severance of the tumor from the patient.
completed upward. For adrenals greater than 5 em, the lateral and superior dissections are completed first; dissection is then carried caudally to identify the adrenal vein, which is clipped and divided. RETROPERITONEAL LAPAROSCOPIC ADRENALECTOMIES
Laparoscopic surgery of the adrenal glands is described in detail in Chapter 74. The largest experience has been with nonfunctioning adrenal masses (incidentalomas) and with aldosteronomas. The laparoscopic dissection of Cushing's adenoma has been described as moderately difficult due to the relatively higher retroperitoneal fat content present in these patients. Bilateral adrenalectomies for Cushing's disease have been described in patients who failed transsphenoidal pituitary ablation. Laparoscopic removal of pheochromocytoma has proved to be a safe alternative in skilled hands. The role of laparoscopic adrenalectomy for isolated adrenal metastases is still controversial. Contraindications to laparoscopic adrenalectomy include adrenal carcinoma and adrenal masses greater than 10 em.
One approach used by some surgeons is to create a space around the adrenal gland with an air-filled balloon inserted retroperitoneally. This allows for minimal trauma to organs within the peritoneal cavity. The patient is placed in prone jackknife position and a balloon trocar is placed in the retroperitoneal space, insufflated, and then removed. Operative and retracting ports are placed. Left Adrenalectomy. Laparoscopic ports to insert a camera and instruments (usually three or four ports) are positioned below the left rib cage. The left adrenal gland is exposed after the spleen is freed up from attachments over the adrenal, the colon is moved down, and the tissue over the upper pole of the kidney opened to reveal the adrenal gland. The inferomedial border of the gland is identified and dissected, exposing the left renal vein. The vein is divided along with remaining vascular twigs. Right Adrenalectomy. Laparoscopic ports (four or five) are inserted along the right rib cage for camera, instruments, and a liver retractor. Mobilizing the right lobe of the liver from the tissues of the back of the abdomen is critical. Once the retroperitoneum is exposed and the liver retracted, the vena cava is exposed and, by following it, the adrenal vein is identified. Depending on the anatomy of the region and the reason for the adrenalectomy procedure, the adrenal vein or veins may be divided early. Alternatively, arterial branches into the gland may be divided at this point before the vein is clipped, stapled, or oversewn.
TRANSABDOMINAL LAPAROSCOPIC ADRENALECTOMY
Summary
Left Adrenalectomy. The splenic flexure is mobilized medially to expose the lienorenal ligament . The ligament is then incised to demonstrate the short gastric vessels posteriorly behind the stomach. This allows the spleen to fall medially, exposing the retroperitoneal space. The adrenal gland, the adrenal mass, and the adrenal vein are identified. Grasping the perinephric fat, the lateral and anterior parts of the adrenal gland are dissected avoiding to grasp the adrenal gland or tumor directly, because the tissue may tear. For smaller adrenals «5 em), the gland is dissected inferomedially. This allows for early identification and clipping of the adrenal vein. As dissection is continued upward, adrenal branches of the inferior phrenic vessels are clipped. For larger glands, dissection proceeds superiorly, clipping the adrenal branches of the inferior phrenic vessels. Right Adrenalectomy. A retractor is placed through the most anterior port and the right hepatic lobe is retracted anteriorly. The lateral right hepatic attachments are divided along with the right triangular ligament. The adrenal and its mass are identified. The inferolateral edge of the right adrenal gland is identified and dissected inferiorly. For glands less than 5 em, the right adrenal vein is visualized early and taken. The adrenal branches of the inferior phrenic vein are clipped and divided as the dissection is
Understanding the embryology, anatomic relationships, and neurovascular supply of the adrenal glands helps the clinician interpret localization studies and choose the appropriate adrenal operation for individual patients.
Laparoscopic Adrenalectomy
REFERENCES 1. Eustachius B. In: Lancisius B (ed), Tabulae Anatomicae Clarissimi Viri Bartholomeai Eustachii. Amsterdam, 1722. 2. Welbourn RB. The History of Endocrine Surgery. New York, Praeger, 1990, p 147. 3. Home E. Lectures on Comparative Anatomy, Vol 5. London, Longman, Ress, Home, Brown & Green, 1828, p 259. 4. Cuvier GLC. Lecons D' Anatomie Comparee. Paris, Baudonin, 1800-1805. 5. Addison T. On the Constitutional and Local Effects of Disease of the Suprarenal Capsules. London, Samuel Highley, 1855. 6. Brown-Sequard CEoRecherches experimentales sur la physiologie et al pathologie des capsules surrenales. Arch Gen Med 1856;8:385. 7. Oliver G, Sharpey-Schafer EA. The physiological effects of extracts of the suprarenal capsules. J Physiol (Lond) 1895;18:230. 8. Abel 11, Crawford AC. On the blood pressure raising constituent of the suprarenal capsule. Johns Hopkins Hosp Bull 1897;8:151. 9. Stolz F. Ueber adrenalin und alkylaminoacetobenzcatechin. Dtsche Chern Ges 1904;37:4149. 10. Von Euler US. Specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relation to adrenalin and noradrenaline. Acta Physiol Scand 1946;12:73.
570 - - Adrenal Gland II. Holtz P, Credner K, Kroneberg G. Uber das sympathomimetishe pressoriche Prinzip des Hams ("urosympathin"). Arch Exp Pathol Pharmakol 1947;204:224. 12. Alquist RP. A study of adrenotropic receptors. Am J Physiol 1948; 153:586. 13. Frankel F. Ein Fall von doppelseitigen vollig latent verlaufenen Nebennierntumor und gleichseitigen Nephritis mit Veranderungen am Circulations-Apparat und Retinitis. Arch Pathol Anat 1886:103. 14. Pick L. Das gangliona embrionale sympathicum. Klin Wochenschr 1912; 19:16. 15. Cushing H. The Pituitary Body and its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebri. Philadelphia, JB Lippincott, 1912. 16. Conn JW. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45:6. 17. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163. 18. Werner P. Endocrine adenomatosis and peptic ulcer in a large kindred: Inherited multiple tumours and mosaic pleiotropism in man. Am J Med 1963;35:205. 19. Pybus Fe. Notes on suprarenal and pancreatic grafting. Lancet 1924;1:550. 20. Reichtenstein T, Shopper CWO The hormones of the adrenal cortex. Vitam Horm 1943;1:345. 21. Kendall Ee. The chemistry and partial synthesis of adrenal steroids. Ann NY Acad Sci 1949;50:540. 22. Vale W, Spiess J, Rivier J, et al. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981;213:1394. 23. Sadler TW. Langman's Medical Embryology, 6th ed. Baltimore, Williams & Wilkins, 1990, p 382. 24. Orth DN, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW (eds), Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, p 489. 25. Anderson DJ. Molecular control of cell fate in the neural crest: The sympathoadrenal lineage. Ann Rev Neurosci 1993; 16:129. 26. Phillippe M. Fetal catecholamines. Am J Obstet Gynecol 1983; 146:840. 27. Le Douarin NM. The Neural Crest. Cambridge, England, Cambridge University Press, 1982. 28. Pitynski K, Skawina A, Polakiewicz J, Walocha 1. Extraorganic vascular system of adrenal glands in human fetuses. Anat Anz 1998; 180:361. 29. Pepe GJ, Albrecht ED. Actions of placental and foetal adrenal steroid hormones in primate pregnancy. Endocr Rev 1995;16:608. 30. Zuckerkandl E. The development of the chromaffin organs and the suprarenal glands. In: Manual of Human Embryology, Vol 2. Philadelphia, JB Lippincott, 1912, p 157. 31. Pearse AGE. The neuroendocrine division of the nervous system: APUD cells as neurones or paraneurones. In: Osborne NN (ed), Dale's Principles and Communication Between Neurones. Oxford, Pergamon Press, 1983.
32. Russel RP, Masi AT, Richter ED. Adrenal cortical adenomas and hypertension: A clinical and pathologic analysis of 690 case-matched controls and a review of the literature. Medicine 1972;51 :211. 33. Neville AM, O'Hare MJ. Histopathology of the human adrenal cortex. Clin Endocrinol Metab 1985;14:791. 34. Williams PL, Warwick RW, Dyson M, Bannister LH (eds). Gray's Anatomy, 36th ed. New York, Churchill Livingstone, 1989, p 1468. 35. Davies J. Anatomy, microscopic structure and development of the human adrenal gland. In: Scott HW (ed), Surgery of the Adrenal Glands. Philadelphia, 18 Lippincott, 1990, p 17. 36. Fawcett DW, Raviola E. The adrenal glands. In: Fawcett DW (ed), Bloom and Fawcett: A Textbook of Histology, 12th ed. New York, Chapman & Hall, 1994, P 503. 37. Kikuta A, Mukarami T. Microcirculation of the rat adrenal gland: A scanning electron microscope study of vascular casts. Am J Anat 1982; 164:22. 38. Monkhouse WS, Khalique A. The adrenal and renal veins of man and their connections with azygos veins. J Anat 1986;146:105. 39. Camey JA, Sizemore GW, Tyce GM. Bilateral adrenal medullary hyperplasia in multiple endocrine neoplasia type 2: The precursor of bilateral pheochromocytoma. Mayo Clin Proc 1975;50:3. 40. Arnold 1. Ein Beitrag zu feineren und dem Chemismus der Nebennieren. Arch Pathol Anat Physiol Klin Med 1866;35:64. 41. Belloni AS, Neri G, Musajo FG, et al. Investigations on the morphology and function of adrenocortical tissue regenerated from the capsular fragments autotransplanted in the musculus gracilis of the rat. Endocrinology 1990;126:3251. 42. Zajicek G, Ariel I, Arber N. The streaming adrenal cortex: Direct evidence of centripetal migration of adrenocytes by estimation of cell turnover rate. J Endocrinol 1986; 111:477. 43. Hornsby PJ. Physiological and pathological effects of steroids on the function of the adrenal cortex. J Steroid Biochem 1987;27: 1161. 44. Gill GN. ACTH regulation of the adrenal cortex. In: Gill GN (ed), Pharmacology of Adrenal Cortical Hormones. New York, Pergamon Press, 1979, p 35. 45. Mihai R, Wong NACS, Luckett M, et al. No correlation between phaechromocytoma catecholamine secretion and granule ultrastructure. Br J Surg 1998;85:1681. 46. Murfitt J. The adrenal glands. In: Sutton D, Young Jw.R (eds), A Short Textbook of Clinical Imaging. New York, Springer-Verlag, 1990, p 498. 47. Hata T, Deter RL. A review of fetal organ measurements obtained with ultrasound: Normal growth. J Clin Ultrasound 1992;20:155. 48. Young HH. Genital abnormalities: Hermaphroditism and related adrenal disease. Baltimore, Williams & Wilkins, 1937. 49. Snell RS. Clinical Anatomy for Medical Students, 5th ed. Boston, Little, Brown, 1995, p 135. 50. Cahill GF. Hormonal tumours of the adrenals. Surgery 1944;16:233. 51. Skandalakis JE, Skandalakis PN, Skandalakis LJ. Surgical Anatomy and Technique. New York, Springer-Verlag, 1995, p 557.
Adrenal Physiology Staffan Grondal, MD, PhD • Bertil Hamberger, MD, PhD
The normal adrenal gland in humans weights 5 to 7 g and is 4 to 5 em long, 2 to 3 em wide, and I em thick. The paired adrenal glands are situated on the anteromedial aspect of the kidneys. The adrenal has two functional entities, the adrenal cortex and the adrenal medulla. Although there are some developmental and functional relationships between the cortex and the medulla, they are discussed separately.
Adrenal Cortex Functional Morphology The adrenal cortex constitutes about 85% of the whole gland. The cortex surrounds the medulla and is arranged in three zones: zona glomerulosa, fasciculata, and reticularis (Fig. 65-1). The zona glomerulosa lies just under the capsule and is thin. It constitutes about 15% of the cortex or may present focally with small round cells with a small cytoplasmic volume. The zona fasciculata is broad. It constitutes about 70% of the cortex, with larger cells with abundant cytoplasm ("clear" cells). Closest to the adrenal medulla lies the zona reticularis, with cells of intermediate size ("compact" cells). The adrenal gland is highly vascularized. Three major arteries from the aorta, inferior phrenic artery, and renal arteries as well as up to 50 arterioles course through the cortex and via capillaries anastomose to veins that pass the medulla and enter a central vein. The blood supply of the cortex is thereby mainly separated from that of the medulla, but the outer part of the medulla is reached by cortisol-rich blood. The right adrenal vein is 2 to 5 mm long and drains directly into the inferior vena cava, whereas the left adrenal vein is longer and drains into the left renal vein.
Functional Zonation Aldosterone is synthesized and released only from the zona glomerulosa, whereas the zona fasciculata synthesizes mainly cortisol, dehydroepiandrosterone (DHEA); other androgens and estrogen are synthesized in both the zona reticularis and zona fasciculata (see Fig. 65-1). DHEA sulfate (DHEA-S) is the quantitatively dominating steroid from the adrenal cortex and is released primarily from the zona reticularis.'
Biosynthesis of Corticosteroids Plasma cholesterol is the major source of substrate used for steroid synthesis by the adrenal cortex." Pregnenolone, the origin of all steroid hormones (C21, C19, CI8), is formed from cholesterol after hydroxylation and enzymatic cleavage of the side chain within the mitochondria. The synthesis of steroid hormones from pregnenolone is dependent on several metabolizing enzymes localized in the mitochondrion and microsomes (Fig. 65-2). Steroid hormones are metabolized by the liver and excreted in the urine as more water-soluble conjugates with glucuronic acid or sulfates.
Aldosterone Pregnenolone is 21-hydroxylated in the endoplasmic reticulum and, after 11- and 18-hydroxylation, aldosterone is formed, It is secreted in its free form and is also bound with low affinity to albumin. The main effects of aldosterone and other mineralocorticoids are to maintain normal Na" and K+ concentrations and extracellular fluid volume. Synthesis and secretion of aldosterone are regulated mainly by angiotensin II and changes of the plasma levels of potassium and sodium.' A decrease of the intravascular volume is registered in the renal juxtaglomerular cells, located in the wall of the afferent glomerular arteriole, and leads to a release of renin. These cells also respond to ~-adrenergic stimuli and prostaglandins. Renin cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II, in itself a potent vasoconstrictor, binds to membrane receptors on the zona glomerulosa cell surface. Aldosterone biosynthetic enzymes are activated through phospholipase C inositol triphosphate diacylglycerol, which increases the intracellular calcium concentration." Increments of serum potassium significantly increase serum aldosterone. Sodium depletion stimulates the conversion of corticosterone to aldosterone, but large changes of plasma sodium are necessary.' Adrenocorticotropic hormone (ACTH, corticotropin) has only a permissive role in the synthesis of aldosterone. Consequently, a prompt control of sodium and potassium intake as well as pharmacologic
571
572 - -
Adrenal Gland
The layers of the adrenal gland and their hormone production
FIGURE 65-1. Schematic of the adrenal glands with the zones and the corresponding hormones produced.
agents affecting the renin-angiotensin system, ~-adrenergic receptors, and prostaglandins are necessary when investigating aldosterone secretion.'
Cortisol In the endoplasmic reticulum, pregnenolone is converted to progesterone and 17a-progesterone is 21-hydroxylated to l l-deoxycortisol, and in the mitochondrion, II-deoxycortisol is hydroxylated to cortisol. After secretion, most of the cortisol (80%) that circulates in plasma is bound with high
affinity to a corticosteroid-binding globulin, transcortin, whereas an additional 15% is bound to albumin and less than 10% is free.' Synthesis of cortisol is completely regulated by ACTH, which binds to receptors of the adrenal cell surface. The action of ACTH is mediated by the adenylate cyclase-cyclic adenosine monophosphate-protein kinase A system." Initially, the conversion rate of cholesterol to pregnenolone increases; more chronic ACTH stimulation increases the corticosteroid enzyme activity, and hypertrophy of the adrenocortical cells occurs.' Serum levels of cortisol show a specific diurnal rhythm, with highest levels in the
Dehydroepiandrosterone
Androstenedione
Estradiol
Estrone
FIGURE 65-2. Steroid biosynthesis in the adrenal cortex and the major urinary metabolites. Mitochondrial and microsomal cytochrome PA50 enzymes catalyze the conversion of steroids.
Adrenal Physiology - - 573 early morning and low levels at night. 1 The serum cortisol level is continuously regulated by a feedback mechanism on the hypothalamus and pituitary. Patients treated with replacement or pharmacologic doses of exogenous glucocorticoids usually have low or absent measurable corticotropin in the serum. Patients receiving pharmacologic doses of steroids are unable to respond with increased endogenous cortisol secretion in response to surgical stress. Accordingly, these patients need to receive a stress dose of steroids when in a physiologically stressful state.
Sex Steroids The adrenocortical sex steroids DHEA and andostenedione are formed after 17a-hydroxylation of pregnenolone or progesterone and side chain removal from carbon 17. They are secreted mainly as sulfates and are converted in peripheral tissues from relatively weak adrenal androgens to testosterone and estrogens. ACTH stimulates the synthesis and secretion of adrenal androgens, but there is no diurnal variation of DHEA-S in serum'?
Physiologic Effects of Corticosteroids Aldosterone Aldosterone regulates electrolyte excretion and the intravascular volume through its effects on the distal tubules and cortical collecting tubes of the kidney. It binds to a mineralocorticoid receptor in the cytosol and moves into the nucleus to increase transcription." The early effect is to increase the Na absorption through the Na channels. Via changes in electrical potential across the renal tubule, K and H secretion are increased. This leads to an expanded intravascular volume and suppresses renin secretion. Chronically increased aldosterone secretion is characterized by increased peripheral vascular resistance and persistent high blood pressure.
Cortisol Cortisol exerts its effect by regulating gene transcription after binding to glucocorticoid receptors within the cell." Cortisol has a large number of metabolic effects on several tissues. However, many of the effects of glucocorticoids are based on studies of patients, animals, and cells with nonphysiologically high or low levels of glucocorticoids. Glucocorticoids are necessary for maintaining hepatic glycogen stores. They stimulate protein catabolism and lipolysis and cause hyperinsulinemia.' Cortisol is required for maintenance of normal blood pressure. The effect on immunologic function of glucocorticoids in physiologic levels is not clear, but glucocorticoid excess suppresses both immunologic and anti-inflammatory responses. Glucocorticoids have a weak mineralocorticoid effect and influence calcium homeostasis by decreasing intestinal calcium absorption and increasing urinary calcium excretion. I In pharmacologic doses, cortisol causes osteoporosis. The effects of cortisol on the central nervous system manifest as changes in excitability, behavior, and mood. 1
Adrenal Androgens The physiologic effects of DHEA-S, DHEA, and androstenedione are relatively weak, and they undergo conversion to testosterone in peripheral tissue. In females, androgens produced by the adrenal glands sustain normal pubic and axillary hair growth, and after menopause the adrenal glands are a major source of estradiol. However, in males, the high amount of androgens produced by the testis exceeds that produced by the adrenal glands. 1
Adrenal Medulla Chromaffin Cells The adrenal medulla constitutes about 15% of the adrenal and is surrounded by the cortex. The major constituent of the medulla, the catecholamine-containing cells, are of two types: the norepinephrine and the epinephrine cells. These cells are often called chromaffin cells because they stain with chromium salts, and this was an early method used to detect these cella.' Chromaffin cells in adults are primarily confined to the adrenal medulla, although they also occur in extra-adrenal locations. They may give rise to extra-adrenal paraganglioma in the organ of Zuckerkandl (distal aorta), in the bladder, in the neck and, more rarely, at other sites.'? In addition, the adrenal medulla contains sympathetic ganglion cells, connective tissue, and blood vessels. The adrenal medulla has an arterial supply via several small arteries and a venous outflow to the central adrenal vein. The epinephrine cells in the medulla are localized close to the cortex, where they are exposed to high cortisol levels of portal venous effluent. Cortisol is required for the induction of phenylethanolamine N-methyltransferase (PNMT), the methylating enzyme that converts norepinephrine to epinephrine (Fig. 65-3). Chromaffin cells in extra-adrenal locations usually do not produce epinephrine, probably because of a lack of cortisol to activate PNMT.11 The preganglionic cell bodies are located in the intermediolateral cell column in the spinal cord. Their axons pass the sympathetic ganglia and reach the adrenal gland via the splanchnic nerves and innervate the chromaffin cells.
Transmitter Mechanisms SYNTHESIS
The catecholamines are synthesized from tyrosine, which is converted to dihydroxyphenylalaline by the cytosolic enzyme tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis (see Fig. 65-3),12 and further converted to dopamine by dopa decarboxylase. Dopamine is taken up into granular vesicles and converted to norepinephrine via dopamine ~-hydroxylase (DBH). This uptake is an adenosine triphosphate (ATP)-requiring process, in which the uptake of dopamine prevents its degradation by cytoplasmic monoamine oxidase. Norepinephrine is stored in the granular vesicles in a complex where one catecholamine molecule is coupled to four ATP molecules. Certain chromaffin cells contain the enzyme PNMT, which converts norepinephrine to epinephrine. Neuropeptide Y (NPY), enkephalins, somatostatin, and chromogranins are also stored in the granular vesicles.
574 - - Adrenal Gland
I
Norepinephrine
I
I
Epinephrine MAO
MAO
~ COMT
/
I
Dihydroxymandelic acid
COMT
~
MAO
When the adrenal medulla is stimulated, the chromaffin cell membrane depolarizes, secretory vesicles fuse with the cell membrane, and the vesicular content is released via exocytosis.P All components of the granular vesicles are released: catecholamines, DBH, NPY, enkephalins, and chromogranins. Because of a rich vascular supply, most released substances are transported away from the medulla and direct reuptake back into the chromaffin cells only plays a minor role compared to sympathetic nerves. The physiologic importance of the released substances in addition to catecholamines is not clear. NPY has been shown to have vasoconstrictive effects, although it is much weaker than the catecholamines.!" Enkephalins may function as analgesics during stress. 15 The chromogranins may be of importance for storage of neurotransmitters and may also serve as peptide precursors. 16 DEGRADATION
The degradation of norepinephrine and epinephrine is shown in Figure 65-4. Monoamine oxidase is present in mitochondria of most cells and catalyzes the deamination of catecholamines. Catechol O-methyltransferase induces methylation of catecholamines or their deaminated metabolites to the major final product, vanillylmandelic acid. In the liver and gut, conjugation with sulfuric or glucuronic acid takes place, and these substancesare then excreted in the urine. Only a small amount is excreted as free dopamine, norepinephrine, and epinephrine in the urine.
Determination of Release from the Adrenal Medulla Free urinary catecholamines most likely reflect an estimation of the sympathoadrenal activity during the sampling period. In urine, vanillylmandelic acid and metanephrine levels also give a good indication of adrenal medulla catecholamine secretion. Plasma catecholamines are usually determined as unconjugated free and protein-bound levels. Under basal conditions, only a small amount of plasma norepinephrine
COMT
IMetanephrine I
INormetanephrine I
SECRETION
I
~
~
FIGURE 65-3. Synthesis of catecholamines in the adrenal medulla. DOPA = dihydroxyphenylalaline.
I
I
MAO
/
Vanillylmandelic acid
I
FIGURE 65-4. Degradation of norepinephrine and epinephrine. MAO = monoamine oxidase; COMT = catechol O-methyltransferase.
(normal, 0.6 to 2 nmol/L) originates from the adrenal medulla, because the major part of the norepinephrine is secreted from the sympathetic nerves. In contrast, plasma epinephrine (normal, 0.1 to 0.3 nmol/L) is secreted only by the adrenal medulla. The half-life of plasma epinephrine and norepinephrine is very short (l to 2 minutes), and the variations in plasma norepinephrine are a reflection of variations in sympathetic tone. Because of the effective mechanism for reuptake into sympathetic nerves, venous plasma catecholamines show variations related to the sampling site. More recently, measurement of plasma normetanephrine and metanephrine has been shown to be more reliable for evaluating hypersecretion of catecholamines from the adrenal medulla because their half-life in plasma is much longer than norepinephrine and epinephrine. I?
Physiologic Effects Catecholamines exert their effect on specific adrenergic receptors. These receptors are transmembrane proteins known to be encoded by separate genes. Initially a- and ~-adrenergic receptors were identified and their subtypes have been characterized. The at receptors mediate vascular stimulation smooth muscle contraction. ~l-receptor increases heart rate and myocardial contractility, whereas ~2 receptors are involved in smooth muscle relaxation. The ~3 receptors regulate lipolysis and energy expenditure. Catecholamines influence almost all tissues and organs in the body. Catecholamines have profound cardiovascular and metabolic effects and also influence the secretion of many hormones.t The major effects are cardiovascular, with contraction of blood vessels and increasing heart rate and force. Catecholamines also exert effects on extravascular smooth muscle, causing both contraction and relaxation. In addition, catecholamines affect metabolism by increasing oxygen consumption and heat production, and they also regulate the mobilization of glucose and fat stores.
Adrenal Physiology - -
Basal secretion of catecholamines from the adrenal medulla is low. Substantial stimulatory conditions such as trauma and surgical stress are required to increase catecholamine secretion from the adrenal medulla. The release of epinephrine is of interest in special conditions. IS Epinephrine is released from the adrenal medulla during an operation at the time of intubation and skin incision. High levels of epinephrine are also found during traumatic events, such as myocardial infarction and pain or fear. During severe hypoglycemia, epinephrine levels may be up to 50 times the basal level, owing to stimulation of glucose-sensitive neurons in the central nervous system.
Summary The adrenal gland has two functioning endocrine units, the cortex and the medulla. The cortex secretes corticosteroids, including the major glucocorticoid, cortisol, and the major mineralocorticoid, aldosterone. The cortex also secretes DHEA-S and, to a lesser extent, androgens and estrogens. Glucocorticoids are necessary for life, and their secretion is regulated by the hypothalamic-pituitary-adrenal axis. The medulla primarily secretes the catecholarnines epinephrine, norepinephrine, and dopamine.
REFERENCES I. Genuth SM. The adrenal gland. In: Levy NM, Berne RM (eds), Physiology. SI. Louis, Mosby 1998, p 930. 2. Brown M, Korvanen P, Goldstein J. Receptor-mediated uptake of lipoprotein-cholesterol and its utilisation for steroid synthesis in the adrenal cortex. Rec Progr Horm Res 1979;35:215.
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3. Quinn S, Williams G. Regulation of aldosterone secretion. Annu Rev PhysioI1988;50:409. 4. Berridge M. Inositol triphosphate and calcium signalling. Nature 1993;361:315. 5. Greenspan FS, Gardner DG. Basic and Clinical Endocrinology. New York, McGraw-Hill, 2001. 6. Gill G. ACTH regulation of the adrenal cortex. Pharmacol Ther 1976;2:313. 7. Simpson E, Waterman M. Regulation of the steroidogenic enzymes in the adrenal cortical cell by ACTH. Annu Rev PhysioI1988;50:427. 8. Horisberger J, Rossier B. Aldosterone regulation of gene transcription leading to control of ion transport. Hypertension 1992; 19:211. 9. Gustafsson J-A, Carlstedt-Duke J, Poellinger L, et al. Biochemistry, molecular biology of the glucocorticoid receptor. Endocr Rev 1987;8:185. 10. Manger WM, Gifford RWJ. Pheochromocytoma. New York, SpringerVerlag, 1977. II. Wurtman R, Axelrod J. Control of enzymatic synthesis of adrenaline in the adrenal medulla by adrenal cortical steroids. J Bioi Chern 1966;241:2301. 12. Kopin I. Catecholamine metabolism and the biochemical assessment of sympathetic activity. Clin Endocrinol Metab 1977;6:525. 13. Dahlstrom A, Belmaker S, Sandler M (eds). Part A: Basic aspects and peripheral mechanisms. In: Progress in Catecholamine Research. New York, Wiley, 1988, p 279. 14. Lundberg 1M, Torssell L, Sollevi A, et al. Neuropeptide Y and sympathetic vascular control in man. Regul Pep 1985;13:41. 15. Lewis JW, Tordoff MG, Sherman IE, et al. Adrenal medullary enkephalin-like peptides may mediate opioid stress analgesia. Science 1982;217:557. 16. Winkler H. The adrenal chromaffin granule: A model for large dense core vesicles of endocrine and nervous tissue. J Anat 1993;183:237. 17. Eisenhofer G, Lenders JW, Linehan WM, et al. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 1999;340:1872. 18. Halter J, Pfug A, Porte OJ. Mechanism of plasma catecholamine increases during surgical stress in man. J Clin Endodrinol Metab 1977;45:936.
Adrenal Imaging Procedures Andreas Zielke, MD • Matthias Rothmund, MD
Modalities for Imaging the Adrenal Gland Evaluation of a patient with an adrenal gland mass is founded on a thorough history and physical examination, followed by appropriate biochemical tests. After the diagnosis has been established, imaging procedures are used for localization and presurgical planning. Improvements of functional and anatomic imaging procedures allow reliable preoperative evaluation of virtually all adrenal masses. Computed tomography (CT) and magnetic resonance imaging (MRI) are the main modalities used to localize adrenal tumors. The best radiologic imaging test is CT scanning, and it is usually the only imaging study required. In this chapter, we review adrenal imaging techniques and discuss their indications and limitations. We also present flowcharts showing how the most prevalent adrenal diseases, including incidentaloma of the adrenal gland, should be approached.
Computed Tomography CT is the modality most commonly used to evaluate a patient suspected of having an adrenal mass.' CT accurately delineates the location, size, and configuration of the mass; local invasion; and affected adjacent lymph nodes or distant metastases.' For routine applications, l-cm contiguous scans in the adrenal area are usually obtained. For smaller masses (e.g., in primary hyperaldosteronism) thinner scans, such as 0.5-cm slices, are necessary. The normal right adrenal gland is a comma-shaped gland of roughly I x 2 x 0.5 cm, and the left adrenal is a lambda-shaped gland of roughly similar size. The normal adrenal gland is approximately the same size as the diaphragmatic stripe seen on CT (Fig. 66-1). The right adrenal gland is usually directly posterior to the inferior vena cava, and the left adrenal is anterior to the upper portion of the kidney and adjacent to the aorta. Although intravenous contrast material is not routinely used, it is useful for differentiating vascular structures from the adrenal or for enhancement characterization of adrenal tumors. Oral contrast media to opacify bowel may be required for extra-adrenal pheochromocytomas and for delineation of adrenal carcinomas. Despite the merits of CT scanning, it lacks specificity. For example, adrenal
576
adenomas, carcinomas, and pheochromocytomas cannot be differentiated by plain CT scanning. Cysts and myelolipomas are the only conditions that are reliably diagnosed by CT. In cases of Addison's disease, CT scanning may reveal atrophy;' but as exemplified in this condition, much of its capacity to differentiate one lesion from another is based on size rather than specific tissue characteristics.' False-negative examinations result largely from trying to image tumors smaller than 1 em in diameter.
Magnetic Resonance Imaging MRI is increasingly used because it can reveal tissue-specific characteristics, which allows the examiner to differentiate metastases, adrenocortical carcinoma, and pheochromocytoma from adenoma, lipoma, myelolipoma, and cysts." Because MRI does not use ionizing radiation, it is an attractive modality for evaluating children and pregnant women." Tl-weighted images allow relatively fast data acquisition, which may be accelerated by using paramagnetic contrast media such as gadolinium-diethylenetriaminepenta-acetic acid (DTPA), resulting in a reduction of motion artifact and increasing the sensitivity for identifying adrenal lesions. T2-weighted sequences reveal characteristic signal intensities in certain conditions and help with the differential diagnosis." Some studies have suggested that MRI can differentiate nonfunctioning from malignant adrenal lesions," but because of similar characteristics of some tumors, the results are not reliable enough to use in selecting therapy.S?
Adrenal Scintigraphy Adrenal scintigraphy provides localization and functional information and is therefore helpful for differentiating certain adrenal neoplasms. Scintigraphy is often used in conjunction with CT or MRI because it offers much less anatomic information than other modalities. Numerous radiolabeled pharmaceuticals are being investigated to provide improved localization tests for the adrenal cortex and medulla. Iodocholesterol-labeled analogs such as l31I-6~-iodomethyl 19-norcholesterol (NP-59) and 75Se-6~-selenomethyl cholesterol are used to scan the adrenal cortex.V' Studies using NP-59 make use of the fact that adrenal lesions can be distinguished on the basis of intact steroidogenesis pathways and
Adrenal Imaging Procedures - - 577
noninvasive, and involving no ionizing irradiation, which makes it attractive for evaluating children and pregnant women. For children, ultrasonography has been very effective, whereas in adults, visualization of the right adrenal is successful in approximately 90% of cases and for the left the success rate is only 75%.14 Ultrasonography delineates lesions of 2 em or larger and is helpful in differentiating cysts from solid masses and in evaluating involvement of large vessels and liver metastases. 15 Ultrasonography is an ideal screening modality for adrenal neoplasms and for following the progression of adrenal masses. Ultrasonography is not as accurate as CT. It requires an experienced interpreter and is notoriously operator dependent.'
Arteriography and Adrenal Venography
FIGURE 66-1. CT images of normal adrenal glands. A, The medial limb of the right adrenal gland (arrow) is dorsal to the inferior vena cava and ventral to the upper pole of the kidney. B. The left adrenal gland (arrow) has an inverted V appearance. (From Davidson AJ, Hartman DS. Radiology of the Kidney and Urinary Tract, 2nd ed. Philadelphia, WE Saunders, 1994, p 716.)
the presence of abundant intracellular cholesterol. However, imaging requires several days, which is unacceptable in some cases. Moreover, in several comparative studies, CT required less time to perform and interpret, cost less, used less ionizing radiation, and provided similar diagnostic accuracy. to Metaiodobenzylguanidine (MIBG) is the most frequently used radionuclide for imaging the adrenal medulla. MIBG is an analog of guanethidine. It is taken up by adrenergic granules and adrenal medulla cells because of its structural similarity to norepinephrine. However, it has essentially no pharmacologic effect. II Because MIBG is concentrated in catecholamine storage vesicles, it allows functional assessment of adrenal medullary tissue and is diagnostic for pheochromocytomas." Iodine 131 MIBG is the most commonly used isotope, but 123I_MIBG has resulted in more accurate delineation of pathologic tissues than 13II_MIBG and provides superior dosimetry. 13 MIBG studies take 3 days to complete, and their spatial resolution is poorer than that provided by CT scans.
Ultrasonography Controversy exists regarding the efficacy of ultrasonography in the evaluation of adrenal tumors. Ultrasonography offers the particular advantages of being less expensive, being
Considered invaluable tools in differentiating hyperplasia from carcinoma in the 1980s, arteriography and adrenal venography have almost completely been replaced by CT and MR!. In general, these invasive methods should be reserved for the rare instance in which CT or MRI provides insufficient information. Arteriography in patients with pheochromocytoma may be hazardous, and venography may be dangerously invasive, especially in children; it has been associated with significant morbidity in pediatric cases. 15 Selective arteriography, however, may be helpful if it is difficult to determine whether a mass on CT is suprarenal or renal in origin. 16 Venography, often used in combination with selective venous sampling, is employed more often than arteriography. I? Although the method successfully approaches the left adrenal gland in virtually all cases, this cannot always be accomplished for the right gland and demands an experienced radiologist. Venography with selective adrenal sampling is useful in examining patients with hyperaldosteronism or Cushing's syndrome when the clinician cannot discriminate by CT or MRI between hyperplasia and adenoma, and it is occasionally useful for determining the source of ectopic corticotropin (ACTH) production. Complications occur in about 5% of patients and consist mainly of contrast extravasation and hematoma and rarely of adrenal vein thrombosis and adrenocortical insufficiency. I?
Hyperadrenocorticism The most common cause of Cushing's syndrome is exogenous administration of corticosteroids. Regarding the remaining organic causes, approximately 70% of patients with Cushing's syndrome have pituitary Cushing's, resulting in bilateral adrenocortical hyperplasia and cortisol excess. Ten percent have adrenal adenomas, 10% have adrenal carcinomas, and 8% to 10% have ectopic Cushing's or extrapituitary ACTHproducing tumors, including small cell lung cancers, cancers of the pancreas, carcinoid tumors, medullary thyroid cancers, and other neoplasms.
Computed Tomography Studies The initial localizing procedure of choice for patients with adrenal Cushing's syndrome is a contrast-enhanced CT scan
578 - - Adrenal Gland gland, and only few adenomas show contrast enhancement. Large or heterogeneous tumors with areas of low density caused by necrosis or hemorrhage and calcifications should raise the suspicion of carcinoma and prompt a search for local invasion or distant metastases. CT may also be helpful in evaluating hyperplasia (Fig. 66-3). In fewer than half of cases with ACTH-dependent Cushing's syndrome, CT reveals bilaterally enlarged adrenal glands with uniform thickening of both limbs. Careful examination of the entire gland is mandatory for differentiating adenoma from the rare incidence of a dominating nodule in macronodular hyperplasia. The absence of an adrenal tumor and an apparently normal adrenal morphologic pattern on CT in biochemically proven Cushing's disease suggests adrenal hyperplasia.
Other Imaging Modalities FIGURE 66-2. CT scan of an adrenocortical adenoma causing
Perinephric fat provides excellent contrast for MR!. Fast, gadolinium-enhanced MRI can detect lesions less than I em in diameter, but it provides little additional information if a CT examination has already been performed. Ultrasonography may be difficult to perform in cases of Cushing's syndrome because of the truncal obesity of the patients. Ultrasonography can identify large tumors, but it is of limited value as a routine adrenal imaging modality for these patients. Adrenal venography with selective venous sampling for cortisol allows differentiation of adrenal tumors (i.e., unilateral peak cortisol concentrations) from hyperplasia (i.e., bilateral increased cortisol concentration). Selective venous sampling, however, is unable to differentiate malignant from benign adrenal lesions, although malignant tumors are more likely to secrete multiple hormones.'?
Cushing's syndrome. Contrast-enhanced CT depicts a 2.5-cm, solid, homogeneous, well-delineated left adrenal tumor. The diagnosis of adrenocorticism was established biochemically.
of 10-mm collimation, with even narrower collimation in equivocal cases. CT can detect virtually all adrenal masses that are large enough to cause Cushing's syndrome. The abundant perinephric fat in most patients with corticoid excess allows the adrenal gland to be displayed clearly, and tumors at least I em in diameter are identified routinely (Fig. 66-2). Adrenal adenomas causing Cushing's syndrome are usually 2 to 5 em in diameter, and CT detection approaches 98%.18 The density, although variable, is mostly similar to the soft tissue density of the adjacent adrenal
Clinical Suspicion of Cushing's Syndrome Biochemistry
I
I
ACTH dependent
I
ACTH independent
I
I
No further adrenal imaging
CT
FIGURE 66-3. The flowchart
I
Typical adenoma or typical carcinoma
shows the procedures used in imaging the adrenal glands for a possible case of Cushing's syndrome. ACTH = corticotropin; 19NP-59 = l3lI-6~-iodomethyl norcholesterol.
I
Equivocal or suspected hyperplasia
I
I
Scintigraphy-NP-59 uptake
I
Surgery None (cancer)
I
Surgery
Bilateral (hyperplasia)
I
Observe/treat
Unilateral (adenoma)
I
Surgery
Adrenal Imaging Procedures - -
579
Because abdominal CT provides excellent results, adrenocortical scintigraphy using NP-59 is recommended only for selected patients. NP-59 scintigraphy has been recommended in cases of adrenal hyperplasia, for which it has an overall accuracy of 90% to 95% in experienced hands. Scintigraphy is performed without dexamethasone suppression, and images are obtained 5 to 7 days after administration of the tracer. Bilateral uptake suggests adrenal hyperplasia, and unilateral uptake, secondary to contralateral adrenal suppression, indicates an adrenal adenoma. Bilateral nonvisualization of the adrenals has been associated with carcinoma because of the lack of tracer uptake by malignant tumors.v" However, other factors resulting in bilateral nonvisualization, such as hypercholesterolemia and glucocorticoid administration, should be excluded. NP-59 scintigraphy has failed to gain popularity in many institutions because of limited experience with the isotope, the time required to complete the study, high costs, and the need for an investigational new drug approval for its use. FIGURE 66-4. Contrast-enhanced CT scan of a patient with primary hyperaldosteronism identifies a 1.5-cm-diameter, wellmarginated, rounded adenoma adjacent to the right adrenal gland. The aldosteronoma is isodense with adjacent adrenal tissue. Notice the normal size and appearance (lambda shape) of the left adrenal gland.
Primary Hyperaldosteronism Seventy-five percent of patients with primary hyperaldosteronism have benign adrenal adenomas, and 25% have idiopathic hyperplasia of the zona glomerulosa. Fewer than 1% have adrenocortical cancer. In patients with primary hyperaldosteronism, it is essential to determine whether it is caused by an adrenal adenoma or by hyperplasia because virtually all patients with adenomas benefit from surgical treatment (i.e., abatement of hypokalemia and lower blood pressure), but most patients with hyperplasia do not. 20
Because of their small size, these tumors may be missed during CT scanning, resulting in a sensitivity of 85% with a positive predictive value of up to 100%.21,22 Five percent to 15% are not identified, leaving a sizable group of patients for whom scintigraphy and venous sampling playa major role (Fig. 66-5). Isodense small lesions close to the apex of the adrenal are the ones most likely to be missed. If CT reveals a unilateral mass in a patient with biochemically proven primary aldosteronism, no further studies are usually required. If CT findings are negative or equivocal, adrenal venous sampling should be performed, Selective adrenal venous sampling has identified a hypersecreting abnormality in almost 100% of cases in selected series.' Combined CT and selective adrenal venous sampling approaches a sensitivity of 100% in identifying the cause of primary aldosteronism.P In the case of an aldosteronoma,
Localization Studies Aldosteronomas are usually small lesions, averaging 0.6 to 1.8 em in diameter. CT scanning, therefore, requires 0.3- to O.5-mmcontiguous slices in the adrenal area, and the patient's cooperation is necessary for achieving adequate sensitivity.P" Aldosteronomas often appear as well-marginated, rounded tumors that are isodense or, less frequently, hypodense compared with adjacent adrenal tissue (Fig. 66-4). They typically are not enhanced after administration of a contrast agent.
Biochemically Confirmed Primary Hyperaldosteronism
I
CT
FIGURE 66-5. The flowchart shows the diagnostic modalities used in imaging the adrenal glands for a suspected case of hyperaldosteronism. NP-59 = 1311-6~-iodomethyl 19-norcholesterol.
I Typical adenoma or typical carcinoma
I
Surgery
I
I
Equivocal or symmetric enlargement
I
I Scintigraphy-NP-59 uptake I - - - IJ'-------
Early unilateral adenoma
Early bilateral hyperplasia
Surgery
Observe
I
I
I
NP-59 not available
\ Late bilateral or none
I
Nond/agnostic
I
Venous sampling
580 - - Adrenal Gland unilateral peak levels are found on the side of the tumor. In bilateral adrenal hyperplasia, venous sampling yields symmetrically elevated levels. When performing selective venous sampling, the clinician must obtain blood samples for aldosterone and for cortisol.P Simultaneous measurement of cortisol permits verification of the source of the sample and correction for a dislodged catheter or dilution. Venous sampling is considered the "gold standard" for localizing aldosteronomas by several researchers, although most clinicians use it only selectively for patients with equivocal studies.s'
Other Imaging Modalities Immunoiodocholesterol-labeled analogs (e.g., NP-59) have been successfully used to image aldosteronomas.P The sensitivity varies greatly among series (50% to 90%), indicating problems inherent in the technique." Pretreatment with dexamethasone enhances accuracy, and discontinuation of diuretics and antihypertensive agents is required. Unfortunately, the test is time consuming, requiring 2 to 7 days. An asymmetric pattern identifies an aldosteronoma taking up the radionuelide. Idiopathic hyperplasia is functionally depicted as bilateral foci of moderate NP-59 uptake within 72 to 120 hours after administration. Bilateral uptake seen after more than 120 hours during constant dexamethasone suppression is considered nondiagnostic.F Sensitivity depends primarily on the adenoma's size, and the results of NP-59 scans are less accurate for patients with very small adrenal neoplasms and negative CT scans. Small and hypovascular aldosteronomas are also difficult to identify by ultrasonography, MRI, or arteriography.
Pheochromocytoma
normal-appearing adrenal gland, contiguous thin sectioning (0.5- to 1.0-cm slices) is recommended" Pheochromocytomas show a wide range of morphologic patterns; most pheochromocytomas are rounded masses with homogeneous densities similar to or less than that of liver tissue, and they may occasionally show a hemorrhagic, cystic ("Swiss cheese") appearance or calcified lesions (Fig. 66-6). Despite this heterogeneity, diagnosis of malignancy is unreliable unless local invasion or metastases are apparent. The diagnostic capability of CT scanning may be increased with contrast enhancement, but there is a small and unpredictable risk of precipitating a hypertensive crisis, making a-adrenergic blockade before invasive localization studies essential.28 Contrast enhancement of the tumors is irregular; the periphery of these tumors is often more intensely enhanced. Plain CT is highly accurate (-95%) for intraglandular lesions, but it is less useful in identifying extra-adrenal lesions and lesions in MEN patients, for which it is only 60% to 80% sensitive. CT scanning is even less accurate in evaluating patients with metastatic or recurrent disease (sensitivity of about 60%).8.26.28 Contrast enhancement is essential to provide acceptable sensitivity for detecting extra-adrenal pheochromocytomas, especially those in the neck and mediastinum.P CT scanning in combination with MIBG (MIBG-CT) appears to be the procedure of choice for identifying extraadrenal, ectopic tumor locations. MIBG is selectively taken up by the adrenal medulla and by pheochromocytomas and has been especially useful in evaluating ectopic disease and malignant pheochromocytomas (Fig. 66-7). It is the recommended procedure for patients with recurrent or metastatic disease." Some experts recommend MIBG scanning as the initial diagnostic procedure for every patient suspected of
In planning the localization of a pheochromocytoma, one should consider whether the tumor is sporadic or familial and whether the patient is an adult or child. Most pheochromocytomas are sporadic (85%), and 15% are familial and occur in patients with multiple endocrine neoplasia (MEN) type 2, neurofibromatosis, or Sturge-Weber syndrome. Although 85% of the tumors are unilateral, bilateral pheochromocytomas are found in 50% of familial cases. About 15% of pheochromocytomas are malignant and are usually distinguishable clinically only by the absence or presence of local invasion and metastases. Tumors in extraadrenal locations, which are more likely to be malignant, are found in only 15% of adults, but in children the incidence rises to about 25%. Fewer than 2% of tumors are found in the mediastinum, neck, or head.
Localization Studies Because pheochromocytomas have usually attained a considerable size before being discovered, CT28.29 and Tl- and T2-weighted MRI scans reliably detect pheochromocytomas, with an accuracy of almost 100%.8.26 After peroral contrast preparation of the bowel, an abdominal CT scan from the diaphragm distal to the aortic bifurcation is performed as the initial imaging procedure. Because tumors may extend superiorly and inferiorly from an otherwise
FIGURE 66-6. Contrast-enhanced CT scan of a patient with pheochromocytoma manifesting as a rounded mass with density similar to or slightly less than that of liver tissue. The tumor has several cystic lesions, giving it a "Swiss cheese" appearance. Despite this heterogeneity, a diagnosis of malignancy is unlikely.
Adrenal Imaging Procedures - - 581 sequences using gadolinium-DTPA enhancement enable determination of vascular invasion by these tumors." However, because the spatial resolution of MRI is inferior to that of CT, routine scanning should be done with CT. Moreover, CT has greater sensitivity in detecting liver metastases than MRI.
Other Imaging Modalities
FIGURE 66-7. Metaiodobenzylguanidine scanning confirms a left adrenal pheochromocytoma, identified as a mark on top of the left of the two symmetrically depicted kidneys, together with an ectopically located second tumor at the level of the aortic bifurcation (marker).
having pheochromocytoma because this modality detects most
tumors.P:" For diagnostic use, a tracer dose of 0.5 mCi is given, imaging the adrenals in only a few normal control subjects. For localizing primary, metastatic, and recurrent disease, this approach has a false-negative rate of 11.4% and a false-positive rate of 1.8%.35 MIBG has been used for radioablative treatment of unresectable or metastatic pheochromocytomas. Although there have been some good responses, overall, it has been disappointing." Positron emission tomography has been used after administration of 2-fluorine-18-fluoro-2-deoxY-D-glucose (FDG). The method was found promising for localization of pheochromocytomas in the 10% of patients with falsenegative MIBG scintigrams." Pheochromocytomas are localized and characterized by MRI. The approach is at least equivalent to CT for localization of adrenal pheochromocytomas that are larger than 2 em.' Tumors tend to be hyperintense on T2-weighted pulse sequences." Because of the consistency of hyperintensity, recurrent tumor, metastatic disease, and extra-adrenal pheochromocytomas are readily identified, and in this instance MRI is more accurate and sensitive than CT. Moreover, owing to the marked hyperintensity of functioning pheochromocytomas on T2-weighted pulse sequences, MRI permits differentiation of pheochromocytomas from nonfunctioning adrenal neoplasms. Tumors of the urinary bladder or the paracardiac region, which are difficult to evaluate by CT, are clearly recognized by MRI. In one study, T2-weighted MRI and MlBG-CT scans were nearly equivalent for localizing and staging adrenal pheochromocytomas.w" T'l-weighted MRI
In the rare event that these noninvasive techniques fail, arteriography may be useful. However, patients must be treated with a-adrenergic blockade (e.g., phenoxybenzarnine) to should be used in a avoid hypertensive crisis. ~-Blockade patient with tachyarrhythmias whose tumor secretes epinephrine rather than norepinephrine. Arteriography should include the superior, middle, and inferior adrenal arteries and may be enhanced by subtraction techniques, especially in the 15% of tumors displaying no or only moderate hypervascularization. Selective venography and selective venous sampling of veins in the abdomen, pelvis, and chest may very occasionally be useful for diagnosing small lesions, especially intraglandular lesions or tumors at ectopic sites. A positive result allows the physician to narrow the specific region for further anatomic imaging. However, these techniques require great care and may be dangerous (Fig. 66-8).
Incidentalomas of the Adrenal Gland and Adrenocortical Carcinoma The frequent use of imaging procedures, especially ultrasonography and CT, results in the discovery of unsuspected adrenal masses. So-called incidentalomas or adrenalomas are the most common reason the clinician becomes concerned about the adrenal gland. Incidentalomas have been found in 0.6% to 4.3% of patients or at autopsy.42,43 The major concern when evaluating a patient with an incidentaloma is whether the tumor is functioning and whether it is benign or malignant (Fig. 66-9). Certain information helps determine management of patients with incidentalomas. Tumors that are homogeneous, have a smooth contour with well-delineated margins, and are smaller than 4 em on ultrasonography or CT are usually benign. Two thirds of adrenal carcinomas are functioning tumors." Most patients with adrenocortical carcinomas present with tumors larger than 6 em in their greatest diameter at the time of diagnosis.s When metastatic disease to the adrenal is suspected, percutaneous biopsy is useful; however, it is unable to distinguish between an adrenocortical adenoma and carcinoma. Most patients with CT-confirmed diagnoses of simple adrenal cysts or adenomyelolipomas do not require adrenalectomies. The masses should be monitored for growth. The most common cause of nonfunctioning adrenal masses is cortical adenomas, followed by metastases to the adrenals, myelolipomas, ganglioneuromas, adrenal cysts, and a multitude of other rare findings, some of which have specific CT and MRI characteristics. Of all incidentally discovered masses, 6.5% are pheochromocytomas'? and
582 - - Adrenal Gland Biochemically Confirmed Pheochromocytoma Abdominal CT
I
I
I
Negative (adrenal)
Positive (adrenal)
I
I
I
Surgery
I
MIBG Scintigraphy-131I uptake
1--1- - 1
Negative
I
I
Negative
I
PET (FOG) scan
I
I
Positive
MRI (abdomen/chest/pelvis)
Surgery
I
I
Repeat using 1231-MIBG or perform MRI
MIBG not available
I
Negative
I
I
Refer for MIBG
I
Positive
FIGURE 66-8. The flowchart shows the diagnostic procedures used in imaging the adrenal glands for a suspected pheochromocytoma. FDG = 2-fluorine-18-fluoro-2deoxy-n-glucose; MIBG = metaiodobenzylguanidine; PET positron emission tomography.
I
Surgery
Positive
I
Surgery
7% are aldosteronomas." The probability of an incidentaloma being an adrenal adenoma producing excess glucocorticoids is estimated at 0.035%; this number falls to 0.01 % in the absence of hypertension and obesity. Primary adrenal carcinomas, overall, are rare tumors, with an estimated annual incidence of 0.06 to 0.27 per 100,000 persons, resulting in an estimated prevalence of less than 0.06% of all incidentalomas.v
FIGURE 66-9. Contrast-enhanced CT scan shows a right adrenal carcinoma of considerable size (13 x 10 ern). In this carcinoma, areas of low attenuation, suggesting tumor necrosis, are not appreciable, but the tumor is heterogeneous.
Adrenal Adenomas Typically, a nonhyperfunctioning adenoma is a welldelineated, rounded, homogeneous mass. Calcification may occur but is uncommon, as is central necrosis or hemorrhage. The sizes of incidentally detected adenomas range from 0.5 to 6 cm.? However, CT does not reliably differentiate benign adenomas from malignant lesions." Densities range from approximately 0 to 30 HU.47 One study suggested that CT attenuation values may enable one to differentiate nonhyperfunctioning adenomas (:::;5 HU) and metastases from hyperfunctioning adenomas (~16.5 HU); values in excess of 20 HU were indicative of malignancy?" If available, NP59 scintigraphy should be performed because increased tracer uptake by a nonhyperfunctioning lesion detected by ultrasonography or CT (i.e., concordant uptake) indicates that the lesion is benign. Discordant uptake indicates that the lesion is a complex adenoma with hemorrhage or calcification (i.e., decreased, absent, or distorted uptake) or not an adenoma at all, requiring further assessment.48 Adrenal adenomas larger than 1.5 em are reliably detected by MRI, and MRI may be used to characterize an adrenal mass. For example, a decrease in the tumor's signal intensity compared with the liver or fat signal intensity on Tl- and T2-weighted MRI images occurs with adrenal adenomas, but relative increases in signal density occur for carcinomas and functioning adenomas. However, at present, the data are insufficient for directing therapy.'"
Metastases The adrenal gland is a common site of metastatic disease. In a series of 1000 consecutive postmortem examinations of patients with epithelial malignancies, adrenal metastases
Adrenal Imaging Procedures - - 583 were found in 27%.50 Despite the impressive figure, even in patients with a predisposition for metastatic disease, such as those with lung cancer, the most likely cause of an incidentally discovered adrenal mass is adrenal adenoma." However, bilateral, nonfunctioning masses in a patient with known cancer are likely to be metastatic disease. Overall, the radiologic appearance of metastases is not specific. During CT scanning, a metastasis usually appears as a solid mass, and if less than 3 em in diameter, it is often homogeneous. Adrenal metastases may be impossible to differentiate from adenomas, pseudocysts, or inflammatory masses. Features suggesting metastases include larger sizes (>3 em), poor definition of margins or invasion of adjacent tissue, inhomogeneous attenuation (i.e., hemorrhage or necrosis), and a thick, perifocal, irregularly enhancing rim. 52 MRI has been used in differentiating metastatic disease from primary adrenal neoplasms with some success, but indeterminate findings occur for about one third of these patients.P Several studies have suggested that there are intensity cutoff points below which all lesions are adenomas and above which all lesions are carcinomas.s-'! However, the accuracy of MRI as a single modality for determination of the nature of these lesions remains to be proved. It appears that percutaneous fine-needle aspiration biopsy is still the most effective and definitive method for confirming metastatic disease. With experienced cytopathologists, the method gains a positive predictive value of approximately 100% and an overall diagnostic accuracy of 80% to 100%. Adrenal biopsy is an invasive method, and complications may occur, including pneumothorax or bleeding. Pheochromocytoma must be ruled out before needle biopsy is done.
Adrenocortical Carcinoma If adrenocortical carcinoma is suspected on clinical grounds, CT scanning should be performed. Characteristics of adrenocortical cancer, such as poorly defined, irregular, or lobulated margins; large, central areas or multiple, scattered areas of decreased attenuation; irregular contrast
enhancement; and signs of local invasion, are helpful in establishing the diagnosis. 54.55 CT scanning also provides information about local tumor extension, liver metastases, and resectability. Differentiating adrenocortical carcinoma from other lesions is usually not a problem because most carcinomas have attained considerable size at the time of diagnosis (Fig. 66-10).8 MRI may be helpful in evaluating a suspected adrenal carcinoma because a high signal intensity on T2-weighted or gadolinium-DTPA Tl-weighted images supports the diagnosis of malignancy and allows the assessment of vascular extension and venous invasion.v-" This finding may eliminate the need for venography or arteriography.
Summary For patients with Cushing's syndrome and adrenal neoplasms, abdominal CT scanning is almost 100% accurate, and falsenegative results in cases of biochemically proven Cushing's syndrome are rare. For these patients, normal adrenal morphologic patterns seen on CT scans suggest adrenal hyperplasia. When CT and MRI findings are nondiagnostic, adrenocortical scintigraphy using iodocholesterols is helpful. For patients with biochemically proven primary hyperaldosteronism, abdominal CT scanning with contiguous 0.3- to 0.5-cm collimation of the adrenal is the localization procedure of choice. When a unilateral adrenal lesion is identified, no further imaging is necessary. When CT scanning is normal, equivocal, or depicts bilateral adrenal masses, adrenal venous sampling with aldosterone and cortisone testing should be done. For patients with biochemically proven pheochromocytomas, abdominal CT scanning has nearly 100% accuracy. When intravenous contrast enhancement is required, patients must be prepared with (l- and ~-adrenergic blockade. For patients with negative studies or for patients with recurrent or metastatic disease, MIBG or MRI scanning is helpful. MIBG scanning is also the modality of choice for patients with MEN syndromes.
Incidentaloma discovered by US or CT History, physical examination, and biochemical test to assess function
I
FIGURE 66-10. The flowchart shows the diagnostic procedures used in imaging incidentalomas. FNAC = fine-needle aspiration cytology; US = ultrasonography.
I
Hormone-secreting tumor
Hormonally silent tumor
Forfurtherimaging referto other algorithms
Repeat or review CT
I
I
I
I
Cyst Adenolipoma Myelolipoma
Carcinoma
Observe
Surgery
I
I
I
Known malignancy
I
FNAC
I
~
3.5 em
I
Surgery
584 - - Adrenal Gland
Incidentalomas are the most common adrenal tumors requiring evaluation by the clinician. Most masses are benign. When CT scanning fails to show a cyst, adenomyelolipoma, or carcinoma, biochemical studies are necessary to determine whether the tumor is functioning. All functioning adrenal tumors and most nonfunctioning adrenal tumors larger than 4 em in the maximal diameter should be removed, especially if the tumor is heterogeneous and has an irregular contour.
REFERENCES I. Bretan PN, Lorig R. Adrenal imaging---Computed tomographic scanning and magnetic resonance imaging. Urol Clin North Am 1989;16:505. 2. Abrams HL, Siegelman SS, Adams PF, et al. Computed tomography versus ultrasound of the adrenal gland: A prospective study. Radiology 1982;143:121. 3. Glazer GM, Francis lR, Quint L, et al. Imaging of the adrenal glands. Invest Radiol 1988;23:3. 4. Thompson NW, Cheung P. Diagnosis and treatment of functioning and nonfunctioning adrenocortical neoplasms including incidentalomas. Surg Clin North Am 1987;67:423. 5. Greenberg M, Moawad AH, Wieties BM, et al. Extraadrenal pheochromocytoma: Detection during pregnancy using MR imaging. Radiology 1986;161:475. 6. Davidson AJ, Hartmann AS. Imaging strategies for tumors of the kidney, adrenal gland and retroperitoneum. CA Cancer J Clin 1987;37:151. 7. Glazer GM, Woolsey EJ, Borello J, et al. Adrenal tissue characterization using MRI imaging. Radiology 1986;158:73. 8. Beierwaltes WH, Wieland DM, Yu T, et al. Adrenal imaging agents: Rationale, synthesis, formulation and metabolism. Semin Nucl Med 1978;8:5. 9. Thrall JH, Freitas JE, Beierwaltes WH, et al. Adrenal scintigraphy. Semin Nucl Med 1978;8:23. 10. Guerin CK, Wahner HW, Gorman CA, et al. Computed tomography versus radioisotope imaging in adrenocortical diagnosis. Am J Med 1983;75:653. II. Wieland DM, Wu JL, Brown LE, et al. Radiolabeled adrenergic neuron-blocking agents. J Nucl Med 1980;21:349. 12. Sisson JC, Beierwaltes WH, Thompson NW, et al. Scintigraphic localization of pheochromocytomas. N Engl J Med 1981;305: 12. 13. Bomanji J, Conry BG, Britton KE, Reznek RH. Imaging neural crest tumors with 1231 MIBG and CT: A comparative study. Clin Radiol 1988;39:502. 14. Marchal G, Gelin J, Verbenken E, et al. High resolution real time ultrasonography of the adrenal glands: A routine examination? J Ultrasound Med 1986;5:65. 15. Richie JP, Gittes RF. Carcinoma of the adrenal cortex. Cancer 1980;45:1957. 16. Fritzsche P, Andreson C, Cahill P. Vascular specificity in differentiating adrenal carcinoma from renal cell carcinoma. Radiology 1977; 125:113. 17. Dedrick CG. Adrenal arteriography and venography. Urol Clin North Am 1988;16:515. 18. White FE, White MC, Dury PL, et al. Value of computed tomography of the abdomen and the chest in investigation of Cushing's syndrome. Br Med J 1982;284:771. 19. Dunnick NR, Doppman JL, Gill JR, et al. Localization of functional adrenal tumors by computed tomography and venous sampling. Radiology 1982;142:429. 20. Auda SP, Brennan MF, Gill JR. Evolution of the surgical management of aldosteronism. Ann Surg 1980;191:1. 21. Ma JTC, Wang C, Lam KSL, et al. Fifty cases of primary hyperaldosteronism in Hong Kong Chinese with a high frequency of periodic paralysis: Evaluation of techniques for tumor localization. Q J Med 1986;61:1021. 22. Dunnick NR, Leight GS, Roubidoux MA, et al. CT in the diagnosis of primary aldosteronism: Sensitivity in 29 patients. AJR Am J RoentgenoI1993;160:321. 23. Geisinger MA, Zelch MG, Bravo EL, et al. Primary hyperaldosteronism: Comparison of CT, adrenal venography and venous sampling. AJR Am J Roentgenol 1983;141:299.
24. Shapiro B, Grekin R, Gross MD, Freitas JE. Interference by spironolactone on adrenocortical scintigraphy and other pitfalls in the location of adrenal abnormalities in primary aldosteronism. Clin Nucl Med 1994;19:441. 25. Gross MD, Shapiro B, Gerkin RJ, et al. Scintigraphic localization of adrenal lesions in primary aldosteronism. Am J Med 1984;77:839. 26. Herd GW, Semple PF, Parker D, et al. False localization of aldosteronoma by dexamethasone-suppressed adrenal scintigraphy. Clin Endocrinol (Ox±) 1987;26:699. 27. van Erkel AR, van Gils APG, Lequin M, et al. CT and MR distinction of adenomas and nonadenomas of the adrenal gland. J Comput Assist Tomogr 1994;18:432. 28. Radin DR, Ralls PW, Boswell WD Jr, et al. Pheochromocytoma: Detection by unenhanced CT. AJR Am J Roentgenol 1986;146:741. 29. Raisanen J, Shapiro B, Glazer GM, et al. Plasma catecholamines in pheochromocytoma: Effect of urographic contrast media. AJR Am J Roentgenol 1984;143:43. 30. Shin MS, Gupta KL, Ho KJ, et al. Thoracic pheochromocytoma: Computerized tomographic characteristics. South Med J 1986;79:244. 31. Quint LE, Glazer GM, Francis IR, et al. Pheochromocytoma and paraganglioma: Comparison of MR and CT with MIBG scintigraphy. Radiology 1987;165:89. 32. Francis IR, Gross MD, Shapiro B, et al. Integrated imaging of adrenal disease. Radiology 1992; 184: I. 33. Mazley PD, Kim CK, Mahsin J, et al. The efficacy of iodine 123 MIBG as a screening test for pheochromocytoma. J Nucl Med 1994;35: 1138. 34. Dunn GD, Brown MJ, Sapsford RN, et al. Functioning middle mediastinal paraganglioma (phaeochromocytoma) associated with intercarotid paragangliomas. Lancet 1986; 1:1061. 35. Shapiro B, Sisson JC, Eyre P, et al. 1311_MIBG_A new agent in diagnosis and treatment of pheochromocytoma. Cardiology 1985;72(Suppl I): 13. 36. Beierwaltes WHo Update on basic research and clinical experience with MIBG. Med Pediatr OncoI1987;15:163. 37. Shulkin BL, Koeppe RA, Francis lA, et al. Pheochromocytomas that do not accumulate MIBG: Localization with PET and administration of FDG. Radiology 1993; 186:711. 38. Falke THM, vanGils APG, vanSeters AP, Sandler MP. Magnetic resonance imaging of functioning paragangliomas. Magn Reson Q 1990;6:35. 39. Velchnik MG, Alavi A, Kressel HY, Engelman K. Localization of pheochromocytoma: MIBG, CT, MRI correlation. J Nucl Med 1990;30:328. 40. van Gils APG, Falke THM, van Erkel AR, et al. MR imaging and MIBG scintigraphy of pheochromocytomas and extraadrenal functioning paragangliomas. Radiographies 1991; II :37. 41. Smith SK, Turner DA, Matalon DAS. Magnetic resonance imaging of adrenal cortical carcinoma. Urol Radiol 1989; II: I. 42. Abecassis M, McLoughlin MJ, Langer B, et al. Serendipitous adrenal masses: Prevalence, significance, and management. Am J Surg 1985; 149:783. 43. Glazer HS, Weymann PJ, Sagel SS, et al. Nonfunctioning adrenal masses: Incidental discovery on computed tomography. AJR Am J Roentgenol 1982; 139:81. 44. Copeland PM. The incidentally discovered adrenal mass. Ann Intern Med 1983;98:940. 45. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma: Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354. 46. Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990;323:1401. 47. Dunnik NR. Adrenal imaging: Current status. AJR Am J Roentgenol 1990;154:927. 48. Gross MD, Shapiro B, Francis IR, et al. Scintigraphic evaluation of clinically silent adrenal masses. J Nucl Med 1994;34:1145. 49. Mezrich R, Banner MP, Pollack HM, et al. Magnetic resonance imaging of adrenal glands. Urol Radiol 1986;8: 127. 50. Abrams HL, Spiro R, Goldstein N, et al. Metastases in carcinoma: Analysis of 1000 autopsied cases. Cancer 1950;3:74. 51. Oliver TW, Bernardino ME, Miller JL, et al. Isolated adrenal masses in non-small cell bronchogenic carcinoma. Radiology 1984;153:217. 52. Berland LL, Koslin DB, Kenney PJ, et al. Differentiation between small benign and malignant adrenal masses with dynamic increment CT. AJR Am J Roentgenol 1988; 151:95.
Adrenal Imaging Procedures - - 585 53. Chezmar JL, Rabbins SM, Nelson RC, et al. Adrenal masses: Characterization with Tl weighted MR imaging. Radiology 1988; 166:357. 54. Dunnick NR, Heaston D, Halvorsen R, et al. CT appearance of adrenal cortical carcinoma. J Comput Assist Tomogr 1982; 6:978.
55. Hussain S, Belldegrumn A, Seltzer SE, et al. Differentiation of malignant from benign adrenal masses: Predictive indices on computed tomography. AJR Am J Roentgenol 1985;144:61. 56. Falke TH, Peetoom JJ, deRoos A, et al. Gadolinium DTPA enhanced MR imaging of intravenous extension of adrenocortical carcinoma. J Comput Assist Tomogr 1988;12:331.
Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) Dimitrios A. Linos, MD, FACS
Historically, the adrenal tumor that was discovered incidentally, usually during an imaging procedure such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography for symptoms unrelated to adrenal disease, (e.g., back pain) was called an incidentaloma:' As more physicians (and patients on their own) ordered these easily available imaging studies for common diseases potentially related to adrenal pathology (and not the known syndromes), such as mild and nonparoxysmal hypertension, diffuse obesity, and diabetes, an increasingly number of unsuspected (but hardly incidental) adrenal tumors were found. I have proposed that these tumors be included with the true incidentalomas under the broader term adrenaloma because they share the same diagnostic and therapeutic dilemmas.? The term adrenaloma implied that the discovered tumor (incidentally or not) derives from the adrenal but is not obviously an aldosteronoma, a Cushing's syndrome adenoma, a pheochromocytoma, a virilizing or feminizing tumor, or a functioning adrenal carcinoma. Recently, at a State of the Science Conference at the National Institutes of Health Conference, the term clinically inapparent adrenal mass was coined.' The widespread teaching is that most adrenalomas are indolent tumors, nonfunctioning and asymptomatic, causing no harm to the patient.t-' Recent studies, however, have shown that a high percentage of these tumors can be subclinically functioning, causing symptoms milder than those encountered in the well-known adrenal-hyperfunctioning syndromes but still harmful to the patient.v!" Thus, the screening tests of serum potassium, urinary vanillylmandelic acid (VMA), and serum cortisol do not suffice and more detailed and in-depth laboratory investigation is necessary. The fear of adrenal carcinoma that dictated the approach to these tumors in the past (with the main emphasis on the size of the tumor) should be changed to the fear of the subtle function of these usually benign adrenal cortical adenomas with coexistent metabolic pathology (e.g., hypertension, obesity, diabetes).
586
Frequency The overall frequency of adrenal adenomas in 87,065 autopsies in 25 studies was 5.9% (range 1.1% to 32%).15 The frequency of adrenal masses discovered by CT, MRI, or ultrasonography is somewhat lower. Abecassis and associates" in a 2-year period examined 1459 patients and found 63 (4.3%) with adrenal masses. Of those, 19 patients (1.3% of examined patients and 30% of patients with adrenal masses) had adrenalomas. At the Mayo Clinic.!? in a 5-year period, 61,054 patients underwent CT scanning. In 2066 patients (3.4%), an adrenal abnormality was found; among these, 259 patients (12.5%) had an adrenaloma or adrenal lesion larger than 1 em, without biochemical evidence or symptoms suggestive of cortical or medullar hypersecretion or general constitutional symptoms suggestive of malignant disease. Similar findings have been described in more recent studies. 18-2o Thus, in the era of widespread use of highresolution ultrasonography, new-generation CT scans, and MRl, we can anticipate a 5% incidence of adrenalomas.
Pathology Most surgically removed clinically inapparent adrenal masses have been classified as nonfunctioning cortical adenomas.v" Benign masses such as nodular hyperplasia, adrenal cysts, myelolipomas, ganglioneuromas, hematomas, hamartomas, hemangiomas, leiomyomas, neurofibromas, teratomas, as well as infections (tuberculosis, fungal, echinococcosis, nocardiosis) are also included in the pathology of these resected tumors (Fig. 67-1). Potentially lethal neoplasms, however, such as pheochromocytomas and primary carcinomas are always first on the list of resected adrenalomas.P'P' Pheochromocytoma is the most frequently found hormoneproducing adrenaloma that occasionally has a normal preoperative laboratory evaluation.P40) should undergo the fludrocortisone suppression test (0.4 mg every day for 4 days) or the acute saline suppression test (2 L of 0.9% NaCl solution infused intravenously over 4 hours) to confirm the diagnosis. Bilateral adrenal venous sampling with measurements of aldosterone and cortisol levels is the necessary next step to lateralize and determine the subtype of primary aldosteronism to identify the patient who will be cured through surgery.
Screening for Adrenal Carcinoma The risk of a clinically inapparent adrenal mass harboring a primary carcinoma of the adrenal is very low." The annual incidence of the latter has been estimated to range from 1 case per 600,000 to 1 case per 1.6 million persons. Its prevalence is approximately 0.0012%.46 In contrast, metastatic carcinoma to the adrenal is a common finding in patients with lung, breast, colon, and other extra-adrenal malignancies. In published series of surgically resected adrenalomas, the frequency of histologically confirmed primary adrenal carcinoma ranges from 4.2% to 25%.7 The frequency of adrenal metastasis from lung cancer at autopsy ranges from 17% to 38%. In patients with adrenal mass in the setting of extra-adrenal malignancy, the probability of this mass being metastatic ranges from 32% to 73%.5,33,47 SIZE OF TUMOR
The size of a clinically inapparent adrenal mass is frequently used to predict potential malignancy and the need for surgery. Although most clinically treated adrenal malignancies are discovered when they are larger than 6 em in diameter, several reports have described very large tumors that never metastasized and small adrenal tumors that did (Fig. 67-2). In several series, adrenocortical carcinomas with a maximum diameter of 3 em or less have been described. 15,33,37,47 The size of a clinically inapparent adrenal mass as reported on a CT scan is usually smaller than the size reported on the histology report. This underestimation ranges from 16% to 47%.48 In an analysis of the CT and histology reports
590 - - Adrenal Gland one may see a irregular, blurred, heterogeneous tumor with areas of necrosis; such lesions are suggestive of malignancy, especially if enlarged lymph nodes or local invasion is also detected." On MRI studies, one should look for heterogeneously increased, early T2-weighted signal, weak and late enhancement after gadolinium injection, or an intravascular signal identical to the tumor signal. When NP-59 scintigraphy is available, the lack of (or very weak) uptake in the tumor and normal contralateral uptake is suspicious for malignancy. Positron emission tomography (PET) can be used following the administration of 2-deoxy-2[18F]-fluoro-D-glucose (lsF-FDG). The 18F_FDG PET scan is a useful tool confirming isolated metastases and selecting patients for adrenalectomy. It has been used in studies to distinguish between primary and metastatic adrenal lesions, especially in patients with other primary malignancies (Fig. 67-3).50 FINE-NEEDLE ASPIRATION
FIGURE 67-2. This larger than 6 em, clinically inapparent adrenal mass was suspicious for malignancy on CT scan (A) but histologically was proved a benign cortical tumor (8).
of 76 patients with various diseases, we found" that the mean estimated diameter of the adrenal tumor was 4.64 em on the CT report when the real size (pathology report) was 5.96 cm. Further analysis of different CT scans revealed a consistent underestimation in all groups. In the group of adrenal tumors with a maximum diameter of less than 3 em, the mean diameter reported on CT was 2.32 em in contrast to the true histologic size of 3.63 em (P < 0.001). We therefore proposed the formula Histologic size = 0.85 + (1.09 x CT size) to correct the underestimated CT size so as to use the size criterion more accurately." A recent study" showed that the above "Linos formula" turned out to be significantly more accurate than direct radiologic measurements in predicting the real pathologic size of the tumor. IMAGING
In addition to assessing distant metastasis and tumor size, imaging studies may suggest malignancy. On a CT study,
Fine-needle aspiration (FNA) biopsy of a clinically inapparent adrenal mass has a limited role. It is useful in cases of coexistent extra-adrenal carcinoma (usually lung cancer) to confirm the radiologic evidence of adrenal metastasis. In a study by Silverman and coworkers," 3 of 33 FNA specimens that contained "benign" adrenal tissue were later proved to be malignant. Each malignant lesion was smaller than 3 em in diameter. In 14 patients in whom the FNA was nondiagnostic, two masses proved to be malignant. Generally, FNA cannot differentiate cortical adenoma from carcinoma because it cannot detect invasion of the tumor into the capsule. Although it has been suggested that FNA is useful in the differential diagnosis of a cystic adrenal mass, we strongly object to such practice because cystic pheochromocytomas are prevalent. Diagnostic puncture of such a lesion (or of a rare cystic echinococcal parasitic cyst) can be harmful to the patient. The possibility of seeding a malignant adrenal neoplasm in the retroperitoneum is an additional reason that FNA should be discouraged.
Genetic and Molecular Biology Studies Currently, the only accepted criteria to determine whether a clinically inapparent adrenal mass is benign or malignant are metastasis (synchronous or metachronous) and local invasion into adjacent structures. The mapping and identification of genes responsible for hereditary syndromes (e.g., multiple endocrine neoplasia type 1, Li-Fraumeni syndrome) have increased our understanding of adrenocortical tumorigenesis. Oncogenes and tumor suppressor genes involved in adrenal carcinomas include mutations in the p53 tumor suppressor gene. Among those, the Ki-67 index (percentage of immunopositive cells), when above 5%, can be a useful indicator in the differentiation of adenomas from carcinomas.P Adrenal carcinomas are monoclonal, whereas adrenal adenomas may be polyclonal in approximately 25% to 40% of cases." Although these findings do not have direct clinical application, it is hoped that future research will facilitate the diagnosis and predict the natural course of these tumors.
Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) - - 591
FIGURE 67-3. The positron emission tomography scandetected a small isolatedadrenal metastasis (arrow) (witha concurrent negative CT scan) in this 69-year-old man who had been treatedfor mesothelioma in the past. Laparoscopic adrenalectomy allowed full extirpationof this single metastasis.
Management of Clinically Inapparent Adrenal Masses: Surgery Versus Follow-Up Several recent studies that we briefly discussed demonstrated the following: 1. A relatively high percentage of clinically inapparent adrenal masses, especially adrenal cortical adenomas, are subclinically functioning. 2. A relatively high percentage of patients with a clinically inapparent adrenal mass display pathologic features such as impaired glucose tolerance, insulin resistance, increased blood pressure, high triglyceride levels, low HDL, central fat deposition and reduced trabecular bone mineral density. 3. When adrenalectomy was done in patients who either had proven subclinical hypercortisolism or even truly nonfunctioning tumors, the associated abnormalities and symptoms (e.g., hypertension, obesity, altered glucose tolerance) were normalized or significantly improved. In the era of laparoscopic adrenalectomy that carries a minimal mortality and morbidity, it appears logical to advocate surgery in patients with a clinically inapparent adrenal
mass when 1. There is laboratory evidence for a subclinically functioning tumor. 2. There are associated pathologic features such as hypertension, impaired glucose tolerance (or diabetes), pathologic triglyceride profile, central fat deposition, and reduced bone mineral density. 3. There is clinical and radiologic evidence for primary or solitary metastatic adrenal carcinoma. The age and the anxiety of the patient should also playa role in the decision to operate or not. Conservative management is recommended for those patients with clinically inapparent adrenal mass in whom 1. There is no clinical or laboratory evidence for subclinical function of the tumor. 2. There are no associated symptoms potentially related to the clinically inapparent adrenal mass. 3. There is no suspicion of adrenal carcinoma. In these patients a yearly check-up should be continued for 5 to 10 years with the main emphasis on the possibility that the silent, nonfunctioning tumor may develop hyperfunction. Limited, complete follow-up studies (with repeated radiologic and hormonal evaluation) have been performed on patients with clinically inapparent adrenal masses. Barzon and associates" followed 75 patients with clinically
592 - -
Adrenal Gland
inapparent adrenal mass, for a median of 4 years, and found 9 of them to have enlargement. Overt Cushing's syndrome developed in two patients, subclinical Cushing's syndrome in three, and clinical pheochromocytoma in one. No patient had a malignancy. The estimated cumulative risks for mass enlargement and hyperfunction were 18% and 9.5%, respectively, after 5 years, and 22.8% and 9.5% after 10 years. In another study,55 53 patients with clinically inapparent adrenal masses were followed for 6 to 78 months (median, 24 months). During the follow-up, 22 lesions (41.5%) increased in size and 6 lesions (11.3%) decreased in size or disappeared. No clinically inapparent adrenal mass grew or developed hypersecretion. Thus, during follow-up of the truly nonfunctioning clinically inapparent adrenal masses, yearly hormonal evaluation should be emphasized rather than repeating imaging studies.
What is the Best Surgical Approach in the Management of Clinically Inapparent Adrenal Masses? Traditionally, surgical approaches to the adrenals have been anterior transperitoneal, posterior extraperitoneal, and thoracoabdominal (for large tumors)." The application of laparoscopic techniques in the surgery of the adrenal glands has essentially replaced all traditional open approaches in the same manner as laparoscopic cholecystectomy has replaced traditional open cholecystectomy. Because there are so many benefits associated with the laparoscopic approach, open adrenalectomy should be reserved for very large adrenal carcinomas invading the surrounding tissue. We have compared the anterior, posterior, and laparoscopic approach in 165 patients who underwent adrenalectomy between 1984 and 1994.57 Although in this study we included our early cases and learning experience, the advantages of the laparoscopic approach were clearly shown in terms of morbidity (12.2% in the anterior approach, 8.1% in the posterior approach, and 0% in the laparoscopic approach), mean operating time, mean length of postoperative hospitalization (8.1 vs. 4.5 vs. 2.7 days), and minimal postoperative pain. The lack of long incisions and their immediate and longterm complications (e.g., wound infection, hernia, esthetic dissatisfaction) and the opportunity for an early return to full activity make the laparoscopic approach the procedure of choice for nearly all clinically inapparent adrenal masses, including the laparoscopically removable primary or secondary carcinomas (see Fig. 67_3).31.58 Although the posterior open adrenalectomy has more advantages than the anterior open adrenalectomy, the advantages of anterior laparoscopic adrenalectomy outweigh the advantages of the posterior laparoscopic approach.v-" The anterior (or lateral) laparoscopic adrenalectomyenables the removal of large tumors, the performance of additional procedures (e.g. cholecystectomy), and the performance of bilateral laparoscopic adrenalectomies when indicated. 61.62 We have simplified'< the anterior laparoscopic technique, which has become easier and more "friendly" to the surgeon compared to the originally described techniques.P Thus, more and more surgeons will switch to the laparoscopic approach for the management of adrenal tumors.
Summary The adrenal tumors that are not apparently clinically functioning and often (but not always) are incidentally found (incidentalomas/adrenalomas) are becoming more prevalent and constitute a diagnostic and therapeutic problem. The purpose of the diagnostic approach is to confirm whether these tumors are (1) subclinically functioning and/or (2) suspicious for malignancy. Therefore the diagnostic process should include the following: 1. The short dexamethasone suppression test (2 mg of dexamethasone) followed by the high-dose test (8 mg of dexamethasone) if serum cortisol is greater than 3 ~g/dL to rule out subclinical Cushing's syndrome. 2. Measurement of 24-hour urine metabolites of catecholarnines (metanephrines, normetanephrines) to rule out subclinical pheochromocytoma (when the patient is normotensive). 3. Measurement of the upright aldosterone level to plasma renin activity (PRA) ratio in addition to the potassium level to rule out subclinical aldosteronism (normotensive or hypertensive with normokalemia patient) Because of the recently described association of these adrenal tumors to the metabolic syndrome, we have to add the following diagnostic tests: • Glucose tolerance test • Bone mineral density studies • Body composition and fat distribution by DEXA The suspicion for malignancy or not is mainly supported by the imaging studies (CT, MRI, PET scan, ultrasonography) as well as the size of the tumor. The role of the FNA biopsy is limited and indicated only when a primary malignancy coexists (to rule out metastasis). The clinical application of genetic and molecular biology tests for these tumors is limited. Once the diagnostic evaluation is complete, the therapeutic management dilemma of conservative versus surgical resection is addressed. All tumors that have no laboratory evidence of hypersecretion and no clinical and/or imaging suspicion for malignancy need to be treated conservatively with annual hormonal and imaging study follow-up. All tumors that have laboratory evidence of autonomy and subclinical functioning, especially in patients who belong to the metabolic syndrome (e.g., hypertension, obesity, glucose intolerance) need to be treated surgically. The anterior laparoscopic adrenalectomy offers minimal cost (e.g., less pain, less hospital stay, faster recovery, excellent cosmetic results). Other factors such as the age of the patients and their overall clinical condition and anxiety level will determine the best management of adrenalomas.
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2. Linos D: Adrenaloma: A better term than incidentaloma. Surgery 1989;105:456.
3. Grumbach M. Biller B. Braunstein G, et a1. Management of the clinically inapparent adrenal mass ("incidentaloma"), Ann Intern Med 2003;138:424.
Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) - - 593 4. Young AE, Smellie WD. The adrenal glands. In: Farndon JR (ed), Endocrine Surgery, 2nd ed. London, WB Saunders, 2001, p 123. 5. Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990;323:1401. 6. Barzon L, Boscaro M. Diagnosis and management of adrenal incidentalomas. J UroI2000;163:398. 7. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab 2000;85:637. 8. Terzolo M, Bossoni S, Ali A, et al. Growth hormone (GH) responses to GH-releasing hormone alone or combined with arginine in patients with adrenal incidentaloma: Evidence for enhanced somatostatinergic tone. J Clin Endocrinol Metab 2000;85:1310. 9. Terzolo M, Pia A, Ali A, et al. Adrenal incidentaloma: A new cause of the metabolic syndrome. J Clin Endocrinol Metab 2002;87:998. 10. Rossi R, Tauchmanova L, Luciano A, et al: Subclinical Cushing's syndrome in patients with adrenal incidentaloma: Clinical and biochemical features. J Clin Endocrinol Metab 2000;85:1440. 11. Midorikawa S, Sanada H, Hashimoto S, et al. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin EndocrinoI2001;54:797. 12. Fernadez-Real JM, Engel WR, Simon R, et al: Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours: Study Group of Incidental Adrenal Adenoma. Clin Endocrinol (Oxf) 1998;49:53. 13. Garrapa GGM, Pantanetti P, Arnaldi G, et al. Body composition and metabolic features in women with adrenal incidentaloma or Cushing's syndrome. J Clin Endocrinol Metab 2001;86:5301. 14. Chiodini I, Torlontano M, Carnevale V, et al. Bone loss rate in adrenal incidentalomas: A longitudinal study. J Clin Endocrinol Metab 2001;86:5337. 15. Young WF: Management approaches to adrenal incidentalomas: A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;29: 159. 16. Abecassis M, McLoughlin MJ, Langer B, et al: Serendipitous adrenal masses: Prevalence, significance, and management. Am J Surg 1985;149:783. 17. Herrera MF, Grant CS, van Heerden JA, et al. Incidentally discovered adrenal tumors: An institutional perspective. Surgery 1991;110:1014. 18. Caplan RH, Srutt PJ, Wickus G. Subclinical hormone secretion by incidentally discovered adrenal masses. Arch Surg 1994;129:291. 19. Prinz RA, Brooks MH, Churchill R, et al. Incidental asymptomatic adrenal masses detected by computed tomographic scanning: Is operation required? JAMA 1982;248:701. 20. Glazer HS, Weyman PJ, Sagel SS, et al. Nonfunctioning adrenal masses: Incidental discovery on computed tomography. AJR Am J Roentgenol 1982;139:81. 21. Belldegrun A, Hussain S, Seltzer SE, et al. Incidentally discovered mass of the adrenal gland. Surg Gynecol Obstet 1986;163:203. 22. Mantero F, Masini AM, Opocher G, et al: Adrenal incidentaloma: An overview of hormonal data from the National Italian Study Group. Horm Res 1997;47:284. 23. Linos DA, Stylopoulos N, Raptis SA: Adrenaloma: A call for more aggressive management. World J Surg 1996;20:788. 24. Bitter DA, Ross DS. Incidentally discovered adrenal masses. Am J Surg 1989;158:159. 25. Caplan RH, Kisken WA, Huiras CM. Incidentally discovered adrenal masses. Minn Med 1991;74:23. 26. Cajraj H, Young AE. Adrenal incidentaloma. Br J Surg 1993;80:422. 27. Geelhoed GW, Druy EM. Management ofthe adrenal "incidentalorna," Surgery 1992;92:866. 28. Didolkar MS, Bescher RA, Elias EG, et al. Natural history of adrenal cortical carcinoma: A clinicopathologic study of 42 patients. Cancer 1984;47:2153. 29. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma: Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354. 30. Proye C, Fossati P, Fontaine P, et al. Dopamine secreting pheochromocytoma: An unrecognised entity? Classification of pheochromocytomas according to their type of secretion. Surgery 1986;100:1154. 31. Kebebew E, Siperstein AE, Clark OH, Duh QY. Results of laparoscopic adrenalectomy for suspected and unsuspected malignant adrenal neoplasms. Arch Surg 2002;137:948. 32. Aso Y, Homma Y. A survey on incidental adrenal tumors in Japan. J Urol 1992;147:1478.
33. Terzolo M, Ali A, Osella G, et al: Prevalence of adrenal carcinoma among incidentally discovered adrenal masses: A retrospective study from 1989 to 1994. Gruppo Piemontese Incidentalomi Surrenalici. Arch Surg 1997;132:8. 34. Yamakita N, Saitoh M, Mercado-Asis LB, et al. Asymptomatic adrenal tumor: 38 cases in Japan including seven of our own. Endocrinol Jpn 1990;37:671. 35. Fernadez-Real JM, Gonzalbez J, Ricart W. Metabolic abnormalities in patients with adrenal incidentaloma [Letters). J Clin Endocrinol Metab 2001;86:950. 36. Terzolo M, Osella G, Ali A, et al: Subclinical Cushing's syndrome in adrenal incidentaloma. Clin Endocrinol (Oxf) 1998;48:89. 37. Chidiac RM, Aron DC: Incidentalomas: A disease of modern technology. Endocrinol Metab Clin North Am 1997;26:233. 38. Beuschlein F, Borgemeister M, Schirra J, et al. Oral glucose tolerance testing but not intravenous glucose administration uncovers hyperresponsiveness of hypothalamo-pituitary-adrenal axis in patients with adrenal incidentalomas. Clin Endocrinol 2000;52:617. 39. Barzon L, Scaroni C, Sonino N, et al: Incidentally discovered adrenal tumors: Endocrine and scintigraphic correlates. J Clin Endocrinol Metab 1998;83:55. 40. Dwamena BA, Kloos RT, Fendrick AM, et al: Diagnostic evaluation of the adrenal incidentaloma: Decision and cost-effectiveness analysis. J Nucl Med 1998;39:707. 41. Ito Y, Obara T, Okamoto T, et al: Efficacy of single-voided urine metanephrine and normetanephrine assay for diagnosing pheochromocytoma. World J Surg 1998;22:684. 42. Linos DA: Management approaches to adrenal incidentalomas (adrenalomas): A view from Athens, Greece. Endocrinol Metab Clin North Am 2000;29:141. 43. Gordon RD, Ziesak MD, Tunny TJ, et al: Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin Exp Pharmacol Physiol 1993;20:296. 44. Gordon R, Stowasser M, Rutherfort J. Primary aldosteronism: Are we diagnosing and operating on too few patients? World J Surg 200 1;25:941. 45. Proye C, Jafari Manjili M, Combemale F, et al. Experience gained from operation of 103 adrenal incidentalomas. Langenbecks Arch Surg 1998;338:330. 46. Schteingart DE. Management approaches to adrenal incidentalomas: A view from Ann Arbor, Michigan. Endocrinol Metab Clin North Am 2000;29:127. 47. Linos DA, Avlonitis VS, I1iadis K: Laparoscopic resection of solitary adrenal metastasis from lung carcinoma: A case report. J Soc Laparoendoscopic Surg 1998;2:291. 48. Linos DA, Stylopoulos N: How accurate is computed tomography in predicting the real size of adrenal tumors? Arch Surg 1997;132:740. 49. Fajardo R, Montalvo J, Velazquez D, et al. Correlation between radiologic and pathologic dimensions of adrenal masses. World J Surg 2004;28:494. 50. Yun M, Kim W, Alnafisi N, et al. 18F_FDG PET in characterizing adrenal lesions detected on CT or MR!. J Nucl Med 2001;42: 1795. 5 I. Silverman SG, Mueller PR, Pinkey LP, et al: Predictive value of imageguided adrenal biopsy: Analysis and results of 101 biopsies. Radiology 1993;187:715. 52. Wachenfeld C, Beuschlein F, Swermann 0, et al. Discerning malignancy in adrenocortical tumors: Are molecular markers useful? Eur J Endocrinology 2001; 145:335. 53. Reincke M, Beuschlein F, Slawik M, Borm K: Molecular adrenocortical tumourgenesis. Eur J Clin Invest 2000;30:63. 54. Barzon L, Scaroni C, Sonino N, et al. Risk factors and long-term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab 1999;84:520. 55. Grossrubatscher E, Vignati F, Posso M, Lohi P: The natural history of incidentally discovered adrenocortical adenomas: A retrospective evaluation. J Endocrinol Invest 2001;24:846. 56. Linos DA: Surgical approach to the adrenal gland. In: van Heerden JA (ed), Common Problems in Endocrine Surgery: Recommendations of the Experts. St. Louis, Year Book, 1989, p 349. 57. Linos DA, Stylopoulos N, Boukis M, et al: Anterior, posterior or laparoscopic approach for the management of adrenal diseases? Am J Surg 1997;173:120. 58. Gagner M, Pomp A, Heniford BT, et al: Laparoscopic adrenalectomy: Lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238.
594 - - Adrenal Gland 59. Thompson GB, Grant CS, van Heerden JA, et al: Laparoscopic versus open posterior adrenalectomy: A case-control study of 100 patients. Surgery 1997;122:1132. 60. Ting Ac, Lo CY, Lo CM: Posterior or laparoscopic approach for adrenalectomy. Am J Surg 1998;175:488. 61. Lanzi R, Montorsi F, Losa M, et al: Laparoscopic bilateral adrenalectomy for persistent Cushing's disease after transsphenoidal surgery. Surgery 1998;123:144.
62. Miccoli P, Raffaelli M, Berti P,et al. Adrenal surgery before and after the introduction of laparoscopic adrenalectomy. Br J Surg 2002;89:779. 63. Linos D. Laparoscopic right adrenalectomy. In: van Heerden JA, Farley DF (eds), Operative Techniques in General Surgery, Vol 4. Philadelphia, WB Saunders, 2002, p 304.
Hyperaldosteronism Takao Obara, MD • Yukio Ito, MD • Masatoshi Iihara, MD
Hyperaldosteronism occurs in primary and secondary forms. In this chapter, we describe the characteristic features of primary hyperaldosteronism and discuss the rational surgical management of this disorder. Primary hyperaldosteronism is characterized by excessive secretion of aldosterone from the adrenal gland associated with suppression of plasma renin activity (PRA), which usually results in hypertension and hypokalemia. Conn first described this syndrome in 1954. I Primary hyperaldosteronism is an uncommon but potentially curable cause of hypertension. The development of simplified testing and improvement of localization studies have allowed this condition to be diagnosed accurately and the tumor removed more precisely, Nevertheless, the most appropriate diagnostic approach for selecting surgically curable forms of primary hyperaldosteronism remains a matter of controversy. There are several subtypes of primary hyperaldosteronism. Aldosterone-producing adrenocortical adenoma and idiopathic hyperaldosteronism (bilateral adrenal hyperplasia) are the two most common subsets and account for 95% of all cases.s-' An aldosterone-producing adenoma is usually treated by unilateral adrenalectomy, whereas idiopathic hyperaldosteronism does not respond to surgical treatment and is best managed medically. Uncommon forms of primary hyperaldosteronism include primary adrenal hyperplasia.v' aldosterone-producing carcinoma.s-' and glucocorticoidsuppressible hyperaldosteronism.s-? Primary adrenal hyperplasia is morphologically similar to idiopathic hyperaldosteronism but mimics aldosterone-producing adenoma in response to biochemical tests and unilateral adrenalectomy. Glucocorticoid-suppressible aldosteronism (familial hyperaldosteronism type 1) is familially inherited in an autosomal fashion and is caused by the presence of a chimeric gene, consisting of the regulatory region of a gene coding for the enzyme ll~-hydroxylase (CYPllBl), adrenocorticotropin (ACTH), and the coding region of the gene for aldosterone synthesis (CYPllB2).8 Hence, aldosterone synthesis is primarily regulated by ACTH, resulting in excessive aldosterone production. This condition can be controlled by glucocorticoid administration. Familial hyperaldosteronism type 2 refers to the familial occurrence of
aldosterone-producing adenoma, adrenal hyperplasia, or both.IO,11 The appropriate treatment of primary hyperaldosteronism depends on the correct differential diagnosis of these subtypes.
Pathologic Features Aldosterone-producing adenomas are usually solitary tumors involving only one adrenal gland (Fig. 68-1). Most adenomas are smaller than 2 em in diameter. The mean diameter in 210 patients with surgically proven aldosteroneproducing adenomas in our series was 1.8 em, which is consistent with previous reports. 12 The cut surface usually has a characteristic golden yellow appearance. Microscopically, the typical tumor is mostly composed of large lipid-laden clear cells. In contrast, idiopathic hyperaldosteronism usually affects both adrenal glands and appears as micronodular or macronodular hyperplasia. Despite these typical pathologic features of adenoma and hyperplasia, there is a pathologic continuity between predominant unilateral adenoma and macronodular and micronodular hyperplasia. For instance, the extratumoral cortex of a solitary adenoma is not always normal: it may be hyperplastic or occasionally atrophic. Macroscopic or microscopic nodules often accompany aldosterone-producing adenoma (Fig. 68-2). Of our patients, 19% had multiple macronodules in association with distinct adenoma and an additional 43% had adenoma-associated micronodules.P Other authors have reported similar frequencies (55% and 42%) of macronodular or micronodular lesions associated with adenoma.lv" Macronodular hyperplasia and nonfunctioning cortical nodules associated with adenoma are not always distinguishable histologically. Patients with macronodules associated with adenoma are likely to have severe, prolonged hypertension. In addition, rare cases of bilateral solitary adrenal adenomas'v" and unilateral adrenal hyperplasia'> have been reported. These variable presentations thus reflect the fact that clinical primary aldosteronism is not a single pathologic entity, and they have important clinical implications with regard to therapy.
595
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Adrenal Gland
FIGURE 68-1. Cut surface of an adrenal gland showing a typical aldosterone-producing adenoma.
Clinical Characteristics The diagnosis of primary hyperaldosteronism is usually made between the ages of 30 and 60 years. The disease is more common in women than in men. The ages of the patients in our series ranged from 17 to 74, with a mean of 47.0 years. The female-to-male ratio was 1.5:1 (131:85) in our series, which corresponds to that in most other studies. 17.23 The hypertension of primary aldosteronism is moderate to severe and is indistinguishable from that seen in other disorders. The highest blood pressure recorded in our series was 3001150 mm Hg, and malignant hypertension is rare in this disorder. The duration of hypertension before recognition of hyperaldosteronism is variable. Among our patients, the duration of documented hypertension ranged from 1 to 480 months (median, 104 months), corresponding to that in other reports.17.22.23 The other characteristic symptomsmuscle weakness, cramping, intermittent paralysis, headaches, polydipsia, polyuria, and nocturia-are mainly attributable to hypokalemia. Because many patients were initially treated medically for hypertension by the referring physician without a diagnosis, the precise incidence of symptoms specific for hyperaldosteronism is not always clear. Periodic paralysis has been considered to be a common presenting symptom in Asian patients.v-" In our series, the incidence was approximately 23%. Hyperparathyroidism or prolactinoma coexistent with primary aldosteronism has been reported. Gordon and Stowasser" reported that 14 of 596 patients with primary hyperaldosteronism had hyperparathyroidism, and 4 had pituitary adenoma. In our series, two patients had primary hyperparathyroidism and another had prolactinoma. Some of these patients may have rare multiple endocrine neoplasia (MEN) type 1.26.28 Whether this combination of endocrine disorders represents a variant of MEN or two sporadic conditions is unknown. Family history and testing for gerrnline MEN I gene mutation on chromosome 11 as well as documenting hypercalcemia and hyperparathyroidism should clarify this situation.
FIGURE 68-2. Cut surfaces of adrenal glands removed from patients with primary hyperaldosteronism, showing an adenoma associated with macronodular lesions (arrows) (A) and double adenomas (B). (From Ito Y, Fujimoto Y, Obara T, et aI. Clinical significance of associated nodular lesions of the adrenal in patients with aldosteronoma. World J Surg 1990;14:331.)
Screening for and Diagnosis of Primary Aldosteronism The prevalence of primary hyperaldosteronism in an unselected hypertensive population is probably around 2%,2.29,30 although several studies have reported higher figures of 10% to 15%.31,32 The recent increase in the reported prevalence of primary hyperaldosteronism is likely to reflect improvement in screening methodologies as well as selection bias. Nevertheless, it seems a reasonable idea that primary hyperaldosteronism is more common than previously estimated, not only in white but also in Asian hypertensive patients.3.33.34 Most patients with primary hyperaldosteronism have hypokalemia (serum potassium concentration less than 3.4 mEq/L), especially on sodium loading. Although diuretic therapy itself is the most common cause of hypokalemia in patients with hypertension, these patients should have both PRA and plasma aldosterone concentration (PAC) measured to test for primary hyperaldosteronism. In 7% to 38% of patients with primary aldosteronism, the serum level of
Hyperaldosteronism - - 597
potassium is reported to be normal. 30,35,36 Therefore, normokalemia does not exclude primary hyperaldosteronism, Because of the high proportion of normokalemic patients, Gordon and colleagues'? recommended extending the screening for aldosteronism from hypertensive patients who are hypokalemic or resistant to medical therapy to all hypertensive patients, Furthermore, approximately 1% of patients with incidentally discovered adrenal masses associated with hypertension have aldosteronoma, Consequently, they need to be tested for hyperaldosteronism, Screening for primary hyperaldosteronism can be performed by measurement of both PRA and PAC. Hiramatsu and coworkers" first described the raised ratio of PAC to PRA as a useful screening tool for diagnosis of aldosteroneproducing adenoma among hypertensive patients, Its diagnostic accuracy was soon confirmed by other investigators.Pr'? The cutoff value of the ratio differs from 20: 1 to 50: 1 when expressing PAC in ng/dL and PRA in ng/ml.Zhr, The screening strategy is further improved by using not only the PAC to PRA ratio but also elevated levels of PAC, thus distinguishing primary aldosteronism from other causes of hypertension, Weinberger and Fineberg" found that the use of a PAC to PRA ratio of more than 30 and a PAC value greater than 20 ng/dL provided a sensitivity of 90% and a specificity of 91 % for identification of primary hyperaldosteronism, Young recommended using a PAC to PRA ratio of 20 and greater with a PAC of 15 ng/dL or higher to diagnose primary aldosteronism.Pv" The ratio of PAC to PRA may be a sensitive screening test even in patients still taking antihypertensive drugs." However, because many antihypertensive medications-particularly spironolactone, angiotensinconverting enzyme inhibitors, and diuretics-affect reninaldosterone regulation, they should be discontinued 4 to 6 weeks before diagnostic studies are performed. Some patients require continued use of antihypertensive medication to avoid severe hypertension. Antihypertensive agents such as prazosin, guanethidine, and guanadrel are recommended, The diagnosis of primary aldosteronism can be confirmed in almost all cases if the PAC (normal 2,2 to 15 ng/dL) is increased in conjunction with suppressed PRA (below 0,2 to 0.5 ng/mL/hr) in a hypertensive patient, specifically one who demonstrates hypokalemia. An elevated basal PAC and a PAC to PRA ratio greater than 50: 1 are also reliable criteria for diagnosis.f'-" When the results of hormonal measurements are equivocal, additional tests are helpful. The diagnosis of primary aldosteronism in a suspected case can be confirmed by demonstrating either inability to suppress aldosterone production with a high-sodium diet or inability to stimulate PRA with a low-sodium diet. Both measurement of urinary aldosterone levels during oral administration of salt and measurement of PAC with intravenous salt loading are used to evaluate the lack of suppressibility of aldosterone secretion,3,30,34,35,42 On sodium loading, primary hyperaldosteronism is confirmed if there is a failure to suppress PAC below 10 ng/dL,30 In primary hyperaldosteronism, 24-hour urinary excretion of aldosterone exceeds 12 Ilg,3,34 However, the risk of increasing the intake of sodium in patients with severe hypertension must be carefully considered, Captopril, an angiotensin-converting enzyme inhibitor, has also been used to demonstrate the lack of the suppressibility of
aldosterone.r' but its true value is limited." Fludrocortisone administration is also used as a confmnatory test for primary hyperaldosteronism.l'r" but its validity has not been fully evaluated.f Lack of stimulation of PRA can be demonstrated after diuretic administration (furosemide) and after the patient has been standing for 2 hours, 16
Biochemical Differentiation between Aldosterone-Producing Adenoma and Idiopathic Hyperaldosteronism When the diagnosis of primary hyperaldosteronism has been made, the distinction between a discrete aldosterone-secreting adrenocortical neoplasm and idiopathic hyperaldosteronism remains critical in the selection of patients who will benefit from adrenalectomy; this operation is more likely to correct hyperaldosteronism and hypertension in patients with aldosterone-producing adenoma than in those with idiopathic hyperaldosteronism, Postural response and decrease in aldosterone concentration can be used to differentiate between aldosteroneproducing adenoma and idiopathic hyperaldosteronism related to bilateral hyperplasia." In patients with idiopathic hyperaldosteronism, PAC usually increases after standing for 4 hours, whereas a postural decrease in PAC is characteristic of patients with aldosterone-producing adenoma, This phenomenon is due to the fact that aldosterone-producing adenomas are relatively unresponsive to angiotensin but still follow the corticotropin circadian rhythm, whereas in idiopathic hyperaldosteronism aldosterone production is influenced by the slight increases in PRA and cortisol levels that occur in an upright position, Unfortunately, this postural test of PAC for differentiating between aldosterone-producing adenoma and idiopathic hyperaldosteronism is not always reliable because falsenegative results for the postural response of PAC have occurred, 12.13,1 8,47,48 In a review of 16 articles, Young and Klee reported that the accuracy of the postural study was 85% in 246 patients with surgically verified aldosteroneproducing adenomas, 12 In our previous series, many patients with adenoma (43%) showed an anomalous response to the postural test." Presumably, stress during the test caused corticotropin release, which resulted in elevation of PAC. Measurement of plasma 18-hydrocorticosterone (I8-0HB) concentration has also been reported to be useful for determining whether a patient with primary hyperaldosteronism has an aldosterone-producing adenoma or idiopathic hyperaldosteronism.t? A plasma 18-0HB level greater than 100 ng/dL is usually associated with an aldosterone-producing adenoma." However, the assay of 18-0HB is not commonly available, and the cumulative diagnostic accuracy for aldosterone-producing adenoma based on four separate studies was reported to be 82%,12 It appears that none of the currently available biochemical studies can correctly distinguish between patients with idiopathic hyperaldosteronism related to bilateral adrenal hyperplasia and those with aldosterone-producing adenoma with 100% accuracy, Diagnosis of idiopathic hyperaldosteronism
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Adrenal Gland
on the basis of biochemical studies alone would exclude a considerable number of patients with aldosterone-producing adenomas from curable adrenalectomy. Moreover, the subtypes termed primary adrenal hyperplasia and aldosteroneproducing renin-responsive adenoma have been said to be correctable by unilateral adrenalectomy.50 The former exhibits the features of aldosterone-producing adenoma in terms of postural response and 18-0HB excess, and the latter responds to postural stimulation in the same way as idiopathic hyperaldosteronism.50
Localization Studies Localization studies are indicated in all patients in whom the diagnosis of primary aldosteronism has been confirmed because aldosterone-producing adenomas and idiopathic hyperaldosteronism are not always distinguishable by biochemical tests. Visualizing an adrenal tumor or detecting unilateral excessive aldosterone production by means of localization studies greatly facilitates the selection of patients for adrenalectomy. Figure 68-3 is an algorithm for selecting the patients who are most likely to benefit from unilateral adrenalectomy. At most institutions, including our own, the adrenal computed tomography (CT) scan is the initial localizing procedure. An adrenal tumor with homogeneous, negative CT attenuation before and after enhancement is likely to be an aldosterone-producing adenoma (Fig. 68-4). The procedure is noninvasive and can be performed on an outpatient basis. The sensitivity of locating adenomas with the new generation of high-resolution CT scanners ranges from 82% to 90%.12.16.18.51 Young and Klee stated that in a patient with primary hyperaldosteronism, if a solitary unilateral adrenal macroadenoma larger than I ern along with a normal contralateral adrenal
gland is found on CT scanning, no other subtype studies are necessary and unilateral adrenalectomy should be considered.F Doppman and colleagues'? also stated that patients with an obvious unilateral nodule and a normal contralateral gland on CT scanning do not require further localization study. It is also worth noting that, although aldosterone-producing adrenal tumors are rarely malignant, unilateral large (4 em and greater) adrenal tumors are likely to be adrenocortical carcinomas. Although the CT-based diagnosis of adenoma is reliable with acceptable certainty, it is worth noting that the CTbased diagnosis of hyperplasia is unreliable.F The presence of non-aldosterone-secreting nodules in the ipsilateral or contralateral adrenal gland associated with an adenoma may result in a misdiagnosis as hyperplasia. In addition, hyperplasia may be associated with a unilateral macronodule and cause an erroneous diagnosis of an adenoma. Therefore, all patients with unilateral adenomas as small as 1 em or bilateral nodules on CT and those with bilateral normal glands require further localization studies using isotope adrenal scanning or selective adrenal venous sampling for aldosterone and cortisol levels, or both. Adrenal scanning with 13II-6~-iodomethyl-19-norcholesterol (NP-59) during dexamethasone suppression is considered the next choice for locating a hyperfunctioning adrenal gland if CT scan results are not definitive.P>' Problems with adrenal scintigraphy include the requirement of 5 to 7 days for completion and the need to block the thyroid to prevent uptake of radioiodine. Furthermore, the laterality of NP-59 uptake depends primarily on the adenoma size.55 Unfortunately, this technique has insufficient diagnostic accuracy for smaller tumors. Adrenal venous catheterization with blood sampling to measure aldosterone and cortisol concentrations is still the most accurate test for the differential diagnosis of
I Confirmed primary hyperaldosteronism I
...
Unequivocal findings I
• Unilateral adrenal tumor >4-5 cm
I Adrenal CT scan I I
Equivocal findings
~
...
• Unilateral attenuated adrenal tumor >1cm
Lateralized
• No tumor found • Unilateral adrenal tumor
