The Handbook of Endocrine Surgery

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The Handbook of

ENDOCRINE

SURGERY

This page intentionally left blank

The Handbook of

ENDOCRINE

SURGERY Rebecca S. Sippel Herbert Chen

University of Wisconsin School of Medicine and Public Health, USA

World Scientific NEW JERSEY

•

LONDON

•

SINGAPORE

•

BEIJING

•

SHANGHAI

•

HONG KONG

•

TA I P E I

•

CHENNAI

Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.

THE HANDBOOK OF ENDOCRINE SURGERY Copyright © 2012 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher.

ISBN-13 978-981-4293-19-8 ISBN-10 981-4293-19-9

Typeset by Stallion Press Email: [email protected] Printed in Singapore.

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Handbook of Endocrine Surgery

We dedicate this book to our endocrine surgery mentors

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Contents

Contributors Foreword Preface

xix xxxv xxxvii

I. THYROID

1

A. Evaluation Chapter I.A.1: Thyroid Evaluation — Laboratory Testing Jennifer L. Poehls and Rebecca S. Sippel

3

Thyroid Function Tests Thyroid Antibodies Thyroid Tumor Markers Selected References

3 9 11 13

Chapter I.A.2: Thyroid Imaging James E. Wiseman, Lilah F. Morris and Michael W. Yeh

15

Introduction Ultrasound Computed Tomography (CT) Magnetic Resonance Imaging (MRI) Radionuclide Scanning Positron Emission Tomography (PET) and PET/CT Selected References Chapter I.A.3: Thyroid Evaluation — FNA Jennifer B. Ogilvie FNA Technique FNA Results and Significance vii

15 16 21 22 22 23 25 27 27 31

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Contents

Recommendations Selected References

32 38

B. Clinical Management Chapter I.B.1:

Chapter I.B.2:

Chapter I.B.3:

Evaluation of a New Thyroid Nodule Adrienne L. Melck and Sally E. Carty

39

Epidemiology History Physical Examination Laboratory Investigations Imaging Indications for Fine Needle Aspiration Biopsy Thyroid Nodule Management after FNAB Molecular Testing of FNA Specimens Management of a Benign Thyroid Nodule Management of Thyroid Cysts Selected References

39 39 40 42 43 44 45 46 46 47 48

Management of Papillary Thyroid Cancer Dina M. Elaraj and Cord Sturgeon

49

Global Treatment Strategy Controversies in Surgical Management Management of Nodal Metastases Radioactive Iodine TSH Suppression Long-Term Followup Management of Recurrent Disease Selected References

49 49 51 54 56 57 58 60

Management of Medullary Thyroid Cancer Scott N. Pinchot and Rebecca S. Sippel

63

Introduction Management of Sporadic MTC Management of Hereditary MTC Genetic Basis of Hereditary MTC Long-Term Followup Management of Recurrent Disease Selected References

63 64 66 69 73 76 78

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Chapter I.B.4:

Chapter I.B.5:

ix

Management of Follicular and Hurthle Cell Cancer Christopher R. McHenry and Scott M. Wilhelm

79

Introduction Operative Management Postoperative Management Long Term Followup Treatment of Metastatic Disease Selected References

79 81 82 84 86 87

Management of Aggressive Variants and Anaplastic Thyroid Cancers Marlon A. Guerrero and Electron Kebebew

89

Overview 89 Tall Cell Variant of Papillary Carcinoma 91 Insular Thyroid Cancer 93 Columnar Cell Variant of Papillary Carcinoma 94 Diffuse Sclerosing Variant of Papillary Carcinoma 95 Anaplastic Thyroid Cancer 96 Poorly Differentiated Thyroid Cancer 99 Selected References 100 Chapter I.B.6:

Chapter I.B.7:

Management of Thyroid Lymphomas, Metastatic Lesions and Other Rare Tumors N. Gopalakrishna Iyer and Ashok R. Shaha

101

Overview Thyroid Lymphomas Metastatic Disease to the Thyroid Gland Rare Tumors of the Thyroid Gland Selected References

101 101 106 107 108

Hyperthyroidism Geeta Lal and Sonia L. Sugg

109

Introduction Treatment Options Specific Conditions Thyroid Storm Selected References

109 109 116 122 123

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Contents

Chapter I.B.8:

Chapter I.B.9:

II.


Management of Complications of Thyroidectomy 125 Jason Long and Peter Angelos Postoperative Hoarseness Recurrent Laryngeal Nerve (RLN) Injury External Branch of the SLN Injury Selected References Neck Hematoma Selected References Postoperative Hypocalcemia/Hypoparathyroidism Selected Reference Management of Injury to the Thoracic Duct or Chyle Leakage Selected References Other Nerves at Risk of Injury During Thyroidectomy Selected References

125 127 128 128 129 131 131 132 133

Thyroid Hormone Replacement/Adjustment Meei J. Yeung and Jonathan W. Serpell

137

Thyroid Hormone Replacement/Adjustment Selected References

137 143

PARATHYROID

134 134 136

145

A. Evaluation Chapter II.A.1:

Parathyroid Laboratory Testing Denise Carneiro-Pla

147

Introduction Sporadic Primary Hyperparathyroidism (SPHPT) Differential Diagnosis Secondary Hyperparathyroidism Tertiary Hyperparathyroidism Familial Hyperparathyroidism Parathyroid Cancer Bone Mineral Density in Parathyroid Disease Selected References

147 147 150 153 154 154 155 156 156

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Chapter II.A.2:

xi

Parathyroid Imaging Christine S. Landry, Elizabeth G. Grubbs, Beth S. Edeiken-Monroe, Thinh Vu, E. Edmund Kim and Nancy D. Perrier

159

Introduction Imaging Modalities Specific Questions for the Endocrine Surgeon Conclusion Selected References

159 161 167 169 169

B. Clinical Management Chapter II.B.1:

Chapter II.B.2:

Clinical Management of Primary Hyperparathyroidism Joel T. Adler, Rebecca S. Sippel and Herbert Chen

171

Introduction Indications Minimally Invasive Parathyroidectomy Bilateral Exploration Ectopic Glands Intraoperative Nerve Monitoring Conclusions Selected References

171 171 173 175 176 176 177 177

Secondary Hyperparathyroidism Mohamed O. Abdelgadir Adam, Patrick H. Pun and John A. Olson, Jr.

179

Definition Historical Background Epidemiology Pathophysiology Genetic Etiologies Clinical Manifestations Diagnosis Medical Therapy Indications for Parathyroidectomy in SHPT

179 179 180 181 182 183 184 185 187

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Chapter II.B.3:

Chapter II.B.4:


Contents

Preoperative Assessment Preoperative Localization Surgical Strategies Intraoperative PTH Monitoring Surgical Outcomes Disease Persistence/Recurrence Type of Parathyroidectomy Percutaneous Ethanol Injection Summary Selected References

188 188 189 191 191 192 192 193 194 194

Tertiary Hyperparathyroidism Steven E. Rodgers, John I. Lew and Carmen C. Solórzano

203

Introduction Diagnosis Surgical Treatment Management of Recurrent Disease Summary Selected References

203 203 204 207 208 208

Parathyroid Carcinoma Elliot J. Mitmaker and Wen T. Shen

211

Introduction Demographic Data Etiology Clinical Presentation Localization Studies Pathology Operative Management Medical Management and Adjuvant Therapies Prognosis and Outcomes Selected References

211 211 212 212 214 215 217 219 220 220

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Chapter II.B.5:

Chapter II.B.6:

Chapter II.B.7:

xiii

Hyperparathyroidism in Familial Disease Charles Tuggle, Julie Ann Sosa and Robert Udelsman

223

Overview Multiple Endocrine Neoplasia 1 (MEN1) Multiple Endocrine Neoplasia 2A (MEN2A) Familial Isolated HPT (FIHPT) HPT-Jaw Tumor Syndrome (HPT-JT) Neonatal Severe HPT (NSHPT) and Autosomal Dominant Mild HPT (ADMH) Neurofibromatosis Type 1 (NF1) Family Screening and Genetic Testing Genetic Testing and Counseling Selected References

223 223 227 229 231 233 237 238 239 239

Management of Hypercalcemic Crisis Carrie C. Lubitz and Antonia E. Stephen

241

Etiology Definition Clinical Manifestations Acute Treatment Options Selected References

241 242 242 243 247

Postoperative Hypocalcemia Daniel Levin and Jacob Moalem

249

Introduction Thyroid Surgery Parathyroid Surgery Reoperative Neck Surgery Pathophysiology Postoperative Monitoring Treatment of Postoperative Hypocalcemia Summary Selected References

249 249 250 252 252 253 254 260 260

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Chapter II.B.8:


Contents

Cryopreservation and Autotransplantation of Parathyroid Tissue Jennifer McAllaster and Mark S. Cohen

265

Introduction Indications for Parathyroid Autotransplantation and Cryopreservation Methods for Cryopreservation of Parathyroid Tissue Long Term Storage, Viability, and Thawing of Cryopreserved Glands Autotransplantation of Parathyroid Tissue Post-Operative Management Following Parathyroid Autotransplantation Reoperation for Hyperfunctional Autografts Selected References

265 266

III. ADRENAL

266 268 270 271 274 274 277

A. Evaluation Chapter III.A.1:

Chapter III.A.2:

Adrenal Incidentaloma Rashmi Roy and James A. Lee

279

Overview Laboratory Evaluation Radiographic Assessment Selected References

279 279 284 286

Cushing’s Syndrome: Laboratory and Imaging 287 Evaluation Geoffrey B. Thompson and William F. Young , Jr. Introduction Case Detection for Endogenous Hypercortisolism: Who Should be Evaluated for Cushing’s Syndrome? Laboratory Evaluation Subtype Evaluation and Imaging Selected References

287 288

289 291 297

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Chapter III.A.3:

Chapter III.A.4:

xv

Pheochromocytoma Goswin Y. Meyer-Rochow and Stan B. Sidhu

299

Introduction Laboratory Testing Genetic Testing Imaging Evaluation Selected References

299 299 306 309 312

Evaluation and Diagnosis of Hyperaldosteronism Xavier M. Keutgen, Rasa Zarnegar and Thomas J. Fahey III

315

Introduction Diagnosis Additional Laboratory Tests Additional Imaging Studies Selected References

315 316 319 324 327

B. Clinical Management Chapter III.B.1:

Chapter III.B.2:

Laparoscopic Adrenalectomy Avital Harari and Quan-Yang Duh

329

Laparoscopic Transabdominal Approach Retroperitoneal Laparoscopic Approach Selected References

329 337 340

Preoperative and Perioperative Management of Adrenal Lesions Tricia A. Moo-Young and Richard A. Prinz

341

Overview Pheochromocytoma Hyperaldosteronism Cushing’s Syndrome (Hypercortisolism) Adrenal Insufficiency Selected References

341 341 348 350 353 355

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Contents

Chapter III.B.3:

IV.

Adrenal Cortical Cancer Daniel T. Ruan and Matthew A. Nehs

357

Diagnosis of Adrenal Cortical Cancer Prognostic Factors and Determinants of Resectability Operative Management Evaluation and Management of Patients with Metastatic Disease Selected References

357 360

ENDOCRINE PANCREAS

361 362 365 367

A. Evaluation Chapter IV.A.1: Evaluation of Carcinoid Tumors Katherine Heiden and Mira Milas Overview Laboratory Evaluation Imaging Evaluation Summary Selected References Chapter IV.A.2: Evaluation of Insulinoma Jui-Yu Chen, Yi-Fang Tsai, Ling-Ming Tseng and Chen-Hsen Lee Introduction Laboratory Evaluation Imaging Evaluation Selected References Chapter IV.A.3: Evaluation of Gastrinoma Adam S. Brinkman and Clifford S. Cho Introduction Presentation Diagnosis Localization

369 369 370 373 375 375 377

377 378 382 390 391 391 391 392 395

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Chapter IV.A.4: Evaluation of “Other” Neuroendocrine Tumors of the Pancreas Rachel Adams Greenup, Tracy S. Wang and Douglas B. Evans Introduction Glucagonoma Clinical Syndrome of Glucagonoma (Think Catabolism!) Serum Glucagon Levels Vipoma Somatostatinoma PPOMA Selected References

xvii

397

397 397 398 399 399 401 403 403

B. Clinical Management Chapter IV.B.1:

Chapter IV.B.2:

Clinical Management of Midgut Carcinoid Tumors Thomas W. T. Ho and Janice L. Pasieka

405

Overview Midgut Small Bowel Carcinoids Appendiceal Carcinoids Goblet Cell Carcinoids Selected References

405 406 420 421 422

Clinical Management of Insulinoma David T. Hughes, Gerard M. Doherty and Paul G. Gauger

423

Preoperative Considerations Operative Planning and Approach Intraoperative Localization Operative Technique Postoperative Management Special Circumstances Medical Management Selected References

423 423 425 425 426 427 429 429

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Chapter IV.B.3:

Chapter IV.B.4:

Index


Contents

Clinical Management of Gastrinoma Steven K. Libutti

431

Overview Medical Management of Primary Gastrinomas Selected References

431 440 441

Clinical Management of Nonfunctional Neuroendocrine Tumors and Management of Metastatic Disease Jennifer Rabaglia, Shelby Holt and Fiemu Nwariaku

443

Overview Preoperative Evaluation Operative Management of nfPNETS Management of Metastatic and Recurrent Disease Selected References

443 444 448 449 453 455

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Contributors

Mohamed O. Abdelgadir Adam, MD Resident in Surgery Department of Surgery Duke University DUMC 2945 Durham, NC 27710, USA Joel T. Adler, MD Resident, General Surgery Massachusetts General Hospital 55 Fruit Street, GRB-425 Boston, MA 02114, USA Peter Angelos, MD, PHD, FACS Professor and Chief of Endocrine Surgery University of Chicago 5841 S. Maryland Ave, MC 4052 Chicago, IL 60637, USA Adam S. Brinkman, MD Surgical Resident University of Wisconsin School of Medicine and Public Health 600 Highland Avenue Madison, WI 53792, USA

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Contributors

Denise Carneiro-Pla, MD, FACS Assistant Professor of Surgery/Endocrine Surgery Department of Surgery Medical University of South Carolina 25 Courtenay Dr., Suite 7018 Charleston, SC 29425, USA Sally E. Carty, MD Professor of Surgery University of Pittsburgh 3471 Fifth Ave., Suite 101 Kaufmann Bldg. Pittsburgh, PA 15213, USA Herbert Chen, MD, FACS Professor, Chairman of General Surgery University of Wisconsin School of Medicine and Public Health K3/703, Clinical Science Center 600 Highland Avenue Madison, WI 53705, USA Jui-Yu Chen, MD Attending Physician and Instructor National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C. Clifford S. Cho, MD Assistant Professor University of Wisconsin School of Medicine and Public Health K4/752, Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA

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Contributors

Mark S. Cohen, MD, FACS Associate Professor of Surgery and Pharmacology Toxicology and Therapeutics Chief of Endocrine Surgery, Vice Chair for Research and Director Surgical Simulation and Skills Laboratory University of Kansas Medical Center 3901 Rainbow Boulevard Mailstop 2005, Room 4008 Murphy Building Kansas City, KS 66160, USA Gerard M. Doherty, MD Norman W. Thompson Professor of Surgery University of Michigan Medical School University of Michigan Hospital 1500 East Medical Center Drive Taubman Center 2920B Ann Arbor, MI 48109-0331, USA Quan-Yang Duh, MD Professor of Surgery University of California, San Francisco and VA Medical Center, San Francisco 4150 Clement Street San Francisco, CA 94121, USA Beth S. Edeiken-Monroe, MD Professor MD Anderson Cancer Center 1500 Holcombe Blvd. Houston, TX 77030, USA Dina M. Elaraj, MD, FACS Assistant Professor Section of Endocrine Surgery Department of Surgery Northwestern University 676 North St. Clair Street, Suite 650 Chicago, Il 60611, USA

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Contributors

Douglas B. Evans, MD Chairman, Department of Surgery Donald C. Ausman Family Foundation Professor of Surgery Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI 53226, USA Thomas J. Fahey III, MD, FACS Professor of Surgery Weill Cornell Medical College 525 East 68th Street, Room A-1027 New York, NY 10021, USA Paul G. Gauger, MD William J. Fry Professor of Surgery University of Michigan Medical School University of Michigan Hospital 1500 East Medical Center Drive Taubman Center 2920D Ann Arbor, MI 48109-0331, USA Rachel Adams Greenup, MD, MPH Chief Resident, General Surgery Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI 53226, USA Elizabeth G. Grubbs, MD Assistant Professor MD Anderson Cancer Center 1400 Hermann Pressler Drive, Unit 1484 Houston, TX 77030, USA Marlon A. Guerrero, MD Assistant Professor University of Arizona Arizona Health Science Center 1501 N. Campbell Ave. Tucson, AZ 85724-5131, USA

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Contributors

Avital Harari, MD Assistant Professor of Surgery University of California, Los Angeles 10833 Le Conte Ave, Suite 72-232 CHS Los Angeles, CA 90095, USA Katherine Heiden, MD Assistant Professor of Surgery Rush University Medical Center 1725 W. Harrison, Suite 818 Chicago, IL 60612, USA Thomas W. T. Ho, MD Resident-Surgical Oncology Department of Surgery/North Tower University of Calgary 1403 29th Street NW, Calgary Alberta, Canada T2N2T9 Shelby Holt, MD Associate Professor of Surgery University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9156, USA David T. Hughes, MD Assistant Professor of Surgery Albert Einstein College of Medicine Montefiore Medical Center 1400 Bainbridge Ave. Bronx, NY 10467, USA N. Gopalakrishna Iyer, MBBS, PHD, FRCS Consultant Head and Neck Surgeon National Cancer Centre Singapore 11 Hospital Drive, Singapore 169610

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Contributors

Electron Kebebew, MD, FACS Head Endocrine Oncology, Senior Investigator National Cancer Institute 10 Center Drive Bethesda, MD 20892-1201, USA Xavier M. Keutgen, MD Surgery Resident Weill Cornell Medical College 525 East 68th Street, Room A-1027 New York, NY 10021, USA E. Edmund Kim, MD Professor MD Anderson Cancer Center 1515 Holcombe Blvd. Houston, TX 77030, USA Geeta Lal, MD Assistant Professor University of Iowa Hospitals and Clinics 200 Hawkins Drive, 4641 JCP Iowa City, IA 52242, USA Christine S. Landry, MD Surgical Oncology Fellow MD Anderson Cancer Center 1400 Hermann Pressler Drive, Unit 1484 Houston, TX 77030, USA Chen-Hsen Lee, MD, FACS Dean of Medicine, Professor, School of Medicine National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C.

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Contributors

James A. Lee, MD Chief of Endocrine Surgery New York Presbyterian Hospital-Columbia University Columbia University Medical Center Herbert Irving Pavilion Room 819 161 Fort Washington Avenue New York, NY 10032, USA Daniel Levin, MD Surgical Resident University of Rochester Medical Center 601 Elmwood Ave, BOX SURG Rochester, NY 14642, USA John I. Lew, MD Assistant Professor of Surgery University of Miami School of Medicine 1120 NW 14th Street (M875) Miami, FL 33136, USA Steven K. Libutti, MD, FACS Vice Chairman of Surgery Albert Einstein College of Medicine and Montefiore Medical Center 3400 Bainbridge Ave, MAP4 Bronx, NY 10467, USA Jason Long, MD Resident in Surgery University of Chicago 5841 S. Maryland Ave, MC 4052 Chicago, IL 60637, USA

xxv

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Contributors

Carrie C. Lubitz, MD Instructor in Surgery Harvard Medical School Massachusetts General Hospital 55 Fruit Street, Yawkey 7B Boston, MA 02114, USA Jennifer McAllaster, MD Chief Resident, Department of Surgery University of Kansas Medical Center 3901 Rainbow Boulevard Mailstop 2005, Room 4008 Murphy Building Kansas City, KS 66160, USA Christopher R. McHenry, MD Vice Chairman, Department of Surgery MetroHealth Medical Center Case Western Reserve University 2500 MetroHealth Drive Cleveland, OH 44109-1998, USA Adrienne L. Melck, MD, MPH Clinical Instructor in Surgery University of British Columbia Rm. C303 – 1081 Burrard Street St. Paul’s Hospital Department of Surgery Vancouver, BC, V6Z 1Y6, Canada Goswin Y. Meyer-Rochow, MB, CHB, FRACS, PhD Waikato Clinical School University of Auckland Waikato Hospital Private Bag 3200 Hamilton 3240, New Zealand

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Contributors

Mira Milas, MD Associate Professor of Surgery Cleveland Clinic 9500 Euclid Ave Endocrine Surgery F20 Cleveland, OH 44195, USA Elliot J. Mitmaker, MD, MSC, FRCSC Endocrine Surgery Fellow University of California, San Francisco 1600 Divisadero Street, C-347 Mount Zion Hospital, Hellman Building San Francisco, CA 94143, USA Jacob Moalem, MD Assistant Professor, Endocrine Surgery University of Rochester Medical Center 601 Elmwood Ave, BOX SURG Rochester, NY 14642, USA Tricia A. Moo-Young, MD Staff Endocrine Surgeon Northshore University HealthSystems 2650 Ridge Avenue Walgreens Building, Suite 2507 Evanston, IL 60201, USA Lilah F. Morris, MD Longmire Administrative Chief Resident in General Surgery Endocrine Surgical Unit, Division of General Surgery David Geffen School of Medicine at UCLA 10833 Le Conte Ave., 72-229 CHS Los Angeles, CA 90095, USA

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Contributors

Matthew A. Nehs, MD Clinical Fellow in Surgery Harvard Medical School 75 Francis Street, ASBII Boston, MA 02115, USA Fiemu Nwariaku, MD Associate Dean for Global Health Associate Professor of Surgery University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9156, USA Jennifer B. Ogilvie, MD, FACS Assistant Professor of Surgery New York University Langone Medical Center 530 First Avenue, Schwartz Health Care Center, 6H New York, NY 10016, USA John A. Olson, Jr., MD, PhD Associate Professor of Surgery Chief, Section of Endocrine and Oncologic Surgery Department of Surgery Duke University DUMC 2945 Durham, NC 27710, USA Janice L. Pasieka, MD, FRCSC, FACS Clinical Professor of Surgery and Oncology Department of Surgery/North Tower University of Calgary 1403 29th Street NW, Calgary Alberta, Canada T2N2T9

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Contributors

Nancy D. Perrier, MD Professor MD Anderson Cancer Center 1400 Hermann Pressler Drive, Unit 1484 Houston, TX 77030, USA Scott N. Pinchot, MD General Surgery Resident University of Wisconsin-Madison H4/7, Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA Jennifer L. Poehls, MD Department of Medicine Division of Endocrinology, Diabetes and Metabolism University of Wisconsin 2226 UW Health West Clinic 451 Junction Road Madison, WI 53717, USA Richard A. Prinz, MD Vice-Chair of Surgery, Staff Endocrine Surgeon Northshore University HealthSystems 2650 Ridge Avenue Walgreens Building, Suite 2507 Evanston, IL 60201, USA Patrick H. Pun, MD, MHS Assistant Professor of Medicine Department of Medicine (Nephrology) Duke University Medical Center DUMC 2747 Durham, NC 27710, USA

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Contributors

Jennifer Rabaglia, MD Assistant Professor of Surgery University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9156, USA Steven E. Rodgers, MD, PhD Assistant Professor of Surgery University of Miami School of Medicine 1120 NW 14th Street (C232) Miami, FL 33136, USA Rashmi Roy, MD Endocrine Surgery Fellow Department of Endocrine Surgery Johns Hopkins University School of Medicine Johns Hopkins Hospital 600 N. Wolfe Street Blalock 6th Floor, Room 606 Baltimore, MD 21287, USA Daniel T. Ruan, MD Instructor in Surgery Harvard Medical School 75 Francis Street, ASBII Boston, MA 02115, USA Jonathan W. Serpell, MBBS, MD, FRACS, FACS Professor, Monash University Endocrine Surgery Unit Alfred Hospital, Melbourne, Victoria, Australia Department of General Surgery, Level 6 Centre Block Alfred Hospital, Commercial Road, Prahran 3181 Melbourne, Victoria, Australia Ashok R. Shaha, MD, FACS Professor of Surgery Jatin P Shah Chair in Head and Neck Surgery Memorial Sloan Kettering Cancer Center 1275 York Avenue New York, NY 10065, USA

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Contributors

Wen T. Shen, MD, MA Assistant Professor University of California, San Francisco 1600 Divisadero Street, C-347 Mount Zion Hospital, Hellman Building San Francisco, CA 94143, USA Stan B. Sidhu, MD, BS, PhD, FRACS Associate Professor, Endocrine Surgical Unit University of Sydney 202/69 Christie St St Leonards, NSW 2065, Australia Rebecca S. Sippel, MD, FACS Assistant Professor, Chief of Endocrine Surgery Department of Surgery University of Wisconsin School of Medicine and Public Health K3/704, Clinical Science Center 600 Highland Avenue Madison, WI 53792, USA Carmen C. Solórzano, MD Associate Professor of Surgery Vanderbilt University School of Medicine 597 PRB, 2220 Pierce Ave Nashville, TN 37232, USA Julie Ann Sosa, MD, MA Associate Professor of Surgery (Surgical Oncology and Endocrine Surgery) Department of Surgery Yale University School of Medicine TMP 204, 333 Cedar Street New Haven, CT 06520-8062, USA Antonia E. Stephen, MD Instructor in Surgery Harvard Medical School Massachusetts General Hospital 55 Fruit Street, Yawkey 7B Boston, MA 02114, USA

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Contributors

Cord Sturgeon, MD, MS, FACS Associate Professor Director of Endocrine Surgery Department of Surgery Northwestern University 676 North St. Clair Street, Suite 650 Chicago, I1 60611, USA Sonia L. Sugg, MD Associate Professor University of Iowa Hospitals and Clinics 200 Hawkins Drive, 4646 JCP Iowa City, IA 52242, USA Geoffrey B. Thompson, MD Chief, Endocrine Surgery Mayo Clinic 200 1st St SW Rochester, MN 55905, USA Yi-Fang Tsai, MD Attending Physician and Instructor National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C. Ling-Ming Tseng, MD Attending Physician and Assistant Professor National Yang-Ming University Department of Surgery, Division of General Surgery Taipei Veterans General Hospital No. 201, Sec. 2, Shipai Rd., Beitou District Taipei City, Taiwan 11217, R.O.C.

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Contributors

Charles Tuggle, BS Department of Surgery Yale University School of Medicine PO Box 208062, 333 Cedar Street New Haven, CT 06520-8062, USA Robert Udelsman, MD, MBA William H. Carmalt Professor of Surgery and Chair Department of Surgery Yale University School of Medicine Surgeon-in-Chief, Yale-New Haven Hospital FMB 102, 310 Cedar Street New Haven, CT 06510, USA Thinh Vu, MD Assistant Professor MD Anderson Cancer Center 1515 Holcombe Blvd. Houston, TX 77030, USA Tracy S. Wang, MD, MPH Assistant Professor, Division of Surgical Oncology Medical College of Wisconsin 9200 W. Wisconsin Avenue Milwaukee, WI 53226, USA Scott M. Wilhelm, MD University Hospitals of Cleveland 11100 Euclid Avenue Cleveland, OH 44106, USA James E. Wiseman, MD Earl Gales Research Fellow in Endocrine Surgery Endocrine Surgical Unit, Division of General Surgery David Geffen School of Medicine at UCLA 10833 Le Conte Ave., 72-229 CHS Los Angeles, CA 90095, USA

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Contributors

Michael W. Yeh, MD Assistant Professor of Surgery and Medicine (Endocrinology) Endocrine Surgical Unit, Division of General Surgery David Geffen School of Medicine at UCLA 10833 Le Conte Ave., 72-228 CHS Los Angeles, CA 90095, USA Meei J. Yeung, MBBS, FRACS Monash University Endocrine Surgery Unit Alfred Hospital, Melbourne, Victoria, Australia Suite 6, 243 New Street, Brighton 3186 Melbourne, Victoria, Australia William F. Young, Jr., MD, MSC Vice Chair, Division of Endocrinology Mayo Clinic 200 1st St SW Rochester, MN 55905, USA Rasa Zarnegar, MD, FACS Assistant Professor of Surgery Weill Cornell Medical College 525 East 68th Street, Room A-1027 New York, NY 10021, USA

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Foreword

I am honored to be invited to write the foreword for this outstanding and up-to-date book titled Handbook of Endocrine Surgery and edited by Rebecca Sippel, MD and Herb Chen MD. The editors, who are expert endocrine surgeons at the University of Wisconsin, Madison, have assembled a talented group of endocrine surgeons from the USA and Australasia as authors. This very practical and clinically oriented book provides valuable information for surgeons who care for patients with endocrine surgical problems. The authors present concise information regarding the preoperative evaluation, surgical technique, approach and decisions on how to avoid complications, and how to manage postoperative problems when they occur. Endocrine surgery is a rapidly evolving specialty of general surgery and head and neck surgery. Recent publications document that patients operated upon by surgeons who perform more endocrine surgical operations have fewer complications than when the same operations are performed by less experienced surgeons. Most major medical centers in the USA and worldwide now have endocrine surgical teams that work closely with endocrinologists, nuclear medicine physicians, radiation therapists, cytologists, pathologists and basic scientists. National and International Endocrine Surgical meetings have been established and are growing rapidly. We must be thankful for the contributions to endocrine surgery by Drs. Theodor Kocher, William Halsted, Harvey Cushing, George Crile, Frank H. Lahey. Charles Mayo, Oliver Cope, Selwyn Taylor, Richard Wellbourn, Per-Ola Granberg, Leon Goldman, Oliver H. Beahrs, Norman Thompson, Charles Proye, Hans Roeher, Thom Reeves, Samuel A. Wells,

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Edwin Kaplan and many other surgeons who have helped to improve the care of patients with endocrine surgical disorders. This book by Drs. Sippel and Chen helps follow this rich tradition.

Orlo H. Clark, MD Professor of Surgery University of California San Francisco

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Preface

While endocrine surgery is a field that demands meticulous operative technique and close attention to detail, it requires just as much if not more in the preoperative and postoperative management of patients. As endocrine surgeons we are not merely technicians removing a thyroid or a parathyroid, but physicians that are curing diseases of the endocrine system through surgery. What separates us from other surgeons that may do the same technical operation is that we understand the diseases we are operating on and how to determine who needs an operation, what operation should be done, and how to best care for the patient before and afterwards. Much of what we know about the practice of endocrine surgery isn’t learned from reading journal articles or book chapters; it was learned from our mentors, who helped to train us in both the art and science of endocrine surgery. It is the clinical pearls that our mentors taught us of “how I do it” that is at the essence of this book. Residents and fellows are taught what tests to order and what is in the differential diagnosis, but when it comes down to interpreting those tests or figuring out how to actually rule out those other conditions in the differential diagnosis they often struggle to find a reference that could help in the actual day to day clinical world. They may know that a patient with suspected Cushing’s syndrome needs to get a dexamethasone suppression test, but don’t really know what that means. When do you give the steroids, when do you check the labs, how do you interpret the results, do you need to stop any medications? There are plenty of books and references that will tell you the correct test to order, but few that tell you exactly how to do it or how to interpret it. Hence the goal of this book is to be a reference that can answer those questions. This book is designed to be a very practical and clinical relevant reference that can guide the

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practicing surgeon through the work up and management of patients with surgical endocrine diseases. The book is divided into four main sections focusing on Thyroid, Parathyroid, Adrenal, and Endocrine Pancreas. Each section is divided into two parts with the first part focusing on diagnosis and the second part focusing on clinical management. The authors of this book are leaders in endocrine surgery both past, present, and future. They share the wisdom of their experience and knowledge, as well as their mentors, and help to shape your understanding of the diseases that they treat. The authors have incorporated the latest tests and techniques and shared their practical experience of “how they do it.” We are grateful to the many contributors to this text. This book represents the efforts of many people whom we consider friends and colleagues as well as leaders in the field. They have put forth a great effort into their contributions and it is our hope that you will appreciate their knowledge and effort and find this text an invaluable resource in your day to day practice.

Rebecca S. Sippel, MD and Herbert Chen, MD

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THYROID


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Chapter I.A.1: Thyroid Evaluation — Laboratory Testing Jennifer L. Poehls, MD and Rebecca S. Sippel, MD, FACS

THYROID FUNCTION TESTS Overview Thyroid-stimulating hormone (TSH) is produced by the anterior pituitary gland and is responsible for thyroid cell growth and hormone production by binding to the TSH receptor on the thyroid cell. TSH secretion is regulated by thyrotropin-releasing hormone (TRH) from the hypothalamus and serum levels of thyroid hormone (T3 and T4). TRH promotes the synthesis and release of TSH. TSH stimulates the production and release of T4 from the thyroid. T4 is converted to T3 in the tissues. High levels of T3 and — to a lesser extent — T4 negatively feed back to the hypothalamus and anterior pituitary to inhibit TRH and TSH secretion. Low levels of thyroid hormone stimulate TRH and TSH release (Fig. 1). TSH (Normal Range 0.4–5.50 mU/L) Serum TSH is the most common test used to screen for thyroid dysfunction, including hypothyroidism and hyperthyroidism. Mild degrees of thyroid dysfunction can be identified with TSH. A normal TSH excludes hyperthyroidism and primary hypothyroidism. Advantages The immunoassay has high sensitivity, wide availability, and low cost, making it a good screening test. 3


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J. L. Poehls and R. S. Sippel _ HYPOTHALAMUS TRH + _ T3

ANTERIOR PITUITARY

Peripheral tissues

TSH + THYROID

Fig. 1

T4 T4/T3

Hypothalamic-pituitary–thyroid axis.

Limitations Changes in serum TSH lag behind changes in T4/T3 levels. In the setting of primary hypothyroidism, TSH should not be checked unless it has been at least 6–8 weeks since the last levothyroxine dose change was made. It may take many weeks to correct the TSH after initiation of treatment for hyperthyroidism, so free thyroid hormone levels should be monitored instead for treatment adjustments. Measuring TSH alone is not appropriate when central hypothyroidism is suspected. Free hormone levels in addition to normal or low TSH are required for diagnosis and for monitoring treatment of central hypothyroidism. Test interpretation (Table 1) Causes of increased TSH: • • • •

Primary hypothyroidism (high TSH, low T4) Subclinical hypothyroidism (TSH of 5–10 with normal T4) TSH-secreting tumor (rare) (high TSH, high T4) Isolated pituitary resistance to thyroid hormone (rare)

Causes of decreased TSH: • •

Hyperthyroidism/thyrotoxicosis (low TSH, high T4/T3) Excess exogenous thyroid hormone (low TSH, normal/high T4)


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Interpretation of thyroid function tests.

Cause Primary hypothyroidism Subclinical hypothyroidism Central hypothyroidism Thyroid hormone resistance TSH-secreting tumor Decreased thyroxine-binding globulin or Drugs: phenytoin, carbamazepine Increased thyroxine-binding globulin or Decreased conversion of T4 to T3 (amiodarone, radiocontrast agents, propranolol) Drugs: glucocorticoids, dopamine Nonthyroidal illness (euthyroid sick syndrome) Subclinical hyperthyroidism or Recently resolved/treated hyperthyroidism or First trimester of pregnancy or Early hyperthyroidism T3 thyrotoxicosis Overt hyperthyroidism (Graves’, toxic multinodular goiter, or thyroiditis)

TSH

Free T4

Free T3

↑ ↑ N or ↓ N or ↑ ↑↑ N

↓ N ↓ ↑ ↑ ↓

N or ↓ N N or ↓ ↑ ↑ N or ↓

N

↑

N or ↓

↓ ↓

N N or ↓

↓ ↓

↓

N

N

↓ ↓

N ↑

↑ ↑

N = normal

• • •

Central hypothyroidism (low TSH, low T4) Subclinical hyperthyroidism (low TSH, normal T4) Drugs which inhibit TSH secretion (corticosteroids, dopamine)

T4 Serum levels of T4 are inversely related to serum TSH. Obtaining a serum T4 level in addition to TSH is usually sufficient to distinguish primary from central hypothyroidism, overt (abnormal TSH and T4) from subclinical (abnormal TSH, normal T4) thyroid disease, or determine the severity of hyperthyroidism. 99.96% of all serum T4 is bound to thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA),


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or albumin. Concentrations of total and free (unbound) T4 are measurable by a variety of assays. Total T4 (Normal Range 5.6–13.7 mcg/dL) This measures both bound and unbound hormones by a radioimmunoassay (RIA), chemiluminometric, or other immunometric technique. Advantages It is widely available and accurate. Limitations Drugs or illness can alter the concentrations of TBG or the binding of TBG with T4, leading to increases or decreases in the total hormone levels, but relatively normal free hormone levels. This can sometimes be the explanation for abnormal thyroid function tests in patients who do not have thyroid dysfunction. Test interpretation Causes of low serum TBG (falsely low total T4): •

Androgens, glucocorticoids, niacin, inherited deficiency of TBG, nephrotic syndrome, cirrhosis

Causes of high serum TBG (falsely elevated total T4): •

Estrogen, tamoxifen, 5FU, methadone, heroin, inherited excess of TBG, pregnancy, hepatitis

Free T4 (Normal Range 0.8–2.7 ng/ml) Several methods are available for measuring free hormone: equilibrium dialysis, free T4 immunoassays, or calculating the free T4 index. With the advent of improved technology, free T4 immunoassays are the most common method used to measure the amount of unbound T4 present.


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Equilibrium dialysis is considered the gold standard for free T4 determination, but it is cumbersome, expensive, and not widely available. Thus, it is best reserved for circumstances in which the diagnosis is not clear. The free T4 index entails measuring the total T4 by immunoassay and estimating the uptake of radiolabeled T3 by plasma proteins and matrix added to the sample. It is calculated as the product of the total T4 multiplied by the percentage of the T3 tracer taken up by the matrix. This “T3 uptake” is unrelated to the T3 level in the serum. Advantages Immunoassays are sufficiently accurate in most settings, automatable, inexpensive, and the most widely used method for free T4 determination. They avoid the confusion related to binding protein abnormalities. Limitations No assay is available to correct for all possible binding protein abnormalities. When there is any doubt about the validity of the value, an equilibrium dialysis measurement should be performed. Test interpretations Free T4 levels can be abnormal in euthyroid patients (normal TSH). Elevated free T4 levels can be seen in patients with unusual plasma-binding protein abnormalities and patients on medications that block T4-to-T3 conversion (IV contrast, amiodarone, glucocorticoids, propranolol). These situations are distinguished from hyperthyroidism by a normal TSH. Decreased levels of free T4 but normal TSH can be seen in patients on antiepileptics like phenytoin and carbamazepine. T3 Serum levels of T3 are also inversely related to serum TSH. They can be useful for recognizing T3 thyrotoxicosis (milder hyperthyroidism with elevated T3 but normal T4), to fully define the severity of hyperthyroidism


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and monitor therapy response. Serum T3 concentrations alone are not accurate for diagnosis of hypothyroidism, because T3 levels are often normal in mild-to-moderate primary hypothyroidism. Most of serum T3 is also bound to TBG, TBPA, and albumin. Concentrations of total and free (unbound) T3 are measurable by similar assays used to measure T4. Total T3 (Normal Range 60–181 ng/dL) This measures both bound and unbound hormones by RIA, chemiluminometric, or other immunometric assay. Advantages It is widely available and accurate. Limitations Drugs or illness altering the concentrations of TBG or the binding of TBG with T3 can lead to increases or decreases in the total hormone levels, but relatively normal free hormone levels. Free T3 (Normal Range 2.3–4.2 pg/mL) This measures only free hormone by immunoassay. Advantages It is sufficiently accurate in most settings, automatable, and inexpensive. It avoids confusion related to binding protein abnormalities. Limitations It is not as widely available as total T3. No assay is available to correct for all possible binding protein abnormalities.


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Reverse T3 (Normal Range 0.19–0.46 ng/mL) Reverse T3 (rT3) is measured by radioimmunoassay. Its concentration is about one-third of the total T3 concentration. There is little or no clinical indication for rT3 measurement. It was previously used to help distinguish thyroid function tests due to nonthyroidal illness from true hypothyroidism, but the assay is not accurate enough.

Clinical Applications • • • •

Screening for thyroid dysfunction = check TSH. Working up a low TSH = check free T4, total T3. Working up a high TSH = check free T4. If on medications or have medical conditions that interfere with TBG, then check free instead of total hormone levels.

THYROID ANTIBODIES Anti-TPO Antibodies (Normal is Negative) Thyroid peroxidase (TPO), formerly known as the microsomal antigen, is an enzyme which catalyzes the iodination and coupling of tyrosine residues within thyroglobulin. The presence of autoantibodies to this antigen suggests the diagnosis of autoimmune thyroid disease, particularly Hashimoto’s thyroiditis. RIA is the most sensitive assay and is generally preferred.

Prevalence • • • • • •

General population 8–27% Graves’ disease 50–80% Autoimmune thyroiditis (Hashimoto’s) 90–100% Relatives of patients with Hashimoto’s 30–50% Type 1 diabetes 30–40% Pregnant women ~14%


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Test interpretation A positive titer suggests thyroid autoimmunity and the propensity for thyroid dysfunction to develop. Patients can have positive anti-TPO antibodies and have normal thyroid function. TSH Receptor Antibodies (Normal < 125% of Basal Activity) TSH receptor antibodies can be stimulating, binding, and inhibiting. Thyroid–stimulating immunoglobulin (TSI) is the most often measured and is present in most patients (90%) with Graves’ disease. Unlike antiTPO, it is rarely detected in patients with other autoimmune thyroid diseases. Usually Graves’ can be diagnosed clinically without measuring TSI. However, in pregnant women with hyperthyroidism TSI is useful for determining the risk of neonatal hyperthyroidism from TSI crossing the placenta. TSI can help differentiate Graves’ from thyroiditis in someone who is unable to receive radioactive iodine, like a breastfeeding mother. TSI can also establish the diagnosis of Graves’ in someone who is euthyroid but has signs of orbitopathy. Prevalence • • • • • •

General population 0% Graves’ disease 80–95% Autoimmune thyroiditis (Hashimoto’s) 10–20% Relatives of patients with Hashimoto’s 0% Type 1 diabetes 0% Pregnant women 0%

Test interpretation The test involves isolating the immunoglobulins, exposing cultured thyroid cells to them, and then measuring their cAMP response compared to reference TSI and TSH standards. • • •

Basal activity is 125%: positive for Graves’. Basal activity is 110–125%: indeterminant; further studies are indicated.


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Antithyroglobulin Antibodies (Normal < 20 IU/mL) Antithyroglobulin antibodies are a general marker of thyroid autoimmunity. Their presence poses a problem for thyroid cancer patients who rely on thyroglobulin measurements to monitor for recurrence. They interfere with the thyroglobulin assay by binding free thyroglobulin in the serum, decreasing the amount available for detection and negating the value of the serum thyroglobulin determination. Prevalence • • • • • •

General population 5–20% Graves’ disease 50–70% Autoimmune thyroiditis (Hashimoto’s) 80–90% Relatives of patients with Hashimoto’s 30–50% Type 1 diabetes 30–40% Pregnant women ~14%

Test interpretation If present in a nonthyroid cancer present, they are an indicator of thyroid autoimmunity. If present in a thyroid cancer patient, they may interfere with the thyroglobulin assay and lead to difficulties with interpretation. Their presistence in a thyroid cancer patient without thyroid autoimmunity more than one year after thyroidectomy and radioiodine ablation may indicate residual thyroid tissue and increased risk of recurrence. However, in thyroid cancer patients with a prior history of thyroid autoimmunity, these autoantibodies may persist longer (median time to disappearance three years).

THYROID TUMOR MARKERS Thyroglobulin (Normal 3.5–56 ng/mL; After Thyroidectomy < 2 ng/mL) Thyroglobulin is the precursor to thyroid hormones and is synthesized only by thyroid follicular cells, making it a good marker for papillary and


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follicular thyroid cancer recurrence after thyroidectomy. It can be measured in the serum by immunoassay, which is limited by interference caused by the presence of circulating antithyroglobulin antibodies. Thyroglobulin is mainly measured when monitoring for residual or recurrent papillary or follicular thyroid cancers after thyroidectomy. It can also be useful in the differentiation of thyrotoxicosis due to exogenous thyroid hormone from endogenous hyperthyroidism (Graves’, thyroiditis). Most thyroid cancer patients are on thyroid hormone suppression therapy after thyroidectomy and radioactive iodine ablation. Thyroglobulin can be measured while the patient is on thyroid hormone suppression, after recombinant TSH stimulation, or withholding thyroid hormone suppression. Advantages When thyroglobulin is measured after withholding thyroid hormone suppression or receiving recombinant TSH, it has a high degree of sensitivity and specificity to detect thyroid cancer after total thyroidectomy and remnant ablation. Limitations Thyroglobulin levels may be low in aggressive or poorly differentiated disease or elevated in patients at low risk for clinically significant morbidity, so they should be interpreted in the setting of pretest probability of clinically significant residual tumor. Test interpretation Ideally, thyroglobulin levels drawn while on thyroid hormone suppression should be 1ng/mL, further testing with recombinant TSH or withholding thyroid hormone suppression should be performed. A recombinant-TSH-stimulated thyroglobulin level (or after withholding thyroid hormone) of >2 ng/mL is suggestive of recurrent disease. In the differentiation of thyrotoxicosis, endogenous forms of hyperthyroidism cause elevations of thyroglobulin and exogenous thyroid hormone causes suppression of thyroglobulin.


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13

Calcitonin (Normal Males 150 is often seen in distant metastatic disease, and frequently the calcitonin is >1000 in this setting. >3000 is suggestive of extensive metastatic MTC.

SELECTED REFERENCES Cooper DS, Doherty GM, Haugen BR, et al. American Thyroid Association Guidelines Taskforce. Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2006;16(2):109–142. Gardner DG, Shoback D. Greenspan’s Basic and Clinical Endocrinology, 8th Edn. McGraw-Hill, 2007. Henderson KE, Baranski TJ, Bickel PE, et al. The Washington Manual Endocrinology Subspecialty Consult, 2nd Edn. Wolters Kluwer/Lippencott Williams and Wilkins, 2009.


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Chapter I.A.2: Thyroid Imaging James E. Wiseman, MD, Lilah F. Morris, MD and Michael W. Yeh, MD

INTRODUCTION It is estimated that 4–7% of the population of North America has palpable thyroid nodules, with an incidence of 0.1% per annum. The superficial location of the thyroid gland contributes to ease in palpation, and clinical assessment of the thyroid is vital to any routine physical examination. The ability of physical examination to detect potentially malignant thyroid masses is limited by a number of factors, including location within the thyroid (posterior lesions being much more difficult to palpate), the size of the nodule, the experience and technique of the examiner, and the physical characteristics of each patient’s neck. Indeed, postmortem studies of patients with clinically normal thyroid glands have reported the presence of grossly visible nodules at autopsy in up to 50% of patients, with 30–40% having lesions larger than 2 cm. The sensitivity of physical examination as a diagnostic tool for thyroid nodules has been reported to be as low as 38%. The prevalence of clinically undetectable thyroid cancer in the United States is estimated to be 0.45–13% based on autopsy data. Moreover, between 4 and 12% of palpable thyroid nodules subsequently demonstrate the presence of malignancy on pathologic evaluation. An overwhelming majority of these “occult” thyroid cancers are of papillary histology, an indolent form of the disease with an excellent prognosis. In fact, up to 35% of thyroid glands removed at autopsy or surgically contain papillary “microcarcinomas” measuring less than 1 cm in diameter, which are generally considered clinically insignificant. Given the prevalence of thyroid nodules, their risk of harboring malignancies, the excellent response of 15


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cancers to current treatment modalities, and the limitations of physical examination, the use of imaging has become vitally important in the evaluation of the thyroid (Fig. 1). In addition, with the general increased use of imaging modalities, many thyroid nodules are incidentally discovered. Surgeons should be familiar with the appropriate imaging modalities for the evaluation of thyroid disease and learn how to interpret imaging results.

ULTRASOUND Ultrasonographic evaluation is currently recommended in the workup of all palpable thyroid nodules by the American Thyroid Association (Cooper et al., 2006). Indeed, they define a thyroid nodule as a discrete lesion that is palpably and/or sonographically distinguishable from the surrounding parenchyma. The principle behind ultrasonography (US) is that differences in density can be detected by analyzing the rate of return of deflected sound waves passed through tissue. The basic unit of ultrasonographic transmission is the completion of one forward and backward wave, commonly referred to as a cycle. Frequency refers to the number of cycles occurring over unit time (cycles per second) — a measure identified as hertz (Hz). Higher frequency corresponds with increased resolution but less depth of tissue penetration. Conversely, lower frequency waves penetrate tissue better but provide lower quality images. US of the thyroid is typically performed with a high frequency transducer (7–13 MHz), resorting to lower frequency transducers (5–7 MHz) when deeper penetration is required, such as in the case of large glands or obese patients. The American Institute of ultrasound in Medicine’s (AIUM) 2007 practice guideline for the performance of thyroid US recommends an optimal frequency of 10–14 MHz (AIUM, 2003). The primary aims of thyroid US in the evaluation of nodular disease are (1) to confirm the presence of a nodule detected by palpation, (2) to identify any additional nodules, and (3) to provide a more accurate measurement of the dimensions and characteristics of these lesions. While benign versus malignant lesions cannot be conclusively discriminated, clues to the histologic behavior of these nodules can be derived from characteristics observed on US (Table 2).

Normal/High TSH

Calcification

Low TSH

“Cold” nodule Diameter 1 cm

SURVEILLANCE

SURVEILLANCE FNA

Fig. 1

Algorithm for imaging workup of thyroid nodules.

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Thyroid Imaging

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Initial Ultrasound Examination Given the prevalence of thyroid nodules in the general population and the uncertainty of their clinical significance, ultrasound has little value as a screening tool. Individuals at high risk for thyroid cancer are an important exception (Table 1), and regular ultrasound screening is recommended. With increasing utilization of sonography to evaluate the neck’s vasculature, an increasing number of nonpalpable nodules, or “incidentalomas,” are being identified. Several nodule features that can be easily defined by US have been studied for their prognostic value. They include the size of the nodule, the sonographic appearance of the margins, the shape of the lesion, echogenicity, and the presence of calcifications (Table 2). Though it may seem counterintuitive, the size of the lesion is of no diagnostic value as benign and malignant disease present equally at all sizes. That said, American Thyroid Association guidelines recommend serial ultrasounds without other workup for asymptomatic, incidentally

Table 1 Risk factors that confer high predisposition on the development of malignant thyroid nodules. Risk factors History of head and neck irradiation Total body irradiation for bone marrow transplantation Family history of thyroid malignancy in a first-degree relative Exposure to radioactive fallout or contamination under 14 years of age

Table 2 Comparison of nodule characteristics seen on US that are suggestive of benign versus malignant disease. US feature Composition Echogenicity Microcalcification “Halo” Margins Central blood flow (color Doppler)

Benign

Malignant

Cystic/mixed Isoechoic Absent Present Well-defined Absent

Solid Hypoechoic Present Absent Ill-defined Present


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discovered nodules 4 cm, symptomatic, enlarging or cystic and recurrent have a higher risk of malignancy and should be considered for diagnostic lobectomy with isthmusectomy or thyroidectomy. 2 Repeat FNA should be performed under ultrasound guidance, with cytopathology present for the most accurate diagnosis. Nodules that are repeatedly nondiagnostic have a slightly higher risk of malignancy and should be considered for diagnostic lobectomy with isthmusectomy or thyroidectomy. 3 Hürthle cell lesions (neoplasms) are also termed “oncocytic lesions” (neoplasms). 4 Features suspicious for papillary thyroid carcinoma include nuclear elongation, chromatin clearing, and nuclear grooves. 5 The extent of resection should take into consideration the rate of malignancy in the suspicious category at each institution.

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Papillary thyroid carcinoma Total thyroidectomy Medullary thyroid carcinoma Poorly differentiated carcinoma Anaplastic thyroid carcinoma Primary thyroid lymphoma Metastasis to the thyroid


Papillary thyroid carcinoma4 Thyroid lobectomy with 50–75% Medullary thyroid carcinoma intraoperative frozen malignant Poorly differentiated carcinoma section or total Anaplastic thyroid carcinoma thyroidectomy5 Primary thyroid lymphoma Metastasis to the thyroid

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Malignant

Suspicious for malignancy

Differential diagnosis

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Alternate FNA diagnoses


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Fig. 2 Benign colloid nodule. Uniform, round follicular cells (small arrow) and dense colloid (large arrow). (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.

Fig. 3 Follicular neoplasm. Uniform clusters of follicular cells with identifiable microfollicles and no colloid (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.


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Fig. 4 Hürthle cell (oncocytic) neoplasm. Enlarged oncocytic cells with abundant cytoplasm, round nuclei, and prominent nucleoli. No colloid. (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.

Fig. 5 Lymphocytic thyroiditis. Hürthle (oncocytic) cells and numerous small round lymphocytes (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.


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Fig. 6 Medullary thyroid carcinoma. Large, plasmacytoid cells (small arrow) and amyloid (large arrow). (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.

Fig. 7 Papillary thyroid carcinoma. Enlarged, irregular nuclei with prominent intranuclear cytoplasmic pseudoinclusion (arrow). (Romanowsky 60X). Reprinted from: Ogilvie JB, Piatigorsky EJ, Clark OH. Current status of fine needle aspiration for thyroid nodules. Adv Surg 2006;40:223–238; with permission from Elsevier.


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SELECTED REFERENCES Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36(6):425–437. Pitman MB, Abele J, Ali SZ, et al. Techniques for thyroid FNA: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36(6):407–424.

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Chapter I.B.1: Evaluation of a New Thyroid Nodule Adrienne L. Melck, MD, MPH and Sally E. Carty, MD

EPIDEMIOLOGY A thyroid nodule is defined as a discrete lesion within the thyroid gland that is palpably and/or ultrasonographically distinct from the surrounding parenchyma. Thyroid nodules are a common clinical finding, being palpable in 4–7% of the North American adult population and being prevalent on cervical ultrasound in at least 50–67% of adults. They are four times more common in women than in men. Other than gender, factors associated with an increased risk of having a thyroid nodule include older age, prior exposure to head and neck irradiation, and iodine deficiency. Fortunately, only 4–5% of thyroid nodules are malignant. Cancer risk is equivalent for palpable and nonpalpable nodules of the same size, and for solitary nodules and nodules within a multinodular goiter. The differential diagnosis of a thyroid nodule includes thyroiditis, benign colloid nodule, colloid cyst, benign follicular neoplasm (functioning or nonfunctioning), thyroid cancer, parathyroid gland, and lymph node.

HISTORY The important historical information to be ascertained from a patient with a thyroid nodule can be conceptualized in two categories. First, an attempt to characterize the nodule can be established by asking the patient how it was first detected and how it may have evolved since the initial detection. In particular, it is important to ask if there has been a change in nodule size; a sudden increase in size usually indicates hemorrhage into a colloid nodule or benign follicular adenoma, but more rarely may suggest an 39


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aggressive lesion such as thyroid lymphoma or anaplastic cancer. The patient should also be asked about associated symptoms; for example, if the nodule is large enough to be compressing surrounding structures, the patient may complain of dysphagia to solids, dysphonia, cough, and/or dyspnea that is pronounced in a particular position (e.g. supine or with their head tilted forward or their arms elevated). Symptoms of either hypo- or hyperthyroidism should be investigated, especially considering the possibility of a functioning nodule as in Plummer’s disease. The second line of questioning revolves around determining the presence of known risk factors for thyroid carcinoma. The patient should be asked whether there is a family history of thyroid cancer or other endocrine tumors, or a personal history of exposure to head and neck irradiation. Both Gardner’s and Cowden’s syndromes are also associated with thyroid cancer, and thus colorectal and breast cancer within the patients’ personal or family history are of interest. “B” type constitutional symptoms, including weight loss, fever, and night sweats, may be present in the setting of thyroid lymphoma. The patient should also be asked about any prior neck or thoracic surgery. This becomes particularly important if thyroidectomy is indicated, because laryngoscopy to investigate the status of the vocal folds preoperatively is advisable in the reoperative setting, as it is for any patient presenting with dysphonia.

PHYSICAL EXAMINATION Examination of the patient should begin with vital signs and inspection of their general status. Tachycardia, tremor, restlessness, and a flushed complexion may indicate hyperthyroidism, while loss of the lateral eyebrows, thickened forearm skin, and pretibial edema may indicate hypothyroidism. Brisk or delayed deep tendon reflexes may also indicate hyper- or hypothyroidism, respectively. Carefully listening to the patient’s speaking voice can yield important information about the status of their recurrent laryngeal nerves. On closer inspection of the head and neck, one should look for exophthalmos, lid lag, and jugular venous distension, and the anterior neck should be palpated for tracheal deviation, tenderness, lymphadenopathy, or any juxtathyroidal nodularity. Pemberton’s sign is the development of


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facial flushing, inspiratory stridor, and jugular venous distension when both arms are raised above the patient’s head, and this sign can indicate superior vena cava syndrome as may occur with substernal goiter. Examination of the thyroid gland itself should ascertain its size, contour, and mobility with deglutition. Any palpable nodule should be assessed for fixation to surrounding structures, tenderness, and degree of firmness/ballotability. The most inferior palpable extent of the gland should be determined, as well as any palpable extent below the sternal notch, indicating a mediastinal component. Repeating the exam in the supine position allows the clinician to assess for symptomatic cervical disk disease, kyphoscoliosis, extent of posterior neck extension, and anterior neck access, which is particularly important in patients with obesity or large breasts. Clinical features suggestive of thyroid malignancy are summarized in Table 1. Table 1

Clinical and radiologic features suggestive of thyroid cancer.

History • • • • • • • •

Extremes of age Male gender History of head and neck irradiation Family history of thyroid cancer Family history of endocrine tumor syndrome (MEN 2A and 2B) Hoarseness Dysphagia Rapid growth

Physical exam • Cervical lymphadenopathy • Firm nodule • Fixation to surrounding structures • Vocal cord paralysis Ultrasound characteristics • • • • • •

Hypoechogenicity Taller-than-side shape Microcalcifications Intranodular vascularity Irregular margins Size >4 cm


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LABORATORY INVESTIGATIONS Basic laboratory investigations should include an assessment of thyroid function, including measurement of the serum thyroid-stimulating hormone (TSH). Free thyroxine (T4), free tri-iodothyronine (T3), and free thyroxine index (FTI) measurements are employed to further evaluate patients with an abnormal TSH. Hyperthyroid patients are managed with an alternate algorithm (Fig. 1). Any patient requiring thyroid surgery should also have measurement of a fasting serum calcium level, given that

Thyroid Nodule History / Physical Exam / TFTs Hyperthyroid

Hypothyroid / Euthyroid

Scintigraphy

Ultrasound

Hot

Warm / Cold

>1 cm / Suspicious features

Treat Thyrotoxicosis

FNAB Cancer / Suspicious for Cancer

Total Thyroidectomy +/- CCND FN/HN/FLUS† Lobectomy or Total Thyroidectomy∗ Nondiagnostic† Repeat FNAB Benign 4 cm), an isolated functioning (“hot”) nodule in a hyperthyroid patient is almost always benign and such patients require only medical management of thyrotoxicosis provided that there are no other concerning features. As multinodularity is common, it is also vital that the


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clinician confirm that a functioning nodule seen on radionuclide imaging corresponds precisely to the one seen on ultrasound before deferring its further cytologic evaluation. The details of thyroid imaging (ultrasound, CT, and scintigraphy) are discussed in detail elsewhere in this book.

INDICATIONS FOR FINE NEEDLE ASPIRATION BIOPSY Due to its safety, accuracy, and cost-effectiveness, fine needle aspiration biopsy (FNAB) has become the gold standard for evaluation of thyroid nodules; its routine use has demonstrably decreased the rate of unnecessary thyroid surgery while increasing the yield of carcinoma in surgical specimens. Performance of FNAB is discussed in detail in another chapter. The American Association of Clinical Endocrinologists (AACE) guidelines recommend that FNAB should universally be done under ultrasound guidance. The American Thyroid Association (ATA) guidelines stress the importance of ultrasound guidance, particularly for lesions that are >50% cystic or located posteriorly in the gland. One challenge for clinicians is deciding which thyroid nodules should be subjected to FNAB. FNAB should be considered for any nodule in a patient with a family history of thyroid cancer or a personal history of radiation exposure, or with concerning ultrasound characteristics (Table 1), including associated lymphadenopathy. In the absence of these concerning features, there is controversy as to the size cutoff that warrants FNAB. The National Cancer Comprehensive Network (NCCN) clinical practice guidelines recommend biopsy of solitary nodules >1 cm, whereas the ATA currently recommends FNAB for any nodule >1–1.5 cm. Multinodular goiters present a particular challenge and there is evidence to suggest that in this setting, ultrasound characteristics are superior to nodule size in determining which nodules are more likely to be malignant and should therefore be biopsied; if no nodule exhibits the concerning sonographic attributes listed in Table 1, then it is appropriate to aspirate only the largest nodules. In this era of the routine use of positron emission tomography (PET) scans for staging and surveillance of cancer patients, it is not uncommon for an incidentally detected thyroid nodule to come to attention. The


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NCCN guidelines recommend that any FDG-avid thyroid lesion be evaluated with FNAB, as up to 50% will be thyroid cancer.

THYROID NODULE MANAGEMENT AFTER FNAB The category of results of FNAB determines thyroid nodule management. Although the topic is covered in detail in another section, in general there are four categories for results of thyroid FNAB: benign, malignant, indeterminate, and inadequate yield. In 2007, the National Cancer Institute sponsored the Thyroid Fine-Needle Aspiration State of the Science Conference, at which a new nomenclature for FNAB diagnoses was proposed, and this is hoped to provide cytopathologists and clinicians with a more uniform and effective way of reporting and communicating malignancy risk (summarized in Table 2). As with the older systems, under this new six-level system it is predicted that the majority of thyroid nodules will fall into the benign category, while 5–15% of FNABs will be nondiagnostic, 10–15% will be indeterminate, and the remaining 5% will be cancer. While FNAB cytology results in the malignant, suspicious, or indeterminate categories prompt thyroidectomy for treatment and/or definitive diagnosis, and benign nodules 4 cm the false negative rate is as high as 50% when follicular and Hürthle cell neoplasms are included in the analysis. Thus, diagnostic lobectomy, despite apparently benign cytology results, is increasingly being recommended by several institutions for thyroid nodules >4 cm in size. FNAB should still be pursued for nodules >4 cm, because results positive for thyroid cancer will indicate an initial total thyroidectomy.

MANAGEMENT OF THYROID CYSTS Thyroid cysts are common findings on cervical ultrasound. FNAB should be pursued for symptomatic cysts and any cyst with a solid component to confirm that they are cytologically benign. For complex cysts , ultrasound guidance for FNAB is crucial for ensuring that cellular material and not just cystic fluid is included in the specimen. Only the minority of simple cysts will resolve spontaneously, and thus these lesions should be serially monitored with ultrasound. Most clinicians will reaspirate a cyst up to three times, but after that surgery is generally recommended for any reaccumulation of fluid. Alternatively, percutaneous ethanol injection has up to an 85% success rate for cyst obliteration, but the patient must be aware of the associated potential complications, including bleeding, local pain, transient recurrent laryngeal nerve injury, and hypotension.


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SELECTED REFERENCES American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 2006;12:63–102. Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425–437. Cooper DS, Doherty GM, Haugen BR, et al. The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:109–142. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22(6):901–911. Hegedus L. The thyroid nodule. New Engl J Med 2004;351:1764–1771. McCoy KL, Jabbour N, Ogilvie JB, et al. The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size. Surgery 2007;142(6):837–844. NCCN Clinical Practice Guidelines in Oncology™ Thyroid Carcinoma (v.1.2009). © 2009 National Comprehensive Cancer Network, Inc. Available at NCCN.org. Accessed August 29, 2009. Nikiforov YE, Steward DL, Robinson-Smith TM, et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab 2009;94(6):2092–2098. Pinchot SN, Al-Wagih H, Schaefer S, et al. Accuracy of fine-needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg 2009;144(7):649–655. Yip L, Nikiforova MN, Carty SE, et al. Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. Surgery 2009;146: 1215–1223.


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Chapter I.B.2: Management of Papillary Thyroid Cancer Dina M. Elaraj, MD and Cord Sturgeon, MD

GLOBAL TREATMENT STRATEGY The global treatment strategy for papillary thyroid cancer (PTC) can be divided into four chief components: 1. Surgical extirpation of the primary tumor and any multifocal or extracapsular disease including nodal metastases; 2. Selective use of radioiodine ablation of the thyroid remnant +/− occult micrometastatic disease; 3. Suppression of the endogenous release of thyroid-stimulating hormone (TSH) through the administration of supraphysiologic doses of levothyroxine; 4. Longitudinal surveillance and treatment for cancer persistence or recurrence.

CONTROVERSIES IN SURGICAL MANAGEMENT There is general agreement that total or near-total thyroidectomy is the optimal surgical strategy for high-risk PTC patients. For years there was debate over the proper extent of surgery for small, low-risk tumors. Most clinicians now agree that total or near-total thyroidectomy is the proper initial operation for PTC ≥1 cm. Utilization of total or near-total thyroidectomy for PTC ≥1 cm has steadily risen in the United States over the past three decades and, since 1993, has plateaued at approximately 90%. Most clinicians also perform total or near-total thyroidectomy for PTC 40 pg/ml when >6 months old

Patients without evidence of extensive disease should undergo prophylactic thyroidectomy within the first 3–5 years but should not undergo prophylactic level VI compartmental dissection.


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Fig. 2

Initial diagnosis and therapy of preclinical hereditary disease.

MEN2B • • • •

•

The age of onset is 2 ng/mL without TSH stimulation or Tg > 10 ng/mL with TSH stimulation is suspicious for recurrence or persistent disease. Cross-sectional imaging with a CT scan or MRI of the neck and chest should be done annually to exclude metastatic disease. A PET scan is useful in patients with Tg-positive but radioiodinenegative disease, especially when done with TSH stimulation. Any suspicious lesions in the neck by ultrasound should be biopsied to exclude metastatic disease or recurrence. Prognosis Patients with TCV have a worse prognosis than patients with classic PTC. Locoregional recurrence and distant metastases develop in a fourth of patients. The 10-year mortality rate in patients with TCV is up to 25%.

INSULAR THYROID CANCER Insular thyroid cancer (ITC) accounts for 2–7% of all thyroid cancers. Women are affected twice as commonly as men, usually during the sixth decade of life. Patients with ITC have more aggressive disease at presentation. These patients have larger primary tumors, extrathyroidal extension (50%), lymph node metastasis (85%), and more distant metastasis (>50%) than patients with well-differentiated thyroid cancer. Treatment Patients who present with resectable thyroid tumors diagnosed with ITC on FNA should undergo a total thyroidectomy. A bilateral central lymph node dissection should also be performed, given the high rate of lymph node metastases and local recurrence. An ipsilateral lateral neck dissection should be performed if there is either preoperative clinical or radiologic evidence of involvement. All patients should receive TSH


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suppression therapy postoperatively. Although the efficacy of postoperative radioactive iodine ablation has not been established, its use should be considered for all patients. Similarly, although external beam radiotherapy has not been proven beneficial, its use should be considered in patients who present with advanced disease and are deemed unresectable or who undergo incomplete surgical resection in the hope of achieving local control. Prognosis Nearly two-thirds of patients who undergo surgical resection develop either local recurrence or distant metastases. Due to this aggressive behavior, the 5-year and 10-year survival rates for patients with ITC are 72% and 52%, respectively. Prognostic factors associated with a worse prognosis include age >45 years and the presence of distant metastases.

COLUMNAR CELL VARIANT OF PAPILLARY CARCINOMA The columnar cell variant (CCV) is a rare variant of PTC and accounts for less than 0.5% of all PTCs. It affects women twice as often as men and the mean age of diagnosis is in the fifth decade of life. Tumors that are confined to the thyroid gland and are well-encapsulated have a good prognosis. However, tumors that are not well-encapsulated have a higher rate of extrathyroidal extension, distant metastases, and mortality. Nearly a third of patients have extrathyroidal extension and half have lymph node metastases at diagnosis. Treatment Patients diagnosed with CCV should have a total thyroidectomy. When extrathyroidal extension is present an en bloc resection of the involved tissue should be performed. A central and lateral neck dissection should be performed when there is clinical or radiologic evidence of lymph node metastases. Postoperative RAI ablation should be considered in all patients. However, the rarity of this cancer precludes adequate assessment


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of the efficacy of RAI ablation. All patients are placed on TSH suppression therapy. Postoperative radiation therapy should be considered in cases where a complete resection could not be performed. Prognosis Despite adequate surgical resection, a third of patients will suffer locoregional recurrence. An additional 36% of patients will develop distant metastases. Overall, CCV is associated with a worse disease-related mortality (29%) than classic PTC.

DIFFUSE SCLEROSING VARIANT OF PAPILLARY CARCINOMA The diffuse sclerosing variant (DSV) of papillary thyroid cancer is similar to other variants, in that it predominately affects women. Unlike the other variants, patients with DSV are diagnosed at a younger age (mean: third decade) and generally present with diffuse thyroid enlargement and neck pain. Lymph node metastasis is common in DSV and up to 70% of patients have lymph node involvement at diagnosis. The rate of distant metastasis varies in the literature, but it may be present in up to 60% of patients at diagnosis. Treatment As with the other variants of PTC, a total thyroidectomy is the treatment of choice. DSV has a high propensity for extrathyroidal extension (40%), so an en bloc resection of any involved soft tissue should be performed. A bilateral central lymph node dissection is also recommended, given the high rate of lymph node metastases. Radioactive iodine ablation should be considered for all patients following surgery. Lifelong thyroid hormone suppression is also started postoperatively. Prognosis Up to 50% of patients with DSV will develop local recurrence and up to 60% will develop distant metastases following surgery. Despite these


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risks, the overall survival of patients with DSV is comparable to that of patients with classic PTC.

ANAPLASTIC THYROID CANCER Anaplastic thyroid cancer (ATC) accounts for approximately 2% of all thyroid malignancies. It rarely occurs in the young and over 90% of patients are older than 50 years at diagnosis. Unlike well-differentiated thyroid cancers, ATC commonly presents as a rapidly enlarging thyroid mass. The majority of patients present with either lymph node metastases or extrathyroidal extension and nearly two-thirds at diagnosis have distant metastases at presentation. The most common site of distant metastases is the lung, followed by bone, skin, and brain. Less than 10% of patients present with ATC confined to the thyroid gland. Imaging The rapid progression of ATC can result in local compression or tissue invasion. Radiographic imaging is recommended for appropriate staging and to determine resectability (Fig. 4). A computed tomography (CT) scan of the neck with intravenous (IV) contrast is obtained to evaluate for potential tumor involvement of the vasculature (internal jugular vein, carotid artery, and the great vessels), trachea, and esophagus. CT scans of the head, chest, abdomen, and pelvis with IV contrast are recommended to accurately exclude the presence of metastatic disease. Determiniation of recurrent laryngeal nerve involvement by evaluating the vocal cords with a fiberoptic laryngoscope may be performed, since nearly half of patients present with vocal cord paralysis. Treatment Surgery There is no effective treatment option for ATC, and no single treatment modality has been shown to improve survival. Although surgery is the


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ATC diagnosed by FNA

Staging CT: Head, neck, chest, abdomen, l i pelvis Resectable

Surgical Resection

Unesectable

Discuss end of life issues with all patients

Neoadjuvant Radiation

Response

No Response

Adjuvant chemoradiation therapy Consider surgery

Adjuvant chemoradiation therapy

Adjuvant chemoradiation therapy

Fig. 4 Treatment algorithm for anaplastic thyroid cancer. FNA — fine needle aspiration; CT — computed tomography.

treatment of choice for other thyroid cancers, complete surgical resection is rarely possible for ATC. Surgery as the initial treatment is generally reserved for the rare patient with a small and well-localized tumor. In this case, a complete macroscopic resection (total thyroidectomy) should be performed with preservation of the pharynx, trachea, esophagus, and carotid artery. A lymph node dissection should be performed when gross lymphadenopathy is apparent and complete resection of the tumor is achieved. Aggressive surgery is not recommended, since it offers no survival benefit. Surgical intervention may also be required in patients with an impending airway obstruction. Tumor debulking or incomplete tumor resection in a patient without an impending airway obstruction is not recommended, because it does not offer any survival benefit.


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Radiation Radiation therapy (RT) alone has not been shown to improve survival. However, it is frequently used as an adjunct to surgery in patients who have undergone complete tumor resection. In this setting, current protocols recommend a total dose of 30–60 Gy. However, the potential benefit of local control must outweigh the complications associated with RT, including pharyngitis, esophagitis, tracheitis, myelopathy, and skin changes. The use of intensity-modulated RT has reduced the risk of many of the side effects of radiotherapy.

Chemotherapy Chemotherapy is beneficial in the treatment of some cases of ATC. The most frequently utilized chemotherapeutic agent is doxorubicin, because it has a radiosensitizing effect. Unfortunately, neither monotherapy (doxorubicin, bleomycin, etoposide, cisplatin, vincristine, melphalan, methotrexate, or paclitaxel) nor combination chemotherapy has improved the survival of patients with ATC. The dismal response of ATC to chemotherapy may be due, in part, to the expression of the multidrug-resistance-associated protein in ATC cells. Regardless of the underlying mechanism of resistance, chemotherapy as a single therapy is not recommended.

Multimodality therapy There is general consensus that ATC is a systemic disease and that a multimodality treatment approach is better than any single treatment option. However, multimodality therapy has not been shown to improve overall disease-specific survival. Another limitation is that consensus on the specific regimen and timing of administration has not been universally adopted. One of the most frequently used regimens is combined pre- and postoperative radiation in patients with potentially resectable tumors. Hyperfractionated radiation is administered in either 1.0 Gy or 1.3 Gy per fraction (twice daily, five times a week) to a total dose of 30 Gy preoperatively and 16 Gy postoperatively. Another protocol consists in


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administering preoperative radiation to 46 Gy in 29 fractions (1.6 Gy per fraction twice daily). Doxorubicin at a dose of 20 mg IV is administered weekly before the radiotherapy. Though these protocols did not improve survival, they did prevent local recurrence in 31–77% of patients. Other protocols have also been used with different dosages and fractions, but the total dosage usually ranges between 30 Gy and 60 Gy. Given the futility of current treatment regimens, all patients should be considered for enrollment in clinical trials. Prognosis The median survival of all patients with ATC is five months. The overall two-year survival is 9–14%, but age ≤45 years, small tumor size ( −1 and < −2.5 SD

The Z-score is used to differentiate other causes of bone loss such as menopause, since it compares patients of the same age and gender. The bone loss caused by SPHPT affects mainly cortical bone, which is the predominant bone type of the forearm. The femoral neck is a mix of cortical and trabecular bone, whereas the lumbar spine is mainly trabecular bone. When evaluating bone loss caused by SPHPT, consider evaluating the forearm bone density. If this site is not evaluated, a lower bone density in the femoral neck compared to the lumbar spine might indicate bone loss caused by parathyroid hyperfunction. In contrast, parathyroidectomy improves bone density in all sites, increasing the density by at least 1%/year after surgery mainly on the lumbar spine.

SELECTED REFERENCES Bilezikian JP, Brandi ML, Rubin M, Silverberg SJ. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005;257:6–17. Carneiro-Pla DM, Irvin GL, 3rd, Chen H. Consequences of parathyroidectomy in patients with “mild” sporadic primary hyperparathyroidism. Surgery 2007; 142:795–799.

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Heath H, 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723–740. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET protooncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994;6:70–74.


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Chapter II.A.2: Parathyroid Imaging Christine S. Landry, MD, Elizabeth G. Grubbs, MD, Beth S. Edeiken-Monroe, MD, Thinh Vu, MD, E. Edmund Kim, MD and Nancy D. Perrier, MD

INTRODUCTION Minimally invasive parathyroidectomy (MIP) is becoming an increasingly popular approach to the management of primary hyperparathyroidism rather than traditional four-gland exploration. Due to this technological advance, imaging of the parathyroid gland is an essential part of preoperative planning. Currently, multiple imaging modalities are available for identifying and localizing hyperfunctioning parathyroid glands. The radiological technique utilized varies across institutions. Approximately 80% of patients with primary hyperparathyroidism have an isolated parathyroid adenoma, while nearly 20% have parathyroid hyperplasia in more than one gland. Less than 1% of patients have parathyroid carcinoma, which typically involves only one gland. Preoperative determination of the exact location of the hyperfunctioning parathyroid gland in patients with a suspected parathyroid adenoma is advantageous for the patient, the surgeon, and the anesthesiologist. For instance, the surgeon can optimize head positioning and the location of the neck incision. The end result is a minimal dissection, a shorter operative time, and a decreased risk of injury to the normal parathyroid glands and the recurrent laryngeal nerves. Also, the anesthesiologist can tailor the length of anesthesia according to the operative complexity and proposed length of the surgical procedure. A nomenclature system for common locations of parathyroid glands has recently been developed at The University of Texas MD Anderson Cancer Center (MDACC) to facilitate multidisciplinary communication (Fig. 1). This system classifies gland locations according to the relationship to the 159


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Fig. 1 Parathyroid nomenclature for classifying common locations of parathyroid adenomas: knowledge of the precise location of a parathyroid adenoma preoperatively is beneficial to the surgeon, anesthesiologist, and patient, as it facilitates a focused dissection.

thyroid parenchyma and recurrent laryngeal nerves. A type A gland originates from the superior pedicle, is lateral to the recurrent laryngeal nerve, and is adherent to the thyroid gland. A type B parathyroid gland is a superior gland in the tracheoesophageal groove behind the thyroid parenchyma. A type C gland is caudal to the thyroid gland in the tracheoesophageal groove, inferior to a type B gland. A type D gland lies near the junction of the recurrent laryngeal nerve and the middle thyroid vein or inferior thyroid artery. A type E gland is located at the inferior pole of the thyroid parenchyma. A type F gland can be found in the thyrothymic ligament, and a type G gland is intrathyroidal. Defining the precise location of a parathyroid adenoma is also beneficial for collaborative efforts with other centers, and enrollment in clinical trials. This chapter describes the most common radiological techniques used to evaluate patients with primary hyperparathyroidism. Likewise, we have


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incorporated our nomenclature system into our radiological interpretations to demonstrate the ease of communication between the radiologist and the surgeon. The imaging modalities that will be discussed include: ultrasound (US), nuclear imaging, four-dimensional computed tomography scan (4D-CT), and magnetic resonance imaging (MRI).

IMAGING MODALITIES Ultrasound Depending on the center, ultrasound of the soft tissues of the neck may be performed by a radiologist, surgical endocrinologist, or medical endocrinologist, and the accuracy is operator-dependent. This technique is performed using a 7.5–12 MHz transducer with the patient in the supine position and the neck extended. Extension of the neck elevates adenomas lower in the neck, which could not otherwise be visualized. Parathyroid glands have a homogenous echogenic appearance that is hypoechoic when compared to the thyroid gland. Color Doppler ultrasound may be helpful in documenting the vascularity within the parathyroid gland (Fig. 2). In addition, a cystic component may be present. Calcifications, rarely seen in parathyroid adenomas, are more common in parathyroid hyperplasia and parathyroid carcinoma. Also, ultrasound may localize glands by side and quadrant, but this modality is not dependable in differentiating superior from inferior glands. For example, a superior parathyroid gland may have migrated inferiorly, and may be mistaken for an inferior gland. Moreover, it should be noted that ultrasound cannot definitively differentiate an adenoma from a carcinoma. Ultrasonography of the cervical region is sensitive for identifying hyperfunctioning parathyroid glands up to 92% of the time, depending on the location of the gland and on the experience of the sonographer. The specificity for this technique ranges from 60 to 80%. Ultrasound cannot image or localize parathyroid adenomas located in the mediastinum, retrotracheal, paratracheal, retroesophageal, and retrosternal areas, because sound waves are unable to penetrate through bone or the trachea. Intrathyroidal adenomas can be identified with ultrasound, but cannot be differentiated from thyroid nodules based on ultrasound characteristics alone.


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(b)

(a)

Th T

C

T –Trachea, Th –Thyroid Gland, C – Carotid Artery (c)

Fig. 2 Ultrasound of the soft tissues of the neck: (a) transverse and (b) longitudinal dimensions demonstrating a 2.9 × 1 × 0.5 cm parathyroid adenoma inferior and lateral to the thyroid gland with (c) vascular flow documented by color Doppler.

In patients with parathyroid disease, ultrasound can be used to identify concomitant thyroid pathology. This is helpful in determining whether a minimally invasive parathyroidectomy is appropriate or another procedure should be performed. In one study of 163 patients, thyroid disease such as thyroiditis or goiter was identified in 84% of patients with primary hyperparathyroidism. Among these patients, 23 of the 39 patients who underwent fine needle aspiration (FNA) for suspicious findings on ultrasound were not candidates for MIP based on abnormal FNA results. At surgical intervention, nine of these patients had a thyroid malignancy on final pathologic review. Ultrasound has also been useful at MDACC in localizing autotransplanted parathyroid tissue. In the absence of an identifying surgical clip, ultrasound-guided FNA has been used preoperatively to confirm the


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location of autotransplanted parathyroid tissue. The use of ultrasound in this way helps to minimize dissection in the reoperative patient. Nuclear Imaging Many nuclear imaging techniques have been described for evaluating patients with primary hyperparathyroidism. Initially, thallium 201technetium was used because the rich mitochondrion of parathyroid cells had a higher uptake of radio tracer when compared to adjacent thyroid parenchyma. Sestamibi trumped thallium scintigraphy when it was demonstrated that sestamibi had a higher uptake than thallium in the hyperfunctioning parathyroid cells due to its physical properties. Even though sestamibi is currently the most common isotope used, it is inaccurate in patients with multiple adenomas or parathyroid hyperplasia because it may not identify all hyperfunctioning glands. Also, sestamibi scans are limited as coexisting thyroid pathology is not visualized. There are three methods associated with technetium scans. First, single-isotope dual-phase scanning obtains cervicothoracic scans 10 min and 2–3 h after the radioisotope is injected. The delayed scan is more useful because the thyroid clears the isotope uptake faster than parathyroid glands or lesions. Second, dual-isotope subtraction scans use 99m Tc-sestamibi with another isotope specific to thyroid cells such as 99m Tc-pertechnetate or 123I sodium iodide to allow for thyroid subtraction. This technique has a sensitivity ranging from 68 to 90% for localizing parathyroid adenomas. Subtraction techniques are limited because separate studies using each isotope are required with the patient in identical positions. Patients who are mobile or uncooperative will have a higher number of artifacts as the subtraction is affected. A more modern technique is dual-phase single-tracer imaging using 99m Tc-sestamibi. This modality is now the predominant method for evaluating primary hyperparathyroidism as it has a sensitivity ranging from 89 to 95% for the localization of parathyroid adenomas (Fig. 3). More recently, it has been combined with single-photon emission computed tomography (SPECT) to provide better localization in a three-dimensional picture (Fig. 3). SPECT-CT using sestamibi, which has a higher sensitivity, can better estimate the location of an enlarged parathyroid gland. It also provides


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Th

P

Th

E

P P: Parathyroid Gland Th: Thyroid Gland

a) (a)

(b)

E: Esophagus

Fig. 3 Sestamibi parathyroid scan with SPECT-CT: (a) 80 min delayed planar image localizing the hyperfunctioning parathyroid gland in the right thyroid bed. This anterior–posterior (A–P) view does not provide enough information for discerning if the parathyroid gland is an inferior or superior gland in origin. More information from a lateral view or a cross-sectional view is necessary in order to localize the gland as being anterior near the trachea or posterior near the spine. (b) SPECT-CT axial image displaying the parathyroid adenoma caudal to the thyroid gland in the tracheoesophageal groove consistent with a type C gland.

characterization of the lesion and additional morphological information. However, as with other sestamibi imaging, SPECT-CT is limited in patients with multiglandular disease. For instance, other centers have found that 12–18% of patients with primary hyperparathyroidism had negative sestamibi scans, and up to 30% of these patients had multiglandular disease. The early phase images of SPECT-CT is dependent on the anatomical location of the parathyroid glands as well as the uptake of tracer in both the thyroid and parathyroid glands. For instance, a parathyroid adenoma that is intrathyroidal or contiguous with the thyroid gland is apparent on early phase imaging only if the uptake is greater in the hyperfunctioning parathyroid gland, or there is asymmetry in the thyroid gland. Parathyroid adenomas often demonstrate a delayed washout pattern when compared with the thyroid gland, which may help differentiate adenomas from thyroid tissue on delayed images. However, because thyroid adenomas can also demonstrate delayed washout patterns, higher


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tracer uptake contiguous with the thyroid gland may not necessarily represent a parathyroid adenoma. Four-Dimensional CT (4D-CT) Even though sestamibi scans can be helpful in identifying hyperfunctioning parathyroid glands, the four-dimensional computed tomography scan (4DCT) is an emerging modality that provides both the anatomical location and the function of the parathyroid gland. Typically, a hyper-functioning parathyroid gland is characterized by a more rapid uptake and washout of 4D-CT when compared to normal parathyroid glands. 4D-CT helps to localize hyperfunctioning glands by incorporating 3D-CT of the neck with attention to changes in enhancement (perfusion) of the parathyroid glands over time. 4D-CT has a markedly higher sensitivity than sestamibi scans or ultrasound when used to lateralize hyperfunctioning parathyroid glands to one side of the neck, or to localize to the correct quadrant of the neck. As described previously, we have applied our nomenclature system to our preoperative imaging to identify the exact location of the hyperfunctioning gland in an effort to minimize dissection (Fig. 4). 4D-CT is especially advantageous for preoperative localization in patients who require reoperative parathyroidectomy. A prospective study at MDACC demonstrated that 4D-CT is superior to the sestamibi scan for preoperative localization in the reoperative setting, with a sensitivity of 88% for 4D-CT and 54% for sestamibi imaging, respectively. Likewise, 4D-CT is advantageous for patients with multiple endocrine neoplasia 2A (MEN 2A), since the surgical management ranges from resection of a single parathyroid adenoma to subtotal parathyroidectomy. This modality is also useful for identifying ectopic or autotransplanted parathyroid issue which may be encountered in MEN 2A patients. MRI MRI is not commonly used in the preoperative setting for localizing parathyroid adenomas because it is expensive, and patients may have claustrophobia or difficulty in remaining immobile during the procedure. However, it can be advantageous in some patients as a contrast medium is


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Th P

(a)

P

P

(b)

(c)

Fig. 4 Preoperative localization of a parathyroid adenoma with 4D-CT: patient with right type A parathyroid adenoma. Axial (a), sagittal (b), and coronal (c) reconstructed maximal intensity projection images are shown. The axial reconstructed image shows a large enhancing parathyroid adenoma lateralized to the right tracheoesophageal groove and opposed to the posterior surface of the right thyroid lobe. The sagittal and coronal reconstructed images localize the parathyroid adenoma superior to the thyroid gland, suggesting an adenomatous superior parathyroid gland. (P — parathyroid adenoma; Th — thyroid gland.)

not required, and there are no artifacts from surgically placed clips. This modality is useful for identifying ectopic glands, especially in the reoperative neck. The sensitivity of MRI for localizing parathyroid adenomas ranges from 50 to 88%. Typically, a parathyroid adenoma has a low intensity on T1 imaging and a high intensity on T2 imaging. Not all parathyroid adenomas have the same imaging characteristics. Often, thyroid nodules and enlarged lymph nodes can lead to false positive results. Likewise, false negative results can occur with parathyroid hyperplasia or when an adenoma is in close proximity to a multinodular goiter.


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Radioguided Parathyroidectomy Some centers perform minimally invasive radioguided parathyroidectomy for primary hyperparathyroidism. With this technique, patients are administered an average of 20 mCi 99Tcm-sestamibi for scanning on the morning of surgery. Delayed imaging is obtained 2 h after injection and the skin is marked over the location of the hyperfunctioning parathyroid gland. The location of the incision is then guided by the location of the highest radioactivity and the ink mark. The gamma probe is used to help identify the location of the parathyroid adenoma. Radioactive levels in vivo, ex vivo, and in the operative basin are recorded during the procedure. If the count of the excised tissue is 20% greater than the background count, this confirms that parathyroid tissue has been removed. This technique works best when the sestamibi scan is considered positive. Limitations associated with this technique include false positive results from concomitant thyroid disease and increased cost.

SPECIFIC QUESTIONS FOR THE ENDOCRINE SURGEON Which patients require preoperative imaging? Preoperative localization helps determine where to start a parathyroidectomy when single-gland disease is suspected as the source of primary hyperparathyroidism. Localization is required of a MIP is planned, and for patients who have undergone previous thyroid or parathyroid surgery. Patients who have secondary or tertiary hyperparathyroidism do not require preoperative imaging because they require four-gland exploration. Likewise, patients with concomitant thyroid disease who will receive a bilateral neck exploration of the central neck do not require preoperative imaging since both sides of the neck will be inspected intraoperatively. In addition, patients with primary hyperparathyroidism and familial disease do not require preoperative imaging since they usually have four-gland disease. Is there a role for invasive localization studies? Invasive localization studies can be helpful when the results of other imaging modalities are inconclusive, negative, or discordant. For


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instance, an ultrasound-guided FNA of a suspected nodule may be helpful in further characterizing whether a nodule is thyroid or parathyroid tissue. The aspirate can be analyzed for elevated parathyroid hormone, which may confirm parathyroid disease. Parathyroid arteriography is a difficult and expensive technique that can identify adenomas with a sensitivity ranging from 60 to 65% when subtraction techniques are used. Selective venous sampling is another option. Venous sampling lateralizes approximately 80% of adenomas, and can help identify mediastinal glands.

What studies should be ordered to evaluate patients with primary hyperparathyroidism? Imaging modalities should be selected on the basis of availability, cost, and the experience of the surgeons and radiologists. First, noninvasive imaging studies should be obtained. At MDACC, we begin our evaluation with a neck ultrasound to identify for any coexisting thyroid pathology or enlarged parathyroid glands, followed by a sestamibi SPECT-CT. If these studies are discordant, or additional anatomical information is required, we perform a 4D-CT.

What studies are required for the reoperative patient with recurrent or persistent disease? As a general rule, if re-exploration is planned for a patient with persistent or recurrent disease, two concomitant concordant images should be obtained. Operative exploration should not be performed without sufficient preoperative information from localization studies. We recommend first evaluating patients with a neck ultrasound and a sestamibi SPECTCT scan. We perform a 4D-CT to provide additional anatomical information. MRI may be beneficial if studies are discordant or 4D-CT is not available. If selective venous sampling is obtained in the patient with recurrent disease, the venous drainage may be affected from previous thyroid surgery.


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What imaging should be performed if parathyroid carcinoma is suspected? In the majority of cases, the diagnosis of parathyroid carcinoma is suspected preoperatively by older age, exceedingly high serum calcium levels, and the visualization of firm or large cystic masses on ultrasound and CT. The diagnosis is confirmed intraoperatively. 4D-CT, SPECT-CT, and ultrasound are excellent tools that can be used to evaluate suspected primary or recurrent parathyroid cancer. A CT scan of the chest and abdomen is useful for identifying mediastinal, lung, and liver metastases. Likewise, a SPECT-CT scan can be an excellent adjunctive study to identify additional parathyroid tissue. What should be done if all the parathyroid imaging is negative and the diagnosis of primary hyperparathyroidism is confirmed biochemically? Negative preoperative imaging does not mean that the patient does not have biochemical primary hyperparathyroidism. Such patients may have had a poor quality imaging study, multiglandular disease, parathyroid hyperplasia, or an adenoma contiguous with the thyroid gland. In these cases, bilateral neck exploration is necessary.

CONCLUSION Parathyroid imaging is an essential part of the preoperative workup for patients undergoing MIP, and for patients with a previous history of thyroid or parathyroid surgery. The preferred imaging techniques varies between institutions, and should be selected based on availability, cost, and experience. Incorporation of a nomenclature system to be used by the radiologist and surgeon can be an excellent tool.

SELECTED REFERENCES Adil E, Adil T, Fedok F, et al. Minimally invasive radioguided parathyroidectomy performed for primary hyperparathyroidism. Otolaryngol Head Neck Surg 2009;141(1):34–38.


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Ahuja AT. The thyroid and parathyroids. In: Practical Head and Neck Ultrasound, (ed.) A Ahuja. New York: Cambridge University Press, 2007, pp. 35–62. Bhure UN. SPECT and PET in benign thyroid and parathyroid disease. In: Molecular Anatomic Imaging: PET-CT and SPECT-CT Integrated Modality Imaging (ed.) GK von Schulthess. Philadelphia: Lippincott Williams & Wilkins, 2007. Eslamy HK, Ziessman HA. Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT. Radiographics 2008;28(5):1461–1476. Kettle AG, O’Doherty MJ. Parathyroid imaging: how good is it and how should it be done? Semin Nucl Med 2006;36(3):206–211. McGreal G, Winter DC, Sookhai S, et al. Minimally invasive, radioguided surgery for primary hyperparathyroidism. Ann Surg Oncol 2001;8(10): 856–860. Monroe DP, Edeiken-Monroe BS, Lee JE, et al. Impact of preoperative thyroid ultrasonography on the surgical management of primary hyperparathyroidism. Br J Surg 2008;95(8):957–960. Mortenson MM, Evans DB, Lee JE, et al. Parathyroid exploration in the reoperative neck: improved preoperative localization with 4D-computed tomography. J Am Coll Surg 2008;206(5):888–895. Perrier ND, Edeiken B, Nunez R, et al. A novel nomenclature to classify parathyroid adenomas. World J Surg 2009;33(3):412–416. Philip M, Guerrero MA, Evans DB, et al. Efficacy of 4D-CT preoperative localization in 2 patients with MEN 2A. J Surg Educ 2008;65(3):182–185. Rodgers SE, Hunter GJ, Hamberg LM, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery 2006;140(6):932–940. Rodriguez JM. Localization studies in persistent or recurrent hyperparathyroidism. In: Textbook of Endocrine Surgery, (eds.) OH Clark, Q-Y Duh. Philadelphia: Elsevier Saunders, 2005, pp. 430–438. Yip L, Pryma DA, Yim JH, et al. Sestamibi SPECT intensity scoring system in sporadic primary hyperparathyroidism. World J Surg 2009;33(3): 426–433.

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Chapter II.B.1: Clinical Management of Primary Hyperparathyroidism Joel T. Adler, MD, Rebecca S. Sippel, MD, FACS and Herbert Chen, MD, FACS

INTRODUCTION Surgical management of primary hyperparathyroidism has evolved into an operation with a greater-than-95% success rate. The complication rate is probably less than 3%, making this a successful and safe operation. This is dependent upon an accurate diagnosis, appropriate selection of patients for surgery, and good operative technique. The open, bilateral exploration of the neck has given way to a minimally invasive technique. Minimally invasive parathyroidectomy (MIP) is made possible by accurate pre- and intraoperative localization of the overactive parathyroid glands, reducing the amount of exploration necessary and resulting in a more targeted operation. It is also aided by intraoperative measurements of parathyroid hormone (ioPTH), which permits the minimally invasive approach by ruling out multigland disease. The potential benefits of MIP include improved cosmesis, reduced postoperative pain, a shorter length of stay, and a quicker return to preoperative activity level. This chapter describes the indications and operative approaches in the clinical management of primary hyperparathyroidism.

INDICATIONS There is little question that surgery is an appropriate therapeutic intervention in patients with the classic symptomatology of “bones, stones, abdominal groans, and psychiatric overtones”: osteitis fibrosa cystica, nephrolithiasis, abdominal pain, and psychiatric disturbances. However, 171


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J. T. Adler, R. S. Sippel and H. Chen Table 1 Criteria for parathyroid surgery in patients with asymptomatic primary hyperparathyroidism. Serum calcium concentration Creatinine clearance (calculated) Bone mineral density Age

1.0 mg/dl above upper limit of normal Reduced to 50% in 95% of the patients, and the PTH level reliably predicted postoperative cure (Pitt et al., 2010). Due to concern about delayed renal clearance of PTH, longer intraoperative PTH monitoring may be indicated in some patients. In theory, intraoperative PTH monitoring could help to avoid persistent HPT secondary to missed glands. However, the true ability of this technique to detect unresected glands in SHPT is unclear (Olson Jr and Leight Jr, 2002).

SURGICAL OUTCOMES Generally, surgery is very effective in improving the biochemical abnormalities, symptoms, and quality of life inherent in SHPT. In a large retrospective series of more than 1000 SHPT patients, there was an improvement in the biochemical indices, neuromuscular and psychiatric symptoms, and radiological signs of osteitis fibrosa cystica (Tominaga et al., 2001). In other studies, parathyroidectomy was successful in ameliorating the symptoms of SHPT 80–95% of the time (Demeure et al., 1990; Punch et al., 1995). Abdelhadi and Nordenstrom reported a bone


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mass index increase of 7–23% after surgery in hemodialysis SHPT patients (Abdelhadi and Nordenstrom, 1998). Transient postoperative hypocalcemia is more prevalent in SHPT than in primary HPT. In a series of 30 uremic patients, transient hypocalcemia developed in 97% (29/30) of the patients. Symptoms including perioral numbness and paresthesia occurred in 45% and the Chvostek sign (spasm of facial muscles upon tapping on the facial nerve trunk) was positive 7% of the time (Mittendorf et al., 2004). Others have reported a similar high incidence of symptomatic hypocalcemia (95%) (McHenry et al., 2001). Thus, thorough postoperative evaluation should be considered to screen for postoperative hypocalcemia, followed by intravenous calcium and/or vitamin D administration if necessary. Hungry bone syndrome is a common complication following parathyroidectomy (Jofre et al., 2003). It is characterized by severe symptomatic hypocalcemia and hypophatemia due to extensive remineralization of the skeleton. These symptoms may become protracted and often require aggressive calcium and vitamin D supplementation.

DISEASE PERSISTENCE/RECURRENCE Persistent SHPT is defined as hypercalcemia within six months of parathyroidectomy. The reported frequency of disease persistence is up to 8% (Demeure et al., 1990). SHPT recurrence is defined as recurrence of hypercalcemia after six months after surgery. The frequency of SHPT recurrence increases over time. In a large series of 1000 SHPT patients, Tominaga and others reported a gradual increase in the recurrence incidence from 10% at three years and 20% at five years to 30% at seven years (Tominaga et al., 2001). This gradual increase in the recurrence rate may reflect the continued growth of either a parathyroid gland remnant or an autograft.

TYPE OF PARATHYROIDECTOMY Comparative studies show no difference in the outcomes of patients treated by either TPTX/AT or SPTX (Takagi et al., 1984; Welsh et al., 1984; Malmaeus et al., 1982; Gagne et al., 1992). It seems that the two


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Table 4 Subtotal parathyroidectomy (SPTX) versus total parathyroidectomy with autotransplantation (TPTX/AT). SPTX Pros

• Technically easier • No need for cryopreservation

Cons

• Risky to reoperate in case of recurrence • Tenuous blood supply to remnant gland

TPTX/AT • Ability to check graft integrity by PTH gradient • Easily accessible for recurrence treatment • Technically complicated • Requires cryopreservation

surgical modalities are equivalent and the selection of either is less important than the surgeon’s preference and experience (Table 4).

PERCUTANEOUS ETHANOL INJECTION Real time ultrasound-guided ethanol injection of the enlarged parathyroid has been proposed to treat refractory SHPT. The technique includes destruction of the dominant parathyroid gland with 90–100% ethanol injection and then controlling the other enlarged gland(s) with vitamin D treatment. Usually, the PTH is measured immediately after the procedure and weeks later to determine if a further round of injections is needed to keep the PTH to the K/DOQI target levels. Successful destruction of the diseased gland can be confirmed by absence of blood flow on the color Doppler flow mapping (Tanaka et al., 2003). Ethanol injection combined with vitamin D treatment is widely used in Japan as an alternative treatment for severe SHPT (Tanaka et al., 2003, 2005; Koiwa et al., 2003, 2007; Kakuta et al., 1999, 2000; Nakamura et al., 2003) with standard practice guidelines (Fukagawa et al., 2003). In a multicenter study from Japan, ethanol injection was effective in treating 63% of the 321 SHPT patients (Koiwa et al., 2007). When ethanol injection was compared to parathyroidectomy in ESRD, the K/DOQI target PTH level was achieved in 67% (14/21) and 18% (2/11) of the patients at one-year followup, respectively (Tanaka et al., 2005).


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Despite the minimaly invasive nature and the reported efficacy of this technique to control refractory SHPT, we believe that there is uncertainty in terms of the safety of the procedure. Given the anatomic complexity of the neck and the inability to monitor for the recurrent laryngeal nerve integrity, potential serious complications may well be associated with this procedure, including recurrent laryngeal nerve paralysis and injury to nearby structures. Moreover, the effectiveness of this procedure appears to be limited in patients with multiple-gland disease (three or four glands) (Tanaka et al., 2003, 2006). Thus, we recommend reserving ethanol injection therapy for inoperable SHPT patients with single-gland disease.

SUMMARY Secondary hyperparathyroidism is very prevalent in CKD patients. It represents an unregulated compensatory response to the continuous hyperphosphatemia and vitamin D deficiency associated with CKD. Parathyroidectomy is still the treatment of choice in patients with severe unresponsive SHPT. It is very effective in correcting biochemical disturbances and alleviating symptoms of SHPT patients. Both subtotal parathyroidectomy and total parathyroidectomy with autotransplantation are acceptable surgical approaches, with similar postoperative outcomes in treating SHPT.

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Owen JP, et al. Critical analysis of the use of skeletal surveys in patients with chronic renal failure. Clin Radiol 1988;39(6):578–582. Packman KS, Demeure MJ. Indications for parathyroidectomy and extent of treatment for patients with secondary hyperparathyroidism. Surg Clin North Am 1995;75(3):465–482. Perie S, et al. Usefulness of combination of high-resolution ultrasonography and dual-phase dual-isotope iodine 123/technetium Tc 99m sestamibi scintigraphy for the preoperative localization of hyperplastic parathyroid glands in renal hyperparathyroidism. Am J Kidney Dis 2005;45(2): 344–352. Pitt SC, et al. Secondary and tertiary hyperparathyroidism: the utility of ioPTH monitoring. World J Surg 2010;34(6):1343–1349. Pons F, et al. Preoperative parathyroid gland localization with technetium-99m sestamibi in secondary hyperparathyroidism. Eur J Nucl Med 1997;24(12): 1494–1498. Portale AA, et al. Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984; 73(6):1580–1589. Punch JD, Thompson NW, Merion RM. Subtotal parathyroidectomy in dialysisdependent and post-renal transplant patients: a 25-year single-center experience. Arch Surg 1995;130(5):538–542; discussion 542–543. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: a randomized trial. World J Surg 1991;15(6):745–750. Russell J, Lettieri D, Sherwood LM. Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 1986;119(6): 2864–2866. Saito H. et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 2005;280(4):2543–2549. Salem MM. Hyperparathyroidism in the hemodialysis population: a survey of 612 patients. Am J Kidney Dis 1997;29(6):862–865. Sancho JJ, et al. Surgical approach to secondary hyperparathyroidism. In: Textbook of Endocrine Surgery (eds.) OH Clark, QW Duh. Philadelphia: WB Saunders, 1997. Sherrard DJ. Renal osteodystrophy. Semin Nephrol 1986;6(1):56–67.


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Slinin Y, Foley RN, Collins AJ. Clinical epidemiology of parathyroidectomy in hemodialysis patients: the USRDS waves 1, 3, and 4 study. Hemodial Int 2007;11(1):62–71. Spasovski G. Strategies to manage low-bone turnover. Nefrologia 2009;29(4): 295–297. Stanbury SW, Lumb GA, Nicholson WF. Elective subtotal parathyroidectomy for renal hyperparathyroidism. Lancet 1960;1(7128):793–799. Takagi H, et al. Subtotal versus total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure. Ann Surg 1984;200(1):18–23. Tanaka M, et al. Combination therapy of intravenous maxacalcitol and percutaneous ethanol injection therapy lowers serum parathyroid hormone level and calcium x phosphorus product in secondary hyperparathyroidism. Nephron Clin Pract 2006;102(1):c1–c7. Tanaka M, et al. Efficacy of percutaneous ethanol injection therapy for secondary hyperparathyroidism in patients on hemodialysis as evaluated by parathyroid hormone levels according to K/DOQI guidelines. Ther Apher Dial 2005;9(1):48–52. Tanaka R, et al. Long-term (3 years) prognosis of parathyroid function in chronic dialysis patients after percutaneous ethanol injection therapy guided by colour Doppler ultrasonography. Nephrol Dial Transplant 2003;18(Suppl 3): iii58–iii61. Tanaka Y, Deluca HF. The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 1973;154(2):566–574. Tokumoto M, et al. Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism. Kidney Int 2002;62(4):1196–1207. Tokuyama K, et al. An epidemiologic analysis of parathyroidectomy in chronic dialysis patients. The Okinawa Dialysis Study Group. Nippon Jinzo Gakkai Shi 1996;38(7):309–313. Tominaga Y, et al. More than 1,000 cases of total parathyroidectomy with forearm autograft for renal hyperparathyroidism. Am J Kidney Dis 2001; 38(4 Suppl 1): S168–S171. Tominaga Y. Management of renal hyperparathyroidism. Biomed Pharmacother 2000;54(Suppl 1):25s–31s.


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Triponez F, et al. Surgical treatment of persistent hyperparathyroidism after renal transplantation. Ann Surg 2008;248(1):18–30. Tsukamoto Y, et al. More on hyperparathyroidism and the vitamin D receptor. Nat Med 1996;2(11):1162. Urena P, et al. Cinacalcet and achievement of the NKF/K-DOQI recommended target values for bone and mineral metabolism in real-world clinical practice — the ECHO observational study. Nephrol Dial Transplant 2009;24(9):2852–2859. Valimaki S, et al. Heterogeneous expression of receptor mRNAs in parathyroid glands of secondary hyperparathyroidism. Kidney Int 2001;60(5): 1666–1675. Wells SA Jr, et al. Transplantation of the parathyroid glands in man. Transplant Proc 1977;9(1):241–243. Wells SA Jr, et al. Transplantation of the parathyroid glands: current status. Surg Clin North Am 1979;59(1):167–177. Wells SA Jr, et al. Transplantation of the parathyroid glands in man: clinical indications and results. Surgery 1975;78(1):34–44. Welsh CL, et al. Parathyroid surgery in chronic renal failure: subtotal parathyroidectomy or autotransplantation? Br J Surg 1984;71(8):591–592. Yano S, et al. Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 2000;58(5):1980–1986.


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Chapter II.B.3: Tertiary Hyperparathyroidism Steven E. Rodgers, MD, PhD, John I. Lew, MD and Carmen C. Solórzano, MD

INTRODUCTION In response to hyperphosphatemia and impaired production of 1,25-hydroxyvitamin D, patients with chronic renal failure often develop derangements of calcium homeostasis leading to hyperplasia and hypersecretion of the parathyroid glands, a process known as secondary hyperparathyroidism (HPT). Following correction of the underlying etiology by kidney transplantation, one or more of these hyperplastic parathyroid glands may fail to involute, resulting in autonomous hyperfunctioning of the glands. This is generally referred to as tertiary HPT. It may manifest itself as hypercalcemia; however, many patients will remain eucalcemic in the face of elevated parathyroid hormone levels. In addition to hypercalcemia, patients with tertiary HPT may present with hypercalciuria, nephrolithiasis, nephrocalcinosis, osteoporosis, bone pain, pathologic fractures, pruritus, and muscle weakness.

DIAGNOSIS The laboratory diagnosis of tertiary HPT should include measurement of serum calcium, phosphorus, intact parathyroid hormone (PTH), creatinine, and 25-hydroxyvitamin D, as well as a 24 h urine calcium level. Following kidney transplant, patients will have varying degrees of renal insufficiency. It is important to note that PTH levels will vary depending on the glomerular filtration rate (GFR). As the GFR drops below 60 (mL/min/1.73 m2), the expected range of intact PTH increases. When 203


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the GFR is between 15 and 30, the expected PTH level is 70–110 pg/mL. When it drops below 15, the PTH level may range from 150 pg/mL to as high as 300 pg/mL (Eknoyan et al., 2003). Bone densitometry is useful for detecting evidence of decreased bone mineral density. A detailed history and physical examination may reveal signs and symptoms of hypercalcemia, including kidney stones, bone pain, prior fractures, muscle weakness, and pruritus. Role of Imaging Whereas the majority of patients with primary HPT are found at operation to have single gland disease, tertiary HPT may be due to one or multiple hyperplastic parathyroid glands. For this reason, an initial four-gland exploration is typically performed in the operating room, and preoperative imaging with sestamibi scanning and cervical ultrasonography (US) is felt by many to be unnecessary. However, the incidence of ectopic parathyroid glands is reported to be between 4 and 22% based on autopsy studies and preoperative imaging (Pitayakorn and McHenry, 2006; Sofferman and Nathan, 1998; Vail and Coller, 1967; Wang, 1976). Furthermore, up to 13% of patients have supernumerary glands at the time of autopsy (Akerstrom et al., 1984). Preoperative imaging with sestamibi scanning has been advocated prior to surgery for tertiary HPT in order to identify ectopic and supernumerary glands; however, this remains controversial. Sestamibi scans are often unable to identify all affected glands. Cervical US frequently allows identification of one or more enlarged parathyroid glands prior to surgical intervention (Fig. 1) and may help visualize glands not seen on sestamibi. In experienced hands, US can localize ectopic parathyroid glands (e.g. undescended glands or superior glands low in the tracheoesophageal groove). Additionally, it can be used to readily identify the presence of concomitant thyroid pathology.

SURGICAL TREATMENT Most patients with end-stage renal disease will have elevated PTH levels. Following kidney transplant, PTH levels slowly return to normal as the hyperplastic parathyroid glands involute. Up to one-third of these patients


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Fig. 1 Cervical ultrasound of a 33-year-old male with tertiary HPT showing (a) a right superior parathyroid gland (1.1 × 0.7 cm), (b) a right inferior parathyroid gland (0.9 cm), and (c) a left inferior parathyroid gland (0.9 × 0.8 cm). The left superior parathyroid gland was not identified on ultrasound. The parathyroid glands are indicated by white arrows. CA — common carotid artery; Tr — trachea.

develop hypercalcemia, but the majority of cases will resolve spontaneously within one year. Although indications for surgery in patients with tertiary HPT are controversial, parathyroidectomy should be considered in patients with hypercalcemia persisting greater than one year after transplant and in any patient with symptoms of hypercalcemia (Table 1). The symptoms include nephrolithiasis or nephrocalcinosis of the renal graft, pruritus, and bone or muscle pain. Additionally, patients with hypercalciuria are at risk of developing stones and should be considered for surgery. There are data to suggest deleterious effects of elevated PTH levels on bone mineralization and on the renal graft in eucalcemic patients (Dumoulin et al., 1997; Traindl et al., 1993). However, the use of parathyroidectomy in patients with elevated PTH levels in the absence of hypercalcemia following kidney transplant has not been properly studied. Extent of Surgical Resection The standard surgical approaches to the treatment of tertiary hyperparathyroidism include subtotal parathyroidectomy and total parathyroidectomy with autotransplantation. Following parathyroidectomy, impaired renal function and increased renal graft rejection have been documented


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S. E. Rodgers, J. I. Lew and C. C. Solórzano Table 1

Indications for parathyroidectomy in patients with tertiary HPT.

Hypercalcemia (>1 year after transplant) Hypercalciuria Nephrolithiasis or nephrocalcinosis Osteoporosis Bone pain Muscle pain or weakness Pruritus

(Schmid et al., 1997; Schwarz et al., 2007). The exact mechanism of this is not understood. However, the same phenomenon has been noted after thyroid surgery and is likely related to an acute drop in serum PTH levels. Following subtotal parathyroidectomy, the drop in serum PTH levels and the decrease in renal function (estimated by the glomerular filtration rate) may be less acute than following total parathyroidectomy with autotransplantation (Schlosser et al., 2007). These data have been employed to support the use of subtotal parathyroidectomy as the procedure of choice for tertiary HPT. More recently, limited parathyroidectomy with removal of only enlarged glands has been advocated for patients found to have one or more normal-appearing glands at the time of surgery. In several studies, long-term followup data of tertiary HPT patients who underwent limited parathyroidectomy showed equivalent or lower rates of recurrent disease when compared to patients who underwent subtotal parathyroidectomy or total parathyroidectomy with autotransplantation. Additionally, patients who underwent limited parathyroidectomy had a lower incidence of postoperative hypocalcemia than patients who underwent the more extensive procedures (Nichol et al., 2002). Based on the high incidence of supernumerary parathyroid glands (commonly located within the thymus gland), some surgeons routinely perform bilateral superior horn thymectomy at the time of parathyroidectomy for patients with tertiary HPT. Others advocate the selective use of thymectomy when all four parathyroid glands cannot be identified intraoperatively. However, the long-term benefit of these strategies has not been demonstrated.


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Intraoperative PTH Monitoring The benefit of intraoperative PTH monitoring (IPM) has been well established in the treatment of primary HPT. IPM has been used in a similar fashion for the treatment of tertiary HPT, in which during subtotal parathyroidectomy a 50% drop in the PTH level signals removal of an adequate amount of parathyroid tissue (Triponez et al., 2006). IPM has also been used during total parathyroidectomy with autotransplantation to signal the complete removal of all parathyroid tissue (Kaczirek et al., 2005). It should be noted that criteria for IPM to determine cure in tertiary HPT have not been clearly established. The use of IPM in patients with tertiary HPT is further complicated by evidence that modern two-site PTH immunoassays crossreact with some truncated fragments of the PTH molecule and that these truncated fragments accumulate to higher levels in patients with renal insufficiency (Brossard et al., 2000; Lepage et al., 1998). IPM may serve to confirm the adequate resection of parathyroid tissue in patients with single or multiple enlarged glands undergoing less-than-subtotal parathyroidectomy. Alternatively, it may help to signal the presence of supernumerary glands in patients undergoing subtotal or total parathyroidectomy.

MANAGEMENT OF RECURRENT DISEASE Recurrence of tertiary HPT following parathyroidectomy is most often related to a decline in renal function and loss of the transplanted kidney. It may also be due to overgrowth of the parathyroid remnant(s) or to the presence of a missed or supernumerary gland. As is the case with primary HPT, many tertiary HPT patients develop elevated PTH levels following parathyroidectomy but remain eucalcemic. The significance of this is unclear, and re-exploration of the neck is generally not recommended. In patients with recurrent tertiary HPT, careful planning is required prior to re-exploration. Imaging with both sestamibi scanning and cervical US should be performed. If no parathyroid tissue is identified, fourdimensional computed tomography (CT), or CT angiography, of the neck may be considered (Harari et al., 2008; Rodgers et al., 2006). An additional technique available for parathyroid localization is differential jugular venous sampling performed either preoperatively or intraoperatively.


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Vocal cord assessment using indirect or fiber-optic laryngoscopy should be considered prior to reoperation for recurrent disease. Subjective evaluation of the voice is an unreliable measure of vocal cord function. Finally, operative reports and pathology results from prior operations in the neck should be carefully reviewed.

SUMMARY Tertiary HPT is characterized by hypercalcemia and elevated PTH after renal transplantation. It usually presents with symptoms of hypercalcemia and/or low bone mineral density. At our institution, patients with tertiary HPT are routinely evaluated using cervical US. A four-gland exploration with subtotal parathyroidectomy (3½ gland excision) is performed in the majority of cases, leaving a portion of the most normal-appearing gland. In cases where one of the inferior parathyroid glands is not found intraoperatively, cervical thymectomy is performed. In the event that one or more glands appear normal, excision of only the enlarged glands is considered; however, the long-term results of this approach are unknown. In all cases, we use IPM to confirm an adequate drop in the PTH level and to rule out the presence of supernumerary glands.

SELECTED REFERENCES Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984;95(1):14–21. Brossard JH, Lepage R, Cardinal H, et al. Influence of glomerular filtration rate on non-(1-84) parathyroid hormone (PTH) detected by intact PTH assays. Clin Chem 2000;46(5):697–703. Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 2005;138(4):583–587; discussion 7–90. Dumoulin G, Hory B, Nguyen NU, et al. No trend toward a spontaneous improvement of hyperparathyroidism and high bone turnover in normocalcemic long-term renal transplant recipients. Am J Kidney Dis 1997;29(5):746–753. Eknoyan G, Levin A, Levin NW. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42(4 Suppl 3):S1–S201.


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Harari A, Zarnegar R, Lee J, et al. Computed tomography can guide focused exploration in select patients with primary hyperparathyroidism and negative sestamibi scanning. Surgery 2008;144(6):970–976; discussion 6–9. Irvin GL, 3rd, Solorzano CC, Carneiro DM. Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg 2004;28(12): 1287–1292. Kaczirek K, Riss P, Wunderer G, et al. Quick PTH assay cannot predict incomplete parathyroidectomy in patients with renal hyperparathyroidism. Surgery 2005;137(4):431–435. Lepage R, Roy L, Brossard JH, et al. A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 1998;44(4):805–809. Nichol PF, Starling JR, Mack E, et al. Long-term follow-up of patients with tertiary hyperparathyroidism treated by resection of a single or double adenoma. Ann Surg 2002;235(5):673–678; discussion 8–80. Phitayakorn R, McHenry CR. Incidence and location of ectopic abnormal parathyroid glands. Am J Surg 2006;191(3):418–423. Rodgers SE, Hunter GJ, Hamberg LM, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery 2006;140(6):932–940; discussion 40–41. Schlosser K, Endres N, Celik I, et al. Surgical treatment of tertiary hyperparathyroidism: the choice of procedure matters! World J Surg 2007; 31(10): 1947–1953. Schmid T, Muller P, Spelsberg F. Parathyroidectomy after renal transplantation: a retrospective analysis of long-term outcome. Nephrol Dial Transplant 1997; 12(11):2393–2396. Schwarz A, Rustien G, Merkel S, et al. Decreased renal transplant function after parathyroidectomy. Nephrol Dial Transplant 2007;22(2):584–591. Sofferman RA, Nathan MH. The ectopic parathyroid adenoma: a cost justification for routine preoperative localization with technetium Tc 99m sestamibi scan. Arch Otolaryngol Head Neck Surg 1998;124(6):649–654. Traindl O, Langle F, Reading S, et al. Secondary hyperparathyroidism and acute tubular necrosis following renal transplantation. Nephrol Dial Transplant 1993;8(2):173–176. Triponez F, Dosseh D, Hazzan M, et al. Accuracy of intra-operative PTH measurement during subtotal parathyroidectomy for tertiary hyperparathyroidism after renal transplantation. Langenbecks Arch Surg 2006;391(6):561–565.


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Vail AD, Coller FC. The parathyroid glands: clinicopathologic correlation of parathyroid disease as found in 200 unselected autopsies. Mo Med 1967; 64(3):234–238. Wang C. The anatomic basis of parathyroid surgery. Ann Surg 1976;183(3): 271–275.


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Chapter II.B.4: Parathyroid Carcinoma Elliot J. Mitmaker MD, MSc, FRCSC and Wen T. Shen, MD, MA

The most reliable clue to the presence of malignancy in our experience is a fibrous inflammatory-like reaction, which surrounds the tumor and binds it firmly to adjacent structures. The fibrosis involves the capsule and is found also inside the tumor in thick stromal bands. Such a fibrous reaction is not seen either around or inside the benign adenomas or the hyperplastic glands. — Oliver Cope, Carcinoma of the parathyroid glands: 4 cases among 148 patients with hyperparathyroidism. Ann Surg 1953;138(4):661–671.

INTRODUCTION Parathyroid carcinoma is a rare endocrine neoplasm, accounting for approximately 1% of all cases of primary hyperparathyroidism. As opposed to the more commonly encountered benign parathyroid adenoma, patients afflicted with parathyroid cancer usually are more symptomatic and have higher calcium and parathormone (PTH) levels. This chapter summarizes the demographic data, clinical presentation, diagnostic studies, and surgical approach, as well as the role of adjuvant and medical therapies in the management of both primary and recurrent or metastatic parathyroid cancer.

DEMOGRAPHIC DATA Worldwide, there have been approximately 700 cases of parathyroid carcinoma reported in the medical literature. Parathyroid cancer accounts 211


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E. J. Mitmaker and W. T. Shen Table 1

Demographic data for parathyroid cancer.

Gender (M:F) Age of diagnosis Incidence (of 1° HPT) Prevalence (in the US)

1:1 5th decade ~1% 0.005%

for 0.005% of all cancers and is the cause of 1% of cases of hyperparathyroidism, with some centers reporting incidences of up to 5% of cases (Table 1). In 1999, the National Cancer Database (NCDB) published their report of 286 prospectively accrued patients who were diagnosed with parathyroid cancer between 1985 and 1996. They found no differences with respect to gender, ethnicity, income, and geographic location. More recently, analysis of the Surveillance, Epidemiology and End Results (SEER) cancer registry revealed a significant increase of 60% in the incidence of parathyroid cancer from the years 1988–1991 to 2000–2003. This dramatic increase may be due to the fact that more cases of asymptomatic hyperparathyroidism are being discovered by biochemical screening for calcium and immunoassays of PTH levels. As a result, more parathyroidectomies are being performed with subsequent detection of parathyroid carcinoma on final pathology.

ETIOLOGY The etiology of parathyroid cancer is largely idiopathic. There are some reports of parathyroid carcinomas that are associated with multiple endocrine neoplasia type I (an autosomal dominant form of familial hyperparathyroidism), hereditary hyperparathyroid–jaw tumor syndrome (HPT-JT, a condition associated with tumors of the parathyroid glands and fibro-osseous tumors of the jaw), and external radiation exposure.

CLINICAL PRESENTATION The majority of cases diagnosed as parathyroid carcinoma are of the hyperfunctioning variety with markedly elevated levels of both PTH and calcium. A few anecdotal cases have been reported as nonfunctional with


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normal levels of PTH and calcium; however, they are only a minority. The classic signs and symptoms associated with parathyroid cancer are similar to primary hyperparathyroidism. The following is a list of the signs and symptoms commonly seen in these patients. 1. 2. 3. 4. 5. 6. 7.

Fatigue Weakness Polyuria Polydipsia Depression Nausea Kidney stones

8. 9. 10. 11. 12. 13. 14.

Pathologic bone fractures Subcortical bone resorption Bone pain Peptic ulcers Recurrent pancreatitis Anorexia Dehydration

Parathyroid cancer should be suspected in patients presenting with severe “classic” signs and symptoms of hyperparathyroidism. On the other hand, patients with benign primary hyperparathyroidism rarely have severe symptoms, and are usually diagnosed earlier when they are asymptomatic or minimally symptomatic, by screening blood tests demonstrating elevated calcium levels and PTH. Parathyroid cancers are hormonally active and secrete markedly elevated levels of PTH. In the long term, the effects of prolonged secretion of PTH on the skeleton and of calcium on the kidneys are the ultimate debilitating morbidities that characterize this disease. Generally speaking, patients with parathyroid cancer tend to have much higher levels of calcium and PTH as compared to patients who have benign primary hyperparathyroidism. One should suspect parathyroid cancer in a patient with the following biochemical profile: • • • • •

Calcium levels greater than 14 mg/dL, or 2–4 mg/dL above the normal calcium level High PTH levels (3–10 times normal) Renal and skeletal abnormalities in conjunction with an elevated PTH level Palpable cervical mass Compression or local invasion (evidence of the recurrent laryngeal nerve paralysis)


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The last two findings are occasionally noted on physical exam, but in the majority of cases the clinician establishes a high index of suspicion based upon clinical and biochemical findings. The next step in establishing the diagnosis is to perform localization studies prior to surgery. Fine needle aspiration biopsy is to be avoided, due to the risk of tumor seeding along the needle tract.

LOCALIZATION STUDIES Several imaging modalities are available for preoperative planning, including neck ultrasound, computed axial tomography (CT), magnetic resonance imaging (MRI), and sestamibi scan. If four-gland exploration is the operative procedure of choice, then preoperative localization studies are considered to be superfluous. However, as unilateral gland exploration and minimally invasive parathyroidectomy (MIP) are becoming more popular, the need for preoperative imaging is growing stronger. Unfortunately, there is little radiographic information to help distinguish benign from malignant parathyroid tumors. Ultrasound provides information with respect to the number of parathyroid glands, their location with respect to adjacent structures, and the visualization of the thyroid gland in order to rule out any coexisting thyroid nodules. It also has the advantage of being used intraoperatively to help guide surgical management. The sestamibi scan is a nuclear medicine study in which a very mild dose of a radioactive material (technetium Tc 99m sestamibi radiopharmaceutical) is injected intravenously. Its main goal is to help localize the hyperfunctioning parathyroid gland, as opposed to making the diagnosis of primary hyperparathyroidism. In addition, it can help distinguish between unigland and multigland disease, and also help detect metastatic disease. When ultrasound and sestamibi scans are equivocal, second-line imaging should consist of CT scanning or MRI. Although imaging studies for the initial operation for hyperparathyroidism are useful for guiding the surgeon’s operative strategy, they are of critical importance in the reoperative setting. In the case of parathyroid carcinoma, these tumors are associated with high local recurrence rates and distant metastasis. Ultrasound is generally accurate in identifying the location of the recurrence and its relationship to any surrounding


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structures. On the other hand, sestamibi scanning maintains its role in being able to identify hyperfunctioning parathyroid lesions and distant metastases. If the aforementioned methods fail, then the patient is sent for a contrast CT to look for recurrence. MRI with gadolinium represents the ideal method for detecting recurrence of parathyroid cancer, as it is not limited by clip artifacts from previous operations (in contrast to CT scans). If all noninvasive studies are equivocal in locating the recurrence of parathyroid cancer, then an invasive approach using selective venous catheterization is the procedure of choice.

PATHOLOGY The distinguishing histologic features of parathyroid cancer are difficult to define. There are a variety of gross and microscopic features that aid in establishing the diagnosis of a parathyroid carcinoma as opposed to the more common parathyroid adenoma (Table 2). Unfortunately, none of these features is pathognomonic of parathyroid cancer and some can be found in parathyroid adenomas as well. Due to the lack of defining histopathologic features, attention has turned to molecular and genetic studies to help distinguish between adenoma and carcinoma. Several studies using flow cytometry and mean nuclear DNA Table 2 Macroscopic and microscopic pathologic features of parathyroid carcinoma. Macroscopic features • • • • • •

Typically large (>3 cm) (see Figs. 1 and 2) Grayish-white Often adherent to adjacent tissues More common in inferior glands Irregular and firm Occasionally found in ectopic location

Microscopic features •

Fibrous trabeculae (thick fibrous bands) • Mitotic figures • Vascular or capsular invasion • •

Chief cell — predominant cell type Cellular atypia


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Fig. 1 Parathyroid carcinoma — left inferior gland (courtesy of M. R. Vriens, MD, PhD, Utrecht, The Netherlands).

Fig. 2 4.8 cm parathyroid cancer (courtesy of M. R. Vriens, MD, PhD, Utrecht, The Netherlands).


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have shown a difference between benign and malignant parathyroid tissue. Immunohistochemical analysis has demonstrated the lack of staining of the retinoblastoma (Rb) protein, which is usually present in benign parathyroid tissue. In addition, molecular studies have shown increased expression of the PRAD1 oncogene (which codes for cyclin D1) and mutations in the tumor suppressor gene HRPT2.

OPERATIVE MANAGEMENT The only successful long-term treatment of parathyroid cancer is surgical. En bloc removal of the entire parathyroid tumor along with the ipsilateral thyroid lobe, isthmus, and ipsilateral central lymph node compartment (starting inferiorly at the level of the upper mediastinum to the larynx superiorly) should routinely be performed when parathyroid cancer is suspected preoperatively either from a needle biopsy or based on the biochemical results. The reason for the thyroid lobectomy is to obtain clear resection margins (not necessarily for the possibility of a lesion arising from within the thyroid gland itself). If there is evidence of local invasion, then all tumor tissue should be removed with careful attention to avoid disruption of the capsule of the parathyroid gland so as to prevent tumor seeding (parathyromatosis). If the tumor is clearly invading the recurrent laryngeal nerve, then the nerve needs to be sacrificed. On the other hand, if it appears as though the lesion could be shaved off the nerve, then every attempt should be made to preserve the function of the recurrent laryngeal nerve. Although more aggressive surgical approaches to the treatment of parathyroid carcinoma have been described in the literature, most studies have shown no benefit when it comes to performing wide local excision with free margins and prophylactic neck dissection. It is not always possible to make the diagnosis of parathyroid cancer preoperatively or even intraoperatively. Approximately 20% of the time, the diagnosis is confirmed only by the final pathologic report. In such cases, if the patient continues to be symptomatic with biochemical evidence of hypercalcemia or evidence of vascular or capsular invasion on pathology, then reoperation is indicated. The patient should then undergo ipsilateral thyroidectomy along with ipsilateral central node compartment dissection,


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ensuring that all nodal tissue in the ipsilateral tracheoesophageal groove is removed. If the patient is normocalcemic and there is only microscopic evidence of disease, then the consensus is to follow the patient with serial laboratory determinations of calcium and PTH, along with serial neck ultrasounds to detect local recurrence. Unfortunately, disease recurrence is common (up to 50%) in patients diagnosed with parathyroid carcinoma. Parathyroid cancer is a slowgrowing disease that can present with local invasion, lymph node metastases, or with distant metastases most commonly to the liver, lungs, or bones. Most recurrent disease occurs within the first 2–3 years after initial treatment (the median time to recurrence is 33 months and can range from 1 to 228 months). Patients with recurrence usually present with an elevated calcium and/or elevated PTH level. These patients are rarely symptomatic, thus stressing the need for lifelong followup with their surgeon and endocrinologist. As with other forms of malignancy, a short disease-free interval is associated with a poor prognosis. The decision for further surgery on these patients should be discussed with the patient, their family, as well as the endocrinologist or primary care physician in order to clarify the goals and potential outcomes of the operation. Reoperative neck surgery is associated with a high morbidity and cures are rarely achieved. The goal for the majority of these patients is symptomatic palliation by reducing tumor load and normalizing calcium levels in an attempt to minimize the devastating effects of this cancer on the kidneys and bones. Even in the presence of locoregional recurrence and concomitant distant metastases, every attempt should be made to resect both the recurrent and distant metastases in order to induce periods of normocalcemia. An additional advantage of removing metastatic tumor deposits is to allow the patient being treated medically to achieve better control of their symptoms. A question often discussed in the literature is whether there is a limit to the number of times the surgeon should re-explore a reoperative neck for recurrence. Some studies have shown that the best results achieved for controlling calcium and PTH levels are achieved within the first two reoperations. Subsequent re-exploration has been associated with higher morbidities and less-than-satisfactory control of the patient’s symptoms and biochemistry. However, resectable lesions that are found outside of the neck should be excised for the purpose of palliation.


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MEDICAL MANAGEMENT AND ADJUVANT THERAPIES Just as operative management is of central importance in the initial treatment of parathyroid cancer, so is the medical management of its associated hypercalcemia. Patients presenting with hyperfunctioning malignant parathyroid tissue require prompt attention to prevent irreversible end organ effects of hypercalcemia on the cardiovascular, renal, and musculoskeletal systems. The first step in the medical management of severe hypercalcemia is the administration of intravenous fluids (normal saline) to restore the intravascular volume of the patient and increase the glomerular filtration rate. Once intravascular volume is restored, loop diuretics are given (such as furosemide, starting at 40 mg IV) if renal function is adequate. Loop diuretics aid in excreting excess calcium by blocking calcium resorption at the level of the ascending loop of Henle. Other drugs that decrease serum calcium include calcitonin, plicamycin, and the bisphosphonates. Calcitonin is a short-acting osteoclast inhibitor and acts by decreasing serum calcium levels through inhibition of bone resorption. Plicamycin, another short-acting osteoclast inhibitor, acts in a similar fashion but can be a problem due to its gastrointestinal side effects. There are three commercially available bisphosphonates: pamidronate, etidronate, and clodronate. These agents tend to be more potent osteoclast inhibitors and are long-acting, with a reduced side effect profile. A new agent for the treatment of patients with unresectable parathyroid cancer and/or refractory hypercalcemia is Cinacalcet (Sensipar). Cinacalcet is a calcimimetic drug that binds to the calcium-sensing receptors via allosteric activation. It reduces the synthesis of PTH, thereby lowering the serum calcium levels. Its ability to reduce serum calcium levels and maintain those levels (up to three years) in patients with metastatic parathyroid cancer has made this drug an effective treatment. Many case studies and reports have looked at the efficacy of chemotherapeutic regimens in the treatment of parathyroid cancer. These studies were based on a small number of patients and looked at a variety of different chemotherapeutic regimens (alone or in combination) using 5-fluoruracil, cyclophosphamide, dacarbazine, adriamycin, vincristine, actinomycin D, and lomustine. To date, there has been little evidence that chemotherapy is effective for metastatic parathyroid cancer, nor in its


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ability to control PTH and calcium levels. Radiotherapy, in the past, has generally been considered ineffective for local control of this disease. However, recent studies published by the Mayo Clinic and MD Anderson Cancer Center have suggested that radiotherapy may have a role in improving the disease-free survival of these patients. Further studies are needed to define the exact role of chemotherapy and radiotherapy in the treatment of metastatic parathyroid cancer.

PROGNOSIS AND OUTCOMES The prognosis of parathyroid carcinoma is variable, as reported in the literature. Five-year survival rates range from 46% to 90%, with the National Cancer Database (NCDB) reporting 5-year and 10-year survival rates of 85.5% and 49.1%, respectively, over a 10-year period (1985–1995). The Swedish Cancer Registry database reported a 10-year overall survival rate of 70%. Although survival has been shown to be favorable, the rate of recurrence still remains elevated at about 50%. Once recurrence occurs, the potential for local invasion, as well as lymphatic and hematogenous spread to distant sites, often leads to a significant burden of disease with no hope of achieving cure. The cause of mortality from parathyroid cancer is directly related to the physiologic and metabolic consequences of hypercalcemia, as opposed to the tumor burden itself. The SEER database (1988–2003) reported an all-cause 5-year mortality rate of 16% and a 10-year mortality rate of 33%. Overall, patients whose tumors are discovered early have a favorable prognosis, while those patients who develop recurrence may require multiple reoperations and will likely succumb to the metabolic complications associated with severe hypercalcemia.

SELECTED REFERENCES Amos KD, Habra MA, Perrier ND. Carcinoma of the thyroid and parathyroid glands. In: The MD Anderson Surgical Oncology Handbook, 4th Edn. BW Feig (ed.). Philadelphia: Lippincott Williams & Wilkins, 2006, pp. 441–463. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med 1992;326:1196–1203.


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Bukowski RM, Sheeler L, Cunningham J, Esselstyn C. Successful combination chemotherapy for metastatic parathyroid carcinoma. Arch Intern Med 1984;144:399–400. Calandra DB, Chejfec G, Foy BK, et al. Parathyroid carcinoma: biochemical and pathologic response to DTIC. Surgery 1984;96:1132–1137. Chahinian AP, Holland JF, Nieburgs HE, et al. Metastatic nonfunctioning parathyroid carcinoma: ultrastructural evidence of secretory granules and response to chemotherapy. Am J Med Sci 1981;282:80–84. Cope O, Nardi GL, Castleman B. Carcinoma of the parathyroid glands: 4 cases among 148 patients with hyperparathyroidism. Ann Surg 1953;138(4): 661–671. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985–1995: A National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1999;86:538–544. Kebebew E, Arici C, Duh QY, Clark OH. Localization and reoperation results for persistent and recurrent parathyroid carcinoma. Arch Surg 2001;136:878–885. Lee PK, Jarosek SL, Virnig BA, et al. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 2007;109:1736–1741. Marcocci C, Cetani F, Rubin MR, et al. Parathyroid carcinoma: is there a role for adjuvant radiation therapy? Cancer 2003;98:2378–2384. Marcocci C, Cetani F, Rubin MR, et al. Parathyroid carcinoma. J Bone Miner Res 2008;23(12):1869–1880. Rawat N, Khetan N, Williams DW, Baxter JN. Parathyroid carcinoma. Br J Surg 2005;92(11):1345–1353. Sandelin K. Parathyroid carcinoma. In: Textbook of Endocrine Surgery, 2nd Edn. OH Clark (ed.) Philadelphia: Elsevier Saunders, 2005, pp. 549–554. Shane E. Clinical review 122: parathyroid carcinoma. J Clin Endocrinol Metab 2001;86:485–493. Silverberg SJ, Rubin MR, Faiman C, et al. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab 2007;92:3803–3808.


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Chapter II.B.5: Hyperparathyroidism in Familial Disease Charles Tuggle, BS, Julie Ann Sosa, MD, MA and Robert Udelsman, MD, MBA

OVERVIEW Primary hyperparathyroidism (HPT) occurs at all ages, with a predominance in elderly, white women; sporadic disease represents >95% of incident cases. Inherited syndromes are rare but must be considered during evaluation. Detection necessitates a thorough history and physical examination, with an emphasis on family history and a complete review of systems (Fig. 1).

MULTIPLE ENDOCRINE NEOPLASIA 1 (MEN1) (Online Mendelian Inheritance in Man [OMIM] 131100, gene locus 11q13) This accounts for the majority of familial HPT. Epidemiology and Presentation •

• • •

Evaluate for recurrent HPT, gastrointestinal ulcers, pancreatic neuroendocrine tumors, pituitary tumors, lipomas, truncal collagenomas, and facial angiofibromas Incidence: 0.015 per 1000 Autosomal dominant inheritance HPT

First clinical manifestation in 90% of carriers Typical presentation at age 20–25 223


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C. Tuggle, J. A. Sosa and R. Udelsman

Fig. 1 Algorithm for detection and management of familial HPT (fHPT) in adult patients.

•

90% of carriers present by age 50 Pathology: multigland hyperplasia (often asymmetric), increased incidence of supernumerary glands

Penetrance of at least one associated clinical feature is >50% by age 20, and >95% by age 40

Diagnosis •

Clinical criteria: ≥2 MEN1-associated endocrine tumors [parathyroid, anterior pituitary, or gastroenteropancreatic (GEP) neuroendocrine tumors]


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Hyperparathyroidism in Familial Disease

•

225

Familial criteria: family with at least one index case of MEN1 and a first-degree relative with ≥1 MEN1-associated endocrine tumors

Genetic Testing (Table 1) •

Candidates are:

• •

10% of incident cases result from a de novo mutation and lack a family history Commercially available sequence analysis of coding regions (exons 2–10)

•

Patients with ≥2 MEN1-associated tumors Family members at risk of inheritance of a known mutation

80–90% sensitivity

Subsequent deletion/duplication analysis if sequence analysis fails to detect a mutation

Offered by select laboratories; will detect an additional 1–3% of cases

Parathyroid Imaging • •

Unnecessary before primary surgery; only utility is to exclude ectopic glands Required before remedial surgery (see Chapter II.A.2)

Surgery Primary surgery Parathyroidectomy should be thought of as a “debulking” procedure, as the risk of recurrence is high. Early parathyroidectomy reduces exposure to chronic hypercalcemia, but predisposes to earlier recurrence and need for remedial surgery. Delayed surgery allows the glands to enlarge so as to facilitate identification. In patients with Zollinger–Ellison syndrome, parathyroidectomy should be performed prior to, or at the time of, pancreatic surgery.


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Initial surgery is either subtotal parathyroidectomy or total parathyroidectomy with heterotopic autotransplantation and transcervical thymectomy. Cryopreservation should be considered (see Chapter II.B.8). The risk of remedial cervical exploration is greater with the former strategy, while the risk of hypoparathyroidism is greater with the latter. A thorough search for supernumerary and ectopic glands should be performed; thymectomy removes occult parathyroid glands and helps prevent development of thymic carcinoid tumors. A minimally invasive approach should not be used.

Remedial surgery Recurrent HPT arises from remnant tissue in the neck following sub-total resection, ectopic and/or supernumerary tissue in the neck or mediastinum missed at the primary procedure, autotransplantation graft, or a combination. Remedial surgery comes at increased risk of complications. •

Preoperative evaluation

•

Confirm diagnosis Review all previous operative and pathology reports Perform laryngoscopy to assess recurrent laryngeal nerve function Image to localize recurrence site; this can include ultrasound, sestamibi with SPECT (to include graft site if present), 4D-CT, MRI, ultrasound-guided parathyroid aspiration, and angiography with venous sampling (see Chapter II.A.2)

Surgery

Minimally invasive approach can be employed if recurrence is in forearm or well-localized in neck

Surveillance • •

Low genotype-to-phenotype correlation Carriers should be checked periodically for common expressions of MEN1


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•

•

227

Biochemical testing annually; abdominal and pituitary imaging every 3–5 years Cost-effective panel — serum calcium corrected for albumin or ionized calcium (henceforth referred to as serum calcium), iPTH, gastrin, prolactin (from age 5) Complete biochemical panel — serum calcium, iPTH, gastrin, prolactin; consider glucagon, fasting glucose, insulin, proinsulin, insulin-like growth factor 1, chromogranin-A Imaging — abdominal CT or MRI (from age 20) and head MRI, pituitary protocol When genetic testing fails to identify a mutation in a patient with clinical MEN1 syndrome, children should undergo cost-effective biochemical testing every three years. If testing remains negative through age 30, the risk of being a carrier falls to 10%, and testing intervals can be lengthened.

MULTIPLE ENDOCRINE NEOPLASIA 2A (MEN2A) (OMIM 171400, gene locus 10q11.2) Initial presentation and management of carriers is dominated by medullary thyroid cancer (MTC) (see Chapter I.B.4). Epidemiology and Presentation • • • •

•

Evaluate for MTC, uni/bilateral pheochromocytoma, hypertensive sudden death, cutaneous lichen amyloidosis, Hirschprung’s disease Prevalence: estimated at 1 in 30,000 Autosomal dominant inheritance with incomplete penetrance, variable disease pattern HPT Mild and often asymptomatic Pathology: typically single-gland enlargement; multigland disease does occur Strong genotype–phenotype correlation The specific REarranged during Transfection proto-oncogene (RET ) mutation and the familial pattern of disease predict the likelihood and age of onset of associated tumors


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HPT is most commonly associated with codon 634 mutations, which account for ∼85% of families with MEN2A

Diagnosis •

Clinical criteria: ≥2 MEN2A-associated endocrine tumors [MTC (>95% in carriers), pheochromocytoma (∼50%), or parathyroid tumor(s) (20–30%)]

Genetic Testing (Table 2) • • • •

• • •

Follows biochemical testing for MTC if thyroid is in situ in the proband and MEN2 is suspected Appropriate for all cases of MTC; likelihood of mutation is 1–7% in patients with apparently sporadic MTC Not indicated in cases of HPT without other suggestive features of MEN2 In a patient with MTC, no evidence of C-cell hyperplasia in thyroidectomy specimen, and a negative family history, the probability of hereditary disease is 4 L/24 h). When the clinical picture is consistent with CS and the baseline 24 h urinary free cortisol exceeds five times the upper limit of the reference range (e.g. >300 µg/24 h), no additional studies are needed to confirm CS. An overnight 1mg dexamethasone suppression test is most useful for demonstrating autonomous cortisol secretion. The 8 a.m. plasma cortisol level in a healthy patient will be suppressed to below 5 µg/dL with this test. There are, however, many causes for cortisol nonsuppression with the overnight 1mg dexamethasone suppression test. They include: patient error, increased corticosteroid-binding globulins (CBGs) due to estrogen therapy or pregnancy, alcoholism, OSA, depression, panic attacks, obsessive–compulsive disorder, obesity, drugs that accelerate dexamethasone metabolism (such as anticonvulsants, primidone, and rifampin), renal failure, and stress. Another option is the 8 mg overnight dexamethasone suppression test. Normal patients should have an a.m. cortisol of nearly zero. Failure to suppress is considered positive and warrants a two-day, low-dose dexamethasone suppression test. The above-mentioned tests are most useful for demonstrating autonomous cortisol production in an adrenal incidentaloma. With equivocal findings and a 24 h urinary free cortisol excretion of less than 300 µg, hypercortisolism should be confirmed with the two-day, low-dose dexamethasone suppression test. Dexamethasone 0.5 mg is orally given every 6 h for 48 h. A 24 h urinary free cortisol, collected during the second day of suppression, ≥5 µg, is consistent with the diagnosis of CS. This test is approximately 79% sensitive and 74% specific, with an overall accuracy of 71%. It is most efficacious for ruling out CS in those patients for whom the index of suspicion for CS is low. However, some patients with mild pituitary-dependent CS may suppress with a low-dose dexamethasone suppression test. In an effort to correct the suppression with a low-dose dexamethasone suppression test observed in some patients with pituitary CS, the

b1117_Chapter-III_A2.qxd

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CRH dexamethasone suppression test was developed. A serum cortisol concentration >1.4 µg/dL at 15 min following corticotropin-releasing hormone administration is consistent with CS. Although it is purported to be highly accurate, false positive results have been seen in our clinic. Other diagnostic testing includes the use of late night plasma or salivary cortisol. A midnight, sleeping, serum cortisol concentration >1.8 µg/dL is 100% sensitive in patients with CS. Precision, however, usually requires hospitalization. Alternatively, measurement of salivary cortisol correlates well with serum cortisol levels. This is performed by giving the patient instructions to chew on a special cotton swab for 2 min, followed by placement in a specially designed plastic container. Salivary cortisol levels obtained at 11 p.m. >100 ng/dL are highly sensitive for CS. This test is becoming increasingly popular and may be used as a first-line screening test in some centers. No single test is satisfactory for case detection and confirmation of CS. Patients suspected of having endogenous hypercortisolism on clinical grounds should be evaluated with multiple tests for diagnostic confirmation. These would include, at a minimum, a 24 h urinary free cortisol, 11 p.m. salivary cortisol and, less often, the two-day low-dose dexamethasone suppression test or CRH dexamethasone suppression test.

SUBTYPE EVALUATION AND IMAGING (FIGS. 3 AND 4) With CS confirmed, subtype evaluation and localization are the appropriate next steps. Since 70% of patients with endogenous hypercortisolism have pituitary-dependent CS and 80% have ACTH-dependent CS, a plasma ACTH concentration is the first step in subtype evaluation. Normal plasma ACTH levels, when measured with an immunoradiometric assay (IRMA), are 10–60 pg/mL. Plasma ACTH levels 200 pg/mL range often represent patients with ectopic ACTH syndrome. When ACTH levels are less than 5 pg/mL, computerized crosssectional imaging with computed tomography (CT) or, less often, magnetic resonance imaging (MRI) of the adrenal glands will most often


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G. B. Thompson and W. F. Young , Jr.

Fig. 3 Cushing’s syndrome (subtype evaluation). *TSS in appropriate clinical setting. † Chest abdomen. ‡Octreoscan, MIBG scan, FDG-PET. §Calcitonin, 5-HIAA, gastrin, metanephrines (plasma).

Fig. 4

Cushing’s syndrome (subtype evaluation).


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Fig. 5

293

CT scan of cortisol-secreting adrenocortical adenoma.

delineate adrenal pathology. As with any high-resolution imaging, the presence of incidental findings is common. Five to ten percent of the population harbor adrenal nodules >1 cm. Typically, benign cortisolsecreting adrenal adenomas range from 2 to 6 cm in diameter and have a rather smooth, regular border with a homogenous appearance (Fig. 5). A homogenous adrenal lesion with 83 nmol/dL). Patients fitting these descriptions are considered to have a high probability of APA, regardless of the CT findings. Studies have shown that up to 41% of patients with “high probability of APA” and normal adrenal CT scan prove to have unilateral aldosterone secretion. Idiopathic Hyperplasia (IHA) adrenal glands may be normal on CT or show nodular changes. Aldosterone-producing adrenal carcinomas are very rare and always above 4 cm in diameter and have an inhomogenous imaging phenotype on CT. In our experience CT imaging that indicates a unilateral unequivocal adrenal tumor >1 cm with a normal contralateral gland is consistent with


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adenoma. 98% of patients with unilateral adrenal tumors that underwent adrenalectomy had improvement in their hypertension, and 100% had resolution of their hypokalemia. Biochemical cure was achieved in over 95% of patients with a normalization of aldosterone levels postoperatively. Nevertheless, adrenal CT scan is not always accurate in distinguishing between APA and IHA, particularly for small adrenal lesions less than 1 cm in diameter. In addition, in some cases, CT may show normalappearing adrenals, minimal unilateral limb thickening, unilateral microadenomas or bilateral micro/macroadenomas, which are nonspecific findings and do not allow differentiation between APA and IHA. In those selected cases, additional testing is essential in order to differentiate between APA and IHA.

ADDITIONAL LABORATORY TESTS A PAC/PRA ratio >20 is highly sensitive and specific diagnostic laboratory test for PH. However, in borderline cases more extensive testing should be considered to confirm inappropriate aldosterone secretion. Confirmatory tests are based on the concept that aldosterone is secreted in an unregulated fashion in PH and therefore cannot be suppressed by the usual physiologic regulatory inputs. In a similar fashion, PRA is chronically and tonically suppressed and cannot be stimulated. There are several ways to measure aldosterone suppression, but the list of medications affecting the renin–angiotensin–aldosterone system axis is extensive (i.e. spironolactone, amiloride) and frequently falsifies the test results (Table 1). Notably, certain medications — like calcium channel blockers or α-adrenergic receptor blockers — do not interact with the measurement of aldosterone levels and therefore should be considered for primary treatment of hypertension in patients with suspected hyperaldosteronism, until the final diagnosis has been confirmed. In patients already receiving treatment with a mineralocorticoid receptor antagonist or high dose amiloride for hypertension, these agents should be discontinued at least six weeks prior to aldosterone level measurements. Keeping this in mind, several tests have been described to confirm the diagnosis of PH if necessary.


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X. M. Keutgen, R. Zarnegar and T. J. Fahey III

Table 1 Effects of the main antihypertensives on the renin–angiotensin system following sustained treatment. Medication class

Plasma rennin activity

Aldosterone levels

Diuretics ACE I Angiotensin receptor blockers β blockers α blockers Direct vasodilators Central sympathetic agonists Dihydropyridine calcium channel blockers Non-dihydropyridine calcium channel blockers

↓ ↑ ↑ ↓ No effect No effect No effect ↑ or no effect

↑ ↓ ↓ ↓ No effect No effect No effect ↓

↑ or no effect

No effect

Measurement of PRA After Salt and Water In PH, PRA is less than 1 ng/mL/h and fails to rise above 2 ng/mL/h following salt and water depletion, furosemide administration or 4 h of erect posture. Captopril Suppression Test PRA and aldosterone levels are measured before and 2 h after administration of a single dose of captopril (25–50 mg). The test is considered positive if plasma aldosterone levels cannot be suppressed below 15 ng/dL. It has a sensitivity of 90–100% but a specificity of only 50–80%. Measurement of Serum Aldosterone Levels After three days of an unrestricted sodium diet and 1 h of full recumbency, healthy individuals have aldosterone levels of less than 15 ng/dL. When serum aldosterone is elevated above 22 ng/dL and renin is suppressed, the serum aldosterone test virtually confirms the diagnosis of PH. However, because aldosterone secretion is variable, the negative and the positive


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predictive value of a single random aldosterone level are limited. As many as 40% of patients with PH have serum aldosterone levels that remain within the reference range on repeat testing, as is typically the case in essential hypertension. Oral Sodium Loading Test After hypokalemia and hypertension are controlled, patients should receive a high sodium diet for three days, with a target sodium intake of 218 mmol of sodium (12.8 g of sodium chloride). On day 3, a 24 h urinary specimen is collected and aldosterone, creatinine and sodium levels are measured. To document adequate sodium repletion, the 24 h urinary sodium excretion should exceed 200 mmol. Urinary aldosterone excretion of more than 33 nmol/d in this setting is consistent with autonomous aldosterone secretion. Notably, potassium levels should be measured daily and replaced in those patients, since a high salt diet can cause kaliuresis and hypokalemia. Intravenous Salt Loading Test Another way of measuring aldosterone suppression is the intravenous infusion of 2 L of 0.9% sodium chloride solution over 4 h (intravenous saline infusion test). The patient’s blood pressure and heart rate are monitored during the infusion. At the completion of the infusion, blood is drawn and PAC levels are measured. Normal subjects show a suppression of PAC after volume expansion with isotonic saline (< 139 pmol/L, 5 ng/dL). Patients with primary aldosteronism do not suppress to less than 277 pmol/L (10 ng/dL). Notably, post-saline-infusion PAC values between 139 and 277 pmol/L (5 and 10 ng/dL) are indeterminate and can be seen in patients with IHA. Fludrocortisone Suppression Test Another less commonly used test is the fludrocortisone suppression test. Fludrocortisone acetate is administered orally for four days (0.1 mg every 6 h) in combination with sodium chloride tablets (2 g three times daily with food).


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Blood pressure, heart rate and serum potassium levels are monitored daily. On day 4 plasma aldosterone should be measured in the midmorning and the patients should be upright for at least 30 min prior to veinpuncture. Since patients with hyperaldosteronism are in a state of salt retention and excess sodium is lost in the urine, sodium loading with a sodium-retaining steroid will have no effect on plasma aldosterone (hence PAC

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