Endocrine Neoplasia (Cancer Treatment and Research)

Cancer Treatment and Research

Series Editor Steven T. Rosen Robert H. Lurie Comprehensive   Cancer Center Northwestern University Chicago, IL USA

For further volumes, go to http://www.springer.com/series/5808

Cord Sturgeon Editor

Endocrine Neoplasia



Editor Cord Sturgeon Northwestern University Feinberg School of Medicine Section of Endocrine Surgery Chicago, IL, USA [email protected]

ISSN 0927-3042 ISBN 978-1-4419-0856-8 e-ISBN 978-1-4419-0857-5 DOI 10.1007/978-1-4419-0857-5 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2009940800 © Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer ScienceþBusiness Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

Endocrine neoplasms are fascinating tumors. Rare but usually dramatic diseases caused by the unchecked elaboration of hormones from endocrine fascinomas have been favorites of generations of medical students and professors alike. From an oncologic standpoint, endocrine tumors, even those arising from the same tissues, represent an amazingly heterogenous group of mostly indolent tumors (such as aldosteronoma or papillary thyroid cancer), with an occasional tumor of extraordinary malignant potential (such as adrenocortical carcinoma or anaplastic thyroid cancer). A detailed understanding of the biology of these tumors has allowed us to select the proper steps in treatment, before, during, and after surgery. There are many textbooks covering the subject of endocrine surgery, ranging from the comprehensive or specialized text to the abbreviated handbook. The purpose of this book is to describe the biology of disease and, within that context, discuss the proper clinical management of the endocrine tumors of the thyroid, parathyroid, pancreas, and adrenal glands. The book is divided into five sections addressing neoplasms of the thyroid, parathyroid, adrenal gland, neuroendocrine pancreas, and multiple endocrine neoplasia. Experts from the United States, Canada, and Australia have contributed chapters addressing both the biology of endocrine tumors and the clinical management of disease. Recent discoveries regarding the genetic underpinnings of disease are highlighted. Updated consensus guidelines were used for clinical recommendations. The management of complex and often confusing clinical problems is discussed in detail. Endocrine Neoplasia is a comprehensive, updated, and clearly written text covering the diseases for which endocrine surgical expertise is often needed. We look towards advances in the science and the art of endocrine surgery to continuously improve outcomes for our patients. The goal of this text was to provide a detailed description of both the underlying science of disease as well as the art of clinical management. I would like to acknowledge the hard work of all the contributors to the text as well as the editing and production team at Springer. I would also like to acknowledge the inspiration that I have received from countless patients with diseases of endocrine neoplasia whom I have had the privilege to treat. Last, but not least, special thanks are due to my family, Jane, Kate, and Cassidy, for their support and patience which helped to make this book possible. Chicago

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Contents

Part I  Thyroid 1 The Biology of Thyroid Oncogenesis........................................................ Insoo Suh and Electron Kebebew

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2 Evaluation of the Thyroid Nodule............................................................ Dina M. Elaraj

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3 Differentiated Thyroid Cancers of Follicular Cell Origin...................... Linwah Yip and Sally E. Carty

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4 Sporadic Medullary Thyroid Cancer....................................................... Adrian Harvey and Janice L. Pasieka

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5 Anaplastic Thyroid Cancer....................................................................... Alan P .B. Dackiw

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Part II  Parathyroid 6 Primary Hyperparathyroidism................................................................. Kaitlyn J. Kelly, Herbert Chen, and Rebecca S. Sippel

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7 Parathyromatosis and Parathyroid Cancer............................................. 105 Wen T. Shen Part III  Adrenal 8 Incidentaloma............................................................................................. 119 Jacob Moalem, Insoo Suh, and Quan-Yang Duh 9 Pheochromocytoma and Paraganglioma................................................. 135 Goswin Y. Meyer-Rochow and Stan B. Sidhu

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10 Functional Cortical Neoplasms............................................................... 163 Ali Zarrinpar and Michael W. Yeh 11 Adrenocortical Carcinoma...................................................................... 187 Patsy S.H. Soon and Stan B. Sidhu Part IV  Pancreatic Neuroendocrine Tumors 12 Gastrinoma............................................................................................... 213 Anthony J. Chambers and Janice L. Pasieka 13 Insulinoma................................................................................................ 235 Kimberly Vanderveen and Clive Grant 14 Rare Neuroendocrine Tumors of the Pancreas..................................... 253 Shih-Ping Cheng and Gerard M. Doherty Part V  Multiple Endocrine Neoplasia 15 The Menin Gene....................................................................................... 273 Hsin-Chieh Jennifer Shen and Steven K. Libutti 16 Multiple Endocrine Neoplasia Type 1: Clinical Manifestations and Management............................................. 287 Anathea C. Powell and Steven K. Libutti 17 The RET Protooncogene.......................................................................... 303 Amber L. Traugott and Jeffrey F. Moley 18 Multiple Endocrine Neoplasia Type 2: Clinical Manifestations and Management...................................................................................... 321 Amber L. Traugott and Jeffrey F. Moley Index.................................................................................................................. 339

Contributors

Sally E. Carty Professor of Surgery, Chief of Endocrine Surgery, University of Pittsburgh School of Medicine, Pittsburgh PA USA Anthony J. Chambers Fellow in Endocrine Surgery and Surgical Oncology, University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta Canada Herbert Chen Professor of Surgery, University of Wisconsin, Madison, WI USA Shih-Ping Cheng Department of Surgery, Mackay Memorial Hospital, Taipei Taiwan Alan P. B. Dackiw Assistant Professor of Surgery, Section of Endocrine Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA Gerard M. Doherty NW Thompson Professor of Surgery, University of Michigan, Ann Arbor, MI USA Quan-Yang Duh Professor of Surgery, University of California San Francisco, San Francisco, CA USA Dina M. Elaraj Assistant Professor of Surgery, Section of Endocrine Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL USA Clive Grant Professor of Surgery, Department of Surgery, Mayo Clinic, Rochester, MN USA Adrian Harvey Endocrine Surgical Fellow, Cleveland Clinic Foundation, Cleveland, OH USA

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Contributors

Electron Kebebew Senior Investigator, Head of Endocrine Oncology, National Cancer Institute, Surgery Branch, Bethesda, MD USA Kaitlyn J. Kelly Resident in Surgery, Department of Surgery, University of Wisconsin, Madison, WI USA Steven K. Libutti Professor of Surgery, Vice Chairman, Department of Surgery; Director, Montefiore-Einstein Center for Cancer Care.Bronx, NY USA Goswin Y. Meyer-Rochow Royal North Shore Hospital, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW Australia Jacob Moalem Assistant Professor, University of Rochester Medical Center, Rochester, NY USA Jeffrey F. Moley Professor of Surgery, Chief, Endocrine and Oncologic Surgery Section, Associate Director, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO USA Janice L. Pasieka Clinical Professor of Surgery and Oncology, Department of Surgery, Foothills Medical Centre, Calgary Canada Anathea C. Powell Clinical Fellow, Tumor Angiogenesis Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD USA Hsin-Chieh Jennifer Shen National Cancer Institute, National Institute of Health, Bethesda, MD USA Wen T. Shen Assistant Professor of Surgery, University of California San Francisco, San Francisco, CA USA Stan B. Sidhu Clinical Associate Professor of Surgery, Department of Endocrine and Oncology Surgery, Royal North Shore Hospital, St. Leonards, NSW Australia Rebecca S. Sippel Assistant Professor of Surgery, Department of Surgery, University of Wisconsin, Madison, WI USA

Contributors

Patsy S.H. Soon Bankstown Hospital and University of New South Wales, Kolling Institute of Medical Research, Kensington, University of Sydney, NSW Australia Insoo Suh Resident in Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA USA Amber L. Traugott Resident in General Surgery, Washington University School of Medicine, St. Louis, MO USA Kimberly Vanderveen Fellow in Endocrine Surgery, Mayo Clinic, Department of Surgery, Rochester, MN USA Michael W. Yeh Assistant Professor of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA Linwah Yip Assistant Professor of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA USA Ali Zarrinpar Resident in Surgery, Ronald Reagan UCLA Medical Center, Los Angeles, CA USA

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Part I

Thyroid

Chapter 1

The Biology of Thyroid Oncogenesis Insoo Suh and Electron Kebebew

Introduction Over the past 20 years, our understanding of the molecular biology of thyroid cancer has advanced significantly. These new insights have in turn unleashed a vast potential for clinical application across the diagnostic, prognostic, and therapeutic spectrum. A classic example of this is the identification of the RET proto-oncogene responsible for hereditary medullary thyroid cancer (MTC), which has led to earlier diagnosis by genetic screening, and thus better patient outcomes. It is one of the few hereditary cancers for which at-risk individuals can be identified by genetic testing and be advised a prophylactic thyroidectomy, as they will certainly develop MTC over their lifetime. Thyroid cancer is the most common form of endocrine cancer, with over 35,000 new cases expected to be diagnosed in the United States in 2008. Of these, approximately 95% are well-differentiated tumors of follicular cell origin (papillary, follicular, Hürthle cell), 4–5% are MTCs which originate from the parafollicular or calcitonin (C) secreting cells, and 1% or less are undifferentiated or anaplastic thyroid cancer (ATC). Unlike the RET proto-oncogene that is responsible for hereditary MTC and is present in 75% of sporadic MTC as a somatic mutation, many genetic alterations, commonly in the mitogen signaling pathway, have been identified in thyroid cancer of follicular cell origin. This suggests that most thyroid cancers of follicular cell origin are genetically heterogeneous. This chapter will focus on the key genetic and epigenetic changes associated with most thyroid cancers of follicular cell origin, the clinicopathologic associations observed, and their possible clinical application to the management of thyroid cancer. In addition, the emerging theory of the role of stem cells in the etiology of thyroid cancer will be discussed.

E. Kebebew (*) Surgery Branch, National Cancer Institute, 10 Center Drive, Room 4W–5952, Bethesda, MD 20892–1201 e-mail: [email protected] C. Sturgeon (ed.), Endocrine Neoplasia, Cancer Treatment and Research, vol 153, DOI 10.1007/978-1-4419-0857-5_1, © Springer Science+Business Media, LLC 2010

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Common Genetic Alterations Papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are the two main thyroid cancer subtypes that are derived from follicular epithelial cells. Together, they account for the vast majority of thyroid cancer cases. Recent discoveries have shed new light on the genetic foundations behind PTC and FTC development, many of which involve the activation of the mitogen-activated protein kinase (MAPK) signaling pathway (Fig. 1.1). This pathway is activated by growth factors

Fig. 1.1  The mitogen-activated protein kinase (MAPK) signaling pathway, activated by the binding of growth factors to receptor tyrosine kinases (RTKs), such as RET and TRK, leading to an intracellular phosphorylation cascade involving the activation of RAS, BRAF, MAPK/ERK kinase (MEK), and extracellular signal-regulated kinase (ERK) proteins. Activated ERK translocates into the nucleus and regulates the transcription of genes responsible for cell differentiation, proliferation, and survival (From Nikiforov 2008, used with permission.)

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binding to cell-surface transmembrane tyrosine kinase receptors; this in turn causes an intracellular signaling cascade that ultimately regulates the intra-nuclear transcription of genes responsible for cell proliferation, differentiation, migration, invasion, and survival. The relevance of the MAPK signaling pathway is underscored by the finding that up to 80% of PTCs carry activating genetic changes of at least one of four MAPK-related genes – BRAF, RET/PTC, RAS, and TRK [1]. Despite its importance, the MAPK pathway activation does not appear to be the sole mediator of follicular cell-origin thyroid cancers. In particular, the mutational profile of FTC is largely distinct from that of PTC, with a higher rate of activating RAS (HRAS, KRAS, NRAS) mutations and a PAX8/PPARg chromosomal rearrangement [2, 3]. This may, in part, be due to the preferential activation of another distinct signaling cascade known as the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. The PI3K/AKT pathway, like the MAPK pathway, also involves a progressive series of phosphorylation reactions starting with a transmembrane protein kinase. This cascade ultimately leads to the activation of AKT, which in turn phosphorylates proteins both in the cytosol and in the nucleus. Downstream targets of AKT regulate apoptosis, proliferation, cell-cycle progression, cytoskeletal integrity, and energy metabolism [4]. Constitutive activation of AKT has been demonstrated to be an important mechanism in the pathogenesis of FTC. This was first discovered when an inactivating germline mutation of PTEN, an inhibitor of AKT activation, was found to be responsible for Cowden’s syndrome, in which 50% of patients develop follicular thyroid neoplasms. An analogous somatic PTEN mutation is responsible for only 6–8% of sporadic FTCs; however, AKT activation appears to be important in sporadic FTC independent of PTEN inactivation, possibly via RAS- or PAX8/PPARgmediated mechanisms. The PI3K/AKT pathway also appears to play a central role in PTC and FTC progression, possibly by upregulation of genes involved in epithelial-to-mesenchymal transition, such as osteopontin [4]. ATC, the most aggressive and lethal of thyroid tumors, is often thought to be derived from differentiated follicular cell-origin cancers under the “multi-hit” theory of carcinogenesis, and is associated with several other distinct mutations, but is almost always positive for p53-inactivating mutations [5]. Table 1.1 lists the most common genetic alterations associated with thyroid carcinogenesis. We will discuss the most common and important of these genetic changes below.

BRAF The BRAF gene is located on chromosome 7q23, and encodes a 95 kDa cytoplasmic protein that belongs to the RAF family of serine/threonine kinases. Activation of BRAF by phosphorylation occurs downstream of the membrane or cytoplasmic receptor, which in turn relays signals through the MAPK pathway [6]. Somatic mutations in BRAF have been found in a wide variety of human cancers, and have mostly been confined to exons 11 and 15 [7]. In the thyroid, BRAF mutations

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Table 1.1  Common genetic alterations in thyroid carcinogenesis Mutation Prevalence (%) Resulting phenotype(s) Main molecular function BRAF 30–80 PTC MAPK pathway activation RET/PTC 5–35 PTC MAPK pathway activation 55–85 Radiation-induced PTC RAS 20–50 FTC, fvPTC, FA MAPK and PI3K-Akt pathway activation TRK 5–10 PTC MAPK pathway activation PAX8/PPARg 35–60 FTC Unknown PTEN 4 cm, history of radiation exposure, and personal or family history of conditions known to be associated with thyroid cancer [5]. In addition to increasing a patient’s risk for developing thyroid nodules, a history of radiation exposure, particularly in childhood, increases a patient’s risk of developing thyroid cancer [11]. Multiple studies have shown an increase in the number of thyroid cancers diagnosed in children who lived within a 150  km radius of Chernobyl, in adult survivors of the atomic bombings of Hiroshima and Nagasaki, and in patients who received head and neck radiotherapy in childhood for the treatment of conditions such as enlarged tonsils, an enlarged thymus, tinea capitis, or acne [12, 13]. A family history of thyroid cancer also increases a patient’s risk of thyroid cancer. While only 3% of thyroid cancers are heritable, there are multiple syndromes that are associated with an increased risk of papillary or medullary thyroid cancer. A family history of papillary thyroid cancer in two first-degree relatives increases the risk of thyroid cancer three- to ninefold, and these families are likely part of a familial nonmedullary thyroid cancer (FNMTC) kindred [14, 15]. Other syndromes associated with papillary thyroid cancer include familial adenomatous polyposis (FAP) and its variant, Gardner’s syndrome (both due to a mutation in the APC gene), Cowden’s syndrome (also known as multiple hamartoma syndrome, due to a mutation in the PTEN gene), and Carney complex (due to a mutation in the

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PRKAR1A gene) [5, 16]. Familial syndromes known to be associated with medullary thyroid cancer include multiple endocrine neoplasia types 2A and 2B (MEN-2A and B), and familial medullary thyroid cancer (FMTC), all due to a mutation in the RET gene [17]. Eliciting a personal or family history of conditions which are known to be components of the above syndromes, therefore, is an important part of the risk factor assessment of a patient with a thyroid nodule. In addition to evaluating a patient’s personal and family history, other factors that may increase the risk or suspicion of thyroid cancer should be assessed including recent onset, rapid rate of growth, dysphagia, hoarseness, male gender, and age [18].

Physical Examination A detailed physical exam is done, with particular attention to voice quality, characteristics of the nodule, and the adjacent nodal basins. Hoarseness raises the concern for recurrent laryngeal nerve invasion by an aggressive thyroid cancer. Firmness or consistency of the nodule is not particularly reliable in discriminating benign from malignant processes as some benign processes can be heavily calcified and firm and some papillary cancers can be cystic or soft. Fixation of the nodule to adjacent or overlying structures, or the presence of (especially ipsilateral) cervical or supraclavicular lymphadenopathy substantially increases the probability of cancer. Deficits in neurologic function should be carefully sought and documented, particularly for those nerves that pass through the central and lateral cervical compartments of the neck. Characteristics of syndromic endocrinopathies should be evaluated. Cutaneous lichen amyloidosis, usually in the intrascapular area, may be found in patients with MEN-2A. Medullary thyroid cancer, mucosal neuromas, and marfanoid habitus are almost universally present in patients with MEN-2B beginning in infancy or early childhood. Elevated blood pressure might raise the suspicion for pheochromocytoma in the correct clinical context. Pheochromocytoma must always be treated before thyroid surgery is performed.

Laryngoscopy Many clinicians perform mirror or fiberoptic laryngoscopy on a routine basis for all patients with thyroid pathology, while others perform these tests more selectively. Several reports have concluded that routine preoperative laryngoscopy should be done on all patients with thyroid cancer [19, 20]. This practice is supported by the fact that some patients with compensated recurrent laryngeal nerve palsy will have a normal voice. Discovery of a preoperative vocal cord paralysis suggests that there is extrathyroidal extension of the tumor and may change the operative technique and postoperative expectations of the patient. Most experts, however, recommend

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laryngoscopy only for symptomatic patients or for patients who have previously undergone thyroid or parathyroid surgery. Many clinicians employ laryngoscopy selectively because of the paucity of compelling evidence to recommend for or against routine laryngoscopy. All patients with hoarseness, history of vocal cord paralysis, or prior neck surgery should undergo preoperative laryngoscopy to evaluate for recurrent laryngeal nerve palsy [21].

Diagnostic Tests Multiple organizations including the American Thyroid Association (ATA), National Comprehensive Cancer Network (NCCN), American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi (AACE/AME), and Society of Radiologists in Ultrasound (SRU) have published guidelines for the evaluation and management of thyroid nodules [5–7, 22]. The following is an approach based on aspects of several of the above consensus guidelines.

Imaging All patients with palpable thyroid nodules should be evaluated by cervical sonogram. Ultrasonographic features generally thought to increase the suspicion of thyroid cancer include microcalcifications, irregular borders, and central hypervascularity. The sensitivity and specificity of these features are not very high, when considered independently. The SRU guidelines report a sensitivity of 26–59% and specificity of 86–95% for microcalcifications, a sensitivity of 17–78% and specificity of 39–85% for irregular margins, and a sensitivity of 54–74% and specificity of 79–81% for central hypervascularity [22]. The presence of more than one of the above features, however, increases the probability that a thyroid nodule represents a malignancy. The presence of a hypoechoic nodule in conjunction with at least one of the above independent risk factors was able to identify 87% of malignancies in one study of 494 consecutive nonpalpable thyroid nodules [23]. Figure 2.1 illustrates a hypoechoic 1.2  cm thyroid nodule with microcalcifications and irregular borders on ultrasound which was a papillary thyroid cancer. Cervical sonography is the imaging study of choice for the evaluation of thyroid nodular disease. Computed tomography (CT) and magnetic resonance imaging (MRI) are useful to assess size, substernal extension, and relationship of a large thyroid nodule or goiter to surrounding structures or when adjacent tissue invasion is suspected. Cross-sectional imaging is not recommended for the routine evaluation of a thyroid nodule, however, because of low resolution of small nodules, and because the iodine load from intravenous contrast is considered undesirable if the patient might have differentiated thyroid cancer. Fluorodeoxyglucose positron emission tomography (FDG-PET) is very effective in identifying many primary and metastatic thyroid cancers. Although PET scanning

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Fig. 2.1  Transverse and longitudinal ultrasound images of a 1.2 cm thyroid nodule with microcalcifications and irregular borders in a 24-year-old woman, which was a papillary thyroid cancer on fine needle aspiration biopsy

is very sensitive for cancer, it is not highly specific. Graves’ disease, thyroiditis, and some benign nodules may also have FDG-PET uptake. The literature demonstrates a high incidence of malignancy within FDG-PET avid thyroid incidentalomas, with most studies revealing a malignancy rate of approximately 35% [24–27]. The high sensitivity of PET scan in detecting thyroid cancer underscores the importance of working up FDG-PET avid thyroid lesions, but the low specificity prevents PET scanning from being useful in the routine evaluation of thyroid nodules. In hyperthyroid patients, a radionuclide thyroid scan should be performed. If there is increased tracer uptake in the nodule compared to the surrounding thyroid parenchyma (i.e., a “hot” nodule) and there are no suspicious features on ultrasound, then the risk of malignancy is extremely low [5–7].

Laboratory Studies All patients with thyroid nodules should have a serum thyrotropin (thyroid-stimulating hormone, TSH) measurement. Interestingly, several recent studies have found that a higher TSH concentration, even if within the normal range, may be associated with an increased risk of thyroid cancer in a thyroid nodule [18, 28, 29].

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The routine use of serum calcitonin measurement to screen all patients with thyroid nodules for medullary thyroid cancer has, thus far, not been advocated in the U.S. Several European studies, and now one study in the U.S., have demonstrated that the routine evaluation of serum calcitonin level in the initial evaluation of all thyroid nodules would be cost-effective [30–33].

Fine Needle Aspiration Biopsy FNA biopsy should be considered for all patients depending on nodule size, appearance on ultrasound, and patient risk factors for thyroid cancer. FNA biopsy, particularly when done under ultrasound guidance, is the most cost-effective and accurate way to evaluate a thyroid nodule [7]. FNA biopsy has decreased the cost of care of thyroid nodules by 25% [34]. The sensitivity of FNA biopsy is 65–98% with a specificity of 72–100%. Any thyroid nodule in the setting of a suspicious-appearing cervical lymph node, especially when ipsilateral, should undergo FNA biopsy (as should the cervical lymph node) [22]. Consensus guidelines vary regarding clinical thresholds for FNA biopsy. The ATA guidelines recommend FNA biopsy of all nodules >1–1.5 cm [7]. The NCCN and AACE/AME guidelines recommend FNA biopsy of all nodules >1  cm or of those