Thyroid Cancer (Endocrine Updates, Vol. 30)

Endocrine Updates Series Editor: Shlomo Melmed, M.D.

For further volumes: http://www.springer.com/series/5917

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Glenn D. Braunstein, MD Editor

Thyroid Cancer

Editor Glenn D. Braunstein, MD Professor and Chairman, Department of Medicine The James R. Klinenberg MD Chair in Medicine Director of the Thyroid Cancer Center of Excellence Cedars-Sinai Medical Center Los Angeles, CA, USA [email protected]

ISSN 1566-0729 ISBN 978-1-4614-0874-1 e-ISBN 978-1-4614-0875-8 DOI 10.1007/978-1-4614-0875-8 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011938203 © Springer Science+Business Media, LLC 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business 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

The American Cancer Society has estimated that in 2011, 48,020 new cases of thyroid cancer will be diagnosed in the United States, with three-quarters occurring in women. About two-thirds of the patients will be between the ages of 20 and 55. The disease will cause close to 1,740 deaths, of which 43% will be men. The overall 5-year survival rate is 97%, making it one of the least lethal cancers. The incidence of thyroid cancer has more than doubled over the last three decades, rising from 4.85 cases per hundred thousand ­people in 1975 to almost 12 cases per hundred thousand in 2007. This increase is seen exclusively in the well-differentiated thyroid cancers, which account for the vast majority of patients and carry the best prognosis. A good portion of this rise is due to increased detection of small tumors (microcarcinomas measuring less than 1 cm) because of the increased use of neck ultrasounds, CT scans, MRI, and PET scans, which detect these “incidentalomas.” This may account for the rise in the incidence of microcarcinomas, but does not adequately explain the fact that the incidence of larger tumors also is increasing, and this increase is occurring around the world. The rise does not appear to be related to the two known causative factors for well-differentiated thyroid cancer: radiation exposure or genetic predisposition. Thus, it is likely that environmental ­factors such as the amount of iodine intake, industrial toxins (e.g., ­plasticizers, fire retardants, and pesticides), and other unknown exposures may contribute to the rising incidence of thyroid cancer. Although numerically less frequent than the differentiated thyroid ­cancers, medullary cancer of the thyroid, anaplastic carcinoma, and thyroid lymphoma are important tumors to know about because their prognosis is less favorable and their treatment generally requires a more aggressive approach. The management of thyroid cancer has changed greatly over the last ­several decades with the advent of new imaging techniques, the improved detection of biomarkers, a marked increase in our understanding of the genetic abnormalities that result in or accompany oncogenesis, and the development of targeted therapies that take advantage of the known molecular defects that result in thyroid cancer. One of the positive developments has been the emergence of multidisciplinary teams devoted to the management of the disease. The Cedars-Sinai Thyroid Cancer Center residing in our Samuel Oschin Comprehensive Cancer Institute is composed of endocrinologists, surgeons, oncologists, radiation therapists, nuclear medicine physicians, pathologists, radiologists, nurses, speech therapists, and psychiatrists all of whom have a subspecialty interest in thyroid cancer. The team has developed protocols for v

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Preface

the surgical management of patients and for determining who should or should not receive radioactive iodine or external beam radiotherapy, and have active clinical trials for patient management. Patients with complex or aggressive disease are presented at our monthly Thyroid Cancer tumor board, and continuing education is accomplished through a monthly Thyroid Cancer Grand Rounds. Since our Center is the only one for a wide geographic area, we see a large number of patients with thyroid nodules and cancer. Therefore, our medical students, residents, and fellows have extensive exposure to all aspects of thyroid disease. Both basic and clinical research is carried out under the Center’s auspices. When Shlomo Melmed, MD, Editor of the Endocrine Updates Series, and Springer Science+Business Media, LLC, invited me to edit a book on thyroid cancer, I readily agreed because I knew that I had a group of experts readily available within our Thyroid Cancer Center. Each was requested to write a chapter in their area of expertise, which together provides a broad overview and in-depth analysis of the current thinking in the diagnosis and management of differentiated, medullary, and anaplastic thyroid carcinoma, as well as thyroid lymphoma. We appreciate the professionalism and excellence of the people who have been involved with this project from Springer, especially Ellen C. Green, Developmental Editor, and Richard Lansing, Executive Editor, Medicine. Also, we are grateful for the support of Boris Catz, MD, the Levy family and all of the staff of our Thyroid Cancer Center and, of course, to all of our patients who teach us many lessons daily about the complexity and natural history of thyroid cancer. Los Angeles, CA, USA

Glenn D. Braunstein, M.D.

Contents

  1  Pathology and Classification of Thyroid Tumors....................... Gretchen E. Galliano and David P. Frishberg

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  2  Molecular Biology of Thyroid Cancer........................................ Wenwen Chien and H. Phillip Koeffler

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  3  Thyroid Nodules............................................................................ Glenn D. Braunstein and Wendy Sacks

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  4  Ultrasound Imaging of Thyroid Cancer..................................... Michelle Melany

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  5  Fine Needle Aspiration of the Thyroid........................................ Shikha Bose

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  6  Staging Systems for Differentiated Thyroid Carcinomas......... 109 Ronnie Meiyi Wong and Glenn D. Braunstein   7  Papillary Thyroid Carcinoma...................................................... 133 Wendy Sacks and Glenn D. Braunstein   8  Follicular Thyroid Carcinoma..................................................... 155 Jerome Hershman and Adam Lyko   9  Medullary Thyroid Carcinoma.................................................... 171 Nicole M. Tyer and Run Yu 10  Anaplastic Thyroid Carcinoma................................................... 189 Marina Vaysburd 11  Thyroid Lymphoma...................................................................... 201 Basil Rapoport and Sandra M. McLachlan 12  Surgical Management of Thyroid Cancer.................................. 207 C. Suzanne Cutter, Kenneth W. Adashek, Michel Babajanian, and Babak Larian

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13  Radioactive Iodine Therapy......................................................... 243 Wendy Sacks and Alan D. Waxman 14  External Beam Radiation Therapy in the Treatment of Differentiated Thyroid Cancers.............................................. 271 C. Michele Burnison 15  Targeted Therapy of Thyroid Cancer......................................... 301 Stephen W. Lim Index....................................................................................................... 317

Contents

Contributors

Kenneth W. Adashek, MD, FACS  Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA Michel Babajanian, MD, FACS  Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA Shikha Bose, MD  Department of Pathology and Lab Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Glenn D. Braunstein, MD  Divison of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA C. Michele Burnison, MD  Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Wenwen Chien, PhD  Division of Oncology/Hematology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA C. Suzanne Cutter, MD  Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA David P. Frishberg, MD  Department of Pathology and Lab Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Gretchen E. Galliano, MD  Department of Pathology and Lab Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Jerome Hershman, MD, MS  Divisions of Endocrinology, Diabetes and Metabolism, Greater Los Angeles VA and Cedars–Sinai Medical Center, Los Angeles, CA, USA H. Phillip Koeffler, MD  Division of Oncology/Hematology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Babak Larian, MD, FACS  Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA Stephen W. Lim, MD  Department of Medicine and Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

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Adam Lyko, MD  Divisions of Endocrinology, Diabetes and Metabolism, Greater Los Angeles VA and Cedars–Sinai Medical Center, Los Angeles, CA, USA Sandra M. McLachlan, PhD  Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Michelle Melany, MD  Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA, USA Basil Rapoport, MB, ChB  Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Wendy Sacks, MD  Divison of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Nicole M. Tyer, MD  Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Marina Vaysburd, MD  Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Beverly Hills, CA, USA Alan D. Waxman, MD  Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA, USA Ronnie Meiyi Wong, MPH, MSW  Divison of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Run Yu, MD, PhD  Divisions of Endocrinology, Diabetes, and Metabolism, Carcinoid and Neuroendocrine Tumor Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Contributors

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Pathology and Classification of Thyroid Tumors Gretchen E. Galliano and David P. Frishberg

Introduction

Intraoperative Diagnosis

Nodules of the thyroid gland are common and frequently problematic specimens encountered by the diagnostic surgical pathologist. It is estimated that 4–7% of adults have a palpable thyroid nodule, and several times that many have nodules which are detectable at autopsy or by ultrasound [1]. Of the estimated 10–20 million clinically detectable thyroid lesions in the United States [2], approximately 5–30% will be ­malignant [3]. Thyroid nodules are more common in women, in people with a history of radiation exposure, and in those with goitrogenic-rich diets or iodinedeficient diets [1]. Carcinomas of follicular cell origin are the most common and greatly outnumber carcinomas of C-cell origin [4]. Secondary malignancies and lymphomas are far less common than follicular origin tumors, but they do occur and must be considered in the differential diagnosis of both benign and malignant thyroid abnormalities. The majority of carcinomas of follicular origin are indolent, with approximately 90% 10-year survival rates [4].

General Considerations

G.E. Galliano Department of Pathology and Lab Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room 8725, Los Angeles, CA 90048, USA D.P. Frishberg () Department of Pathology and Lab Medicine, CedarsSinai Medical Center, Los Angeles, CA, USA e-mail: [email protected]

Intraoperative consultation (IOC) for properly selected cases can be a useful tool for the surgical management of patients with thyroid nodules, but has significant limitations of which both the practicing pathologist and surgeon must be aware. In this regard, the application of clinical findings and fine-needle aspiration (FNA) results are of great help in selecting appropriate cases for IOC. These selection criteria depend on the two major limitations of sensitivity for intraoperative detection of cancer: the need to confirm (1) cytologic features of malignancy in papillary carcinoma and (2) vascular or capsular invasion in follicular carcinoma and its variants.

Technique When a nodule, lobe, or gland is received for IOC, the surgical margins are inked, and the specimen is sectioned at 2–3-mm intervals, following which careful gross examination of the cut surfaces is performed, with notation of overall nodularity, the appearance of the cut surface, and encapsulation (if any) of identified lesion(s). A representative section of the nodule or tumor is sampled at the capsule or tumor interface with non-neoplastic thyroid [5]. This section is frozen in a semi-liquid medium and thin sections are

G.D. Braunstein (ed.), Thyroid Cancer, Endocrine Updates 30, DOI 10.1007/978-1-4614-0875-8_1, © Springer Science+Business Media, LLC 2012

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made and placed onto slides for staining. Our practice (and strong recommendation) is to make concurrent cytology preparations from the cut surface of the lesion. The histologic section(s) allow(s) for examination of the tumor and its capsule for interface irregularities with the adjacent non-neoplastic thyroid, morphology of the nodule, capsular or vascular invasion, and thyroid parenchymal invasion. Cytology preparations permit optimum evaluation of nuclear features. Representative sampling of the tumor or nodule of interest is performed; examination of the entire capsule is not routinely performed or recommended [5]. Increased colloid, lymphocytic thyroiditis, FNA biopsy site artifact, infarct, and freezing artifact can all hinder the diagnosis of papillary thyroid carcinoma (PTC), frequently making the cytology preparation essential for identification of diagnostic features.

Accuracy The reported overall sensitivity of FS ranges from 68 to 77% [6], but this figure is misleadingly reassuring, as it reflects the high prevalence of benign lesions and thus a relatively high predictive value of a negative (benign) result. Sensitivity is, in fact, heavily dependent upon the type of lesion being evaluated, and can be abysmal for certain tumors of clinical importance. FS has a sensitivity as low as 21% for certain follicular lesions [2, 6]. The sensitivity drops even further, to 17%, for encapsulated and minimally invasive follicular carcinomas [6] because the entire capsule cannot be evaluated in routine frozen section (FS). FS has a higher sensitivity for papillary carcinomas (94% for classic PTC) than follicular carcinomas (44%), and a lower sensitivity for follicular variant of PTC (FVPTC) (27%) [6]. The specificity of FS is high (range 96–100%) [2, 7, 8], but the intraoperative management with respect to the FNA diagnosis of a thyroid lesion is rarely (3–5%) altered by FS diagnosis [2, 8–10], largely because FNA can preoperatively diagnose PTCs in > 90% of cases [5], permitting definitive surgical management. In addition, ­FS diagnosis of well-circumscribed or

G.E. Galliano and D.P. Frishberg

encapsulated follicular lesion must often be deferred pending complete permanent section examination of the lesion due to the low sensitivity of FS for follicular carcinoma and follicular variant of papillary carcinoma (17 and 27%, respectively) [6]. These limitations yield a 50–87% FS deferral rate in patients with a preoperative FNA diagnosis of follicular lesion/ neoplasm [5, 9, 11]. Thus, the associated estimated cost per useful FS that ranges from $7,800 to $12,000 [9–12]. A further limitation of FS accuracy is in the diagnosis of malignancy associated with multinodular goiter. In one study of FS of 197 multinodular goiter patients with clinically suspicious nodules, FS was only 19% sensitive for malignancy and changed the operative management in 3% [13]. The greatest influence on the low sensitivity in this patient group was the size of tumor, with most false negatives seen in carcinomas 50% [4, 15, 16]. As many as 20% are metastatic at presentation [25]. The tumors are usually > 1  cm, tan to brown with irregular borders, and extensive invasion into or complete effacement of the fibrous capsule [4, 25] (Fig. 1.7). Microscopically, widely invasive FCs are highly cellular and can show solid, microfollicular, or trabecular growth patterns and may have an associated poorly differentiated or insular component [26]. Capsular and/or vascular invasion is/are readily identified and may be extensive (Figs.  1.8 and 1.9). Other variants of follicular carcinoma include oncocytic variant (Hurthle cell carcinoma, discussed below) and clear cell variant, which is composed of clear cells and signet ring cells from glycogen, mucin, or lipid [4] (Table 1.2).

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G.E. Galliano and D.P. Frishberg Table 1.2  Follicular carcinoma – Widely invasive

Fig. 1.8  Widely invasive follicular carcinoma with extensive growth beyond capsular breach (H&E)

Definition • Follicular patterned lesion with grossly or clinically apparent vascular and/or capsular invasion • More common in areas with endemic goiter and iodine deficiency • Lack of cytologic features of papillary thyroid carcinomaa Gross features • Tan mass with irregular borders • Clinically and grossly detectable invasion into cervical veins or extrathyroidal extension Microscopic features • Highly cellular with various growth patterns • Solid, microfollicular, and trabecular growth • May have poorly differentiated areas Metastatic spread and outcome • Metastasizes hematogenously to brain, bone, liver with low prevalence lymph node metastases (50%) a See text. Features of papillary thyroid carcinoma can be multifocal and subtle

Fig. 1.9  Vascular invasion in widely invasive follicular carcinoma (H&E)

Most minimally invasive FCs have a good prognosis. This tumor grossly resembles a follicular adenoma and is typically a solitary well-defined tan nodule with a thick or variably thick fibrous capsule [4, 15, 16] (Fig.  1.10). Extensive histologic evaluation of the tumor–capsule–­thyroid interface reveals foci of capsular (Fig. 1.11) invasion with at least focal complete capsular penetration or vascular invasion (Fig.  1.12) into the fibrous capsule vessels or larger vessels outside of the main nodule [15, 16, 18, 21]. The tumor/ capsule–normal surrounding thyroid interface reveals tongues or invasive “hooks” of tumor infiltrating the capsule with connection to the main

Fig. 1.10  Minimally invasive follicular carcinoma. Tumor largely replaces lobe, but gross encapsulation appears maintained

tumor [15, 16, 18, 21, 27]. Vascular invasion is defined as the presence of tumor embolus in capsular ­vessels or vessels outside the capsule [15, 21]. Archtypically, tumor emboli are intermixed with fibrin and blood and show attachment to the endothelial wall. If the tumor thrombus is not attached to the vessel wall in the examined section, to qualify as defining vascular invasion it should be covered by endothelium on at least three sides [15, 21] (Table 1.3).

1  Pathology and Classification of Thyroid Tumors

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Fig. 1.11  Early transcapsular invasion in minimally invasive follicular carcinoma (H&E)

Table 1.3  Follicular carcinoma – Minimally invasive

Fig. 1.12  Vascular invasion in minimally invasive follicular carcinoma (same case as seen in Fig. 1.11; H&E)

Capsular irregularities are frequently found in encapsulated thyroid tumors. These irregularities, and changes at FNA biopsy sites, often make interpretation of capsular and vascular invasion challenging for even experienced surgical pathologists [15, 16, 19, 20]. Tumor impingement on blood vessels and/or the presence of nonendothelialized tumor in blood vessels are not considered vascular invasion [15, 16, 21]. There has been significant debate on accepted criteria for minimally invasive FC. Several stud-

Definition • Follicular patterned lesion with multifocal and minimal capsular and vascular invasion • Extensive capsular sampling may be required for diagnosis • Lack of cytologic features of papillary thyroid carcinomaa Gross features • Solitary, encapsulated tan or red-brown mass • Resembles follicular adenoma grossly Microscopic features • Foci of capsular invasion seen at tumor thyroid interface and/or vascular invasionb • Patterns can be microfollicular or normofollicular or a mix of patterns Metastatic spread and outcome • Metastases can present 10 years or more after presentation • Risk of metastatic spread is associated with increased number of foci of invasion (especially ³4) • Overall prognosis is good (mortality of 3–5% with survival curves approaching normal population) a See text. Features of papillary thyroid carcinoma can be multifocal and subtle b see text for definitions and controversies in vascular and capsular invasion

ies have shown high interobserver variability in the diagnosis of follicular carcinoma and encapsulated follicular lesions [14, 28]. Most minimally

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invasive FCs show several foci of capsular or vascular invasion [15, 16, 29], but detection of these multiple foci may require exhaustive examination of the complete tumor capsule with multiple histologic sections on several paraffin blocks. Rarely, an encapsulated follicular lesion may present with a single focus of capsular invasion, causing great difficulty in classification. Such lesions are controversial, with differing opinions on how to classify them. Some authorities state that encapsulated follicular tumors with partial capsular invasion only have little to no chance of causing metastatic disease and in order to avoid overtreatment may use the term “thyroid tumor of uncertain malignant potential” [15, 16, 29, 30]. Conversely, several studies have shown evidence for the metastatic potential of such tumors, and equally prominent authorities assert that encapsulated follicular tumors with any capsular invasion (partial or complete) or vascular invasion should be classified as minimally invasive follicular carcinoma [4, 15, 16, 21, 27, 29]. Metastases can present long after resection (>10 years are more) [4, 21]. The risk of metastatic disease is associated with the number of foci of vascular invasion and capsular invasion (especially > 4 foci) [4, 27].

Hurthle Cells A Hurthle cell is a follicular cell with distinctive cytomorphology. The cell size is larger (2–3×) than that of an ordinary follicular cell, the cytoplasm is brightly eosinophillic and granular, the nucleus is larger, and the nucleolus is prominent (Fig.  1.13). Ultrastructurally, the cytoplasm is swollen with numerous mitochondria, possibly the result of abnormalities in mitochondrial DNA [31, 32]. Commonly in histologic and cytologic samplings, follicular cells are observed which have overlap features between Hurthle cells and ­non-Hurthle follicular cells. Pathologists may call such cells as “Hurthle-like,” “Hurthleoid,” “oncocytic,” “oxyphilic,” and “Hurthle cell transition” forms. Hurthle cells are common in many conditions including thyroiditis, Grave’s dis-

G.E. Galliano and D.P. Frishberg

Fig. 1.13  Hurthle cells. Note abundant granular eosinophilic cytoplasm, coarse chromatin, and prominent nucleoli (H&E)

ease, goiter, aging, adenomatoid nodules, and neoplasms [31, 33]. Hurthle cell neoplasms were historically considered all malignant [4, 31, 33], but the current WHO [4] classification categorizes Hurthle cell adenomas and carcinomas as variants of follicular adenomas and carcinomas, respectively, with the same criteria for malignancy as non-Hurthle neoplasms [4, 33]. Hurthle cell lesions display the same immunophenotype as non-Hurthle follicular cells (TTF-1 positive, CK7 positive, thyroglobulin positive, and CK20 negative) [4].

Hurthle Cell Adenomas (Follicular Adenoma, Oncocytic Variant) Hurthle cell adenomas are solitary, well circumscribed, encapsulated, and composed of > 75% Hurthle cells [4, 31, 33]. Other terms for such lesions are follicular adenoma, oncocytic variant, and oncocytic adenoma. Oncocytic adenomatoid nodules, especially in Hashimoto’s thyroiditis, can be difficult to distinguish from adenomas [4, 31]. Grossly, cut surfaces are mahogany brown to yellow-tan and can have a central area of scarring [4]. Microscopically, Hurthle cell adenomas can show the variety of growth patterns of follicular adenomas with microfollicular, macrofollicular, trabecular, and solid growth patterns. Occasional

1  Pathology and Classification of Thyroid Tumors

Fig. 1.14  Thickly encapsulated Hurthle cell adenoma (H&E)

papillary structures can be seen [4,  31,  33]. There is a lack of capsular and vascular invasion (Fig. 1.14). Some nuclear features of PTC (such as chromatin clearing and nuclear grooves) may be seen focally in rare cases, but are neither extensive nor diagnostic of PTC. Occasionally, Hurthle cell adenomas can undergo infarction, spontaneously or following FNA [31, 33]. Extensive necrosis is not a criterion of malignancy and other features such as capsular and vascular invasion remain the defining features [4, 27, 31, 33, 34]. Hurthle cell adenomas with cytologic atypia, increased mitotic activity, spontaneous infarction and necrosis, and trapping of tumor cells within the capsule may be considered “atypical Hurthle cell adenomas”; however, since these behave in a benign fashion with long-term follow-up [31], the value of this term as a taxonomic category is dubious.

Hurthle Cell Carcinoma Hurthle cell carcinomas are malignant tumors composed of >75% oncocytic cells and which lack the cytologic features of papillary carcinoma. Hurthle cell carcinomas account for up to 3–4% of thyroid cancers [4]. The age at diagnosis is about 60, with a female predominance (female to male 6.5:3.5) [4]. Patients most commonly present with a solitary thyroid mass but can present with

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Fig. 1.15  Widely invasive Hurthle cell carcinoma (H&E)

increasing pressure after long-standing goiter [35]. Aggressive carcinomas can present with hoarseness, stridor, and dyspnea [35]. In up to 23–39% of patients there is a history of radiation [36, 37]. Criteria for malignancy are the same for both Hurthle and non-Hurthle neoplasms, but the rate of malignancy may be higher in Hurthle cell tumors than in follicular tumors (30–45% compared to 2–3% of classic follicular neoplasms) [31, 33]. Hurthle cell carcinomas metastasize to cervical lymph nodes as well as bone and lung and metastases can be present in up to 9–17% of patients at initial diagnosis [35, 36]. Hurthle cell carcinomas are divided into minimally invasive and widely invasive (Fig.  1.15), similar to non-Hurthle cell FCs and are considered variants of FC under the WHO [4]. However, oncocytic tumor type may be associated with a worse prognosis compared to classical follicular carcinomas [31, 38]. Stage for stage, Hurthle cell carcinomas behave more aggressively than nonHurthle follicular carcinomas [31]. Grossly, widely invasive Hurthle cell carcinomas are large dominant masses with irregular borders. Cut surfaces show a mahogany brown to tan tumor with scarring and hemorrhages and a capsule remnant may or may not be present. Microscopically, oncocytic carcinomas show the same variety of growth patterns seen in other FCs [4, 31]. Widely invasive tumors have extensive transcapsular and vascular invasion [4, 31] (Fig. 1.15). Oncocytic carcinomas may undergo

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infarction, especially after FNA [4, 33]. Infarction alone is not a criterion for malignancy or biologically aggressive behavior, but can render specimens difficult to interpret with regard to potential biologic behavior. The prognosis for widely invasive Hurthle cell carcinoma is poor with a mortality of 50–60% at 5  years [31]. Stage, age, and size (>4 cm) are predictors of prognosis [36]. Minimally invasive oncocytic carcinomas are grossly indistinguishable from oncocytic adenomas, present as a dominant encapsulated mahogany brown to tan mass composed of >75% oncocytes, and lack the cytologic features of ­papillary carcinoma [4, 31]. The microscopic patterns of growth are similar to those found in widely invasive oncocytic carcinoma and nonHurthle follicular carcinomas. Increased cellularity, nuclear atypia, tumor necrosis, and increased mitoses are not determinant criteria for malignancy nor predict biologically aggressive behavior. Minimally invasive oncocytic carcinoma exhibits capsular or vascular invasion with the same criteria applied as for FC [15, 34]. In general, minimally invasive Hurthle cell carcinoma is associated with a good prognosis, with survival curves similar to non-Hurthle minimally invasive follicular carcinomas [4, 31, 34]. However, minimally invasive Hurthle cell carcinomas have a propensity to present with more extensive vascular invasion than their non-Hurthle counterparts [34]. As with conventional FC, vascular invasion, especially if greater than 4 foci are present, is associated with a poorer prognosis [27, 34].

G.E. Galliano and D.P. Frishberg

gain-of-function mutations in the RET oncogene in the multiple endocrine neoplasia syndromes MEN 2a and MEN 2b [4].

Clinical Most patients present with a solitary nodule and increased serum calcitonin and CEA levels [4, 41]. Mean patient age ranges from 45 to 51 years [4, 40, 42]. Lymph node metastases are present in up to 50% of patients, and extensive local growth is associated with vocal cord paralysis, dysphagia, or other signs of upper airway obstruction [4]. Familial forms are often detected at an earlier stage due to screening by serum calcitonin levels [40, 41] and thus present as microcarcinomas. MTC is not associated with neck radiation [4], and it has been suggested that chronic hypercalcemia may be a contributing factor for some patients [4, 41, 43].

Gross Pathology The tumor is more often located in the upper twothirds of the gland [43] where a higher concentration of C cells is found. Most medullary carcinomas are circumscribed but nonencapsulated firm tan to yellow or grayish tumors (Fig. 1.16). Some tumors infiltrate the surrounding thyroid parenchyma. Occasionally, necrosis or hemorrhage may be seen [43].

Medullary Carcinoma Medullary thyroid carcinoma (MTC) is a malignant tumor of C-cell derivation. C cells (also called parafollicular cells) are neuroendocrine cells that produce calcitonin in response to hypercalcemia. C-cells can undergo hyperplasia (unifocal and multifocal) or form large neoplastic nodules as microcarcinomas (1  cm). MTCs account for 3–10% of thyroid cancers and are either sporadic or familial, with inherited forms accounting for about 30% [4, 39, 40]. These are associated with

Fig. 1.16  Medullary carcinoma. Note circumscription but lack of encapsulation

1  Pathology and Classification of Thyroid Tumors

Microscopic MTCs vary both in their architectural growth patterns and in cytomorphology. The tumors may grow in tongues, nests, cords, in a pseudopapillary fashion, in trabecular, or as solid bands (Fig. 1.17). There are thin intervening fibrous bands and a fine capillary network throughout the tumor [43]. Often, there is dense amorphous eosinophillic material with the staining characteristics of amyloid, e.g., Congo Red positivity [4, 43] (Fig. 1.18). In a Swedish study with long-term follow-up, Bergholm et  al. showed that an association of a paucity or absence of amyloid is associated with a poorer prognosis [40]. MTCs can also produce

Fig. 1.17  Medullary carcinoma. Nested growth of polygonal cells in amyloid stroma (H&E)

Fig. 1.18  Amyloid in medullary carcinoma (Congo Red, polarized)

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mucin, melanin, and an array of polypeptides (such as VIP and somatostatin) [4, 43]. Cells of MTC may be round, polygonal, plasmacytoid, or spindled. Nuclei are round to oval with coarse chromatin. Nucleoli are not prominent, but can be seen. The cytoplasm has both eosinophilic and basophilic staining properties and irregular margins so that distinction between adjacent cells may not be possible [4]. Tumor cells can also show “small cell” change, causing confusion with other small-cell tumors such as lymphomas or insular carcinoma. MTC cells may show large nuclei, hyperchromasia, and irregular nuclear membranes, but these features do not portend more aggressive behavior. Mitotic ­figures are typically rare. Variants of MTC include pseudopapillary, glandular, giant cell, spindle cell, paragangliomalike, oncocytic cell, clear cell, angiosarcoma-like, melanin producing, and squamous cell. MTCs stain with TTF-1, but do not express thyroglobulin. They are immunopositive for calcitonin (Fig. 1.19), carcinoembryonic antigen, cytokeratin, and neuroendocrine markers such as synaptophysin and chromogranin. C-cell hyperplasia may be present in the background, more frequently, but not exclusively in familial cases [41]. Chronic lymphocytic thyroiditis can be found but its association with MTC is unclear [4]. The histologic differential diagnosis includes hyalinizing trabecular adenoma, oncocytic tumors,

Fig. 1.19  Medullary carcinoma (Calcitonin immunoper­ oxidase)

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Table 1.4  Medullary carcinoma Definition • Malignant tumor of thyroid C-cell derivation • Can be inherited, most are sporadic • Can present with elevated serum CEA and/or calcitonin Gross features • Nonencapsulated firm tan to grayish tumor Microscopic features • Variable growth patterns • Round, polygonal, plasmacytoid or spindled cells • Dense amyloid deposits • Round to oval nuclei with coarse chromatin, can have nuclear pseudoinclusions Metastatic spread and outcome • Can spread to regional lymph nodes • Older age, higher stage, extrathyroidal extension, male sex associated with lower survival

paraganglioma, follicular carcinoma with trabecular growth pattern, parathyroid tumors, papillary carcinoma, and lymphoma (if small-cell pattern MTC) [4, 43]. The 10-year survival for MTC ranges from 61 to 75% and overall 15-year survival is about 65% [39, 40, 42, 44]. Patients with familial MTC may have a better prognosis due to early detection by serum calcitonin levels [40, 41]. When familial cases of MTC were excluded from a study of 247 Swedish patients, the 10-year and 15-year survival rates dropped to 60.8% and 53.7%, respectively. Older age, higher stage ­(>  stage I), extrathyroidal extension, and male sex are associated with lower survival rates and higher recurrence rates [4, 42, 44] (Table  1.4). Incomplete removal of the tumor, tumor necrosis, and decreased amyloid are factors associated with poorer prognosis [40, 42, 44]. N1 (regional lymph node metastases) patients have a risk of disease progression higher than N0 patients (2–6 fold higher) [44], in contrast to patients with PTC. The staging scheme for medullary carcinoma is different from papillary and follicular carcinoma [45].

Hyalinizing Trabecular Tumor Hyalinizing trabecular tumor (HTT) is a tumor of follicular cell origin which shows overlapping morphologic features with PTC and MTC. Most HTTs behave in a benign fashion, but because rare

Fig. 1.20  Hyalinizing trabecular tumor. Well-circumscribed firm mass

cases with lymph node metastases have been reported the term hyalinizing trabecular tumor is preferred over hyalinizing trabecular adenoma [4].

Clinical Features HTT typically presents as a palpable solitary mass lesion in the 4th decade [4, 46]. A few patients have goiter or a history of radiation [4, 46].

Gross Pathology HTTs are solitary well-circumscribed and/or encapsulated tumors ranging in size from less than 1 cm to 4 cm. Cut surfaces are firm, tan to yellow, and show bulging of their capsules [46] (Fig. 1.20).

Microscopic Pathology HTTs are solid with thin fibrous capsules. Growth is trabecular (Fig. 1.21) or lobular; when present, trabeculae are two to four cells thick. There is a fibrovascular network coursing throughout the tumor with associated pink hyaline material [4, 46]. The hyaline material resembles amyloid but is PAS positive and Congo Red negative [4].

1  Pathology and Classification of Thyroid Tumors

13 Table 1.5  Hyalinizing trabecular tumor

Fig. 1.21  Trabecular growth pattern in hyalinizing trabecular tumor (H&E)

Definition • Tumor of follicular cell origin with overlapping morphologic features between papillary thyroid carcinoma and medullary carcinoma • Most behave in a benign fashion Gross features • Well-circumscribed and/or encapsulated tumor with tan or light yellow cut surface Microscopic features • Trabecular or lobular growth • Associated with pink hyaline stromal material • Intranuclear cytoplasmic inclusions, which may be more abundant than papillary thyroid carcinoma Metastatic spread and outcome • Rare cases of lymph node spread • Can have RET/PTC rearrangements (up to 28%)

operatively diagnosed as papillary carcinoma on FNA, as the distinction between these tumors can be impossible on cytologic grounds.

Prognosis

Fig. 1.22  Hyalinizing trabecular tumor. Nuclear features show striking overlap with papillary carcinoma, including nuclear enlargement and envelope irregularities, dispersed chromatin, and many intranuclear inclusions (H&E)

The cells are medium sized with clear, amphophillic, or pink granular cytoplasm with variable epithelioid and spindled morphology [4, 46] (Fig.  1.22). The nuclear to cytoplasmic ratio is typically low and chromatin is dispersed [46, 47]. Nuclei are round to oval and there are abundant intranuclear cytoplasmic inclusions, nuclear grooves, and nuclear overlapping. Intranuclear cytoplasmic inclusions are more abundant than in papillary carcinoma [47]. Mitotic figures are sparse to absent [46]. Psammomatous calcifications may be identified, and multinucleated giant cells are typically absent [4, 47]. It is important for clinicians to be aware that HTTs may be pre-

There are isolated reports of HTT with capsular and vascular invasion [48–50], but the classification of such cases is controversial [4]. Eleven were reported by Carney et  al., with no recurrence or evidence of metastatic disease over a mean follow-up period of 10  years [46]. HTTs have been shown to have rearrangements of the RET/PTC oncogene and these rearrangements occur in a comparable proportion to PTC [51]. The morphologic and molecular similarities with PTC further support “hyalinizing trabecular tumor” as the preferred term for this entity. The differential diagnosis of this tumor includes PTC due to overlapping nuclear features, MTC due to the pink matrix, and variable spindled and epithelioid appearance of the cells. Immunohistochemical stains can help to exclude MTC, but are not helpful in distinguishing HTT from papillary carcinoma. HTT is immunopositive for thyroglobulin and TTF-1 and negative for calcitonin, and the hyaline matrix is negative for Congo Red. MTC is positive for CEA, synaptophysin, and calcitonin and negative for thyroglobulin and its pink matrix (amyloid) is positive for Congo Red (Table 1.5).

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Papillary Carcinoma General PTC is a primary thyroid cancer of follicular ­epithelial cell origin with distinctive nuclear ­features, and is the most common cancer of the endocrine system with approximately 22,000 new cases a year in the US [4, 22]. There is an increasing incidence of PTC, particularly of ­cancers 1 cm and smaller due in part to increasingly s­ ensitive detection methods [52].

Clinical Features

Fig. 1.23  Papillary carcinoma, classical variant. Pale, sclerotic cut surface with infiltrative borders

Most PTCs occur in adults from 20 to 50 years of age, but can be encountered in children and in the elderly [53]. There is a female predominance with a female to male ratio of 4:1 [4, 22]. Prior radiation exposure to the thyroid is an important risk factor, but many PTCs occur in patients with no radiation history [4]. There is also an association with environmental factors (iodine deficiency) and genetics [4, 22]. Patients with chronic thyroiditis (especially chronic lymphocytic thyroidits) are at a higher risk. PTC can occur in any part of the thyroid or in ectopic thyroid tissue (mediastinum and ovary).

Gross Pathology PTC typically presents as an irregular tan to gray firm mass (Fig. 1.23), but the gross features may vary considerably. The tumor can be encapsulated (follicular variant), cystic, nodular, and/or ­sclerotic with abundant calcifications. Microscopic foci of PTC may not be visible on the gross level, especially in the presence of concomitant lymphocytic thyroiditis, goiter, or prior biopsy. Calcifications can occasionally be identified grossly.

Microscopic Pathology The diagnosis of PTC depends on its nuclear characteristics, irrespective of whether features overlapping with other thyroid malignancies are

Fig. 1.24  Papillary carcinoma, classical variant. Nuclear irregularities including elongation, crowding with overlap, and chromatin clearing (“Orphan Annie” nuclei; H&E)

seen. The classic features that define papillary carcinoma include nuclear crowding with overlap, nuclear enlargement, chromatin clearing or ground glass appearance (“Orphan Annie eyes”), nuclear elongation, nuclear grooves, irregular nuclear membranes, intranuclear cytoplasmic inclusions, and eccentric inconspicuous nucleoli [4, 19, 54] (Figs.  1.24 and 1.25). Other minor ­features that can be seen, but which are insufficient for a diagnosis of papillary carcinoma if seen without the nuclear features, include papillary architecture (classical variant; Figs. 1.26 and 1.27) with complexity, psammomatous calcifications (Fig.  1.28), squamous metaplasia, dense

1  Pathology and Classification of Thyroid Tumors

Fig. 1.25  Papillary carcinoma. Nuclear elongation, crowding with overlap, grooves, and prominent intranuclear inclusions. This focus was present in a lymph node metastasis (H&E)

Fig. 1.26  Papillary   architecture in classical variant of papillary carcinoma. Note small focus of lymphocytic thyroiditis on the upper right (H&E)

cytoplasm, brightly eosinophilic (“bubble gum”) colloid , and multinucleated giant cells [4]. Other than classical PTC, many variants have been described, of which a few are considered clinically important.

Follicular Variant of PTC FVPTC represents 9–22% of PTCs [27]. Grossly, these tumors are well circumscribed and often encapsulated (Fig.  1.29). FVPTC is composed

15

Fig. 1.27  Papillary carcinoma, classical variant, ­showing papillary architecture. Nuclei are crowded and overlapping, elongated, and many show grooves (H&E)

Fig. 1.28  Psammoma body in papillary carcinoma (H&E)

nearly entirely of small to medium-sized follicles lined by cells with the nuclear features of PTC [4, 27] (Figs. 1.30 and 1.31). Colloid is brightly eosinophllic (“bubble gum”), with the follicles often showing circumferential scalloping [4]. Many cases of FVPTC show diffuse nuclear features of PTC and the diagnosis is straightforward. However, there is a subset of tumors that are entirely encapsulated and show follicular patterned growth with multiple discrete foci having nuclear features of PTC, but other areas lacking these features. There is high interobserver and intraobserver variability in the diagnosis of such lesions, even among expert thyroid pathologists,

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Fig. 1.29  Follicular variant, papillary thyroid carcinoma. Note circumscription and fleshy appearance with greater similarity to follicular tumors than to classical papillary carcinomas

Fig. 1.30  Follicular variant, papillary thyroid carcinoma. Follicular growth pattern with “bubble gum” colloid, but nuclear features of papillary carcinoma (H&E)

Fig. 1.31  Optically clear (“Orphan Annie”) nuclei in follicular variant, papillary carcinoma (H&E)

with differing thresholds for diagnosis in different centers and different countries [28, 55, 56]. On one side of the controversy are those experts who assert that these lesions are overdiagnosed as PTC, leading to overtreatment with total ­thyroidectomy in a tumor that has excellent ­long-term prognosis [57]. Anchoring the counterargument is Baloch and Livolsi’s series of five cases of encapsulated tumors with microscopic features that simulated follicular adenomas with only focal nuclear fea-

tures of papillary carcinoma that metastasized to bone [58]. In the absence of evidence pointing otherwise, it is a common practice (and our own) to diagnose lesions with unequivocal multifocal nuclear ­features of papillary carcinoma as encapsulated FVPTC and to measure the whole nodule for staging purposes; [15] however, clinicians should be aware that this diagnostic assignment is subjective and that there is no industry-wide “gold standard” for the diagnosis.

1  Pathology and Classification of Thyroid Tumors

Fig. 1.32  Tall cell variant, papillary thyroid carcinoma. Cell height is at least twice the cell width; such cells must comprise at least 50% of tumor (H&E)

17

Fig. 1.33  Columnar cell variant, papillary thyroid carcinoma. Elongated columnar cells with nuclear stratification. Nuclear overlapping and envelope irregularities are prominent, but chromatin is coarser than in other papillary carcinoma variants (H&E)

Tall Cell Variant Tall cell variant of PTC is uncommon, but important for its association with a more aggressive clinical course [4, 59, 60]. By convention, tall cells have a height that is at least twice the width of the cell, eosinophillic cytoplasm, and characteristic nuclear features of papillary carcinoma [59] (Fig.  1.32). The tumor typically grows as cords, but solid, papillary, cribriform, and rare follicular growth patterns may all be seen. The proportion of cells with tall cell features deemed needed to make the diagnosis of tall cell variant has ranged from 30 to70% in the literature [59, 60], but a cutoff of > =50% is proposed [59]. Regardless of the definitional threshold for tall cell composition, there is a higher frequency of extrathyroidal extension, presentation at higher stage, larger size, and older age at diagnosis (mean 57  years), and death due to tumor compared to other variants [59, 60].

Columnar Cell Variant Columnar cell variant is a rare variant of PTC that is also associated with a more aggressive clinical course [61, 62]. Growth patterns may be papillary, follicular, solid, cribriform, or fascicular [62]. The cells are elongated columnar cells

with prominent nuclear stratification (comprising >50% of the tumor) and elongated nuclei. Chromatin ranges from finely granular to coarse, and optically clear nuclei may not be found. Similarly and importantly, intranuclear cytoplasmic inclusions may not be found and nuclear grooves may be rare. Cytoplasm ranges from clear to amphophillic. Subnuclear cytoplasmic vacuoles may be identified [4, 62] (Fig.  1.33). Columnar cell variant is more often associated with extrathyroidal extension, recurrence, and aggressive local growth [4, 62] , but tumors that present at a low stage and are entirely encapsulated appear to have low metastatic potential [4].

Macrofollicular Variant Macrofollicular PTC, the rarest variant, is composed of greater than 50% macrofollicles lined by cells with nuclear features of PTC [4, 63, 64]. The importance of this variant is not prognostic, but rather for pathologists its easy diagnostic confusion with adenoma or adenomatous hyperplasia [4]. Mean age at presentation is 35 years (range 15–69  years) [64]. Extrathyroidal extension, metastases, and dedifferentiation have been reported [63, 64]. Metastases can retain the macrofollicular architecture [4].

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Oncocytic Variant Oncocytic variant of PTC is a rare variant with grossly mahogany brown to tan appearance, papillary or follicular growth pattern, oncocytic cytoplasm, and nuclear features of PTC [4]. It is important to recognize for its distinction from oncocytic variants of follicular adenoma and follicular carcinoma [33]. Making the distinction between oncocytic variant of PTC and a Hurthle cell neoplasm may be difficult in some cases, as “true” Hurthle cell neoplasms can show cleared nuclei and papillary and pseudopapillary structures [33]. Mean age at presentation is 57  years (range 34–86  years) [65]. There is a “Warthin-like” variant with prominent papillary structures and lymphoid follicles and aggregates present within the papillae in a thyroid with background lymphocytic thyroiditis [4, 65, 66], simulating Warthin’s tumor of the salivary gland. This variant can be mistaken for a lymphoepithelial lesion of the thyroid commonly seen in lymphocytic thyroiditis [66]. The prognosis is similar to usual PTC and is dependent upon stage [4].

Fig. 1.34  Diffuse sclerosing variant, papillary thyroid carcinoma. Note inflammatory background, prominent intralymphatic tumor, and psammoma bodies (H&E)

Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma Diffuse sclerosing variant of PTC is an uncommon variant of papillary carcinoma which presents in younger patients (mean age 18  years; range 6–49 years) and which is biologically more aggressive [4, 67]. Tumors can present with a dominant mass, but are more often bilateral [4,  67]. All cases show conventional papillary, solid, or follicular growth pattern with increased stromal fibrosis and sclerosis, squamous metaplasia, ­lymphocytic infiltrate, and psammoma bodies [4, 67] (Figs.  1.34 and 1.35). Extensive lymphovascular invasion with small papillae within lymphatic spaces, extrathyroidal extension, and increased incidence of cervical lymph node metastases are also characteristic [4, 67, 68]. There is an increased incidence of lung metastases as well [68]. Despite the high metastatic rate, 5-year survival can be 95% and higher

Fig. 1.35  Diffuse sclerosing variant, papillary thyroid carcinoma. Note abundant eosinophilic cytoplasm of tumor cells (H&E)

with appropriate treatment [67, 69]. Chronic lymphocytic thyroiditis is often found in the background [4, 69].

Cribriform-Morular Variant of Papillary Thyroid Carcinoma Cribriform-morular variant of PTC is a rare one, but clinically important for its association with familial adenomatous polyposis syndrome; [4] however, sporadic cases do occur. Typically, the

1  Pathology and Classification of Thyroid Tumors

growth pattern is solid, trabecular, or follicular with cribriform areas (glands within glands) and epithelial morules – whorled cellular balls of tumor cells with dense squamoid cytoplasm [70]. Nuclear features of papillary carcinoma are present throughout the tumor.

Papillary Microcarcinomas The term microcarcinoma is applied to PTCs less than 1  cm in greatest dimension. These tumors are discovered incidentally, and in up to 24% of thyroids removed for other reasons such as chronic lymphocytic thyroiditis, goiter, and Graves’ disease [71]. They can also be found in otherwise normal thyroids at autopsy in up to one-third of patients who have died of nonendocrine causes [4]. Histologic mimics include ultimobrachial body rests or reactive nuclear changes in chronic lymphocytic thyroiditis [71]. Up to 11% can exhibit local recurrence or regional metastases [4, 71]. Multifocality can be seen in up to 20–46% of cases; the chance of recurrence or metastasis increases with multifocality [71]. However, a majority of these tumors have an indolent behavior [4, 71].

Prognosis Overall, the prognosis for PTC is excellent, with a 10-year survival of over 90% [4, 53]. While the most important prognostic indicator is stage, age (>45  years), larger size (>1  cm), extrathyroidal extension, large vessel invasion, and insular component are all poor prognostic indicators [4, 53]. (Table 1.6)

Poorly Differentiated Thyroid Carcinoma Poorly differentiated thyroid carcinoma is a follicular cell-derived tumor with solid/trabecular/ insular growth pattern and one that lacks the nuclear features of PTC. The prognosis is intermediate

19 Table 1.6  Papillary thyroid carcinoma Definition • Primary epithelial carcinoma of the thyroid with distinctive nuclear features • Most common cancer of the thyroid gland Gross features • Irregular tan scirrhous mass • May also have variable gross appearance – cystic, encapsulated, nodular Microscopic features • Nuclear overlapping • Chromatin clearing or ground glass appearance • Nuclear grooves • Intracytoplasmic nuclear inclusions • Psammomatous calcifications, squamous metaplasia, and papillary architecture • Tall cell variant, diffuse sclerosing variant, columnar cell variant associated with aggressive clinical course Metastatic spread and outcome • Spreads via lymphatic channels • RAS mutation in 10%, BRAF mutation in up to 70%, • 10-year survival of over 90% with treatment

between differentiated thyroid carcinoma (FC and PTC) and anaplastic thyroid carcinoma. The concept of this tumor as a distinct entity began to evolve in the early 1980s and has a controversial history, including varying criteria for diagnosis by experts and high intraobserver variability [26, 72, 73]. The prevalence is variable (up to 4–6% of thyroid carcinomas in some countries) and possibly related to the variable thresholds for diagnosis [4, 74]. Poorly differentiated thyroid carcinoma often arises in association with a smaller component of conventional PTC or FC, and it is postulated that the poorly differentiated component represents dedifferentiation of these entities [4, 26]. However, it can arise de novo (or at least without morphologic evidence of PTC or FC) [4]. A synonym for this entity is insular carcinoma, which characterizes a common growth pattern seen in these tumors. This neoplasm presents as a dominant thyroid mass or as a rapidly growing area in a longstanding mass [4]. The mean age at presentation is comparable to conventional PTC (55 years old, SD 18 years) [74].

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Fig. 1.36  Poorly differentiated carcinoma. Tumor largely replaces lobe

Gross Features Most tumors are singular and large (3–5  cm), with pushing borders [4, 74]. An entire lobe may be replaced. Partial encapsulation or pseudoencapsulation can be seen [4, 73]. Cut surfaces are gray to tan and firm and satellite nodules are common [4] (Fig. 1.36).

Microscopic Features Solid, insular, trabecular, and alveolar patterns may all be seen [72]. For insular growth pattern, tumor cells are arranged in cellular solid nests with occasional microfollicles surrounded by a thick hyalinized stroma [75] (Fig.  1.37). Cells are small to intermediate in size with deceptively bland nuclei [4]. On closer inspection, the nuclei are hyperchromatic with finely granular chromatin and convoluted with raisin-like, cupshaped, or trifold forms [72]. The mitotic rate is typically elevated (>3 per 10 high power field, range 1–10 per high power field) [72, 74]. Tumor necrosis is frequently present [72] (Fig. 1.38). Occasional groves and pseudoinclusions can be seen, especially when a PTC is dedifferentiated [72].

Fig. 1.37  Insular growth pattern in poorly differentiated carcinoma (H&E)

Differential Diagnosis The differential diagnoses are MTC, solid variant PTC, and follicular carcinoma with solid growth [4, 72]. Distinction from MTC can be aided with immunohistochemistry. MTC is immunopositive for synaptophysin, calcitonin, and CEA, and negative for thyroglobulin. Distinction from solid variant PTC can be difficult and subject to great intraobserver variability [72]. A panel of experts in thyroid pathology has proposed “Turin criteria”

1  Pathology and Classification of Thyroid Tumors

21 Table 1.7  Poorly differentiated thyroid carcinoma

Fig. 1.38  Cellular necrosis in poorly differentiated carcinoma (H&E)

for poorly differentiated carcinoma. If typical nuclei of PTC are present throughout a thyroid tumor with solid, trabecular, or insular growth, then it is more aptly classified as solid variant PTC. If nuclear features of PTC are absent, and there is also a lack of the convoluted nuclei, mitoses, and necrosis in a thyroid carcinoma with solid, trabecular, or insular growth that characterize poorly differentiated thyroid carcinoma, then a diagnosis of solid variant FC is likely [72].

Prognosis Poorly differentiated thyroid carcinoma has a worse prognosis than PTC, with a 5-year survival rate from 20 to 60% [4, 73–75]. Patients with poorly differentiated thyroid carcinoma have a higher rate of metastatic spread to regional lymph nodes (84.6% vs. 73% for PTC) [75]. Lung metastases and bone metastases are also more frequent than in papillary and follicular carcinomas [75]. There may also be a higher frequency of extrathyroidal extension [73]. The proportion of the poorly differentiated component also has a negative impact on survival. Patients with a predominantly poorly differentiated component (>50% of tumor is poorly differentiated) have a poorer outcome and significantly higher rate of metastatic disease than patients with a focal poorly differentiated component (50% in adults are malignant [4,  91, 92]. Patients present with a mass in the neck and may experience dyspnea or stridor [4, 90]. Other congenital anomalies may be present in newborns [4]. Grossly, tumors can range from 2 to 13 cm with a smooth or bosselated surface and gray to yellow cut surfaces with solid and cystic areas with white creamy material within cysts in mature teratomas (sebaceous material/cyst contents) [4, 90]. Microscopically, there are a variety of growth patterns within one  lesion [90]. Cystic epithelial elements can include respiratory, squamous, columnar, or transitional epithelium [4]. Cartilage, bone, smooth muscle, and skeletal muscle can be seen [4]. Immature neural elements have hyperchromatic, medium-sized nuclei with associated mitotic figures arranged in sheets or rosettes [4,  90]. Immunohistochemical stains used to identify neural tissue or skeletal muscle (S100 and myoD1) may be helpful in characterizing immature ­elements [4]. Malignant teratomas can recur and metastasize in 30% of cases [4, 90].

Mesenchymal Tumors Teratoma Primary teratomas of the thyroid are extremely rare and comprise 1 cm ³1–1.5 cm

B C

³1.5–2.0 cm ³2.0 cm ³2.0 cme FNA not indicatedf

B C C E

Strength of Recommendation: A = Strongly recommends based on good evidence; B = Recommends based on fair evidence; C = Recommends based on expert opinion; E = Recommends against based on fair evidence; I = Recommends neither for or against – evidence insufficient b High-risk history: History of thyroid cancer in one or more first degree relatives; history of external beam radiation as a child; exposure to ionizing radiation in childhood or adolescence; prior hemithyroidectomy with discovery of thyroid cancer; 18FDG avidity on PET scanning; MEN2/FMTC-associated RET protooncogene mutation, calcitonin >100 pg/ mL. MEN multiple endocrine neoplasia; FMTC familial medullary thyroid cancer; 18FDG 18flurodeoxyglucose; PET positron emission tomography c Suspicious features: microcalcifications; hypoechoic; increased nodular vascularity; infiltrative margins; taller than wide on transverse view d FNAB cytology may be obtained from the abnormal lymph node in lieu of the thyroid nodule e Sonographic monitoring without biopsy may be an acceptable alternative f Unless indicated as therapeutic modality a

all agree that lesions that are suspicious for cancer based upon ultrasound criteria should be biopsied rather than just performing a biopsy on the largest lesion in a gland with multiple nodules.

Radioisotope Thyroid Scan Radioiodine scans, preferably using 123I, are useful for determining whether or not a thyroid nodule is

autonomous in a patient with a suppressed TSH. A “hot” nodule, which suppresses the surrounding normal thyroid tissue, or a “warm” nodule, which is functioning but has not suppressed the surrounding tissue, has a