Fine Needle Aspiration Cytology.pdf

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FINE NEEDLE ASPIRATION CYTOLOGY © 2007, Elsevier Inc. All rights reserved. ISBN-13: 978-0-443-06731-0 ISBN-10: 0-443-06731-7 No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the Publishers. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department, 1600 John F. Kennedy Boulevard, Suite 1800, Philadelphia, PA 19103–2899, USA: phone: (+1) 215 239 3804; fax: (+1) 215 239 3805; or, e-mail: healthpermissions@ elsevier.com. You may also complete your request on-line via the Elsevier homepage (http://www. elsevier.com), by selecting ‘Support and contact’ and then ‘Copyright and Permission’.

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List of Contributors Fadi W Abdul-Karim, MD

Shahla Masood, MD

Professor of Pathology Department of Pathology University Hospitals of Cleveland Cleveland, OH USA

Professor and Associate Chair University of Florida Chief of Pathology Department of Pathology Shands Jacksonville Medical Center Jacksonville, FL USA

Syed Z Ali, MD Associate Professor of Pathology and Radiology Associate Director, Division of Cytopathology Johns Hopkins University School of Medicine Baltimore, MD USA

Ema A Berbescu, MD Assistant Professor of Pathology Division of Anatomic Pathology Medical College of Virginia Virginia Commonwealth University Health System Richmond, VA USA

Katherine Berezowski, MD Assistant Professor Department of Pathology The George Washington University Washington, DC USA

Martha Bishop Pitman, MD Associate Professor of Pathology Harvard Medical School Assistant Director of Cytopathology Director of the Fine Needle Aspiration Biopsy Service Massachusetts General Hospital Boston, MA USA

Yener S Erozan, MD Professor of Pathology Department of Pathology The Johns Hopkins University School of Medicine Baltimore, MD USA

Michael O Idowu, MD

Ritu Nayar, MD Associate Professor and Director of Cytopathology Department of Pathology Feinberg School of Medicine Northwestern University Chicago, IL USA

Marlo M Nicolas, MD Genitourinary Fellow Department of Pathology University of Texas, MD Anderson Cancer Center Houston, TX USA

Anil V Parwani, MD, PhD Assistant Professor Department of Pathology University of Pittsburgh Medical Center Pittsburgh, PA USA

Celeste N Powers, MD, PhD Professor and Chair Division of Anatomic Pathology Medical College of Virginia Virginia Commonwealth University Health System Richmond, VA USA

Natasha Rekhtman, MD, PhD Assistant, Department of Pathology Division of Surgical Pathology Johns Hopkins University Baltimore, MD USA

Assistant Professor of Pathology Division of Anatomic Pathology Medical College of Virginia Virginia Commonwealth University Health System Richmond, VA USA

Mary K Sidawy, MD

Igor Jovanovic, MD, PhD

Professor of Pathology The George Washington University Washington, DC USA

Cytopathology Fellow Department of Pathology George Washington University Washington, DC USA

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Professor of Pathology, Director of Anatomic Pathology Georgetown University Washington, DC USA

Sana O Tabbara, MD

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LIST OF CONTRIBUTORS

Paul E Wakely Jr, MD

Maureen F Zakowski, MD

Department of Pathology The Ohio State University College of Medicine Columbus, OH USA

Attending Pathologist Department of Pathology Memorial Sloan-Kettering Cancer Center New York, NY USA

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Foreword The study and practice of anatomic pathology is both exciting and overwhelming. Surgical pathology, with all of the subspecialties it encompasses, and cytopathology have become increasingly complex and sophisticated, and it is not possible for any individual to master the skills and knowledge required to perform all of these tasks at the highest level. Simply being able to make a correct diagnosis is challenging enough, but the standard of care has far surpassed merely providing a diagnosis. Pathologists are now asked to provide large amounts of ancillary information, both diagnostic and prognostic, often on small amounts of tissue, a task that can be daunting even to the most experienced pathologist. Although large general surgical pathology textbooks are useful resources, they by necessity could not possibly cover many of the aspects that pathologists needs to know and include in their reports. As such, the concept behind Foundations in Pathology was born. This series is designed to cover the major areas of surgical and cytopathology, and each edition is focused on one major topic. The goal of every book in this series is to provide the essential information that any pathologist, whether general or subspecialized, in training or in practice, would find useful in the evaluation of virtually any type of specimen encountered. Dr. Mary Sidawy from Georgetown and Dr. Syed Ali from Johns Hopkins Hospital, both outstanding and renowned cytopathologists, have edited what I believe to be an outstanding state-of-the-art book covering the essential aspects of fine needle aspiration cytology. This book cuts to the essentials of what all pathologists who practice the art of cytopathology need to know about this challenging field. The list of contributors is truly impressive and includes authors who have not

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only written extensively in these areas, but, more importantly, have been practicing cytopathologists with vast practical experience. As with other editions in the Foundations in Diagnostic Pathology series, the information is presented in a straightforward and accessible manner, including numerous practical tables and impressive photomicrographs. Where appropriate, the authors seamlessly integrate ancillary diagnostic techniques including immunohistochemistry, electron microscopy and molecular techniques, which are also an important part of the cytopathologist’s diagnostic armamentarium. This edition is organized into ten chapters covering the full spectrum of fine needle aspiration cytology in an organ-by-organ fashion. The first three chapters focus on aspiration cytology of salivary glands, thyroid and lymph nodes. Drs. Abdul-Karim and Massood provide superb discussions on the finer points of fine needle aspiration of soft tissue tumors and tumors of the breast. Separate chapters covering the lung, mediastinum, liver, pancreas, kidney and adrenal gland are also provided. The chapters are uniformly well organized, concisely written and beautifully photomicrographed. I wish to extend my sincerest gratitude to Drs. Sidawy and Ali for leading this outstanding effort. Clearly, they poured their heart and soul into this edition of the Foundations in Diagnostic Pathology series, and for this I am truly grateful. I would also like to extend my appreciation to the authors who took time from their busy schedules to contribute their expertise and knowledge. I sincerely hope you enjoy this volume of Foundations in Diagnostic Pathology. John R. Goldblum, M.D.

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To our families, Tony, Michelle, and Nicholas Tehmina, Adeel, and Sabeen

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Preface In 1930, Martin and Ellis, recognizing the value of cytologic sampling, published a cornerstone article entitled “Biopsy by Needle Puncture and Aspiration.” Fine needle aspiration (FNA) began gaining momentum in Europe in the 1950s; however, it was not until the 1980s when it became widely accepted in the United States. FNA of palpable and deep-seated lesions has quickly grown to become a powerful diagnostic tool in the diagnosis of neoplastic, reactive, and infectious processes. But as we acquired more experience and knowledge we developed a better appreciation of the pitfalls and limitations in interpreting cytologic samples. There is no paucity of published scientific material on aspiration cytopathology; we have seen an exponential growth in the cytopathology literature paralleling its widespread success as a medical discipline. This volume in the series Foundations in Diagnostic Pathology, offers several notable features. FNA of most commonly sampled sites are presented in ten chapters authored by experts in the field. The template format throughout the book provides a high degree of consistency in style and presentation. Furthermore, the use of Facts and Features boxes allows easy access to key information. High resolution images are the cornerstone of morphologic discussion of any given entity with the text revolving around issues of practical diagnostic and clinical importance. Differential diagnoses, potential pitfalls, and the use of ancillary techniques are emphasized. Cross

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referencing the histopathologic characteristics with the cytologic features reflects our conviction that the two disciplines are complementary. Cytopathologists enjoy a position at the forefront of diagnostic anatomic pathology; we intimately interact with many disciplines of clinical medicine. Therefore, emphasis was placed on the interpretation of morphologic findings in the proper clinicoradiologic context leading to a more meaningful and valid list of differential diagnoses of FNA interpretation. The book is aimed primarily at pathology residents and fellows, as well as practicing pathologists looking for a practical overview of FNA cytopathology. Our ultimate goal is the best patient care based on timely and accurate FNA interpretation. It is our hope that this book will further the understanding of FNA and its role in patient management. We would like to thank wholeheartedly the authors that contributed time and effort to this project; our mentors who inspired us, and our residents and fellows for constantly challenging us at the microscope. We sincerely hope that this book will convey our enthusiasm to the discipline of cytopathology, an area that we find exciting, challenging and fulfilling in our daily practice and teaching. Mary K. Sidawy, M.D. Syed Z. Ali, M.D. October 2006

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Salivary Glands Sana O Tabbara

INTRODUCTION Fine needle aspiration (FNA) of salivary glands is widely used in the initial diagnosis of salivary gland swellings. It is a simple procedure with limited complications that provides rapid and valuable information for the subsequent planning of patient management. The cytologic features of common salivary gland neoplasms and inflammatory processes are well recognized, and accurate diagnosis is possible in most cases. Salivary gland lesions involve most commonly the parotid glands, followed by the submandibular glands and the minor salivary glands. FNA of masses in the salivary gland area serves multiple purposes: it helps determine the origin of the mass (salivary versus nonsalivary), it sorts neoplastic from non-neoplastic processes, and in most neoplastic cases it distinguishes benign from malignant tumors. Reported sensitivity for presence of tumor and specificity for absence of neoplasm are >90%, but accuracy for a specific diagnosis is lower. False negative diagnoses result mostly from sampling errors and inadequately sampled cystic lesions, whereas false positive diagnoses are encountered mostly in benign neoplasms with cytologic atypia and in basaloid lesions. In FNAs of salivary gland neoplasms where a specific diagnosis cannot be reached, it is important to indicate if the tumor is a low- or a high-grade neoplasm in order to guide surgical management. Non-neoplastic salivary gland lesions range between 50% and 60% in some large series. FNA truncates patient management in such instances and prevents unnecessary surgery, resulting in a 30% decrease of surgical excisions of salivary gland lesions. Eventually, 10–15% of non-neoplastic cases on FNA will require surgery for definitive diagnosis. FNA of a normal salivary gland tissue yields a sparsely cellular smear that contains a mixture of acinar cells, ductal cells, mature adipose tissue, and scattered small acinar bare nuclei (Fig. 1-1). Serous acinar cells are seen in FNAs from all salivary glands. They are pyramidalshaped and have abundant granular or finely vacuolated cytoplasm containing periodic acid–Schiff (PAS)positive diastase-resistant zymogen granules, and a small eccentric round nucleus with an inconspicuous nucleolus. Outside the parotid, acinar cells show both serous and mucinous differentiation. Mucinous acinar cells are columnar and have a pale vacuolated cyto-

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plasm. Acinar cells are arranged in acinar clusters that appear to have a grape-like configuration and are sometimes attached to sheets of ductal cells. Ductal cells are less numerous than acinar cells. They are small, bland cuboidal cells with scant dense cytoplasm and are organized in small honeycomb sheets or occasionally branching tubules. This chapter will address mass-producing lesions of the salivary gland that are evaluated by FNA. These lesions will be presented according to their line of differentiation.

NON-NEOPLASTIC LESIONS SIALADENOSIS Sialadenosis is a condition associated with malnutrition, diabetes, bulimia, alcoholism, cirrhosis, and some drugs such as antihypertensives. Sialadenosis occurs mostly in the parotid and is often bilateral. Typically, smears are cellular and comprise normal salivary gland elements. The features differentiating such from normal salivary gland tissue are the hypertrophic, enlarged acinar cells; however, the size difference from normal acinar cells is usually difficult to appreciate. When normal tissue without an inflammatory background is aspirated from an enlarged gland, a sampling error should be entertained, unless the patient is proven to have no mass lesion by additional evaluations, including re-aspiration, radiographic evaluation, and clinical follow-up. If all evaluations are negative, the diagnosis of sialadenosis should be considered.

SIALADENITIS CLINICAL FEATURES Acute sialadenitis is usually related to infection (viral, bacterial, fungal) and may develop as a postoperative complication or in relation to sialolithiasis. It presents with diffusely enlarged, tender glands, most frequently the parotids. 1

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FIGURE 1-1 Normal salivary gland. An aggregate of salivary gland acini surrounds a portion of ductal epithelium arranged as a branching tubular structure. Acinar cells have abundant granular or finely vacuolated cytoplasm, and small, regular, round nuclei located peripherally within the individual cell. The ductal epithelium consists of uniform cuboidal cells with bland round nuclei arranged in orderly pattern. Alcoholfixed, Papanicolaou stain, medium power.

SIALADENITIS – DISEASE FACT SHEET Clinical Features ៉ Acute sialadenitis: infectious (viral, bacterial, fungal); enlarged

tender gland ៉ Chronic sialadenitis: duct stricture, obstruction, trauma; diffuse

gland enlargement or mass; exacerbations and remissions ៉ Granulomatous sialadenitis: infectious, systemic autoimmune

disease, rarely neoplasms

SIALADENITIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Acute sialadenitis: neutrophils, fibrin, necrotic debris ៉ Chronic sialadenitis: variable with duration of disease; mixed mononuclear infl ammatory cells; salivary gland epithelium, predominantly ductal; fibrous stroma; squamous and mucous cell metaplasias; crystalline material ៉ Granulomatous sialadenitis: epithelioid histiocytes, multinucleated giant cells, possible necrosis

Treatment ៉ Variable, treat etiology

Differential Diagnosis and Pitfalls ៉ Predominance of lymphoid cells, lack of epithelium: intraparotid

lymph node ៉ Lymphocyte-rich lesions: lymphoepithelial lesion, Warthin

tumor, malignant lymphoma

Chronic sialadenitis is more commonly found in the submandibular glands and is often associated with duct stricture, obstruction (e.g. sialolithiasis), or trauma. Clinically, it is characterized by exacerbations and remissions associated with eating. Chronic sialadenitis typically presents with a diffuse gland enlargement but may produce a mass (Kuttner tumor) that must be differentiated from a neoplastic process. Granulomatous sialadenitis may result from a variety of infections, including mycobacterial, fungal, cat scratch, and toxoplasmosis, or may be associated with systemic diseases such as sarcoidosis. Rarely, granulomatous sialadenitis is a manifestation of malignant neoplasms such as Hodgkin or T-cell lymphoma or metastatic carcinoma.

CYTOPATHOLOGIC FEATURES FNA smears of acute sialadenitis contain neutrophils, fibrin, and necrotic debris. Material for special stains

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៉ Epithelial metaplasia: mucoepidermoid carcinoma (SCC not

discussed)

and cultures must be obtained and may identify the causative organisms. In chronic sialadenitis, the cellular composition of the FNA material varies with the duration of the disease. Smears contain a heterogeneous population of lymphocytes admixed with benign salivary gland tissue. Both acinar and ductal epithelium may be present. In disease of long duration, the acinar epithelium may atrophy, decreasing the number and size of the acinar cells and making the ductal component more prominent (Fig. 1-2). The smear background may contain mucus, debris, and/or various crystalloids (Fig. 1-3). Spindle-shaped fibroblasts and collagenous stromal fragments may also be noted (Fig. 1-4). Duct obstruction may cause squamous or mucinous metaplasia (Fig. 1-5). Granulomatous sialadenitis is characterized by the presence of aggregates of

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FIGURE 1-2 Chronic sialadenitis. Numerous lymphocytes and scattered epithelial and stromal fragments are compatible with chronic sialadenitis. Typically there is a decrease in acinar cells and a predominance of ductal epithelium. Alcohol-fixed, Papanicolaou stain, low power.

FIGURE 1-3 Chronic sialadenitis. Rhomboidshaped crystalloids are present in a background of mononuclear infl ammatory cells including lymphocytes and histiocytes. Fibrin and cellular debris are also noted. Alcohol-fixed, Papanicolaou stain, medium power.

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FIGURE 1-4 Chronic sialadenitis. A collagenous stromal fragment containing bland spindle cells is a common finding in long-standing chronic sialadenitis. A rare acinar structure is noted in the vicinity. Alcohol-fixed, Papanicolaou stain, high power. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center.

submandibular) and lacrimal glands. FNA smears consist of an abundant mixed population of lymphocytes, plasma cells, and tingible-body macrophages with rare epithelial elements arranged in cohesive clusters and infiltrated by lymphocytes, forming the characteristic lymphoepithelial islands. Because these lesions have a propensity to develop into lymphomas, immunophenotypic studies and flow cytometry may be useful in selected cases. Aspirate smears from glands with patchy involvement by chronic sialadenitis may look normal, with benign salivary gland epithelial cells and little or no inflammation. Extensive squamous and mucinous metaplasia in chronic sialadenitis may produce atypical cells that can mimic necrotizing sialometaplasia or mucoepidermoid carcinoma. Necrotizing sialometaplasia occurs almost exclusively in the minor salivary glands, particularly the palate, in contrast to the typical submandibular gland presentation of chronic sialadenitis. Moreover, the relatively low cellularity of the epithelial component and the presence of an inflammatory background in sialadenitis should aid in its distinction from low-grade mucoepidermoid adenocarcinoma. Radiation sialadenitis can result in the presence of atypical epithelial cells, but the cellularity of these aspirates is low, in contrast to the high cellularity of malignant neoplasms. Intraparotid lymph nodes yield a cellular aspirate containing a polymorphous population of lymphoid cells with large and small lymphocytes and immunoblasts with few or no epithelial cells and no stromal fragments. Aspirate from Warthin tumors that are poor in epithelium may mimic chronic sialadenitis. Care must also be taken to distinguish sheets of oncocytes from sheets of squamous metaplastic cells that can be seen in chronic sialadenitis. Lastly, malignant lymphoma, if suspected, can be identified by ancillary testing.

NON-NEOPLASTIC CYSTIC LESIONS epithelioid histiocytes and associated multinucleated giant cells (Fig. 1-6). Epithelioid histiocytes are recognized by their elongated, finely vacuolated cytoplasm and bland, occasionally bent nuclei. Their presence is an indication for the performance of special stains or culture for the identification of microorganisms.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis for chronic sialadenitis includes other patterns of sialadenitis and other salivary gland lesions containing lymphocytes. Autoimmune sialadenitis or lymphoepithelial sialadenitis (LESA) is most commonly related to Sjögren syndrome. The diagnosis is usually made by the unique clinical presentation of bilateral enlargement of the salivary glands (parotid and, in a minority of cases,

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A cystic lesion is encountered in about 5% of FNAs of salivary glands. A cystic component in a salivary gland mass may be neoplastic or non-neoplastic in nature. The two most common non-neoplastic cystic lesions encountered are HIV-associated cystic lymphoepithelial lesions and mucocele/retention cysts. HIVassociated cystic lymphoepithelial lesions may be one of the presenting criteria for the HIV-related complex. They occur almost exclusively in the parotid glands of both adults and children and, in contrast to simple lymphoepithelial cysts that are solitary and unilateral, they are commonly multiple and bilateral. The pathogenesis of these cysts may be due to duct obstruction, lymphoid hyperplasia, or duct destruction related to cell-mediated immunity. FNA produces clear to turbid, yellow–brown fluid. Mucocele/retention cysts are common in the submandibular and sublingual glands. A mucocele lacks a

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FIGURE 1-5 Chronic sialadenitis. Long-standing infl ammation and metaplastic changes may produce cytologic atypia of the ductal epithelium represented as nuclear enlargement, hyperchromasia, and nucleoli. The isolated nature of the change should preclude from making a malignant diagnosis. Air-dried, DiffQuik stain, high power.

FIGURE 1-6 Granulomatous sialadenitis. In a background of lymphocytic infiltrate, clusters of epithelioid histiocytes and a multinucleated giant cell are the highlights of granulomatous sialadenitis. The differential diagnosis includes infectious, autoimmune, and, less likely, neoplastic diseases. Alcohol-fixed, Papanicolaou stain, high power.

lining, whereas a retention cyst may have a mixture of squamous, columnar and oncocytic epithelial lining. They both result from obstruction associated with sialolithiasis.

CYTOPATHOLOGIC FEATURES The cytologic findings in aspirates of HIV-associated cystic lymphoepithelial lesions include a mixed population of lymphoid cells, vacuolated and multinucleated histiocytes, lymphohistiocytic aggregates, and scattered

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mature or anucleated squamous cells in a thick proteinaceous background (Fig. 1-7). Some cases may show squamous metaplastic cells or glandular cells, some ciliated or mucinous. Normal salivary gland tissue is scant and degenerated or absent. Cholesterol crystals have been noted in some cases. FNA of mucus-containing cysts are usually scantly cellular and contain scattered histiocytes and inflammatory cells in an abundant mucinous background. Extracellular mucin may be recognized as pale-green (Papanicolaou stain) to pink– red hyaline material (Romanowsky stain). Occasional mucinous/metaplastic cell or normal salivary gland elements may be present (Fig. 1-8). A ruptured cyst can incite a fibroblastic reaction that shows numerous

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FIGURE 1-7 HIV-associated cystic lymphoepithelial lesion. Numerous small lymphocytes, histiocytes, some with multinucleation, and a thick proteinaceous and granular background dominate the smears. Scattered mature or anucleated squamous cells are also present. Alcohol-fixed, Papanicolaou stain, medium power. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center.

FIGURE 1-8 Mucocele/retention cyst. Abundant thick mucoid material contains only a rare, if any, group of benign epithelial cells. Alcohol-fixed, Papanicolaou stain, low power.

elongated spindle-shaped cells associated with abundant thick mucoid material.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis for benign non-neoplastic cystic lesions includes both non-neoplastic conditions such as LESA and chronic sialadenitis with cyst formation, as well as neoplastic diseases such as Warthin tumor. Typically, aspirates from neoplasms are highly

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cellular; however, in scanty aspirates, these tumors may be difficult to differentiate from non-neoplastic conditions based on cytomorphology alone. The correct diagnosis of a neoplastic lesion relies on the identification of the characteristic cell type. Lymphoepithelial cysts are lymphocyte-rich and a malignant lymphoma may enter the differential diagnosis. Flow cytometric analysis will resolve that differential. Lymphangioma can produce a lymphocyte-rich fluid on aspiration. The clinical presentation for this lesion is essential in its recognition. Retention cysts/mucoceles yield abundant mucoid material with very few cells. This pattern can overlap

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Salivary Glands

with that of an inadequately sampled mucoepidermoid carcinoma. A residual mass and the identification of an occasional cluster of intermediate and squamous cells may distinguish low-grade mucoepidermoid carcinoma. Clinical correlation and follow-up are essential in the management of these lesions. Furthermore, surgical excision may be recommended to exclude malignancy in the event of an unresolving residual mass.

TUMORS WITH STROMAL/MESENCHYMAL DIFFERENTIATION BENIGN MIXED TUMOR CLINICAL FEATURES Benign mixed tumor is the most common salivary gland neoplasm and accounts for up to 75% of the neoplasms in some series. They are benign, slowgrowing tumors that occur predominantly in the superficial lobe of the parotid (90%), involving the tail or the anterior portion. The submandibular gland and minor salivary glands are less frequently affected. Benign mixed tumor occurs in all age groups, including children, but are seen more frequently in women (M : F = 1 : 4) in their fourth and fi fth decades. Benign mixed tumors are treated with superficial parotidectomy with a good margin of normal salivary gland, since enucleation may leave small tumor extensions behind and may lead to recurrences (0–4%). Recurrences are slow growing, require a lengthy follow-up, and may be difficult to eradicate. With deep-seated tumors, multifocal tumors, and scarring, the facial nerve may be compromised, resulting in injuries. If not excised, benign mixed tumors may reach an enormous size and potentially undergo malignant transformation.

CYTOPATHOLOGIC FEATURES The cytologic image of benign mixed tumor is varied and the smear appearance may differ from one FNA pass to another, emphasizing the importance of adequate sampling of these tumors. Typically, highly cellular smears contain variable combinations of bland epithelial cells, fibrillar stroma, and myoepithelial cells (Figs 1-9 & 1-10). Epithelial cells are cuboidal, usually arranged in honeycomb sheets and clusters; ducts, trabeculae, glands, and papillae can be identified (Fig. 1-11). Fragments of chondromyxoid stroma, intensely metachromatic in Diff-Quik-stained smears, and pale blue–green in Papanicolaou-stained smears, are fibrillar with frayed and irregular borders and are the clue to the diagnosis. Spindle or stellate myoepithelial cells are embedded within the stroma. Epithelial-stromal interdigitation and transition from spindle to epithelial cells are characteristic features of benign mixed tumor. Single myoepithelial cells may be present in the background and may be plasmacytoid in appearance. Single, clear or epithelioid myoepithelial cells are typically difficult to distinguish from single epithelial cells. Minor variations may occur in a tumor with the typical background and include isolated cytologic atypia, mucinous, squamous, and, less frequently, oxyphilic and sebaceous metaplasia (Fig. 1-12) of ductal epithelium, and variability in the stromal cellularity and appearance from myxoid to fibrocollagenous, chondroid, or osteoid. Crystal and crystalloid deposition and intranuclear inclusions may be seen. Occasionally, mixed tumor may harbor a cystic component (7%). The cystic

BENIGN MIXED TUMOR – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Interdigitating ductal epithelial cells, some with metaplastic changes ៉ Myoepithelial cells ៉ Chondromyxoid stroma Histopathologic Findings

BENIGN MIXED TUMOR – DISEASE FACT SHEET Incidence and Location ៉ Most common salivary gland neoplasm (75%) ៉ Parotid (90%) > submandibular > minor salivary glands

Gender and Age Distribution ៉ Male to female ratio is 1 : 4 ៉ Age: 40 years

៉ Gross: rubbery, bosselated, well-circumscribed mass with small

extensions into the surrounding normal tissue ៉ Microscopic: biphasic appearance with varied epithelial and

stromal components in variable proportions Ancillary Studies ៉ Immunoreactivity with glial fibrillary acidic protein (GFAP) is

useful in differentiating benign mixed tumor from adenoid cystic carcinoma and basal cell adenoma Differential Diagnosis and Pitfalls

Prognosis and Treatment ៉ Slow growing, may reach enormous size if not removed ៉ Potential for malignant transformation if not excised ៉ Surgical excision with good margins ៉ Enucleation associated with high recurrence rate

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៉ Cylindromatous areas: adenoid cystic carcinoma ៉ Scant stroma: basal cell adenoma ៉ Squamous and/or mucinous metaplasia: mucoepidermoid

carcinoma ៉ Cytologic atypia: carcinoma ex-pleomorphic adenoma

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FIGURE 1-9 Benign mixed tumor. Cellular smears show the characteristic biphasic cellular component. Epithelial and stromal elements interdigitate with each other. The stroma is pale blue– green and has irregular edges and a fibrillar nature. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Alcohol-fixed, Papanicolaou stain, low power.

FIGURE 1-10 Benign mixed tumor. The stroma appears metachromatic and can vary from dense to more diffuse in the smear background. A number of single epithelial and myoepithelial cells are typically present and are not a sign of malignancy. Air-dried, Diff-Quik stain, low power.

proteinaceous background is thin and should not be misinterpreted as mucin.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Cellular mixed tumors account for about 30% of mixed tumors and FNA may sample the predominant epithelial/myoepithelial component but not the scant stromal/ mesenchymal component, leading to misclassifying the tumor as basal cell adenoma. These cellular mixed

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tumors have a distinctive low-power pattern composed predominantly of loosely cohesive branching and arborizing groups of cells having indistinct community borders. Frequently, the stroma associated with cellular mixed tumor is fibrocollagenous, dense, and courses within the branching epithelial clusters (Fig. 1-13). The cells have scant cytoplasm, oval to round nuclei with finely granular chromatin, and lack distinct nucleoli. Occasional spindling of the cells is observed (Fig. 1-14). Nuclear overlap and haphazard arrangement is a common finding. Scattered plasmacytoid single cells with moderate amount of cytoplasm are seen in most cases.

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FIGURE 1-11 Benign mixed tumor. Bland epithelial cells are embedded into the fibrillar mesenchymal stroma and there is gradual transition into spindle and stellate mesenchymal cells that also populate the stroma. Alcohol-fixed, Papanicolaou stain, high power.

FIGURE 1-12 Benign mixed tumor. Sebaceous metaplasia is rare in salivary gland neoplasms. The metaplastic cells resemble histiocytes. Round uniform nuclei are centrally located in an abundant vacuolated cytoplasm. The vacuoles are small and punched out and distend the cytoplasm. Single myoepithelial cells and a stromal fragment are present in the background. Air-dried, Diff-Quik stain, high power.

Increased cellularity coupled with focal cytologic atypia is encountered in about 20% of tumors and should not be considered a sign of malignancy when the overall picture is that of benign mixed tumor. A cylindromatous pattern occurs in 5% of mixed tumors and should not elicit a diagnosis of adenoid cystic carcinoma if occasional (Fig. 1-15); and scattered squamous and mucinous metaplasia should not result in a diagnosis of mucoepidermoid carcinoma. In some tumors, these metaplastic changes may be present in association with a highly myxoid background mimicking a mucinous background, which may further confound the situation. A predominant plasmacytoid/hyaline cell population

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may mimic the intermediate cells of mucoepidermoid carcinoma. Mucoepidermoid carcinoma is a difficult diagnosis to make in FNA and requires the identification of squamous, intermediate polygonal cells and vacuolated mucinous cells, in an acellular mucinous stringy background. Tumors rich in plasmacytoid/hyaline myoepithelial cells may also be interpreted as myoepitheliomas, acinic cell carcinoma, or oncocytic. Predominance of spindle myoepithelial cells elicits the differential diagnosis of spindle cell proliferation including benign reactive processes such as nodular fasciitis, pseudotumors, peripheral nerve sheath tumors, and spindle cell sarcomas.

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FIGURE 1-13 Cellular mixed tumor. Branching and arborizing clusters of epithelial cells are found amidst numerous single cells. The stroma appears dense, fibrocollagenous rather than the typical fibrillar stroma seen in benign mixed tumor, and courses within the epithelial clusters. Alcohol-fixed, Papanicolaou stain, medium power.

FIGURE 1-14 Cellular mixed tumor. Single cells in the background show variability in shape and size. Some are plasmacytoid in appearance, while others are more spindled, suggesting myoepithelial differentiation. The presence of variable nuclear atypia including dark but smudgy chromatin is not sufficient for a diagnosis of carcinoma. Alcohol-fixed, Papanicolaou stain, high power.

Myoepithelial cells have a characteristic immunoprofile that allows their recognition and helps in the classification of such tumors.

MALIGNANT MIXED TUMOR Carcinoma ex-pleomorphic adenoma is rare and develops in up to 10% of cases of benign mixed tumor. Malignant changes are suggested by sudden rapid growth, pain, and facial paralysis in a patient with a long-

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standing, slow-growing mass. The malignant changes occur in a background of mixed tumor, and the diagnosis requires microscopic documentation of previous benign mixed tumor. The malignant tumor is usually a high-grade carcinoma, and could show differentiation toward any of the usual primary carcinomas of the salivary gland. The carcinoma is characterized by high cellularity with cellular groups or sheets, and papillary clusters of large cells with pleomorphic nuclei, prominent nucleoli, and finely vacuolated cytoplasm dominating the smears. Necrosis may be prominent in the background and mitoses are increased (Fig. 1-16). As opposed to the focal nature of metaplasia and atypia

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11

Salivary Glands

FIGURE 1-15 Benign mixed tumor. A focal cylindromatous pattern in this tissue fragment is characterized by the small metachromatic globules of extracellular matrix embedded within the epithelial group. These findings overlap with those of basal cell adenoma and resemble architectural features of adenoid cystic carcinoma. The background proteinaceous material reflects the cystic nature of this lesion. Air-dried, Diff-Quik stain, medium power.

A

B

FIGURE 1-16 Malignant mixed tumor. A, Superimposed on findings of mixed tumor is a carcinoma with atypical discohesive cells with hyperchromatic pleomorphic nuclei, coarsely granular chromatin, and a high N/C ratio. Alcohol-fixed, Papanicolaou stain, high power. B, Similar malignant cytologic features are noted in addition to a mitotic figure. Air-dried, Diff-Quik stain, high power.

Ch001-F06731.indd 11

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FINE NEEDLE ASPIRATION CYTOLOGY

A

B

FIGURE 1-17 Carcinosarcoma. A, A malignant epithelial cluster consists of crowded overlapping cells with cytologic atypia. B, Mesenchymal cells with atypical nuclei are embedded in a chondromyxoid matrix material and establish the presence of a biphasic malignant neoplasm. Alcohol-fixed, Papanicolaou stain, high power.

associated with cellular mixed tumor, features of malignancy are cytologically obvious in malignant mixed tumor. These tumors have a good prognosis if the changes are confined to the pre-existing mixed tumor. The prognosis depends on the histologic type, grade, proliferative index, and extent of invasion beyond the capsule of the pre-existing tumor.

ponent is ductal and the mesenchymal component is chondrosarcomatous. These tumors are highly aggressive and rapidly fatal.

CARCINOSARCOMA

Myoepithelioma may be considered a variant of pleomorphic adenoma and is thought to consist solely of myoepithelial cells. Myoepithelial cells have three different appearances to include plasmacytoid or hyaline cells with dense, moderate to abundant, welldemarcated cytoplasm, glycogen-rich clear cells, and spindle cells. Myoepitheliomas can display a mixture of those cell types. Most hyaline cell-type tumors occur in minor salivary glands such as in the palate, whereas spindle and clear cell myoepitheliomas are primarily encountered in the parotid gland. Most hyaline cell

True malignant mixed tumor is extremely rare and has a biphasic composition of malignant epithelial and mesenchymal elements. The aspirate is cellular and contains large cell clusters and dissociated cells with marked atypia and a background amorphous substance (Fig. 1-17). The diagnosis can be established on cytology only if both sarcomatous and carcinomatous elements are sampled. Frequently, the epithelial com-

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MYOEPITHELIAL NEOPLASMS

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CHAPTER 1

13

Salivary Glands

FIGURE 1-18 Myoepithelioma. A loosely cohesive sheet and single cells with plasmacytoid features have eccentrically placed nuclei and a moderate amount of dense well-demarcated cytoplasm. Mild nuclear variability is noted. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Alcoholfixed, Papanicolaou stain, high power.

myoepitheliomas will behave as benign neoplasms, whereas some spindle and clear cell tumors will present with malignant infi ltrative features and may have malignant potential with possible local recurrence, metastases, and tumor-related death. Cytologically, myoepitheliomas differ from mixed tumors by the absence of stroma and epithelial cells and by the presence of a dominant myoepithelial cell population arranged in loose groups and single cells (Fig. 1-18). Hyaline cell myoepithelioma can be distinguished from plasma cell neoplasm by the nuclear chromatin pattern and lack of perinuclear Hoff and plasma cell markers (CD79a and CD138). Spindle cell neoplasms such as peripheral nerve sheath tumors and low-grade spindle cell sarcomas should be considered in the differential diagnosis of spindle cell myoepitheliomas. Lastly, clear cell myoepithelioma enters the differential diagnosis of other clear cell neoplasms occurring in the salivary glands, such as acinic cell carcinoma, mucoepidermoid carcinoma, epithelial-myoepithelial carcinoma, and metastatic renal cell carcinoma. The myoepithelial nature of such tumors can be confirmed by the demonstration of staining with one or more of the following: S-100 protein, smooth muscle actin, calponin, cytokeratin, and glial fibrillary acidic protein (GFAP). Additionally, a myoepithelial-rich mixed tumor should always be considered in the evaluation of an aspirate from a myoepithelial-dominant tumor. Epithelial-myoepithelial carcinomas are low-grade myoepithelial-rich tumors that are locally aggressive. They consist of two cell populations: the small dark ductal cells arranged in tight clusters and the larger clear myoepithelial cells with moderate to abundant cytoplasm, vesicular nuclei, and conspicuous nucleoli, which predominate. The clear cells are large, polygonal, and glycogen-rich, with mildly atypical nuclei and small

Ch001-F06731.indd 13

nucleoli, and demonstrate S-100 positivity characteristic of myoepithelial differentiation. Some tumor cell clusters may be surrounded by amorphous hyaline material. Cellular arrangements with acellular basement membrane material reminiscent of adenoid cystic carcinoma may also be found (Fig. 1-19). These tumors may share features with both mixed tumors and basaloid neoplasms, as they consist of basaloid cells and stroma that forms spherules or has an irregular, somewhat fibrillar appearance.

ONCOCYTIC NEOPLASMS WARTHIN TUMOR CLINICAL FEATURES Warthin tumors occur almost exclusively in the parotid and are thought to arise from entrapped salivary duct remnants within intra- or periparotid lymph nodes. They are more common in men in the sixth decade and older. The incidence in women is on the rise, as this tumor shows a statistical relationship with smoking. Warthin tumors are commonly multicentric (10–15%), and bilateral; they constitute 70% of all bilateral salivary gland neoplasms. The treatment is surgical excision, and recurrences may occur but are uncommon. Malignant transformation in Warthin tumors is a rare event, and may occur in either the epithelial or lymphoid component.

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FINE NEEDLE ASPIRATION CYTOLOGY

A

B

FIGURE 1-19 Myoepithelial carcinoma. A, Metachromatic stromal fragment with features similar to those seen in benign mixed tumor contains a large number of basaloid cells. Air-dried, Diff-Quik stain, high power. B, Oval hyperchromatic nuclei with finely granular chromatin and scant cytoplasm with short tapered cytoplasmic ends suggest a myoepithelial rather than epithelial differentiation of the basaloid cells. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Alcohol-fixed, Papanicolaou stain, high power.

WARTHIN TUMOR – DISEASE FACT SHEET Incidence and Location Second most common salivary gland neoplasm (5–10%) Most common bilateral salivary gland neoplasm (70%) Exclusively in the parotid Multicentric

៉ ៉ ៉ ៉

WARTHIN TUMOR – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Mixed population of lymphocytes ៉ Small sheets of oncocytes ៉ Granular proteinaceous background ៉ Metaplastic cells

Gender and Age Distribution

Histopathologic Findings

៉ Male to female ratio is 5 : 1 ៉ Age >50 years

៉ Gross: lobulated mass, multicystic with fl uid-filled spaces

Prognosis and Treatment ៉ Surgical excision with good margins ៉ Potential for recurrence

separated by grayish septae; hemorrhagic infarcts post FNA are common ៉ Microscopic: typically, cystic lesion with prominent lymphoid tissue containing frequent germinal centers covered by oncocytes arranged in two layers, resulting in a papillary-like architecture Differential Diagnosis and Pitfalls ៉ Cystic lesions: lymphoepithelial cyst, branchial cleft cyst,

papillary cystadenoma

CYTOPATHOLOGIC FEATURES Characteristically, Warthin tumors are multicystic and yield a turbid brown fluid. Microscopically, a classic dirty proteinaceous background (Fig. 1-20), and a mixed but maturing population of lymphocytes and scattered groups of oncocytes characterize these tumors (Fig. 1-21). The lymphoid population is comprised predominantly of small lymphocytes and fewer larger cells showing an ordered maturational sequence and portions of germinal centers. A variable amount of uniform oncocytic epithelium is present in small sheets without crowding. The oncocytes have abundant granular cytoplasm, round uniform nuclei, even chromatin, and conspicuous nucleoli (Fig. 1-22). Frequently, the two cell populations are intermixed within the same cellular

Ch001-F06731.indd 14

៉ Lesions with lymphoid component: chronic sialadenitis, benign

៉ ៉ ៉ ៉

lymphoepithelial cyst, lymph node, lymphoma, acinic cell carcinoma Oncocytic neoplasms Intraductal papilloma Other neoplasm such as squamous carcinoma or mucoepidermoid carcinoma in association with epithelial metaplasia Infarct-like necrosis: malignant neoplasms

groups. Occasionally, pseudopapillary arrangements may be present, consisting of two oncocytic cell layers surrounding lymphoid aggregates. Cytologic variants may include the presence of focal squamous or mucinous metaplasia similar to that seen in benign mixed tumor. Granulomas formed by

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15

Salivary Glands

FIGURE 1-20 Warthin tumor. Large pools of thick proteinaceous material are easily identified among numerous lymphocytes and scattered small epithelium groups. The proteinaceous material, which may have some similarity to mucin pools, corresponds to the aspirated cyst fluid. Air-dried, Diff-Quik stain, high power.

FIGURE 1-21 Warthin tumor. Small fl at sheets of oncocytes and lymphocytes in all stages of maturation are the two cell populations characteristic of this tumor. Alcohol-fixed, Papanicolaou stain, medium power.

both epithelioid histiocytes and multinucleated giant cells (sarcoid type) can be seen in some cases. The pathogenesis of granulomas is unknown, and could be related to a toxic effect of the cyst content. Non-tyrosine crystalloids similar to those seen in sialolithiasis and sialadenitis, as well as corpora amylacea have been described in association with Warthin tumors, and are found in highest concentration in cystic and luminal spaces.

Ch001-F06731.indd 15

DIFFERENTIAL DIAGNOSIS AND PITFALLS Potential sources of diagnostic pitfalls in Warthin tumors may be caused by the presence of dominant morphologic features or atypical features. Such factors may involve the epithelial component or the lymphoid component. A scanty lymphoid component with a predominance of oncocytic cells may suggest a neoplasm

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FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 1-22 Warthin tumor. Uniform oncocytes are orderly arranged in this sheet and appear to line up at the edge, suggesting a papillary configuration. The cells have the characteristic round nuclei with conspicuous nucleoli and abundant dense but granular cytoplasm. Air-dried, DiffQuik stain, high power.

such as oncocytoma or a bland oncocytic carcinoma. In oncocytic neoplasms, oncocytes are organized in large sheets rather than in the small clusters seen in Warthin tumors; there is also a lack of the background proteinaceous material. Intraductal papilloma of the salivary gland is another cystic neoplasm that may have a predominance of oncocytic epithelium. In these rare cases, the oncocytes are arranged in a striking papillary configuration with a total absence of lymphocytes in the background. Squamous metaplasia can occur in Warthin tumors. Such metaplastic changes have been reported in patients with a previous history of FNA and in patients with spontaneous infarction of a Warthin tumor. Infarcted Warthin tumors may yield necrotic material that may suggest a malignant neoplasm. Also included in the differential diagnosis are lesions of the salivary glands with lymphoid component. Benign lymphoepithelial cysts overlap with Warthin tumors. The lymphoid population is similar in both lesions. Separating the two entities requires focusing on the epithelial component, and identifying oncocytes for Warthin tumor, or occasional mature and parakeratotic squamous cells or columnar cell ghosts for lymphoepithelial cysts. Variants of chronic sialadenitis or benign lymphoepithelial lesions may mimic Warthin tumor but are typically characterized by an intense inflammatory response and a different mix of epithelial cells, including ductal and some acinar epithelium. Lymph nodes present within salivary glands constitute another diagnostic pitfall, but may be easily recognized when an almost complete absence of an epithelial component is noted. Acinic cell carcinoma with lymphoid component will also enter the differential diagnosis. Acinic cell carcinoma will typically have a more abundant epithelial component. The cytoplasm in acinic cell carcinoma will

Ch001-F06731.indd 16

show vacuolization and granularity and will be more delicate than the cytoplasm of oncocytes. Architecturally, attempt at acinar formation can be found in acinic cell carcinoma, whereas acini or glandular aggregates are lacking in Warthin tumors. Patients with Warthin tumors are at increased risk of developing malignant lymphoma. When malignant lymphoma is suspected, clonality of the cytologic material can be proven by immunocytochemistry, flow cytometry, or molecular studies to demonstrate gene rearrangement.

ONCOCYTOMA AND ONCOCYTIC CARCINOMA Oncocytoma is a rare benign neoplasm that involves mainly the parotid gland in patients over 70 years of age. Oncocytomas produce a well-defined, solid, partially encapsulated mass and yield a pure population of oncocytes by FNA. Oncocytes have abundant dense granular cytoplasm, central round nuclei, and conspicuous nucleoli. They occur in large sheets in a clean background devoid of lymphocytes and proteinaceous material. The differential diagnosis of oncocytoma is oncocytosis and Warthin tumor. The malignant counterpart of oncocytoma is oncocytic carcinoma, which may not always be easy to diagnose based on cytologic features alone. Oncocytic carcinoma is a diagnosis of exclusion after ruling out oncocytic variants of other more common tumors such as mucoepidermoid carcinoma. Oncocytic carcinoma may be suspected in cytologic preparations in the presence of atypia, mitosis, and necrosis.

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Salivary Glands

BASALOID NEOPLASMS This section addresses a group of salivary gland neoplasms that share cytologic features and cellular composition, therefore resulting in overlapping findings on FNA and creating diagnostic dilemmas and pitfalls. These tumors consist of epithelial and myoepithelial cells with bland nuclear features and scant cytoplasm, giving them a basaloid appearance. They also have variable amounts of extracellular matrix that may be hyalinized, forming globules and cylinders enrobed within the cells. This group of tumors includes basal cell adenoma, basal cell adenocarcinoma, adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and some myoepithelial neoplasms. As a result of their shared features, they also share their differential diagnoses.

BASAL CELL ADENOMA CLINICAL FEATURES Basal cell adenomas are tumors of the parotid gland that have a slight female predilection. Their clinical presentation is similar to that of benign mixed tumors, although they tend to occur in an older age group. Specific subtypes have been recognized, such as the membranous type for its more aggressive clinical course and association with skin tumors (cylindromas), and the canalicular type for its location in the upper lip. Treatment of these tumors is by complete excision.

BASAL CELL ADENOMA – DISEASE FACT SHEET Location ៉ Parotid Gender and Age Distribution ៉ Slight predilection for females ៉ Age >50 years

Clinical Features ៉ Presentation similar to benign mixed tumor Prognosis and Treatment ៉ Surgical excision with good margins ៉ Potential for malignant transformation to adenoid cystic

carcinoma or basal cell adenocarcinoma

CYTOPATHOLOGIC FEATURES Smears are moderately cellular and consist of variably sized, dark-appearing, densely packed clusters of monomorphic basaloid cells. Some clusters may display irregular branching and trabecular patterns. Peripheral palisading of basaloid cells may be noted. A variable number of single cells and naked nuclei are present in the background (Fig. 1-23). The basaloid cells are uniform with round nuclei, scant cytoplasm, welldefined cell borders, and a high nuclear to cytoplasmic (N/C) ratio. The chromatin is bland and nucleoli are inconspicuous. Single basaloid cells lack the characteristic plasmacytoid appearance of single myoepithelial

FIGURE 1-23 Basal cell adenoma. Single basaloid cells with bland uniform oval nuclei and scanty well-defined cytoplasm lack the plasmacytoid appearance of myoepithelial cells of benign mixed tumor. Some cells are arranged in a pseudoacinar formation surrounding the extracellular matrix. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Air-dried, Diff-Quik stain, high power.

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FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 1-24 Basal cell adenoma. Cluster of basaloid cells containing small uniform metachromatic stromal globules of extracellular matrix. The globule edges are poorly defined and interdigitate with the surrounding cells. Air-dried, Diff-Quik stain, high power.

BASAL CELL ADENOMA – PATHOLOGIC FEATURES Cytopathologic Findings Monomorphic bland basaloid cells Variably sized clusters, branching and trabecular pattern Peripheral palisading Single cells and bare nuclei Small hyaline globule and cylinders of extracellular matrix Thick ribbon of extracellular matrix around nests and tubules (membranous type) ៉ Poorly defined stromal–epithelial interface ៉ ៉ ៉ ៉ ៉ ៉

Histopathologic Findings ៉ Gross: encapsulated, often cystic ៉ Microscopic: ៉ Tubular, trabecular, or solid ៉ Peripheral palisading of cells at the edge of epithelial nests ៉ Abundant extracellular matrix at periphery and within nests (cylindromatous pattern) in membranous type (unclear)

cells seen in pleomorphic adenoma. Within the clusters, metachromatic/clear (Romanowsky/Papanicolaou stains) stromal hyaline globules and cylinders surrounded by basaloid cells are easily identified. Typically, the globules are small and the stromal edge is poorly defined and interdigitates with the surrounding cells (Fig. 1-24). Irregularly shaped stromal fragments may be focally encountered within or at the periphery of the clusters and represent the fibrous supporting stroma. The fibrillar stroma of benign mixed tumor is absent. The cytologic findings in the membranous type of basal cell adenoma are distinctive and allow for its

Ch001-F06731.indd 18

identification by FNA. Solid nests and tubular structures formed by basaloid cells are surrounded by a thick ribbon of hyalinized basement membranelike material. The neoplastic cells show peripheral palisading at the periphery of the clusters (Fig. 1-25). Scattered hyaline globules can be seen within the cell groups.

DIFFERENTIAL DIAGNOSIS AND PITFALLS See page 22.

BASAL CELL ADENOCARCINOMA Basal cell adenocarcinoma is a rare, recently recognized entity. It affects patients in the sixth decade of life and occurs predominantly in the parotid. It is cytologically similar to basal cell adenoma. The presence of mitoses and nuclear atypia including prominent nucleoli may point to the malignant nature of the tumor. However, the malignant nature of the process may be difficult to ascertain, as it is impossible to determine from FNA material the invasive nature of the tumor. Invasion is primarily a histologic feature that sets it apart from basal cell adenoma. Basal cell adenocarcinoma is associated with perineural invasion and tends to overexpress p53, bcl2, and EGFR. Its clinical course may include local recurrences, and lymph node and distant metastases, primarily to the lung. For the differential diagnosis, see page 22.

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Salivary Glands

FIGURE 1-25 Basal cell adenoma. Basaloid cells show peripheral palisading at the edge of this large solid cluster of monomorphic cells. A ribbon of stroma is noted surrounding the cluster, a feature that suggests a membranous pattern of basal cell adenoma. Alcohol-fixed, Papanicolaou stain, medium power.

ADENOID CYSTIC CARCINOMA CLINICAL FEATURES Adenoid cystic carcinoma is rare, and occurs with less frequency than mucoepidermoid and acinic cell carcinoma in the parotid gland. It is, however, the most common malignancy in minor salivary glands. Adenoid cystic carcinoma occurs more frequently in women in the fi fth to sixth decade and has a slow, relentless growth. It may present with a painful mass or facial nerve paralysis. Radical resection is the treatment of choice, and cure following recurrence is difficult to

achieve. Radiation therapy is not curative but may produce temporary regression in unresectable cases. Prognostic factors include tumor grade and stage, status of surgical margins, anatomic site, and tumor size. Adenoid cystic carcinoma has a high recurrence rate even in well-differentiated tumors and is associated with frequent lung and bone metastases. It has a protracted course and a low 15–20-year survival.

CYTOPATHOLOGIC FEATURES Well-differentiated tumors are composed of small basaloid cells, both ductal and myoepithelial, in solid

ADENOID CYSTIC CARCINOMA – DISEASE FACT SHEET Incidence ៉ Rare in major salivary glands ៉ Most common malignancy in minor salivary gland Gender and Age Distribution ៉ More frequent in women in the 5th and 6th decade

Clinical Features ៉ Slow relentless growth ៉ Pain and facial nerve paralysis Prognosis and Treatment ៉ Radical surgical excision with clear margins ៉ High recurrence rate and metastases to lung and bone ៉ Low survival rate

Ch001-F06731.indd 19

ADENOID CYSTIC CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Small basaloid cells ៉ Solid clusters, spherules, cylinders ៉ Hyalinized, acellular, large stromal fragments ៉ Well-defined stromal edges ៉ Sharp stromal–epithelial interface Histopathologic Findings ៉ Gross: solid mass, infiltrative borders ៉ Microscopic: ៉ Cribriform nests with pseudocysts ៉ Tubular and solid patterns ៉ Perineural invasion ៉ Strong staining with CD117 (c-kit protein)

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FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 1-26 Adenoid cystic carcinoma. Large variably sized metachromatic stromal globules and small clusters of bland basaloid cells are the classic finding. Some of the stromal globules are rimmed by a row of basaloid cells that are barely touching the stromal fragment. Note the size difference of the stromal globules and the lack of cell/stroma interdigitation in comparison with basal cell adenoma. Air-dried, Diff-Quik stain, medium power.

FIGURE 1-27 Adenoid cystic carcinoma. The cells are uniform with a high N/C ratio, round to oval nuclei, and an occasional angulated nuclear membrane. Chromatin is fine and even, and nucleoli are small but conspicuous. ThinPrep, Papanicolaou stain, oil.

clusters, spherules, and cylinders, or in cribriform groups (Fig. 1-26). The cells are uniform with round to oval, sometimes angulated nuclei, scant cytoplasm, and a high N/C ratio. The chromatin varies from fine to coarse and nucleoli are small but conspicuous (Fig. 1-27). The basaloid cells surround intensely metachromatic (Romanowsky stain) or pale and glassy (Papanicolaou stain) stromal spheres and cylinders. The stromal fragments are larger than those seen in monomorphic adenoma; they are variably sized, acellular, and sharply demarcated with smooth rounded edges (Fig. 1-28). In some cases, the predominant finding is that of spherical

Ch001-F06731.indd 20

or cylindrical stromal fragments lying bare or surrounded by a single discontinuous rim of basaloid cells that seem to hardly touch the stromal surface. Conversely, the poorly differentiated or solid form of adenoid cystic carcinoma will have few stromal globules, a predominance of basaloid cells, and more prominent nuclear atypia (Fig. 1-29). Special stains and immunocytochemistry do not provide significant differentiating features, except for CD117 (c-kit), which is strongly immunoreactive in adenoid cystic carcinoma in comparison with other basaloid tumors and may be of diagnostic consideration.

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21

Salivary Glands

DIFFERENTIAL DIAGNOSIS AND PITFALLS See page 22.

POLYMORPHOUS LOW-GRADE ADENOCARCINOMA Polymorphous low-grade adenocarcinoma is a neoplasm of minor salivary glands. It has rarely been reported in the parotid gland and affects women more often than men. Its most common location is the palate, where it follows adenoid cystic carcinoma in frequency. Smears are characterized by the presence of tubules, cords, linear groupings, and branching papillary sheets and

POLYMORPHOUS LOW-GRADE ADENOCARCINOMA – DISEASE FACT SHEET Incidence and Location ៉ Second most common salivary gland neoplasm in palate ៉ Minor salivary glands, palate Gender and Age Distribution ៉ More common in females ៉ Age: adult

Prognosis and Treatment FIGURE 1-28 Adenoid cystic carcinoma. A bare stromal fragment may be the predominant finding. Note the dense hyalinized appearance of the stroma and the sharply demarcated contour. Globules, as well as cylindrical and more complex structures, are common. Air-dried, Diff-Quik stain, medium power.

៉ Comprehensive surgical excision with clear margins ៉ Potential for recurrence and lymph node metastases ៉ No distant metastases

FIGURE 1-29 Adenoid cystic carcinoma. Poorly differentiated tumors consist of densely packed basaloid cells with more obvious nuclear atypia and a scant stromal component. The lack of nuclear molding and neuroendocrine chromatin pattern helps differentiate this tumor from a small cell undifferentiated carcinoma. Air-dried, Diff-Quik stain, medium power.

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FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 1-30 Polymorphous low-grade adenocarcinoma. Large tissue fragments composed of monotonous uniform cells display a branching papillary architecture, one of the patterns encountered in this tumor. Airdried, Diff-Quik stain, low power.

FIGURE 1-31 Polymorphous low-grade adenocarcinoma. Within the sheet of uniform basaloid-appearing cells are small stromal globules that bear resemblance to those seen in basal cell adenoma and adenoid cystic carcinoma and help differentiate this lesion from other papillary neoplasms. Air-dried, Diff-Quik stain, high power.

clusters (Fig. 1-30). Hyaline globules are identified within the sheets of basaloid epithelium. Cytologic uniformity or monomorphism is key; the tumor is composed of basaloid, bland, uniform cells with round to oval nuclei, dispersed chromatin, inconspicuous or absent nucleoli, and scant cytoplasm (Fig. 1-31). Mild nuclear variability can be seen, and mitoses are absent. Treatment is by surgical excision with clean margins, as recurrences are difficult to eradicate. Like adenoid cystic carcinoma, this tumor has a predilection for perineural invasion; however, it typically is a favorable actor, with local recurrences and regional lymph nodes metastases described, but overall absent distant metastases.

Ch001-F06731.indd 22

DIFFERENTIAL DIAGNOSIS AND PITFALLS Tumors comprised of basaloid cells, such as basal cell adenoma, adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and basal cell adenocarcinoma, share cytologic features, and therefore all enter the same differential diagnosis. Distinction between basal cell adenoma and cellular mixed tumor may be difficult, but is of no significant consequence since both are benign tumors that are treated in a similar fashion. Cells of basal cell adenoma show a uniform orderly cellular arrangement with no loss of polarity, as opposed to the haphazard arrangement in cellular pleomorphic

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23

Salivary Glands

POLYMORPHOUS LOW-GRADE ADENOCARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Monomorphous bland basaloid cells ៉ Tubules, cords, linear groupings, and branching papillary sheets ៉ Hyaline globules within sheets of epithelial cells Histopathologic Findings ៉ Uniformity of cell type ៉ Architectural variability: tubular, cribriform, papillary, solid,

logic grounds, and with a high degree of certainty, the benign from the malignant neoplasms. In the individual case, it is important to recognize the limitation of the technique and classify the difficult lesions as ‘salivary gland neoplasm’, listing a differential diagnosis, and deferring classification to histologic examination.

MUCOEPIDERMOID CARCINOMA

and fascicular ៉ Infiltrative border ៉ Perineural invasion

Differential Diagnosis and Pitfalls (for all basaloid neoplasms) Basal cell adenoma Cellular pleomorphic adenoma Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma Basal cell adenocarcinoma Myoepithelial carcinoma Metastatic basal cell carcinoma

៉ ៉ ៉ ៉ ៉ ៉ ៉

adenoma. The individual cells in basal cell adenoma have a small rim of cytoplasm and lack the plasmacytoid appearance of myoepithelial cells seen in benign mixed tumor. Basal adenoma closely resembles adenoid cystic carcinoma and may be difficult to distinguish from it cytologically in the individual case. The unique appearance of the cell–stroma interface is useful in distinguishing between basal adenomas and adenoid cystic carcinoma. In basal cell adenoma the collagenous stroma interdigitates with the adjacent cells, whereas in adenoid cystic carcinoma there is a sharp demarcation of cells and stroma. The spherules in basal cell adenoma are small and somewhat uniform in size, whereas in adenoid cystic carcinoma they are large and variable in size and shape. The stroma of basal adenoma may contain some spindle cells and capillaries, whereas the stroma of adenoid cystic carcinoma is acellular. The stroma of solid adenoid cystic carcinoma may mimic that seen in cellular mixed tumor. It, however, represents a desmoplastic stroma. Any abnormality of the chromatin and the presence of prominent nucleoli favor a diagnosis of adenoid cystic carcinoma over basal cell adenoma. The solid variant of adenoid cystic carcinoma may also resemble small cell undifferentiated carcinoma or basaloid squamous carcinoma. Basal cell adenocarcinoma, as previously stated, cannot be differentiated cytologically from basal cell adenoma since presence of invasion is the determining factor. Polymorphous low-grade adenocarcinoma may be suspected because of its location and the detection of architectural patterns that are not characteristic of adenoid cystic carcinoma, such as papillary features. Although less common, other tumors such as myoepithelial carcinoma and metastatic basal cell carcinoma should also be considered in the differential diagnosis. The major dilemma in this group of tumors is to separate, on cyto-

Ch001-F06731.indd 23

CLINICAL FEATURES Mucoepidermoid carcinoma comprises 5–10% of all salivary gland neoplasms. It is the second most common primary neoplasm of the salivary glands in adults (30%), and the most common primary malignancy in children. It is mostly located in the parotid, but may also involve other major and minor salivary glands. In adults, these tumors typically occur in the third to fifth decades. Mucoepidermoid carcinomas are divided according to grade and are most often classified as low-grade and high-grade tumors, although some classification schemes include an intermediate grade. Their presentation, treatment, and prognosis are dependent on grade. Low-grade tumors tend to develop slowly over a period of years. They may recur locally, but distant metastases are rare. The 5-year survival for low-grade tumors approaches 98%. The tumors tend to be well circumscribed and may become cystic, containing mucinous material. These tumors are treated and may be cured with limited excision. High-grade tumors grow rapidly, recur locally, and metastasize to regional lymph nodes, lung, and bone. Their 5-year survival rate is around 56%. High-grade tumors are infi ltrative and tend to be solid. They are treated aggressively with surgery, and possible lymph node dissection and radiation therapy. Most of these tumors manifest their poor behavior within the first year after surgery.

MUCOEPIDERMOID CARCINOMA – DISEASE FACT SHEET Incidence and Location ៉ Most common salivary gland malignancy in children and adults ៉ Predominantly parotid Age Distribution ៉ 20–40 years

Clinical Features ៉ Slow-growing mass for low-grade tumors, rapidly growing for

high-grade tumors Treatment ៉ Wide local excision, regional node dissection if nodes clinically

involved

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FINE NEEDLE ASPIRATION CYTOLOGY

Extraglandular extension, vascular invasion, necrosis, and high mitotic rate are poor prognostic features.

MUCOEPIDERMOID CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings

CYTOPATHOLOGIC FEATURES

៉ Variable combination of mucous, intermediate, squamous, and

clear cells ៉ Low grade: abundant mucoid background with predominance of

bland mucous and intermediate cells

The FNA diagnosis of mucoepidermoid carcinoma is one of pattern recognition. Aspirates from these tumors contain a variety of cell types: mucin-producing, squamous, intermediate, and clear. Intermediate cells are small and bear resemblance to squamous metaplasia. In low-grade mucoepidermoid carcinoma, extracellular stringy mucin is seen in the smear background of a majority of cases. The cellular components are quantitatively variable and include epithelial cell groups that are multilayered with overlapping nuclei, mucincontaining cells, intermediate cells without identifiable keratin, squamous cells, and finely vacuolated clear cells. In cellular clusters, a gradual transition from intermediate to mucus-producing cells is readily identifiable (Fig. 1-32). The nuclei of these cells are generally small, uniform, round or oval, and not overtly malignant. Mucin-producing cells typically predominate. They may have a columnar or signet-ring appearance or may resemble histiocytes when present singly. Aspirates from high-grade tumors demonstrate poorly differentiated cells with frankly malignant features including pleomorphic nuclei, hyperchromasia, coarse chromatin, and prominent nucleoli; glandular/mucous cells may be few in number and difficult to recognize, requiring a special stain for mucin for identification (Fig. 1-33). The squamous cells are more easily recognized and, together with intermediate cells, predominate. Predominant bizarre forms of squamous cells, pearl formation, extensive necrosis, and frequent mitoses are not classic features of high-grade mucoepidermoid carcinoma.

A

៉ High grade: predominance of squamous and intermediate cells,

sparse mucous cells, overtly malignant features Histopathologic Findings ៉ Gross: ៉ Low grade: well circumscribed, cystic ៉ High grade: solid, infiltrative growth pattern ៉ Microscopic: ៉ Low grade: cysts containing mucinous material, lined by well-

differentiated mucinous cells ៉ High grade: solid, infiltrative sheets of squamous intermediate

and clear cells with scattered mucin-producing cells Differential Diagnosis and Pitfalls ៉ Low grade: mucocele, Warthin tumor with squamous/mucinous metaplasia, pleomorphic adenoma with squamous/mucinous metaplasia ៉ High grade: salivary duct carcinoma, carcinoma ex-pleomorphic adenoma, adenosquamous carcinoma, oncocytic carcinoma, metastatic squamous cell carcinoma

DIFFERENTIAL DIAGNOSIS AND PITFALLS Low-grade mucoepidermoid carcinoma is commonly cystic, and may be difficult to diagnose by FNA. Adequate sampling of these tumors is critical to accuracy in interpretation.

B

FIGURE 1-32 Mucoepidermoid carcinoma, low grade. A, Intermediate and mucin-producing cells are mingled within the same cluster. Intermediate cells, centrally located in the cluster, are small with round uniform nuclei and moderate to scant cytoplasm, whereas mucinous cells have similar nuclear features but ample vacuolated mucin-containing cytoplasm and are noted at the periphery of the cluster. Cells are multilayered and overlapping, a clue to their neoplastic nature, and display a gradual transition from intermediate to mucous cells. Wisps of mucinous material are present in the background. Alcohol-fixed, Papanicolaou stain, medium power. B, A sheet of streaming, elongated cells with moderate amount of cytoplasm suggests squamous differentiation. Alcohol-fixed, Papanicolaou stain, medium power.

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FIGURE 1-33 Mucoepidermoid carcinoma, high grade. Nuclear pleomorphism, hyperchromasia, nucleoli, cellular crowding, and discohesion are easily recognizable features of malignancy. An occasional mucin-producing cell is identified within the cluster. Alcohol-fixed, Papanicolaou stain, medium power.

Aspiration of these tumors may yield mucoid cyst fluid containing inflammatory cells, histiocytes (which may mimic glandular cells), and few epithelial cells. This presentation must be distinguished from a mucous retention cyst or mucocele, which is typically less cellular and lacks the intermediate or squamous cell component seen in low-grade mucoepidermoid carcinoma. Another clue in separating a benign cyst from a neoplasm is the persistence in neoplastic processes of a mass post FNA. Squamous and mucinous metaplasia accompanied by inspissated mucus or thick proteinaceous fluid can be seen in chronic sialadenitis, sialolithiasis, and Warthin tumor, and may mimic the cells seen in low-grade mucoepidermoid carcinoma. These cells are usually found focally and do not constitute the predominant cell population. Rarely, mucoepidermoid carcinoma may present with oncocytic features that renders its distinction from Warthin tumor or oncocytoma problematic. The thick mucoid material in the smear background of low-grade mucoepidermoid carcinoma may be metachromatic with Diff-Quik staining and resemble the myxoid matrix characteristic of benign mixed tumor. This material, however, lacks the spindle cells seen in the stroma of mixed tumors. High-grade mucoepidermoid carcinoma shows obvious cytologic features of malignancy and can mimic other poorly differentiated primary or metastatic tumors such as carcinoma ex-pleomorphic adenoma, salivary duct carcinoma, adenosquamous carcinoma, and metastatic squamous cell carcinoma. The correct diagnosis of mucoepidermoid carcinoma relies on the identification of both squamous and glandular components. In high-grade tumors, squamous differentiation is more easily recognized, but the mucous glandular cells are few in number or difficult to identify without the use of special stains for mucin. The only indication of

Ch001-F06731.indd 25

glandular differentiation may be scattered mucin vacuoles in sheets of intermediate and squamous cells. Salivary duct carcinoma has extensive necrosis and may have a papillary architecture. The presence of extensive keratinization and prominent pearl formation favors the diagnosis of squamous cell carcinoma over mucoepidermoid carcinoma. Finally, the clinical history is helpful in excluding a metastasis or identifying a preexisting mass such as in carcinoma ex-pleomorphic adenoma. In the final evaluation, all primary high-grade carcinomas of the salivary gland are treated similarly and a definitive classification is not essential for appropriate therapy.

ACINIC CELL CARCINOMA CLINICAL FEATURES Acinic cell carcinoma is an uncommon neoplasm, comprising only 1–6% of all salivary gland neoplasms. However, it is the second most common primary salivary gland malignancy, occurs mostly in the parotid gland, and can be bilateral in approximately 3% of cases. It is most frequently encountered in the third to fourth decade, and shows prevalence in women. Acinic cell carcinoma forms a well-circumscribed, mobile, slowly growing mass, and although it appears as a lowgrade malignancy, it often demonstrates a protracted course and has a propensity for local recurrence and regional and distant metastases. Treatment requires wide local excision with regional node dissection if necessitated by the presence of clinically involved

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ACINIC CELL CARCINOMA – DISEASE FACT SHEET Incidence and Location ៉ Uncommon salivary gland neoplasm (1–6%) ៉ Predominantly parotid

Gender and Age Distribution ៉ Female predominance ៉ 30–40 years

Clinical Features ៉ Slow-growing mass ៉ Occasionally painful

ACINIC CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Sheets and tissue fragments with loose acinar formation ៉ Polygonal cells with bland nuclei and abundant granular/ vacuolated cytoplasm, indistinct cell border ៉ Background bare nuclei ៉ Vascular component ៉ Possible lymphoid background Histopathologic Findings ៉ Gross: encapsulated round mass, solid, friable, grey–white cut

surface; occasionally cystic ៉ Microscopic: variable growth patterns (solid microcystic,

papillary cystic, follicular) and variable appearance of neoplastic cells (acinic, intercalated duct, vacuolated, clear, glandular NOS)

Treatment ៉ Wide local excision, regional node dissection if nodes clinically involved

lymph nodes. The role of radiation therapy is controversial. Markers of poor prognosis include pain or fi xation, gross invasion, desmoplasia, cytologic atypia, and increased mitotic activity.

CYTOPATHOLOGIC FEATURES Aspiration smears are cellular and contain cell fragments with vague, irregular acinar configurations. Occasionally, a papillary configuration may be present. Some tissue fragments will include portions of vascular structures surrounded by neoplastic cells, reflecting the vascular nature of the neoplasm. Within sheets and clusters, cell borders are not distinct. When well differentiated, the tumor cells resemble normal acinar cells. They have a bland appearance with abundant

A

Differential Diagnosis and Pitfalls Non-neoplastic salivary gland Cytoplasmic granularity: oncocytic neoplasms Lymphoid background: Warthin tumor Clear/vacuolated cytoplasm: mucoepidermoid carcinoma, epi-myoepithelial carcinoma, metastatic renal cell carcinoma, sebaceous neoplasms ៉ Cytologic atypia: other high-grade carcinomas ៉ ៉ ៉ ៉

granular to foamy cytoplasm, small dark nuclei, and small nucleoli (Fig. 1-34). The cytoplasmic granules (zymogen granules) are variable in quantity and characteristically PAS-positive, diastase-resistant. Ductal structures are absent. Cells with foamy cytoplasm have few, if any, granules and have a clear cell appearance. Although usually bland, nuclei can show variable degrees of atypia, including a more granular chromatin pattern and prominent nucleoli. The smear background contains numerous bare nuclei that must be differentiated from lymphocytes. Lymphocytes are usually

B

FIGURE 1-34 Acinic cell carcinoma. A, A loose cellular aggregate consists of bland-appearing cells with delicate granular and finely vacuolated cytoplasm. Cytoplasmic borders are indistinct and true acinar formation is absent. Bare nuclei of neoplastic cells are present in the background. Alcohol-fixed, Papanicolaou stain, medium power. B, Irregular acinar formation, lack of ductal epithelium, and granular nature of the cytoplasm are characteristic features. Air-dried, Diff-Quik stain, high power.

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absent; however, in approximately 10% of acinic cell carcinomas (follicular variant), the stroma is rich in lymphoid cells with germinal centers. These tumors produce aspirates with abundant lymphoid elements in addition to the tumor cells. Poorly differentiated acinic cell carcinoma is uncommon and demonstrates easily recognizable features of malignancy and may be difficult to differentiate from other high-grade malignancies involving the parotid. The papillary cystic variant may present with sheet or papillary clusters of neoplastic cells resembling ductal epithelium. They will also be associated with material from cyst content, such as debris and histiocytes, and may yield laminated, calcified structures that resemble psammoma bodies. This variant may be diagnostically challenging and difficult to recognize as acinic cell carcinoma.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Well-differentiated acinic cell carcinoma must be differentiated from normal salivary gland tissue or sialadenosis. The absence of ductal structures and associated adipose tissue seen in normal salivary gland tissue can help in the diagnosis of neoplasia. In acinic cell carcinoma, there is discohesion of neoplastic cells, the acinar-like arrangements are loose, the groups are poorly formed, and crowded sheets are seen. The grapelike arrangement of acini in association with ductal structures seen in normal salivary gland tissue and the orderly array of cells within acini showing basally located nuclei are lacking. Acinic cell carcinoma with lymphocyte-rich stroma must be differentiated from Warthin tumor. Although cells from both lesions have

27 abundant cytoplasm, the cytoplasm of oncocytes in Warthin tumor is very dense in comparison to the granular, foamy cytoplasm of acinic cell carcinoma cells. This distinction would also aid in the differential diagnosis with oncocytic neoplasms. The cytoplasmic granularity of oncocytes results from the abundance of mitochondria which stain positively with phosphotungstic acid–hematoxylin (PTAH). The presence of clear cells can raise the possibility of clear cell tumors, both primary and metastatic, especially mucoepidermoid carcinoma and metastatic renal cell carcinoma. Although aspirates from mucoepidermoid carcinoma can contain cells with abundant foamy cytoplasm resembling acinar cells, the presence of background mucin and mucin-producing cells would exclude a diagnosis of acinic cell carcinoma, which is negative for mucin. Metastatic renal cell carcinoma is characterized by the presence of clear cells showing nuclear pleomorphism and prominent nucleoli. This tumor may show numerous small vessels within the tissue fragments, a finding that is compatible with the diagnosis of acinic cell carcinoma. Specific immunomarkers for renal cell carcinoma, such as CD10, and clinical correlation will help resolve this differential. The rare epithelial-myoepithelial carcinoma will present with clear cells; however, it may be distinguished by the identification of a biphasic cell population. The presence of small ductal cells forming tubules within sheets of clear cells is a useful clue to the correct diagnosis. Acinic cell carcinoma with vacuolated cytoplasm may mimic tumors with sebaceous differentiation, such as sebaceous lymphadenoma and sebaceous carcinoma (Fig. 1-35). The absence of acinar structures typical of acinic cell carcinoma in all of the tumors considered in the differential diagnosis can aid in the accurate interpretation.

FIGURE 1-35 Acinic cell carcinoma. Punched-out small vacuoles are similar to those seen in cells with sebaceous differentiation and are present in association with cytoplasmic granularity. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Air-dried, Diff-Quik stain, high power.

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SALIVARY DUCT CARCINOMA CLINICAL FEATURES Salivary duct carcinoma is an uncommon and highly aggressive neoplasm that arises in Stensen’s duct of the parotid gland or in the submandibular gland, and has a predilection for men (M : F = 8 : 1). Although it can occur at any age, patients are usually older and range in age from 62 to 89 years (median, 69 years). Treatment consists of surgical excision followed by radiation therapy. The prognosis of this tumor is dependent on the proportion of invasive and in-situ component and on the histologic grade. Overall, the tumor has a poor prognosis, and approximately two-thirds of the patients die within 4 years of initial diagnosis. Tumor size, presence of distant metastases, and c-erbB-2 amplification are independent prognostic parameters in patients with salivary duct carcinoma. Salivary duct carcinoma’s immunophenotypic profi le is more closely related to prostate carcinoma. A rare case report describes its association with elevated serum prostate-specific antigen (PSA) levels.

SALIVARY DUCT CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Branching and cribriform sheets and clusters of cells ៉ Background necrosis ៉ Frequent marked cytologic atypia: polygonal cells with granular or vacuolated cytoplasm and prominent nucleoli ៉ Rare low-grade cytologic features Histopathologic Findings ៉ Similar to ductal carcinoma of the breast, comedo ៉ Solid, cribriform, papillary, mucinous, infiltrating, and

sarcomatoid patterns Ancillary Studies ៉ Immunoreactivity for low and high molecular weight

cytokeratins, GCDFP-15, and androgen receptor (>90%) ៉ Moderate positivity for PAP and PSA ៉ Rare positivity for ER and PR ៉ Overexpression of p53 and c-erbB-2

Differential Diagnosis and Pitfalls ៉ High-grade cytologic features: high-grade mucoepidermoid

carcinoma, carcinoma ex-pleomorphic adenoma, adenosquamous carcinoma, intraductal papillary adenocarcinoma, metastatic squamous cell carcinoma, malignant melanoma ៉ Low-grade cytologic features: oncocytoma, Warthin tumor

CYTOPATHOLOGIC FEATURES Smears are variably cellular but obviously malignant. The most characteristic features of salivary duct carcinoma are broad flat and branching sheets of cells with a cribriform, papillary, or gland-like pattern in a variably necrotic background (Fig. 1-36). Dense fibrous fragments may also be seen in the background. The tumor cells are large and polygonal with round to oval, pleomorphic, eccentric or centrally placed nuclei, and

SALIVARY DUCT CARCINOMA – DISEASE FACT SHEET Incidence and Location ៉ Uncommon salivary gland neoplasm ៉ Parotid > submandibular Gender and Age Distribution ៉ Male to female ratio is 8 : 1 ៉ Wide age range, more often 60–90 years Clinical Features ៉ Aggressive growth

Prognosis and Treatment ៉ Regional and distant metastases frequent, 70% mortality ៉ Surgical excision and radiation therapy

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prominent nucleoli (Fig. 1-37). The cytoplasm varies from dense granular to vacuolated. Cases with bland or mildly pleomorphic nuclei are reported. Salivary duct carcinoma mostly resembles breast carcinoma in all its variable patterns and features, but shares an immunophenotypic profi le with both ductal-type adenocarcinoma and prostatic adenocarcinoma. Malignant cells are diffusely immunoreactive for low and high molecular weight cytokeratins. Salivary duct carcinoma will show positivity for estrogen receptor (ER) and progesterone receptor (PR) in a minority of cases only – 1.3% and 6%, respectively – but immunoreactivity to GCDFP15 is present in most cases. Androgen receptor, a marker expressed in prostate carcinoma, is expressed in over 90% of salivary duct carcinomas, whereas 60% of cases show scattered moderate positivity for prostatic acid phosphatase (PAP), and 17% diffuse moderate positivity for PSA. Overexpression of p53 is reported in 53% of cases and c-erbB-2 in 63%. A rare sarcomatoid variant has been described in association with usual-type salivary duct carcinoma. It presents as a spindle and anaplastic cell tumor. Another rare variant of salivary duct carcinoma is small cell undifferentiated carcinoma. While some immunohistochemical studies have demonstrated luminal, basal, and myoepithelial differentiation compatible with origin of the tumor from the salivary duct, other studies have demonstrated neuroendocrine differentiation of this tumor.

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FIGURE 1-36 Salivary duct carcinoma. Broad complex epithelial sheets with a branching papillary and cribriform appearance usually occur against a necrotic background. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Airdried, Diff-Quik stain, low power.

FIGURE 1-37 Salivary duct carcinoma. Large polygonal cells with pleomorphic round nuclei, prominent nucleoli, and abundant dense granular cytoplasm are crowded in this ductlike structure with central debris. Although the cytologic features are somewhat similar to those of oncocytes, the nuclear atypia and necrosis should preclude a benign diagnosis. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Air-dried, Diff-Quik stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS FNAs of salivary duct carcinoma are difficult to interpret because of the morphologic spectrum of this tumor. In high-grade tumors where pleomorphism is evident, other high-grade malignant tumors enter the differential diagnosis. Such group of malignant tumors includes high-grade carcinoma not otherwise specified (NOS), high-grade mucoepidermoid carcinoma, and carcinoma ex-pleomorphic adenoma. If papillary structures pre-

Ch001-F06731.indd 29

dominate, an intraductal papillary adenocarcinoma should be considered. Intraductal papillary adenocarcinoma, a low-grade carcinoma and the malignant counterpart of intraductal papilloma, shows cytologic atypia and microinvasion, and has a better prognosis than salivary duct carcinoma. Metastatic tumors such as squamous cell carcinoma and malignant melanoma should also be excluded. Low-grade tumors are a source of false negative diagnoses. When bland features are present, the neoplastic cells may show similarities to oncocytes, and the tumor may be mistaken for oncocytoma or Warthin tumor.

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MALIGNANT LYMPHOMA CLINICAL FEATURES Most patients with malignant lymphoma will present with a unilateral salivary gland mass. Primary malignant lymphoma can arise in the gland itself, mostly involving the parotid gland, and occasionally the submandibular gland. In the area of the parotid gland, malignant lymphoma also arises in intra- or periparotid lymph nodes and has the features or clinical course of a nodal lymphoma. Salivary glands may also be secondarily involved by lymphoma as an expression of disseminated disease. Most malignant lymphomas in the salivary gland are of B-cell lineage, and Hodgkin lymphoma is unusual. Malignant lymphoma is known to

MALIGNANT LYMPHOMA – DISEASE FACT SHEET Incidence ៉ 2–5% of salivary gland neoplasms

Clinical Features ៉ Primary or secondary ៉ Unilateral mass, most commonly involving parotid or lymph nodes

within area ៉ Behavior and treatment similar to that of nodal lymphoma

arise in a background of LESA, Sjögren syndrome, or Warthin tumor. The MALT/marginal zone lymphomas, frequently encountered in the salivary glands, have an indolent clinical course and an excellent prognosis.

CYTOPATHOLOGIC FEATURES Most commonly, salivary glands are involved by B-cell lymphomas, which in the majority of cases comprise small lymphocytes and belong to the extranodal marginal zone B-cell lymphoma of MALT type. Typically in such cases, smears show a population of small to intermediate lymphocytes with round to slightly angulated nuclei, and occasional larger cells with features of immunoblasts (Fig. 1-38). Follicular lymphomas occur in the salivary gland with a high frequency as well (35–50%) and are composed of small and large cleaved cells and large noncleaved cells that impart a polymorphous appearance to the aspirate material. Conversely, diffuse large B-cell lymphomas consist of large centroblastic and immunoblastic lymphoid cells that are overtly malignant. T-cell lymphoma in the salivary gland is rare and cannot be distinguished from a B-cell tumor on a morphologic basis only. Another rare entity is plasmacytoma that can present as a salivary gland mass with cytologic features varying from mature to anaplastic plasma cells, similar to those seen in other sites (Fig. 1-39). Patients with plasmacytoma can later develop multiple myeloma.

FIGURE 1-38 Malignant lymphoma, marginal zone. Small to intermediate cell lymphocytes with round to slightly angulated nuclei are the predominant cell population. Scattered larger cells and a mitotic figure are present. Air-dried, Diff-Quik stain, high power.

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FIGURE 1-39 Plasmacytoma. Mature plasma cells with round eccentric nuclei, clockface chromatin, and a moderate amount of cytoplasm may resemble hyaline myoepithelial cells. The chromatin pattern and perinuclear Hoff are distinguishing features. Alcohol-fixed, Papanicolaou stain, medium power.

MALIGNANT LYMPHOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Single discohesive cells ៉ Monotonous population of lymphocytes ៉ Variable cell size and degree of atypia, dependent on cell type ៉ B-cell lymphomas most common Pathologic Findings Follicular diffuse or sclerosing growth pattern Commonly, cleaved or small cells Immunoblastic, plasma cell, or T-cell less frequent T-cell associated with prominent lymphoepithelial lesions Hodgkin lymphoma rare

៉ ៉ ៉ ៉ ៉

Ancillary Studies ៉ Flow cytometric studies

flow cytometry is necessary to support the diagnosis of lymphoma. A predominantly lymphoid infi ltrate can be aspirated from neoplasms such as Warthin tumor, sebaceous lymphadenoma, and acinic cell carcinoma in which the epithelial cells have not been sampled. A thorough search for epithelial cells or identification of such cells by immunocytochemistry may be helpful in identifying a non-lymphoid neoplasm. Lymphoepithelial carcinoma that consists of a mixture of large anaplastic-appearing cells in a background of small lymphocytes is also a consideration in the differential diagnosis of large cell lymphoma. Malignant melanoma may need to be excluded if the lymphoma is immunoblastic in nature. The last two non-lymphoid malignant neoplasms can be identified by immunocytochemical staining for cytokeratin and for S-100 protein, Melan A, or HMB-45, respectively.

Differential Diagnosis and Pitfalls ៉ Chronic sialadenitis ៉ Lymphoepithelial lesion ៉ Poorly sampled lymphocyte-rich lesions (Warthin tumor,

RARE TUMORS

sebaceous lymphadenoma) ៉ Lymphoepithelial carcinoma in large cell lymphoma ៉ Malignant melanoma in immunoblastic lymphoma

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of malignant lymphoma in the salivary gland includes a number of lymphocyterich conditions, both neoplastic and non-neoplastic. Low-grade lymphomas have to be differentiated from chronic sialadenitis, LESA, lymphoepithelial cysts, and intraparotid lymph nodes. Immunophenotyping by

Ch001-F06731.indd 31

The following section addresses in brief both benign and malignant tumors that are only exceptionally encountered. Benign tumors such as vascular tumors, lymphangioma, lipomas, schwannomas, skin adnexal-type tumors such as pilomatrixoma, and solitary fibrous tumors have all been described in the salivary glands. Malignant neoplasms include the following: Primary small cell carcinoma of the salivary gland is extremely rare and can be diagnosed only after excluding other primary sources. It affects predominantly men in their sixth decade and has morphologic and cytologic features similar to small cell undifferentiated carcinoma in other locations. It also has a similar aggressive course

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FIGURE 1-40 Small cell undifferentiated carcinoma. Poorly cohesive clusters and syncytia of small blue cells with a high N/C ratio. The nuclei are angulated and molded, the chromatin is granular, and nucleoli are inconspicuous. Alcohol-fixed, Papanicolaou stain, high power.

and poor prognosis. Cellular smears contain poorly cohesive clusters and syncytia of small blue cells with a high N/C ratio. The nuclei are angulated and molding, the chromatin is granular, and nucleoli are inconspicuous (Fig. 1-40). Mitotic figures are easily found. Ultrastructurally, it is characterized by neurosecretory granules and demonstrates neuroendocrine features by immunocytochemistry, including dot-like positivity for cytokeratin and staining with chromogranin, synaptophysin, neuron-specific enolase, and CD56. Similar to Merkel cell tumors and unlike lung primaries, small cell carcinoma of salivary gland origin is positive for CK20. The main differential diagnostic consideration in the salivary gland, apart from a metastasis from lung or skin, is a solid variant of adenoid cystic carcinoma. Adenocarcinoma not otherwise specified is a diagnostic category that is used for high-grade tumors without recognizable specific features. Squamous cell carcinoma as a primary tumor in the salivary gland is unusual. Some squamous-appearing tumors may represent adenosquamous carcinoma, as demonstrated by scattered mucin-containing cells. These tumors are highly aggressive and are treated with radical surgery and radiation therapy. More commonly, squamous carcinoma results from secondary involvement of the salivary gland either by direct extension or by metastasis to an intra- or periglandular lymph node from a head and neck or skin primary. Cystic metastases are frequently aspirated and show keratinizing and non-keratinizing atypical squamous cells in a necrotic background (Fig. 1-41). Lymphoepithelial carcinoma of the salivary gland has an incidence of less than 0.5% of salivary gland neoplasms, and occurs predominantly in Greenlanders, Inuits, and Southern Chinese. It presents as a solitary mass of the parotid or submandibular gland, and, like its nasopharyngeal counterpart, is associated with Epstein-Barr virus, which can be demonstrated by

Ch001-F06731.indd 32

in-situ hybridization or by serology. Cytologically, it consists of syncytial sheets of large, highly pleomorphic cells with vesicular chromatin, prominent nucleoli, and delicate poorly defined cytoplasm, in an abundant background of mixed lymphocytes and plasma cells (Fig. 1-42). The main differential diagnosis is malignant lymphoma and can be resolved by a positive cytokeratin immunostain in the large atypical cells of lymphoepithelial carcinoma. Clear cell carcinomas do not constitute a homogeneous group of tumors but comprise tumors with abundant cytoplasmic glycogen, lipid, or mucin. Such tumors include clear cell myoepitheliomas, neoplasms with sebaceous differentiation or oncocytic features, mucoepidermoid carcinoma, acinic cell carcinoma, and metastatic renal cell carcinoma. If all such possibilities are excluded, the diagnosis of hyalinizing clear cell carcinoma should be considered, particularly in a tumor occurring in the oral cavity. Sarcomas may arise in salivary glands. In adults, those are malignant spindle cell neoplasms that should be distinguished from metaplastic carcinomas, myoepithelial tumors, or spindle cell melanoma. Sarcomas described in that location include malignant peripheral nerve sheath tumor, synovial sarcoma, Kaposi sarcoma, malignant fibrous histiocytoma, primitive neuroectodermal tumors/Ewing sarcoma, and, in children, embryonal rhabdomyosarcoma.

SECONDARY TUMORS Metastatic tumors to the region of the salivary glands occur not infrequently, and involve intraparotid and submandibular lymph nodes. If metastasis is suspected,

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33

FIGURE 1-41 Squamous cell carcinoma. Keratinizing and non-keratinizing atypical squamous cells in a necrotic background are compatible with a cystic tumor of the head and neck primary. The definite nuclear atypia and cellularity separate this lesion from non-neoplastic branchial cleft cysts and cystic lymphoepithelial lesions. Alcohol-fixed, Papanicolaou stain, high power.

FIGURE 1-42 Lymphoepithelial carcinoma. Syncytial sheets of large highly pleomorphic cells with vesicular chromatin, prominent nucleoli, and delicate, poorly defined cytoplasm in an abundant background of mixed lymphocytes and plasma cells may mimic a large cell malignant lymphoma. Courtesy of Ms Jamie L Covell, The University of Virginia Health Sciences Center. Alcoholfixed, Papanicolaou stain, high power.

a clinical history of a primary tumor elsewhere, and comparison of aspirate to pathology material from the primary are always helpful. Most frequently, head and neck squamous cell carcinoma forms a cystic necrotic mass that may mimic some of the primary benign squamous-lined cystic lesions. Identifying atypia within the squamous cell is the way to a correct diagnosis. Malignant melanoma metastasizes to the salivary gland and may mimic some of the primary high-grade carcinomas or lymphomas. Malignant melanoma consists of large polygonal cells arranged in loosely cohesive clusters and single cells. Cells typically have a moderate to abundant amount of dense cyto-

Ch001-F06731.indd 33

plasm, eccentrically placed nuclei, and prominent nucleoli. A pronounced discohesive pattern, intranuclear pseudoinclusions, binucleation, and melanin pigment are diagnostic clues. In the absence of melanin pigment, positive immunostaining for S-100 protein, HMB-45, and Melan A confirms the diagnosis. Tumors in the lung, kidney, breast, and, to a lesser extent, prostate and colon metastasize to the salivary glands. Lung, breast, and prostate carcinomas may mimic high-grade adenocarcinomas arising in the salivary gland. However, these metastases may be distinguished from salivary gland primaries by a thorough clinical history and immunostains that are site-specific.

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FIGURE 1-43 Renal cell carcinoma. Large neoplastic cells with abundant translucent, granular, or vacuolated cytoplasm have large round centrally located nuclei and are arranged around and in between capillaries. These findings may overlap with those of an acinic cell carcinoma; however, cells of renal cell carcinoma may be larger and display a more abundant delicate and vacuolated cytoplasm. Airdried, Diff-Quik stain, medium power.

TTF-1 stains a significant number of lung adenocarcinoma; PSA and PAP, and ER and PR may help detect prostate and breast carcinoma, respectively. A tall columnar glandular population associated with mucin production or a necrotic background may suggest a colonic primary. Immunostains for the main mucin protein cores (MUC1, MUC2, MUC3, MUC5AC), CDX2, and villin may help confirm the site of origin of the tumor. Metastases from renal cell carcinoma may pose a challenge to the cytopathologist, as they mimic acinic cell or mucoepidermoid carcinoma. Neoplastic cells are large with abundant translucent, granular or vacuolated cytoplasm. Nuclei are large, round, and may display prominent nucleoli. Renal cell carcinoma is rich in vessels that may be easily visualized in the FNA material (Fig. 1-43). A positive CD10 immunostain will help support the renal origin of the tumor.

diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 1997;17: 183–190. Cheuk W, Chan JK. Kuttner tumor of the submandibular gland: fine-needle aspiration cytologic findings of seven cases. Am J Clin Pathol 2002; 117:103–108. Lopez-Rios F, Diaz-Bustamante T, Serrano-Egea A, Jimenez J, de Agustin P. Amylase crystalloids in salivary gland lesions: report of a case with a review of the literature. Diagn Cytopathol 2001;25:59–62.

Cystic Lesions Chhieng DC, Argosino R, McKenna BJ, Cangiarella JF, Cohen JM. Utility of fine-needle aspiration in the diagnosis of salivary gland lesions in patients infected with human immunodeficiency virus. Diagn Cytopathol 1999;21:260–264. Elliot JN, Oertel YC. Lymphoepithelial cysts of the salivary glands – histologic and cytologic features. Am J Clin Pathol 1990;93:39–43. Layfield LJ, Gopez EV. Cystic lesions of the salivary glands: cytologic features in fine-needle aspiration biopsies. Diagn Cytopathol 2002;27: 197–204. Stewart CJR, MacKenzie K, McGarry GW, Mowatt A. Fine-needle aspiration cytology of salivary gland: a review of 341 cases. Diagn Cytopathol 2000;22:139–146.

SUGGESTED READINGS Non-neoplastic Lesions

Tumor with Mesenchymal Differentiation

Sialadenosis

Benign Mixed Tumor

Henrey-Stanley MJ, Beneke J, Bardales HR, Stanley MW. Fine-needle aspiration of normal tissue from enlarged salivary glands: sialosis or missed target? Diagn Cytopathol 1995;13:300–303. Young NA, Mody DR, Davey DD. Misinterpretation of normal cellular elements in fine-needle aspiration biopsy specimens: observations from the College of American Pathologists Interlaboratory Comparison Program in Non-Gynecologic Cytopathology. Arch Pathol Lab Med 2002; 126:670–675.

Chhieng DC, Cohen JM, Cangiarella JF. Fine-needle aspiration of spindle cell and mesenchymal lesions of the salivary gland. Diagn Cytopathol 2000;23:253–259. Das DK, Anim JT. Pleomorphic adenoma of salivary gland: to what extent does fine needle aspiration cytology reflect histopathological features? Cytopathology 2005;16:65–70. Elsheikh TM, Bernacki EG. Fine needle aspiration cytology of cellular pleomorphic adenoma. Acta Cytol 1996;40:1165–1175. McLeod CB, Frable WJ. Fine-needle aspiration biopsy of the salivary gland: problem cases. Diagn Cytopathol 1993;9:216–225. Mooney EE, Dodd LG, Layfield LJ. Squamous cells in fine-needle aspiration biopsies of salivary gland lesions: potential pitfalls in cytologic diagnosis. Diagn Cytopathol 1996;15:447–452. Viguer JM, Vicandi B, Jimenez-Heffernan JA, Lopez-Ferrer P, Limeres MA. Fine needle aspiration of pleomorphic adenoma. An analysis of 212 cases. Acta Cytol 1997;41:786–794.

Sialadenitis Allen EA, Ali SZ, Mathew S. Lymphoid lesions of the parotid. Diagn Cytopathol 1999;21:170–173. Chai C, Dodd LG, Glasgow BJ, Layfield LJ. Salivary gland lesions with a prominent lymphoid component: cytologic findings and differential

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Malignant Mixed Tumor Anand A, Brockie ES. Cytomorphologic features of salivary duct carcinoma ex-pleomorphic adenoma: diagnosis by fine needle aspiration biopsy with histologic correlation. Diagn Cytopathol 1999;20:375–378. De la Torre M, Larsson E. Fine-needle aspiration cytology of carcinosarcoma of the parotid gland: cytohistological and immunohistochemical findings. Diagn Cytopathol 1995;12:350–353. Nigam S, Kumar N, Jain S. Cytomorphologic spectrum of carcinoma ex pleomorphic adenoma. Acta Cytol 2004;48:309–314. Pitman MB. Mucoepidermoid carcinoma ex-pleomorphic adenoma of the parotid gland. Acta Cytol 1995;39:604–606.

Myoepithelial Neoplasms Darvishian F, Lin O. Myoepithelial cell-rich neoplasms: cytologic features of benign and malignant lesions. Cancer 2004;102:355–361. Das DK, Haji BE, Ahmed MS, Hossain MN. Myoepithelioma of the parotid gland initially diagnosed by fine needle aspiration cytology and immunocytochemistry: a case report. Acta Cytol 2005;49:65–70. Gupta RK, Naran S, Dowle C, Simpson JS. Coexpression of vimentin, cytokeratin and S-100 in monomorphic adenoma of salivary gland; value of marker studies in the differential diagnosis of salivary gland tumors. Cytopathology 1992;3:303–309. Kumar PV, Sobhani SA, Monabati A, Hashemi SB, Eghtadari F, Hamidi SA. Myoepithelioma of the salivary glands. Fine needle aspiration biopsy findings. Acta Cytol 2004;48:302–308. Ng W, Choy C, Ip P, Shek W, Collins RJ. Fine needle aspiration cytology of epithelial-myoepithelial carcinoma of salivary gland – a report of three cases. Acta Cytol 1999;43:675–680. Schultenover SJ, McDonald EC, Ramzy I. Hyaline-cell pleomorphic adenoma: diagnosis by fine needle aspiration biopsy. Acta Cytol 1984;28:593– 597.

Warthin Tumor/Oncocytic Neoplasms Allen EA, Ali SZ, Mathew S. Lymphoid lesions of the parotid. Diagn Cytopathol 1999;21:170–173. Ballo MS, Shin HJ, Sneige N. Sources of diagnostic error in fine-needle aspiration diagnosis of Warthin’s tumor and clues to a correct diagnosis. Diagn Cytopathol 1997;17:230–234. Chai C, Dodd LG, Glasgow BJ. Salivary gland lesions with a prominent lymphoid component: cytologic findings and differential diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 1997;17:183– 190. Chhieng DC, Cangiarella JF, Cohen JM. Fine-needle aspiration cytology of lymphoproliferative lesions involving the major salivary glands. Am J Clin Pathol 2000;113:563–571. Klijanienko J, Vielh P. Fine-needle sampling of salivary gland lesions II. Cytology and histology correlation of 71 cases of Warthin’s tumor (adenolymphoma). Diagn Cytopathol 1997;16:221–225. Mooney EE, Dodd LG, Layfield LJ. Squamous cells in fine-needle aspiration biopsies of salivary gland lesions: potential pitfalls in cytologic diagnosis. Diagn Cytopathol 1996;15:447–452. Parwani AV, Ali SZ. Diagnostic accuracy and pitfalls in fine-needle aspiration interpretation of Warthin tumor. Cancer 2003;99:166–171. Ryska A, Seifert G. Adenolymphoma (Warthin’s tumor) with multiple sarcoid like granulomas. Pathol Res Pract 1999;195:835–839. Sherman ME, Magro C, Berry Y, Syzyfelbein WM. Oncocytic nodule. An unusual case of a submaxillary gland mass in an elderly patient. Acta Cytol 1990;34:827–830. Williamson JD, Simmons BH, EL-Naggar A, Medeiros LJ. Mucoepidermoid carcinoma involving Warthin tumor. A report of five cases and review of the literature. Am J Clin Pathol 2000;114:564–570.

Basaloid Neoplasms Basal Cell Adenoma/Basal Cell Adenocarcinoma Pisharodi LR. Basal cell adenocarcinoma of the salivary gland. Diagnosis by fine-needle aspiration. Am J Clin Pathol 1995;103:603–608. Stanley MW, Horwitz CA, Bardales RH, Stern SJ, Korourian S. Basal cell carcinoma metastatic to the salivary glands: differential diagnosis in fine-needle aspiration cytology. Diagn Cytopathol 1997;16:247–252.

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Stanley MW, Horwitz CA, Henry MJ, Burton LG, Lowhagen T. Basal cell adenoma of the salivary gland: a benign adenoma that cytologically mimics adenoid cystic carcinoma. Diagn Cytopathol 1988;4:342– 346. Stanley MW, Horwitz CA, Rollins SD, et al. Basal cell (monomorphic) and minimally pleomorphic adenomas of the salivary glands. Distinction from the solid type of adenoid cystic carcinoma in fine-needle aspiration. Am J Clin Pathol 1996;106:35–41. Adenoid Cystic Carcinoma Nagel H, Hotze HJ, Laskawi R, Chilla R, Droese M. Cytologic diagnosis of adenoid cystic carcinoma of salivary glands. Diagn Cytopathol 1999;20: 358–366. Stanley MW, Horwitz CA, Rollins SD, et al. Basal cell (monomorphic) and minimally pleomorphic adenomas of the salivary glands. Distinction from the solid type of adenoid cystic carcinoma in fine-needle aspiration. Am J Clin Pathol 1996;106:35–41. Yu GH, Caraway NP. Poorly-differentiated adenoid cystic carcinoma: cytologic appearance in fine-needle aspirates of distant metastases. Diagn Cytopathol 1996;15:296–300. Polymorphous Low-Grade Adenocarcinoma Frierson HF Jr, Covell JL, Mills SE. Fine-needle aspiration cytology of terminal duct carcinoma of minor salivary gland. Diagn Cytopathol 1987;3: 159–162. Gibbons D, Saboorian MH, Vuitch F, Gokaslan ST, Ashfaq R. Fine-needle aspiration findings in patients with polymorphous low grade adenocarcinoma of salivary glands. Cancer 1999;87:31–36. Saenz, Santmaria J, Catalina-Fernandez I. Polymorphous low grade adenocarcinoma of the salivary gland. Diagnosis by fine needle aspiration cytology. Acta Cytol 2004;48:52–56. Mucoepidermoid Carcinoma Al-Khafaji BM, Nestok BR, Katz RL. Fine-needle aspiration of 154 parotid masses with histologic correlation: ten-year experience at the University of Texas M.D. Anderson Cancer Center. Cancer (Cancer Cytopathol) 1998;84:153–159. Cajulis RS, Gokaslan ST, Yu GH, Frias-Hidvegi D. Fine needle aspiration biopsy of the salivary glands – a five-year experience with emphasis on diagnostic pitfalls. Acta Cytol 1997;41:1412–1420. Chan MKM, McGuire LJ, King W, Li AKC, Lee JCK. Cytodiagnosis of 112 salivary gland lesions – correlation with histologic and frozen section diagnosis. Acta Cytol 1992;36:353–363. Cohen MB, Fisher PE, Holly EA, Ljung BM, Lowhagen T, Bottles K. Fine needle aspiration biopsy diagnosis of mucoepidermoid carcinoma – statistical analysis. Acta Cytol 1990;34:43–49. Jakobson PA , Blanck C, Eneroth C-M. Mucoepidermoid carcinoma of the parotid gland. Cancer 1968;22:111–124. Klijianienko J, Vielh P. Fine-needle sampling of salivary gland lesions. IV. Review of 50 cases of mucoepidermoid carcinoma with histologic correlation. Diagn Cytopathol 1997;17:92–98. Kumar N, Kapila K, Verma K. Fine needle aspiration cytology of mucoepidermoid carcinoma. A diagnostic problem. Acta Cytol 1991;35:357– 359. Layfield LJ, Glasgow BJ. Aspiration cytology of clear-cell lesions of the parotid gland: morphologic features and differential diagnosis. Diagn Cytopathol 1993;9:705–712. MacLeod CB, Frable WJ. Fine-needle aspiration biopsy of salivary gland: problem cases. Diagn Cytopathol 1993;9:216–225. Palombini L. Challenges in the interpretation of FNAs from the salivary glands. Diagn Cytopathol 1997;17:417–421.

Acinic Cell Carcinoma Ali SZ. Acinic-cell carcinoma, papillary-cystic variant: a diagnostic dilemma in salivary gland aspiration. Diagn Cytopathol 2002;27:244–250. Al-Khafaji BM, Nestok BR, Katz RL. Fine-needle aspiration of 154 parotid masses with histologic correlation: ten-year experience at the University of Texas M.D. Anderson Cancer Center. Cancer (Cancer Cytopathol) 1998;84:153–159.

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36 Baccato P, Altavilla G, Blandamura S. Fine-needle aspiration of salivary gland lesions – a reappraisal of pitfalls and problems. Acta Cytol 1998;42:888–898. Cajulis RS, Gokaslan ST, Yu GH, Frias-Hidvegi D. Fine needle aspiration biopsy of the salivary glands – a five-year experience with emphasis on diagnostic pitfalls. Acta Cytol 1997;41:1412–1420. Klijanienko J, Vielh P. Fine-needle sampling of salivary gland lesions V: cytology of 22 cases of acinic cell carcinoma with histologic correlation. Diagn Cytopathol 1997;17:347–352. Layfield LJ, Glasgow BJ. Aspiration cytology of clear-cell lesions of the parotid gland: morphologic features and differential diagnosis. Diagn Cytopathol 1993;9:705–712. Lewis JE, Olsen KD, Weiland LH. Acinic cell carcinoma – clinicopathologic review. Cancer 1991;67:172–179. Nagel H, Laskawi R, Buter JJ, Schroder M, Chilla R, Droese M. Cytologic diagnosis of acinic-cell carcinoma of salivary glands. Diagn Cytopathol 1997;16:402–412. Palombini L. Challenges in the interpretation of FNAs from the salivary glands. Diagn Cytopathol 1997;17:417–421. Sheyn I, Yassin R, Seiden A, Nestok BR. Papillary-cystic variant of acinic cell carcinoma of the salivary gland diagnosed by fine needle aspiration biopsy. A case report. Acta Cytol 2000;44:1073–1076. Salivary Duct Carcinoma Dee S, Masood S, Isaacs JH Jr, Hardy NM. Cytomorphologic features of salivary duct carcinoma on fine needle aspiration biopsy. A case report. Acta Cytol 1993;37:539–542. Domson KK, Wakely PE Jr. Aspiration and imprint cytopathology of salivary duct carcinoma. Cancer 1997;81:281–286. Elsheikh TM, Bernacki EG, Pisharodi L. Fine-needle aspiration cytology of salivary duct carcinoma. Diagn Cytopathol 1994;11:47–51. Ersoz C, Cetik F, Aydin O, Cosar EF, Talas DU. Salivary duct carcinoma expleomorphic adenoma: analysis of the findings in fine needle aspiration cytology and histology. Diagn Cytopathol 1998;19:201–204. Fyrat P, Cramer H, Feczko JD, et al. Fine needle aspiration biopsy of salivary duct carcinoma: report of five cases. Diagn Cytopathol 1997;16: 526–530. Gilcrease MZ, Guzman-Paz M, Froberg K, Pambiccian S. Salivary duct carcinoma. Is a specific diagnosis possible by fine needle aspiration cytology? Acta Cytol 1998;42:1389–1396. James GK, Pudek M, Berean KW, Diamandis EP, Archibald BL. Salivary duct carcinoma secreting prostate-specific antigen. Am J Clin Pathol 1996; 106:242–247. Kapadia SB, Barnes L. Expression of androgen receptor, gross cystic disease fluid protein, and CD44 in salivary duct carcinoma. Mod Pathol 1998;11:1033–1038. Khurana KK, Pitman MB, Powers CN, Korourian S, Bardales RH, Stanley MW. Diagnostic pitfalls of aspiration cytology of salivary duct carcinoma. Cancer 1997;81:373–378. Moriki T, Ueta S, TakahashiT, Mitani M, Ichien M. Salivary duct carcinoma: cytologic characteristics and application of androgen receptor immunostaining for diagnosis. Cancer 2001;93:344–350. Lymphoproliferative Disorders Allen EA, Ali SZ, Mathew S. Lymphoid lesions of the parotid. Diagn Cytopathol 1999;21:70–73.

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FINE NEEDLE ASPIRATION CYTOLOGY Chhieng DC, Cangiarella JF, Cohen JM. Fine-needle aspiration cytology of lymphoproliferative lesions involving the major salivary glands. Am J Clin Pathol 2000;113:563–571. Crapanzano JP, Lin O. Cytologic findings of marginal zone lymphoma. Cancer 2003;99:301–309. MacCallum PL, Lampe HB, Cramer H, Matthews TW. Fine-needle aspiration cytology of lymphoid lesions of the salivary gland: a review of 35 cases. J Otolaryngol 1996;25:300–304. Ustun MO, Ekinci N, Payzin B. Extramedullary plasmacytoma of the parotid gland. Report of a case with extensive amyloid deposition masking the cytologic and histopathologic picture. Acta Cytol 2001;45: 449–453. Rare Tumors Chhieng DC, Cohen JM, Cangiarella JF. Fine-needle aspiration of spindle cell and mesenchymal lesions of the salivary glands. Diagn Cytopathol 2000;23:253–259. Gnepp DR, Wick MR. Small cell carcinoma of the major salivary glands: an immunohistochemical study. Cancer 1990;66:185–192. Mair S, Philips JI, Cohen R. Small cell undifferentiated carcinoma of the parotid gland. Cytologic, histologic, immunohistochemical and ultrastructural features of a neuroendocrine variant. Acta Cytol 1989;33: 164–168. Milchgrub S, Vuitch F, Saboorian MH, Hameed A, Wu H, Albores-Saavedra J. Hyalinizing clear-cell carcinoma of salivary glands in fine-needle aspiration. Diagn Cytopathol 2000;23:333–337. Nagao T, Sugano I, Matsuzaki O, Hara H, Kondo Y, Nagao K. Intraductal papillary tumors of the major salivary glands: case reports of benign and malignant variants. Arch Pathol Lab Med 2000;124: 291–295. Thompson MB, Nestok BR, Gluckman JL. Fine needle aspiration cytology of lymphoepithelioma-like carcinoma of the parotid gland. A case report. Acta Cytol 1994;38:782–786. Toyosawa S, Ohnishi A, Ito R, et al. Small cell undifferentiated carcinoma of the submandibular gland: immunohistochemical evidence of myoepithelial, basal and luminal cell features. Pathol Int 1999;49:887– 892. Secondary Tumors Hughes JH, Jensen CS, Donnelly AD, et al. The role of fine-needle aspiration cytology in the evaluation of metastatic clear cell tumors. Cancer 1999;87:380–389. Lussier C, Klijanienko J, Vielh P. Fine-needle aspiration of metastatic nonlymphomatous tumors to the major salivary glands: a clinicopathologic study of 40 cases cytologically diagnosed and histologically correlated. Cancer 2000;90:350–356. Stanley MW, Bardales RH, Farmer CE, et al. Primary and metastatic highgrade carcinomas of the salivary glands: a cytologic-histologic study of twenty cases. Diagn Cytopathol 1995;13:37–43. Yang B, Ali SZ, Rosenthal DL. CD10 facilitates the diagnosis of metastatic renal cell carcinoma from primary adrenal cortical neoplasm in adrenal fine-needle aspiration. Diagn Cytopathol 2002;27:149–152. Zhang C, Cohen JM, Cangiarella JF, Waisman J, McKenna BJ, Chhieng DC. Fine-needle aspiration of secondary neoplasms involving the salivary glands. A report of 36 cases. Am J Clin Pathol 2000;113:21– 28.

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2

Thyroid Katherine Berezowski Mary K Sidawy

INTRODUCTION Clinically detectable thyroid nodules occur in 4% to 10% of the population, of which only 5% are malignant. Fine needle aspiration (FNA) is a powerful diagnostic tool recognized to have the best predictive value in the presurgical evaluation of the thyroid. FNA is regarded as a screening test aimed at distinguishing nodules that require surgery from those that do not. Its introduction has resulted in a decrease in the number of thyroidectomies performed on ‘cold’ nodules, and an increase in the yield of malignancy for excised nodules. The sensitivity of thyroid FNA ranges from 83% to 99%, and its specificity from 70% to 91%. The reported false negative rate ranges from 1% to 8%, but its true frequency is difficult to assess, since only 10% of patients with benign cytologic findings undergo surgery. Since FNA is considered a screening test, particular attention should be given to minimize false negative results at the expense of accepting some false positive diagnoses. Repeat FNA of benign lesions and periodic clinical follow-up are advocated to decrease the false negative diagnoses. Accurate diagnostic interpretation depends upon an adequate sample and optimally prepared slides. Although it is difficult to define what constitutes an adequate specimen, proposed criteria require five to ten groups of well-visualized follicular cells with each group containing 10–20 cells. Rendering a definite diagnosis on suboptimal samples that barely meet the adequacy criteria is a source of pitfall. A good aspiration technique is paramount. The procedure is performed using a 23- or 25-gauge needle. The thyroid is a vascular organ, thus a few milliliters or no suction is recommended. The needle is moved rapidly in the same needle track, and the procedure is stopped as soon as the sample begins to fill the clear hub of the needle. Three or four passes are usually necessary to obtain an adequate sample. When cyst fluid is obtained, the cyst is drained. If any palpable lesion remains, reaspiration should be performed. Ultrasonographic guidance is necessary for sampling non-palpable nodules. The smears may be air-dried and stained with the Diff-Quik stain, alcohol-fixed and stained with the Papanicolaou method, or prepared using a liquid-based

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• Igor Jovanovic •

technology. Each method offers different advantages, and the choice depends upon the familiarity and personal preference of the cytopathologist. The advantages of air-dried smears include enhancement of background and cytoplasmic features and they are ideal for evaluating lymphoid infiltrates. Alcohol-fixed smears are better for preserving nuclear details, showing the chromatin distribution and delineating nucleoli. Liquid-based preparations are advocated as an adjunct to conventional smears. Their exclusive use has not gained popularity. Following each pass, one or two conventional smears are prepared and the remaining sample is rinsed in the appropriate liquid-based medium. The main advantages of liquid-based cytology are the decrease in the number of slides to be screened, the ability to perform immunocytochemical and other special stains, and the enhancement of nuclear details and irregularities in papillary carcinoma. Limitations of liquid-based preparation include loss of colloid during processing, impacting the ability to assess the colloid to cell ratio (Fig. 2-1). In addition, the diagnosis of Hashimoto’s thyroiditis may be missed due to the dispersed appearance of lymphoid cells in these preparations (Fig. 2-2).

CHRONIC LYMPHOCYTIC (HASHIMOTO’S) THYROIDITIS CLINICAL FEATURES Chronic lymphocytic (Hashimoto’s) thyroiditis is the most prevalent form of autoimmune thyroid disease, and is considered to be the most common cause of goitrous hypothyroidism in areas of the world in which dietary iodine is sufficient. In the United States, Hashimoto’s thyroiditis affects approximately 3% to 4% of the population, has a female to male ratio of 8–20 : 1, and is most frequently diagnosed between the third and fi fth decade of life. Although primarily a disease of middle-aged women, it also occurs in children. Genetic predisposition is a risk factor. Hashimoto’s thyroiditis occurs in clusters within families, and is associated with HLA-DR3 and HLA-DR5 major histocompatibility antigens. 37

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B

A

FIGURE 2-1 Adenomatoid nodule: colloid to cell ratio in conventional versus liquid-based preparations. A, Conventional smear demonstrating abundant colloid with only few scattered clusters of follicular cells (high colloid to cell ratio). Diff-Quik stain, low power. B, Liquid-based preparation of the same case, illustrating loss of colloid during processing and concentration of the follicular cells. The colloid to cell ratio is relatively low as compared to the conventional smear. Papanicolaou stain, low power.

A

B

FIGURE 2-2 Hashimoto’s thyroiditis: lymphoid cells in conventional versus liquid-based preparations. A, A cellular streak of lymphoid cells composed of a polymorphous population of lymphoid cells, tingible-body macrophages, germinal centers, and plasma cells. Diff-Quik stain, high power. B, Liquid-based preparation from the same case, showing the dispersed nature of the lymphoid cells. A close-up evaluation of the cells is necessary to distinguish the polymorphous lymphoid nature from follicular epithelial cells and peripheral blood elements. Papanicolaou stain, high power.

HASHIMOTO’S THYROIDITIS – DISEASE FACT SHEET Incidence ៉ Affects 3–4% of the US population

Gender, Race, and Age Distribution ៉ Female predominance ៉ More prevalent in Caucasians ៉ Affects adults and children

Clinical Features Diffusely enlarged gland, occasionally nodular Painless Transient hyperthyroidism, euthyroid, or hypothyroid Increased risk for non-Hodgkin B-cell lymphoma

៉ ៉ ៉ ៉

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The thyroid gland is diffusely slightly enlarged, nontender to palpation, and has a rubbery to firm consistency. Although the disease affects the entire gland, the process may accentuate any asymmetry of the normal thyroid, and some patients present with an asymmetrically enlarged, nodular thyroid. The majority of the patients are either euthyroid or hypothyroid. In some cases, however, the disease may present with a transient hyperthyroidism. Patients with Hashimoto’s thyroiditis are at increased risk of developing non-Hodgkin B-cell lymphomas, particularly large B-cell type. Also, of note is the association of Hashimoto’s thyroiditis and papillary carcinoma of the thyroid; however, the causal relationship between the two has not been established.

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Thyroid

CYTOPATHOLOGIC FEATURES FNA is a reliable technique in the initial diagnosis of Hashimoto’s thyroiditis. It is also instrumental in establishing the diagnosis in patients with negative or low autoantibody titers, which occurs in up to 10% of cases, and in investigating potentially neoplastic dominant nodules. The aspirates are typically cellular and contain an admixture of lymphoid and epithelial cells in variable proportions depending on sampling and the stage of the disease (Fig. 2-3). The follicular cells demonstrate a spectrum of nuclear and cytoplasmic changes ranging from regular follicular cells to Hürthle cells. They are arranged in aggregates, sheets, and occasionally in a microfollicular pattern. Hürthle cells are characterized by abundant granular, dense cytoplasm with well-

defined cytoplasmic borders. Their nuclei are enlarged with variable degrees of pleomorphism. Nucleoli vary from inconspicuous to prominent (Fig. 2-4). The lymphoid cell population is polymorphous, consisting of small, mature lymphocytes, centroblasts, centrocytes, and immunoblasts. Germinal centers, tingible-body macrophages, plasma cells, and multinucleated giant cells may be present (Fig. 2-5). Epithelioid histiocytes may be seen in small aggregates and may resemble granulomas. They occasionally exhibit mitoses. Lymphoid cells are delicate and may appear as crushed tangles of twisted chromatin material – ‘lymphoid tangles’ (Fig. 2-6). Blue cytoplasmic fragments (lymphoglandular bodies) derived from the breakdown of lymphoid cells are noted in the background. It is important to distinguish bare follicular cell nuclei from lymphocytes. The latter retain a rim of blue cytoplasm, while the follicular cells appear as well-preserved stripped nuclei. The amount of colloid is variable. When fibrosis occurs, the aspirates tend to be dry and hypocellular.

HASHIMOTO’S THYROIDITIS – PATHOLOGIC FEATURES Cytopathologic Findings Moderately to highly cellular aspirates Mixture of Hürthle cells and regular follicular cells Polymorphous population of lymphoid cells Germinal center, tingible-body macrophages, lymphohistiocytic aggregates, plasma cells, multinucleated giant cells

៉ ៉ ៉ ៉

ANCILLARY STUDIES The diagnosis of Hashimoto’s thyroiditis is confirmed by the presence of antithyroid autoantibodies (antithyroglobulin and antithyroid peroxidase) in the serum. Antithyroid peroxidase is more specific.

Ancillary Studies ៉ Antithyroid autoantibodies in the serum Differential Diagnosis and Pitfalls ៉ Lymphoma ៉ Hürthle cell neoplasm

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of Hashimoto’s thyroiditis depends on the cellular composition of the smears. In

FIGURE 2-3 Hashimoto’s thyroiditis. A polymorphous lymphoid population admixed with Hürthle cells. Diff-Quik stain, high power.

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FIGURE 2-4 Hashimoto’s thyroiditis. Follicular cells with Hürthle cell change. The cells are arranged in sheets and display abundant granular cytoplasm and nuclear pleomorphism. Diff-Quik stain, high power.

FIGURE 2-5 Hashimoto’s thyroiditis. Liquidbased preparation illustrating a multinucleated giant cell. Note the scattered lymphocytes in the background. The presence of giant cells is a useful clue to the diagnosis of Hashimoto’s in liquid-based preparations, since the lymphoid population is dispersed. Papanicolaou stain, high power.

cases where the lymphoid component predominates, lymphoma needs to be considered. Lymphomas yield a monotonous population of lymphoid cells, unlike the heterogenous population of Hashimoto’s thyroiditis. Whenever the cytologic distinction is in question, flow cytometric analysis should be performed. The sample can be obtained by simply rinsing the needle in the appropriate medium. When the aspirates show a predominance of Hürthle cells, the distinction between Hashimoto’s thyroiditis

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and a Hürthle cell neoplasm may be problematic. Multiple passes increase the chance of sampling the lymphoid component. Moreover, the relatively cohesive nature of the Hürthle cells and the nuclear pleomorphism are features more in keeping with Hashimoto’s thyroiditis. The presence of uniform, loosely cohesive Hürthle cells with macronucleoli favors a neoplasm.

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Thyroid

FIGURE 2-6 Hashimoto’s thyroiditis. Lymphoid tangles that represent twisted chromatin of crushed lymphocytes, and a cluster of Hürthle cells. Diff-Quik stain, high power.

NODULAR GOITER CLINICAL FEATURES Goiter is a clinical term that denotes enlargement of the thyroid, which occurs due to impaired synthesis of thyroid hormones. Clinically, goiter presents in a nodular or diffuse form, and is divided by the functional activity of the thyroid into the non-toxic and toxic variants. Non-toxic nodular goiter is the most common form in the United States, affecting approximately 5% of the population. In essence, it is a compensatory response of the gland for a decrease in hormone secretion. The specific cause of this form of goiter is usually unknown. The basic mechanism

NODULAR GOITER (ADENOMATOID NODULE) – DISEASE FACT SHEET Incidence ៉ Affects 5% of population

Gender and Age Distribution ៉ Female predominance ៉ Occurs in adults

Clinical Features Asymptomatic, euthyroid Slow growing Sudden growth as result of hemorrhage Compressive symptoms

៉ ៉ ៉ ៉

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involves stimulation of the thyroid by TSH due to low levels of the thyroid hormones, which leads to follicular cell hyperplasia and involution. Nodular goiter is the end-stage of a diffuse goiter and is caused by the cyclic changes taking place during hyperplasia and involution. Nodular goiter is a disease of adults and shows a female predominance. Most patients are asymptomatic and, by definition, euthyroid. Multinodular goiter develops over many years and is detected on routine physical examination or by the patient noticing an enlargement in the neck. If the goiter is large enough, it can lead to compressive symptoms. Patients may complain of sudden pain caused by hemorrhage into a nodule.

CYTOPATHOLOGIC FEATURES Cytologic nomenclature of nodular goiter includes adenomatoid, cellular adenomatoid, adenomatous, hyperplastic, and non-neoplastic nodule. The aspirates from nodular goiter are of low to moderate cellularity. They demonstrate an admixture of colloid and follicular cells in variable proportion, reflecting the different phases of evolution of the disease. During the hyperplastic stage, follicular cells are abundant and colloid is scant. As the disease progresses to the involutional stage, follicular cells become fewer and colloid becomes abundant. The presence of abundant colloid and a high colloid to cell ratio are extremely helpful in the cytologic diagnosis of goiter. Macroscopically, smeared unstained colloid resembles varnish. Microscopically, colloid can appear as thick amorphous material with sharply circumscribed edges or as a thin translucent film in the background, often with folds and cracks. When diluted

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NODULAR GOITER (ADENOMATOID NODULE)– PATHOLOGIC FEATURES Cytopathologic Findings ៉ High colloid to cell ratio ៉ Follicular cells arranged in honeycomb sheets, spherules, tissue fragments, or singly ៉ Small round nuclei, naked nuclei, delicate cytoplasm ៉ Hürthle cells ៉ Cystic change: macrophages (pigmented, multinucleated), cyst-lining cells Differential Diagnosis and Pitfalls Cystic papillary carcinoma Follicular neoplasm Follicular variant of papillary carcinoma Parathyroid cyst

៉ ៉ ៉ ៉

by blood, its appearance overlaps with serum. Colloid may be lost during processing, particularly with liquidbased preparations (see Fig. 2-1). Follicular cell nuclei are 1.5–2 times the size of mature lymphocytes. The chromatin is finely granular and uniformly dispersed, with inconspicuous nucleoli. The nuclei are round and may show enlargement and variability in size. The cytoplasm is delicate with indistinct borders (Fig. 2-7). The follicular cells are arranged in groups, honeycomb sheets, spherules, and tissue fragments. A spherule represents an intact non-neoplastic macrofollicle with its basement membrane. It appears as a round structure, with smooth borders and evenly spaced nuclei. A spherule may mimic a giant cell, but the latter can be differentiated by its irregular outline

and unevenly spaced, elongated nuclei (Fig. 2-8). Tissue fragments with supporting vascular stroma may be mistaken for papillary structures and suggest papillary carcinoma. However, attention to the arrangement of the follicular cells within the tissue fragments (spherules and honeycomb sheets with maintained nuclear polarity) should prevent such a pitfall (Fig. 2-9). The follicular cells may also be found dispersed singly and stripped of their cytoplasm (Fig. 2-10). Hürthle cells with enlarged nuclei showing variable degrees of pleomorphism are seen in nodular goiter. In Diff-Quik-stained smears, the follicular cells may reveal abundant intracytoplasmic blue granules, which can obscure the nuclei. These granules are seen in cystic and hemorrhagic lesions, and represent hemosiderin pigments. They are not specific and may be seen in goiter, as well as in benign and malignant neoplasms (Fig. 2-11). These non-specific granules should be distinguished from a different type of granules, ‘paravacuolar granules’ (Fig. 2-12). The latter consist of small blue granules grouped within a vacuole close to the nucleus. They are frequently observed in non-lesional thyroid tissue and occasionally in Hashimoto’s thyroiditis. When the majority of aspirated follicular cells display paravacuolar granules, the cytopathologist needs to consider that the targeted lesion (especially when small) was missed and only adjacent non-lesional thyroid tissue was sampled. Hemorrhage and cystic change are quite common in aspirates from nodular goiters. Cytologically, they manifest by the presence of histiocytes and hemosiderinladen macrophages (many multinucleated), cholesterol crystals, and cyst-lining cells (Figs 2-13 & 2-14). Cystlining cells appear as flat sheets of spindled to polygonal (squamoid) cells with abundant, dense cytoplasm, enlarged pleomorphic nuclei, and prominent nucleoli (Fig. 2-15). Bi- and multinucleation are common.

FIGURE 2-7 Adenomatoid nodule. Follicular cells arranged in a honeycomb sheet. The cells are evenly spaced, with uniform round nuclei and fine evenly dispersed chromatin. The cytoplasm is delicate with illdefined borders. Papanicolaou stain, high power.

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A

B

FIGURE 2-8 Adenomatoid nodule: spherule. A spherule represents an intact non-neoplastic macrofollicle with its basement membrane. It is a tridimensional round structure with smooth borders and evenly spaced nuclei. The latter feature helps distinguishing a spherule from a giant cell (see Fig. 2-5). A, Diff-Quik stain, high power. B, Papanicolaou stain, high power.

FIGURE 2-9 Adenomatoid nodule. Tissue fragment with supporting vascular stroma. Note the presence of intact macrofollicles (spherules). Their presence along with the maintained nuclear polarity are helpful clues for the diagnosis of adenomatoid nodule. Diff-Quik stain, low power.

FIGURE 2-10 Adenomatoid nodule. Follicular epithelial cells dispersed singly and stripped of their delicate cytoplasm. The absence of a small rim of blue cytoplasm helps distinguish follicular cells from lymphocytes. Diff-Quik stain, high power.

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FIGURE 2-11 Adenomatoid nodule. Follicular cells displaying non-specific intracytoplasmic blue granules. These granules are seen in cystic and hemorrhagic lesions and represent hemosiderin pigments. Diff-Quik stain, high power.

FIGURE 2-12 Paravacuolar granules. Small blue granules clustered within a vacuole adjacent to the nucleus. These granules are frequently seen in aspirates of non-lesional thyroid and in Hashimoto’s thyroiditis. DiffQuik stain, high power.

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FIGURE 2-13 Adenomatoid nodule with hemorrhage and cystic change. Liquidbased preparation illustrating regular follicular cells and hemosiderin-laden macrophages (some multinucleated). Papanicolaou stain, high power.

FIGURE 2-14 Cholesterol crystals. Cholesterol crystals in a Diff-Quik-stained preparation appear as negative images. Diff-Quik stain, high power.

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FIGURE 2-15 Adenomatoid nodule: cyst-lining cells. Flat sheet of polygonal cells with abundant dense cytoplasm, enlarged pleomorphic nuclei, and distinct nucleoli. These cells are a source of false positive diagnosis; they can be mistaken for ‘squamoid cells’ seen in papillary carcinoma. Papanicolaou stain, high power.

ANCILLARY STUDIES Ancillary techniques including morphometry, image analysis, DNA measurements by flow cytometry, telomerase activity (by polymerase chain reaction [PCR]), and immunocytochemistry for a variety of antigens have been advocated for discriminating between benign and malignant nodules; however, none of these methods is sufficiently reliable.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of nodular goiter depends on the stage of the disease. Cystic nodules must be differentiated from cystic papillary carcinomas, while the differential diagnosis of cellular adenomatoid (hyperplastic) nodules includes follicular neoplasms and follicular variant of papillary carcinomas. CYSTIC PAPILLARY CARCINOMA

Thirty per cent of thyroid nodules are cystic, most of which are nodular goiter. It is also important to point out that a third of papillary carcinomas are cystic, while cystic degeneration is rare in follicular, medullary, and anaplastic carcinomas. The gross appearance of the fluid (yellow or hemorrhagic) is not reliable in distinguishing goiter from papillary carcinoma. To the uninitiated, the prominent cytologic atypia and squamoid appearance of the cyst-lining cells of nodular goiter

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may lead to the erroneous diagnosis of papillary carcinoma. FOLLICULAR NEOPLASMS

The cytologic features of cellular adenomatoid nodules overlap with those of follicular neoplasms, making the distinction between the two entities unreliable. High cellularity, scant colloid, and follicular cells arranged in acini and occasional microfollicles are shared features of both entities. When the distinction is difficult, the aspirates fall in the indeterminate category and are classified as ‘cellular follicular lesions’. The risk of malignancy with indeterminate thyroid cytology is reported as 15–20%. FOLLICULAR VARIANT OF PAPILLARY CARCINOMA

This is a well-known pitfall, and one of the major sources of false negative diagnoses in thyroid FNA. This variant of papillary carcinoma reveals neoplastic cells arranged in syncytial clusters and microfollicles, and should be considered in the differential diagnosis of cellular follicular lesions. Attention to the nuclear features may help in establishing the correct diagnosis, or at least including papillary carcinoma in the differential diagnosis. PARATHYROID CYST

When crystal-clear fluid is aspirated, the possibility of a parathyroid cyst should be considered. Measuring the level of C-terminal/midmolecule parathyroid hormone in the fluid helps in confirming the diagnosis.

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FOLLICULAR NEOPLASMS CLINICAL FEATURES Follicular neoplasms include follicular adenomas and carcinomas. Follicular adenoma is defined as a benign thyroid neoplasm showing follicular cell differentiation, which is completely encapsulated and lacks capsular and vascular invasion. Follicular adenoma is the most common thyroid neoplasm and may be found in up to 4% of thyroid glands at autopsy. It occurs in adults and shows female predominance. It presents as a painless, solitary thyroid nodule, rarely greater than 3 cm. Most appear as ‘cold’ nodules on radionuclide scanning, but functioning or ‘hot’ adenomas do occur. Follicular carcinoma is the second most common form of thyroid malignancies. It accounts for 5% to 15% of all thyroid carcinomas. Follicular carcinomas are divided histologically into two groups: minimally invasive (encapsulated type) and widely invasive. Follicular carcinoma has a predilection for women, with a peak incidence in the fifth decade of life. It is more common in iodine-deficient areas. Exposure to radiation

FOLLICULAR NEOPLASMS – DISEASE FACT SHEET Definition ៉ Term includes follicular adenomas and carcinomas

Incidence ៉ Adenoma: most common thyroid neoplasm ៉ Carcinoma: 5–15% of thyroid carcinomas

and RAS mutations are also known risk factors. This disease commonly presents as a painless thyroid nodule which appears ‘cold’ on radionuclide scanning. Compressive symptoms such as dyspnea, dysphagia, hoarseness, and cough are rare at presentation and may occur in patients with the widely invasive type. Follicular carcinoma spreads hematogenously, to the lungs and bones most commonly. Prognosis is related to the tumor grade, stage, and clinical presentation. Poor prognostic indicators are high histologic grade (poorly differentiated carcinoma), age above 45 years, tumors more than 4.0 cm in size, extrathyroid extension, and distant metastases. Welldifferentiated follicular carcinomas that are confined to the thyroid have an excellent prognosis, with a 10-year survival rate approaching 90%, whereas widely invasive, poorly differentiated follicular carcinomas with distant metastases have a much worse prognosis, with a 10-year survival rate of approximately 50%.

CYTOPATHOLOGIC FEATURES FNA cannot separate follicular adenomas from welldifferentiated follicular carcinomas. Both entities display similar cytologic features, and the diagnosis of malignancy relies on the histologic demonstration of either capsular or vascular invasion. Thus, the inclusive term follicular neoplasm is recommended in the cytologic literature. The cytologic features of follicular neoplasms are variable, reflecting their histologic types. However, they have in common high cellularity, scant or absent colloid, and follicular cells with enlarged nuclei arranged in syncytial groups displaying nuclear crowding and overlapping. The cytoplasm varies from ill-defined to dense. A prominent repetitive microacinar arrangement is a reliable (although non-diagnostic)

Gender and Age Distribution ៉ Female predominance ៉ Adenoma: middle age ៉ Carcinoma: older age

Risk Factors for Carcinoma

FOLLICULAR NEOPLASMS – PATHOLOGIC FEATURES

Prognosis

Cytopathologic Findings ៉ Cellular aspirates ៉ Low colloid to cell ratio ៉ Repetitive acinar arrangement ៉ Microfollicles ៉ Cytoplasm delicate, ill-defined, or dense ៉ Nuclei: ៉ Enlarged, round ៉ Loss of polarity with crowding and overlapping ៉ Prominent nucleoli

៉ Minimally invasive carcinoma: excellent prognosis ៉ Widely invasive carcinoma: mortality rate 80% ៉ Poor prognostic indicators of carcinoma: ៉ Poorly differentiated ៉ Age >45 years ៉ Tumor >4.0 cm ៉ Extrathyroid extension ៉ Distant metastases

Differential Diagnosis and Pitfalls ៉ Cellular adenomatoid nodule versus adenoma/encapsulated carcinoma ៉ Adenomatoid nodule versus macrofollicular adenoma ៉ Follicular variant of papillary carcinoma ៉ Insular carcinoma versus poorly differentiated follicular carcinoma

៉ Iodine deficiency ៉ Exposure to radiation ៉ Activating RAS mutations

Clinical Features ៉ Solitary ‘cold’ nodule ៉ Carcinoma: hematogenous spread (lungs, bones)

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FIGURE 2-16 Follicular neoplasm (histologically confirmed follicular adenoma). Repetitive microacinar pattern. Note the nuclear crowding and overlapping. The smear is cellular with no colloid in the background. Diff-Quik stain, high power.

FIGURE 2-17 Follicular neoplasm. Microfollicular arrangement characterized by the presence of acini with central drops of colloid. Note the nuclear enlargement, crowding, and overlapping. Diff-Quik stain, high power.

criterion for a neoplasm (Fig. 2-16). Acini with a central lumen containing a drop of colloid represent microfollicles and are characteristic of follicular neoplasms with a microfollicular growth pattern (Figs 2-17 & 2-18). A trabecular pattern is represented by parallel rows of follicular epithelial cells. Poorly differentiated follicular carcinoma may be recognized as malignant cytologically. Cytologic features that should alert the pathologist to the possibility of malignancy include nuclear pleomorphism, marked crowding and overlapping, hyperchromasia, coarse

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chromatin, prominent nucleoli, and the presence of mitotic figures. Adenomas very rarely reveal mitoses.

ANCILLARY STUDIES There are currently no ancillary tests or markers that can reliably distinguish follicular adenomas from follicular carcinomas. Though showing initial

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FIGURE 2-18 Follicular neoplasm. Liquid-based preparation illustrating microacinar arrangement with nuclear enlargement, crowding, and overlapping. Note the similarities with Fig. 2-16. Based on cytologic features, this case cannot be further classified as benign or malignant. Surgical follow-up demonstrated a follicular carcinoma with capsular invasion. Papanicolaou stain, high power.

promising results, telomerase activity (detected by PCR), and immunostains for RET/PTC, CK19, galectin-3, HBME-1, and thyroid-specific transcription factors have limited predictive value in distinguishing follicular-patterned lesions owing to a lack of sensitivity and/or specificity.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Overlapping cytologic features limit the distinction between follicular neoplasms and cellular adenomatoid (hyperplastic) nodules. Up to 15–25% of FNAs reported as follicular neoplasms correlate with hyperplastic nodules in subsequent thyroidectomies. Macrofollicular follicular neoplasms are difficult to recognize as neoplastic and may be misinterpreted as adenomatoid nodules. The cytologic features of both entities overlap and are characterized by the presence of abundant colloid and regular follicular cells arranged in honeycomb sheets. Fortunately, this misclassification bears no negative impact on patient management, since most macrofollicular follicular neoplasms are adenomas. Follicular variant of papillary carcinomas may be misdiagnosed as follicular neoplasms. The syncytial arrangement and microfollicular architectural pattern are shared by both entities. Attention to the nuclear features, i.e. elongated nuclei with irregular nuclear membranes and powdery chromatin, is key and should alert the pathologist to the possibility of papillary carcinoma. Poorly differentiated follicular carcinoma may be difficult to distinguish from insular carcinoma. Both tumors are positive for thyroglobulin and thyroid transcription factor 1 (TTF-1).

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HÜRTHLE CELL NEOPLASMS CLINICAL FEATURES Hürthle cell neoplasms, also known as oncocytic or oxyphilic thyroid neoplasms, are comprised exclusively or predominantly (more than 75%) of follicular cells

HÜRTHLE CELL NEOPLASMS – DISEASE FACT SHEET Definition ៉ Term includes Hürthle cell adenomas and carcinomas

Incidence ៉ Accounts for 5–10% of thyroid neoplasms

Gender and Age Distribution ៉ Female predominance ៉ Occurs in adults

Clinical Features ៉ Solid nodule ៉ ’Cold’ on radionuclide scan ៉ Carcinomas: cervical lymph nodes and hematogenous spread

Prognosis ៉ Poor prognostic indicators of carcinoma: ៉ Age >45 years ៉ Tumor >4.0 cm ៉ Extrathyroid extension ៉ Lymph node and visceral metastases

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50 displaying cytoplasmic granularity due to the accumulation of mitochondria. Hürthle cell neoplasms account for 5% to 10% of all thyroid neoplasms, and include Hürthle cell adenomas and carcinomas. According to the World Health Organization classification, they are considered as a variant of follicular thyroid neoplasms. Hürthle cell neoplasms occur in adults, and have a female predilection, with a female to male ratio of 2– 7 : 1. Hürthle cell adenomas have a peak incidence in the late forties and early fifties, whereas carcinomas tend to affect a slightly older patient population, with a peak incidence in the late fifties. The disease presents as a painless thyroid nodule which appears ‘cold’ on radionuclide scanning. Compared with conventional follicular carcinomas, Hürthle cell carcinomas show a more aggressive clinical course. Extrathyroid extension, and cervical lymph node and distant metastases are commonly seen at the time of diagnosis. Local recurrence and distant metastases occur in up to 50% of patients. Prognosis is related to the stage and clinical presentation. Poor prognostic indicators are: age above 45 years, size of the tumor (more than 4.0 cm), extrathyroid extension, and lymph node and visceral metastases. The 10-year survival rate ranges from 56% to 88%.

CYTOPATHOLOGIC FEATURES Similar to follicular neoplasms, FNA cannot separate Hürthle cell adenomas from carcinomas, since the diagnosis of malignancy is based on the histologic demonstration of either capsular or vascular invasion. Hürthle cell neoplasms yield cellular aspirates with scant or no colloid. The smears are composed of a

FINE NEEDLE ASPIRATION CYTOLOGY

HÜRTHLE CELL NEOPLASMS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirates ៉ Scant to absent colloid ៉ Monomorphic neoplastic cells ៉ Loosely cohesive and dispersed cells ៉ Polygonal and ovoid cells ៉ Large round nuclei with prominent macronucleoli ៉ Abundant granular cytoplasm with distinct borders Ancillary Studies ៉ Positive for thyroglobulin, TTF-1 ៉ Negative for calcitonin

Differential Diagnosis and Pitfalls Dominant Hürthle cell nodule in Hashimoto’s thyroiditis Dominant Hürthle cell nodule in nodular goiter Papillary carcinoma Medullary carcinoma

៉ ៉ ៉ ៉

monotonous population of Hürthle cells arranged in loosely cohesive clusters or dispersed singly (Fig. 2-19). A microfollicular pattern may be seen. The cells are polyhedral and have abundant granular cytoplasm with well-defined cell borders. The nuclei are round to oval, enlarged, and have fine chromatin and a central prominent macronucleolus. Binucleation is seen frequently. Although enlarged, the nuclei appear monotonous with relatively little pleomorphism (Fig. 2-20). Lymphoid cells and an admixture of regular follicular cells are notably absent.

FIGURE 2-19 Hürthle cell neoplasm. Cellular smear composed of a monotonous population of Hürthle cells arranged in loosely cohesive clusters and singly. Compare the relatively monotous nuclei to nuclear pleomorphism noted in non-neoplastic conditions (Fig. 2-4). Diff-Quik stain, high power.

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A

B

FIGURE 2-20 Hürthle cell neoplasm. Loosely cohesive Hürthle cells with abundant granular cytoplasm, uniformly enlarged nuclei, and prominent macronucleoli. Binucleation is frequently seen. Surgical follow-up demonstrated Hürthle carcinoma. A, Liquid-based preparation, Papanicolaou stain, high power. B, Diff-Quik stain, high power.

ANCILLARY STUDIES Hürthle cell neoplasms are immunoreactive for thyroglobulin and TTF-1, and negative for calcitonin.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of Hürthle cell neoplasms includes non-neoplastic Hürthle cell nodule in the setting of Hashimoto’s thyroiditis and nodular goiter, papillary carcinoma, and medullary carcinoma. In Hashimoto’s thyroiditis, the Hürthle cells are cohesive, usually forming sheets, and reveal nuclear pleomorphism. In addition, the aspirates typically contain a mixture of Hürthle cells, regular follicular cells, and a polymorphous population of lymphoid cells. Similar to Hashimoto’s thyroiditis, aspirates from nodular goiter yield cohesive Hürthle cells arranged in clusters and sheets. Nuclear pleomorphism and prominent nucleoli are present, but distinct macronucleoli are not present in every cell. An admixture of regular follicular cells and colloid also favors the diagnosis of nodular goiter. Papillary carcinoma is an important differential diagnostic consideration, since the granular cytoplasm and the well-defined cytoplasmic borders of Hürthle cells may easily be confused with the dense cytoplasm of papillary carcinoma. However, in contrast to papillary carcinomas, a fine powdery chromatin pattern, intranuclear cytoplasmic inclusions, nuclear grooves, and irregular nuclear membranes are not features of Hürthle cell neoplasms. Medullary carcinoma is also a consideration, since a dispersed cellular pattern is a feature seen in both neoplasms. The nuclei of medullary carcinomas display coarsely granular, ‘salt and pepper’ chromatin and lack macronucleoli.

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PAPILLARY CARCINOMA CLINICAL FEATURES Papillary carcinoma is the most common thyroid malignancy, accounting for up to 80% of malignant thyroid

PAPILLARY CARCINOMA – DISEASE FACT SHEET Incidence ៉ Most common malignant thyroid neoplasm Gender and Age Distribution ៉ Female predominance ៉ Peak incidence 35–40 years; occurs in children

Risk Factors ៉ Exposure to radiation ៉ Activating BRAF mutations ៉ RET/PTC gene rearrangement

Clinical Features Slow growing Solid or cystic ’Cold’ on radionuclide scanning Cervical lymph node metastases Hematogenous dissemination uncommon

៉ ៉ ៉ ៉ ៉

Prognosis ៉ Overall prognosis excellent ៉ Less favorable prognostic factors: ៉ Age >40 years ៉ Tumor size >4.0 cm ៉ Extrathyroid extension ៉ Distant metastases ៉ Male gender

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52 neoplasms. It occurs in adults, with a peak incidence between 35 and 40 years. It also occurs in children, and accounts for 90% of all childhood thyroid malignancies. Papillary carcinoma is more common in women, with a female to male ratio of 3–4 : 1. Its predisposing risk factor is exposure to radiation. Papillary carcinoma presents as a solid or cystic, slow-growing, ‘cold’ thyroid nodule. It spreads via lymphatics, resulting in a high incidence of cervical lymph node metastases and multifocal involvement of the gland. Cervical lymphadenopathy may be the initial manifestation of the disease. The involved lymph nodes may be cystic. The incidence of lymph node metastases is inversely related to age, being more common in younger patients. The presence of lymph node metastases does not correlate with a worse outcome, but is associated with an increased risk of recurrences. Infrequently, papillary carcinoma disseminates hematogenously to the lungs, bones, and central nervous system. The overall prognosis is excellent, with a 10-year survival rate exceeding 90%. Less favorable prognostic indicators are: age above 40 years, tumor size more than 4.0 cm, extrathyroid extension, distant metastases, and male gender.

CYTOPATHOLOGIC FEATURES With adequate sampling, the diagnostic accuracy of papillary carcinoma by FNA is over 90%. The aspirates are highly cellular. The neoplastic cells are arranged in papillary clusters, flat/folded monolayered sheets, cohesive groups with finger-like projections, syncytial clusters, microfollicles, or dispersed singly. The distinctive papillary architecture may be difficult to recognize cytologically, since the classic papillae with accompanying fibrovascular cores is not frequently present. Features of papillary architecture include branching groups of cells with or without fibrovascular cores, three-dimensional dome-shaped aggregates, finger-like projections, densely cohesive follicular cells with smooth external contour or peripheral palisading (Figs 2-21 & 2-22). It is important to note that a tissue fragment with central branching vascular stroma does not necessarily mean that the architecture is papillary. Nodular goiter and follicular neoplasms frequently yield tissue fragments that display central branching vascular stroma. The nuclei are enlarged, ovoid, and crowded with small nucleoli adherent to the nuclear membrane. They display longitudinal grooves and intranuclear cytoplasmic pseudoinclusions. The latter are the result of cytoplasmic invaginations; they have well-defined margins and occupy two-thirds of the nucleus (Fig. 2-23). Pseudoinclusions must be distinguished from artifactual vacuoles and red blood cells overlying nuclei. Nuclear membrane irregularities, an important characteristic feature, are best appreciated in liquid-based preparations (Fig. 2-24). Chromatin is pale and powdery. The

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PAPILLARY CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirates ៉ Architectural features: ៉ Papillary with/without fibrovascular cores ៉ Monolayers ៉ Cytologic features: ៉ Enlarged, elongated nuclei ៉ Nuclear pseudoinclusions, grooves ៉ Marginated micronucleoli ៉ Nuclear membrane irregularity ៉ Pale, powdery chromatin ៉ Dense cytoplasm, septate vacuoles ៉ Background features: ៉ ‘Bubble-gum’, ropy colloid, pink ‘blobs’ ៉ Multinucleated giant cells ៉ Psammoma bodies

Ancillary Studies ៉ Immunostains: positive for TTF-1, thyroglobulin, CK19, galactin3, and HMBE-1 Differential Diagnosis and Pitfalls Cystic adenomatoid nodule Adenomatoid nodule Papillary hyperplasia Follicular neoplasm Hürthle cell neoplasm Hyalinizing trabecular adenoma

៉ ៉ ៉ ៉ ៉ ៉

ground-glass appearance of the nuclei seen in histologic sections is an artifact of formalin fixation and is not recognized in cytologic preparations. The cytoplasm is dense with well-defined borders, and may have a squamoid appearance (Fig. 2-25). In some cases, the cytoplasm contains septate vacuoles, which appear as multiple small vacuoles and resemble soap bubbles (Fig. 2-26). Colloid is dense, stringy, and intimately associated with the neoplastic cells, with the so-called ‘bubble-gum’ appearance (Fig. 2-27). Variably sized, round pink blobs of colloid may be noted. In about half of cases, multinucleated giant cells are present; they contain few or numerous nuclei and their cytoplasm contains no pigments or vacuoles (Fig. 2-28). Their presence in the absence of cystic degeneration should raise the suspicion for papillary carcinoma. Psammoma bodies, defined as non-polarizable concentric calcified laminations, are seen in one-third of cases (Fig. 2-29). Dystrophic calcifications need to be distinguished from psammoma bodies, since they do not carry the same diagnostic significance. It is important to emphasize that none of the abovedescribed architectural and cytomorphologic or background features are unique to or diagnostic of papillary carcinoma, since they may be present in various nonneoplastic and neoplastic thyroid diseases. The definitive diagnosis should be based on a constellation of features, rather than on an individual cytologic criterion.

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FIGURE 2-21 Papillary carcinoma. Papillary structure with branching central fibrovascular core. A characteristic finding, but not necessary for the diagnosis of papillary carcinoma. Diff-Quik stain, low power.

FIGURE 2-22 Papillary carcinoma. Threedimensional cohesive group of follicular cells with smooth external contour and peripheral palisading, representing a papillary tip or ‘cap’ in papillary carcinoma. Papanicolaou stain, high power.

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FIGURE 2-23 Papillary carcinoma. The nuclei are enlarged, round to oval, and display intranuclear cytoplasmic pseudoinclusions. The cytoplasm is dense with well-defined borders. Diff-Quik stain, high power.

FIGURE 2-24 Papillary carcinoma. Neoplastic follicular cells arranged in a fl at monolayered sheet. This arrangement must be distinguished from the honeycomb sheet of adenomatoid nodule. Note the presence of nuclear grooves and nuclear membrane irregularities, features helpful in establishing the correct diagnosis of papillary carcinoma. The latter feature is well appreciated in this liquid-based preparation. Papanicolaou stain, high power.

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FIGURE 2-25 Papillary carcinoma. The neoplastic cells in papillary carcinoma have dense cytoplasm with a squamoid appearance. These cells share similarities and must be distinguished from cyst-lining cells in adenomatoid nodules (Fig. 2-15). Diff-Quik stain, high power.

A

B

FIGURE 2-26 Septate vacuoles. Best seen in Diff-Quik stain, septate vacuoles are small multiple intracytoplasmic vacuoles that resemble soap bubbles. They are seen in papillary carcinoma, as well as in benign conditions. A, Papillary carcinoma with septate vacuoles. Diff-Quik stain, high power. B, Septate vacuoles in a histologically confirmed case of papillary hyperplasia. Attention to the nuclear features is paramount in differentiating benign lesions from papillary carcinomas. Diff-Quik stain, high power.

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FIGURE 2-27 Papillary carcinoma. Dense, stringy colloid with a metachromatic ‘bubblegum’ appearance is characteristic of papillary carcinoma. Note the intimate association of colloid with the neoplastic cells. Diff-Quik stain, low power.

FIGURE 2-28 Papillary carcinoma. Multinucleated giant cell with unusual shape, dense cytoplasm, and numerous nuclei. Note the lack of cytoplasmic pigments or vacuoles. Finding giant cells in the absence of cystic degeneration or Hashimoto’s thyroiditis should raise the suspicion for papillary carcinoma. Diff-Quik stain, high power.

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FIGURE 2-29 Papillary carcinoma. Psammoma bodies are refractile concentric calcified laminations. Diff-Quik stain, high power.

FIGURE 2-30 Cystic papillary carcinoma. Threedimensional clusters of ‘histiocytoid’ cells with scalloped borders. The abundant hypervacuolated cytoplasm imparts a histiocytic appearance to these neoplastic cells. Note the presence of psammoma bodies within the center of each group. Liquid-based preparation, Papanicolaou stain, high power.

Cystic papillary carcinomas comprise 25–30% of papillary carcinomas. They are diagnostically challenging, and a well-recognized source of false negative results. Aspirates contain numerous macrophages, some pigmented, some multinucleated, but few or no diagnostic neoplastic cells. If the aspirated fluid contains no follicular epithelial cells, a diagnosis of ‘cystic lesion, not further classified’ must be rendered, with the recommendation to repeat the procedure. In hypocellular samples, the presence of three-dimensional clusters of cells with enlarged nuclei, vacuolated cytoplasm, and scalloped borders, ‘histiocytoid cells’, may be the only clue to the diagnosis (Fig. 2-30). These cells can easily

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be dismissed and misclassified as macrophages. It is also important to emphasize that the cyst-lining cells of cystic papillary carcinoma may be difficult to distinguish for those seen in cystic nodular goiter. Recognizing the risk of false negative diagnoses in cystic lesions, a benign diagnosis should be rendered only when follicular epithelial cell lacking atypia are adequately sampled. Follicular variant of papillary carcinoma also poses a diagnostic challenge. The smears may be misdiagnosed as cellular adenomatoid nodules or follicular neoplasms. The aspirates reveal neoplastic cells arranged in monolayers, syncytial clusters, and microfollicular

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FIGURE 2-31 Papillary hyperplasia. Papillary tissue fragment with finger-like projections and branching central vascular stroma, a finding that may lead to the erroneous diagnosis of papillary carcinoma. The clue to the correct diagnosis rests on the bland nuclear features. Diff-Quik stain, low power.

architectural pattern. Nuclear features (elongated nuclei with irregular nuclear membranes) are the key in establishing the correct diagnosis or at least raising suspicion for papillary carcinoma. The Hürthle cell variant of papillary carcinoma is composed of neoplastic Hürthle cells with nuclear and architectural features of papillary carcinoma. Aggressive variants of papillary carcinoma are rarely encountered by FNA. Tall cell variant is distinguished by neoplastic cells that are twice as tall as they are wide. The cells are characterized by oncocytic cytoplasm, distinct cells borders, and ‘soap-bubble-like’ intranuclear inclusions. Columnar cell variant is composed of columnar cells with scant cytoplasm. The nuclei are elongated, crowded, and stratified. Diffuse sclerosing variant yields fibrotic stromal fragments, psammoma bodies, squamoid cells, and a prominent lymphoid infiltrate.

ANCILLARY STUDIES CK19, HMBE-1, and galectin-3 are helpful in the diagnosis of papillary carcinoma, but lack specificity and sensitivity to be reliable discriminators. For example, the low molecular weight CK19, strongly positive in papillary thyroid carcinoma, is shown to be also positive in follicular adenoma, follicular carcinoma, and Hürthle cell carcinoma. In addition, CK19 is strongly positive in benign follicular epithelium of Hashimoto’s thyroiditis. RET/PTC gene translocation and BRAF mutations are common genetic alterations in papillary carcinomas. RET/PTC expression by immunostains or molecular

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methods is a valuable adjunct in the diagnosis of papillary carcinoma, but it has also been reported in insular carcinoma, and follicular and Hürthle cell adenoma and carcinoma.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of papillary carcinoma varies with each histologic variant. Cystic papillary carcinomas must be distinguished from cystic adenomatoid nodules. The possibility of papillary carcinomas is higher in cysts larger than 4.0 cm, hemorrhagic cysts, and cysts that recur rapidly or repeatedly following FNA. Hypocellular cystic samples should be carefully examined with particular attention to any cytologic evidence of papillary carcinoma. Psammoma bodies and intranuclear pseudoinclusions should be searched for. Papillary hyperplasia is a source of pitfall. The presence of unequivocal papillary elements is not pathognomonic of malignancy. Papillary hyperplasia shares many cytologic features with papillary carcinoma, including high cellularity, papillary fragments with branching fibrovascular cores, septate vacuoles, and occasional psammoma bodies (Figs 2-26B & 2-31). The clues to the correct diagnosis rest on the small, round, uniform nuclei and finely dispersed chromatin seen in hyperplasia. Follicular variant of papillary carcinoma displaying monolayered sheets may be misdiagnosed as adenomatoid nodule, since the flat sheets can be interpreted as honeycomb arrangements indicative of goiter. Attention to the nuclear features (elongated and irregular

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FIGURE 2-32 Hyalinizing trabecular adenoma. The neoplastic follicular cells are associated with fibrillar metachromatic stroma. Diff-Quik stain, high power.

FIGURE 2-33 Hyalinizing trabecular adenoma. Loosely cohesive neoplastic cells with enlarged elongated nuclei and intranuclear pseudoinclusion. This neoplasm needs to be distinguished from papillary and medullary carcinoma. Diff-Quik stain, high power.

versus round) is essential in distinguishing the two entities. On the other hand, follicular variant of papillary carcinoma displaying syncytial arrangements with a microfollicular pattern may be misdiagnosed as a follicular neoplasm. The dense cytoplasm with well-defined borders of papillary carcinoma may be also be confused with the appearance of Hürthle cells. Hyalinizing trabecular adenoma of the thyroid shares cytologic features with papillary carcinoma. Aspiration of these tumors yields cellular aspirates comprised of

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neoplastic cells arranged in loose aggregates, microfollicles, or dispersed singly. The neoplastic cells are typically elongated or spindle-shaped. The nuclei are enlarged, ovoid, with pale chromatin, intranuclear cytoplasmic inclusions, and longitudinal nuclear grooves. Psammoma bodies may be present. A clue to the diagnosis is the presence of metachromatic stromal material, which is found as deposits between the neoplastic cells (Figs 2-32 & 2-33). It differs from colloid by its distinguishable finely fibrillar appearance and fringed rather than sharp edges.

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MEDULLARY CARCINOMA CLINICAL FEATURES Medullary carcinoma is a neuroendocrine malignancy arising from calcitonin-secreting C cells. It accounts for 5% to 10% of all thyroid malignancies and occurs sporadically and in familial forms. The sporadic form accounts for 80% of all cases. The remainder occurs in the setting of the multiple endocrine neoplasia (MEN) syndromes MEN IIA and MEN IIB, or as an isolated familial medullary thyroid carcinoma. The familial forms are characterized by an autosomal dominant mode of inheritance and are associated with germline point mutations in the RET proto-oncogene, which is localized on chromosome 10. Medullary carcinoma shows no particular sex predilection and can occur at any age. The sporadic and isolated familial forms primarily affect middle-aged adults, with a peak incidence in the forties and fi fties. The MEN II-associated forms affect younger patients, and may even occur during childhood. MEN-associated forms occur either in association with adrenal pheochromocytoma and parathyroid chief cell hyperplasia (MEN IIA – Sipple syndrome)

MEDULLARY CARCINOMA – DISEASE FACT SHEET Definition ៉ Neuroendocrine malignancy arising from calcitonin-secreting C cells

or in association with adrenal pheochromocytoma, mucosal neuromas, gastrointestinal ganglioneuromas, and skeletal abnormalities (MEN IIB – mucosal neuroma syndrome, Gorlin syndrome). Patients with the sporadic form present with a solitary, firm, ‘cold’ nodule. In some cases, it is accompanied by intractable diarrhea or Cushing syndrome secondary to the paraneoplastic secretions of hormones and prostaglandins. Only rarely this form is clinically occult. In contrast, in the familial setting, despite being multifocal and bilateral, medullary carcinoma is usually asymptomatic and is discovered by screening of relatives of patients with the disease for elevated calcitonin levels. Medullary carcinoma is an aggressive tumor with metastases to cervical lymph nodes and to distant organs, particularly the lungs, liver, and bones. Local recurrence occurs in up to 35% of patients. Prognosis is related to the stage and clinical presentation. Poor prognostic indicators are extrathyroid extension, age above 40 years, and sporadic form. The 5-year survival rate ranges from 50% to 80%.

CYTOPATHOLOGIC FEATURES The aspirates from medullary carcinoma are highly cellular. Neoplastic cells are dispersed singly and arranged in loose syncytial aggregates. Their cytologic appearance varies. The cells may be oval with eccentric nuclei (plasmacytoid), large polygonal, spindle, triangular, or small round with scant cytoplasm (Fig. 2-34). The cytoplasm is abundant and well-preserved. Spindle cells have a centrally placed elongated nucleus and indistinct cytoplasm. Nuclear pleomorphism, binucle-

Incidence ៉ 5–10% of thyroid malignancies ៉ Sporadic in 80%

MEDULLARY CARCINOMA – PATHOLOGIC FEATURES Gender and Age Distribution ៉ Affects both sexes equally ៉ Occurs in children and adults Risk Factors ៉ Familial forms: autosomal dominant inheritance; associated with

germline point mutations in the RET proto-oncogene Clinical Features ៉ Sporadic form: solitary firm, ‘cold’ nodule, paraneoplastic

Cytopathologic Findings ៉ Cellular aspirates ៉ Single cells, loose syncytial aggregates ៉ Plasmacytoid, spindle, small cells ៉ Coarsely granular, ‘salt and pepper’ chromatin pattern ៉ Intranuclear cytoplasmic inclusions ៉ Inconspicuous nucleoli ៉ Cytoplasmic granules ៉ Amyloid

syndrome ៉ Familial forms: asymptomatic, discovered by screening ៉ Aggressive course: cervical lymph node and distant metastases,

Ancillary Studies ៉ Immunoreactive for calcitonin, chromogranin, TTF-1, and

local recurrence

monoclonal CEA ៉ Negative for thyroglobulin

Prognosis ៉ Poor prognostic indicators: ៉ Extrathyroid extension ៉ Age >40 years ៉ Sporadic form ៉ Five-year survival is 50–80%

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Differential Diagnosis and Pitfalls Hürthle cell neoplasm Papillary carcinoma Anaplastic carcinoma Hyalinizing trabecular adenoma

៉ ៉ ៉ ៉

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FIGURE 2-34 Medullary carcinoma. Highly cellular aspirate characterized by dispersed neoplastic cells with round–oval nuclei and plasmacytoid appearance. Note the presence of intranuclear pseudoinclusions. Nuclear pleomorphism, binucleation, and multinucleation are frequently seen in aspirates of medullary carcinoma. Diff-Quik stain, high power.

FIGURE 2-35 Medullary carcinoma. Cellular smear composed of spindle cells with the characteristic ‘salt and pepper’ chromatin. Papanicolaou stain, high power.

ation, and multinucleation are present. The nuclei have a coarsely granular, ‘salt and paper’ chromatin pattern and inconspicuous nucleoli (Fig. 2-35). Intranuclear cytoplasmic inclusions are present in up to one-half of cases. Intranuclear grooves are infrequently seen. Red cytoplasmic neurosecretory granules are seen in scattered cells and only appreciated in air-dried smears (Fig. 2-36). The presence of amyloid is variable. Amyloid appears as amorphous, cotton-like, acellular material that is metachromatic in Diff-Quik and grayish-green in Papanicolaou stain. It may be confused with colloid

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(Fig. 2-37). Congo red stain examined under polarized light confirms the diagnosis of amyloid.

ANCILLARY STUDIES Medullary carcinoma is negative for thyroglobulin, and immunoreactive for calcitonin (Fig. 2-38), monoclonal carcinoembryonic antigen (CEA), TTF-1, low molecular weight cytokeratin, and chromogranin.

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FIGURE 2-36 Medullary carcinoma. Conventional air-dried smear illustrating red cytoplasmic neurosecretory granules. Multinucleation and nuclear pleomorphism are present. DiffQuik stain, high power.

FIGURE 2-37 Medullary carcinoma. Amyloid appears as amorphous, acellular metachromatic material. Congo red and crystal violet stains can be confirmatory of its presence. Diff-Quik stain, high power.

The detection of germline mutations in the RET oncogene in the serum is highly specific and sensitive in identifying patients who have or will develop familial forms of medullary carcinoma. It is replacing calcitonin stimulation testing as a screening method.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of medullary carcinoma includes Hürthle cell neoplasm, papillary carcinoma,

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anaplastic carcinoma, and hyalinizing trabecular adenoma. In contrast to Hürthle cell neoplasms, macronucleoli are not a feature of medullary carcinoma. High cellularity, cellular discohesion, and intranuclear inclusions are shared features with papillary carcinoma, but other architectural, background, and nuclear features help distinguish between the two. Anaplastic carcinoma is a consideration when medullary carcinoma is composed of spindle cells. The spindle cell variant of medullary carcinoma yields a more uniform population of neoplastic cells and lacks necrosis. Hyalinizing trabecular adenoma and medullary carcinoma are both characterized by high cellularity, poor cellular

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FIGURE 2-38 Medullary carcinoma. Calcitonin immunocytochemical stain performed on a liquid-based preparation demonstrates positive staining in the neoplastic cells. Calcitonin immunostain, high power.

cohesion, spindle cells, and intranuclear inclusions. Moreover, the stromal material in hyalinizing trabecular adenoma may be misinterpreted as amyloid. A negative Congo red and calcitonin immunostain should assist in excluding medullary carcinoma.

INSULAR CARCINOMA – DISEASE FACT SHEET Definition ៉ Poorly differentiated malignancy of follicular cell origin Incidence ៉ Very rare in the United States

INSULAR CARCINOMA CLINICAL FEATURES

Gender and Age Distribution ៉ Female predominance ៉ Peak incidence 55 years

Risk Factors

Insular carcinoma is classified as a variant of poorly differentiated carcinomas. It is a thyroid malignancy of follicular cell origin with a biologic behavior between well-differentiated carcinoma (papillary, follicular carcinoma) and anaplastic carcinoma. Insular carcinoma has a distinct histologic appearance with neoplastic cells arranged in well-formed nests or islands (‘insulae’). Its prevalence varies among different geographic regions. The highest prevalence, 5% of all thyroid malignancies, has been reported from Italy, whereas in the Unites States it is very low. The disease presents in middle-aged and elderly patients, with a mean age of 55 years, and is more common in women, with a female to male ratio of 2 : 1. Insular carcinoma arises de novo or transforms from well-differentiated thyroid carcinomas. It presents as an enlarging thyroid mass which appears ‘cold’ on radionuclide scanning. Extrathyroid extension, and cervical lymph node and distant metastases are commonly present at the time of diagnosis. Insular carcinoma is an aggressive malignancy with a poor prognosis. Recurrences develop in 60% of cases.

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៉ History of papillary or follicular carcinoma

Clinical Features ៉ Aggressive malignancy ៉ Enlarging, ‘cold’ thyroid mass ៉ Extrathyroid extension, cervical lymph node and distant

metastases ៉ Local recurrences ៉ Poor prognosis

The median survival is 3.9 years, and the 5-year survival rate is 40–50%.

CYTOPATHOLOGIC FEATURES The aspirates from insular carcinomas are highly cellular, revealing neoplastic cells arranged in loose

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INSULAR CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings Cellular aspirates Loose clusters, microfollicles, single cells Hyperchromatic small neoplastic cells Increased N/C ratio Mild to moderate anisokaryosis Mitoses, necrosis

៉ ៉ ៉ ៉ ៉ ៉

Differential Diagnosis and Pitfalls Follicular carcinoma Medullary carcinoma Anaplastic carcinoma Metastatic carcinoma

៉ ៉ ៉ ៉

clusters, trabeculae, microfollicles, or dispersed singly. The cells are relatively small and monomorphic, but scattered large pleomorphic cells can also be present. They display an increased nuclear to cytoplasmic (N/C) ratio, irregular nuclei, hyperchromasia, and inconspicuous nucleoli (Figs 2-39 & 2-40). Intranuclear cytoplasmic pseudoinclusions and intranuclear grooves are occasionally seen. The cytoplasm is pale and poorly defined, and occasional intracytoplasmic vacuoles are present. Mitotic figures and necrosis are present.

ANCILLARY STUDIES Insular carcinoma is immunoreactive for thyroglobulin and TTF-1, and negative for calcitonin, chromogranin, and monoclonal CEA.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The diagnosis of malignancy is easy to establish in FNA of insular carcinoma. The differential diagnosis includes poorly differentiated follicular carcinoma, anaplastic carcinoma, medullary carcinoma, and metastatic carcinoma. The microfollicular architecture of insular carcinoma is a feature shared with follicular carcinoma. The high nuclear grade, mitotic figures, and necrosis may suggest anaplastic carcinoma, but insular carcinoma lacks the spindle cells, osteoclast-like giant cells, and bizarre-appearing neoplastic cells of anaplastic carcinoma. Medullary carcinoma may show striking morphologic overlap, but can be distinguished by immunocytochemical stains (calcitonin-positive/ thyroglobulin-negative). Metastatic carcinoma to the thyroid should be also considered. The patient’s clinical history and comparison with previous cytologic or histologic material are recommended.

ANAPLASTIC CARCINOMA CLINICAL FEATURES Anaplastic carcinoma is a highly malignant, undifferentiated thyroid neoplasm that accounts for up to 5% of all thyroid malignancies. It is a disease of older adults, with a peak incidence in the sixth and seventh decades, and is more common in women, with a female to male ratio of 2–3 : 1. Anaplastic carcinoma tends to arise in a background of thyroid disease. A history of pre-existing goiter or

FIGURE 2-39 Insular carcinoma. Atypical follicular cells forming microacini and showing nuclear crowding and overlapping. Note the enlarged nuclei as compared to adjacent red blood cells. Diff-Quik stain, high power.

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FIGURE 2-40 Insular carcinoma. A crowded cluster of neoplastic cells with a high N/C ratio and hyperchromatic nuclei. Papanicolaou stain, high power.

ANAPLASTIC CARCINOMA – DISEASE FACT SHEET

the majority of patients are inoperable due to extensive local disease. The median survival is 3 to 4 months, and the 5-year survival rate ranges from 5% to 10%.

Definition ៉ Undifferentiated thyroid neoplasm Incidence

CYTOPATHOLOGIC FEATURES

៉ 5% of thyroid malignancies

Gender and Age Distribution ៉ Female predominance ៉ Occurs in the elderly

Risk Factors ៉ Pre-existing goiter ៉ Well-differentiated thyroid carcinoma

Clinical Features ៉ One of the most aggressive malignancies ៉ Rapidly enlarging, widely invasive ៉ Compression symptoms due to extrathyroid extension and invasion

The cytologic features of anaplastic carcinoma vary, reflecting the histologic diversity of this malignancy. The smears are variably cellular, and display neoplastic cells that are unequivocally malignant. The cells are arranged in large fragments, small clusters, or dispersed singly. Spindle-shaped cells admixed with polygonal and giant cells are typically seen (Fig. 2-41). Some anaplastic carcinomas contain large numbers of osteoclast-like giant cells (Fig. 2-42); in others, the neoplastic cells demonstrate squamous differentiation.

of adjacent tissues present at the time of diagnosis ៉ Cervical lymph node and distant visceral metastases ៉ Prognosis extremely poor

well-differentiated (papillary or follicular) thyroid carcinoma is common. The disease presents as a rapidly enlarging thyroid mass which appears ‘cold’ on radioactive iodine scan. The carcinoma spreads beyond the thyroid capsule into the adjacent neck structures, causing compression and invasion symptoms such as dyspnea, dysphagia, hoarseness, and cough. Metastases to neck lymph nodes and distant organs, particularly the lungs and liver, are common. Anaplastic carcinoma is a fatal disease. It does not respond well to either radiation or chemotherapy, and

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ANAPLASTIC CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variably cellular aspirates ៉ Spindle, polygonal cells ៉ Osteoclast-like giant cells ៉ Squamous differentiation ៉ Marked nuclear pleomorphism, mitotic figures ៉ Background necrosis and acute infl ammation Differential Diagnosis and Pitfalls Granulomatous infl ammation Medullary carcinoma Metastases Sarcoma

៉ ៉ ៉ ៉

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FIGURE 2-41 Anaplastic carcinoma. Highly atypical spindle and polygonal cells with bizarre nuclei and prominent nucleoli. Diff-Quik stain, high power.

FIGURE 2-42 Anaplastic carcinoma. Osteoclastlike giant cells can be numerous in anaplastic carcinoma. Diff-Quik stain, high power.

The nuclei are very large, have irregular membranes, and display coarsely granular chromatin and macronucleoli. The cytoplasm varies in appearance and it can be dense, granular, or vacuolated. Mitotic figures including bizarre forms are readily identified. The background reveals necrosis and acute inflammation (Fig. 2-43). The cytologic diagnosis is not always straightforward. Extensive desmoplasia yields hypocellular samples with marked crush artifact which are therefore not diagnostic. Necrosis and marked inflammation may also obscure the neoplastic cells, making the interpretation of the aspirate difficult. Nevertheless, when an aspirate

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of a rapidly enlarged thyroid in an older patient reveals rare pleomorphic cells in a necroinflammatory background, the diagnosis of anaplastic carcinoma must be considered.

ANCILLARY STUDIES Cytokeratin positivity is observed in some anaplastic carcinomas, and the vast majority are negative for TTF-1 and thyroglobulin.

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FIGURE 2-43 Anaplastic carcinoma. Necrotic background with no viable tumor cells. Diff-Quik stain, low power.

FIGURE 2-44 Metastatic colonic adenocarcinoma. The tumor cells are columnar, and display nuclear palisading and stratification. Glandular arrangement is prominent. Colloid is absent. Diff-Quik stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The smears are usually diagnostic of malignancy; however, the presence of giant cells associated with necrosis may be misinterpreted as granulomatous inflammation. The differential diagnosis of anaplastic carcinoma includes medullary carcinoma, metastatic carcinoma, and sarcoma. Medullary carcinoma displays a lesser degree of cellular pleomorphism; moreover, the readily identifiable mitoses and necroinflammatory background seen in anaplastic carcinoma are absent. In addition, the presence of amyloid and

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immunoreactivity for calcitonin, chromogranin, and monoclonal CEA support the diagnosis of medullary carcinoma. Metastases to the thyroid are rarely encountered by FNA. Malignant melanoma, lung, breast, kidney, pancreas, and colon are the most common primary sites. Fig. 2-44 illustrates a case of metastatic colonic carcinoma. The differential diagnosis rests on the patient’s clinical history, comparison with any available previous cytologic or histologic material, and performing the appropriate immunocytochemical panel. Sarcoma, although rare in the thyroid, should be considered, and can be excluded by the demonstration of cytokeratin positivity.

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LYMPHOMA CLINICAL FEATURES Lymphoma may involve the thyroid as part of systemic lymphoma (secondary thyroid lymphoma) or may arise primarily in the gland (primary thyroid lymphoma). Primary lymphomas of the thyroid are rare, and account for up to 2% of thyroid malignancies, whereas secondary involvement of the thyroid occurs more frequently. More than 90% of primary thyroid lymphomas are non-Hodgkin B-cell lymphomas. Diffuse large B-cell lymphoma (DLBL), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MZBL), and mixed MZBL/DLBL are the most common variants. Primary thyroid T-cell lymphomas are rare. Hodgkin lymphoma involving the thyroid is almost always by direct extension from a lymph node or thymus. Primary thyroid lymphoma is a disease of older adults, with a mean age of presentation of 65 years, and is more common in women, with a female to male ratio of 3–7 : 1. Its major risk factor is Hashimoto’s thyroiditis. The disease classically presents as a noticeably enlarging thyroid mass which appears ‘cold’ on radioactive iodine scan. Compressive symptoms such as dyspnea, dysphagia, hoarseness, and cough due to extrathyroid extension are present in about one-third of patients at the time of diagnosis. Because of the strong association with Hashimoto’s thyroiditis, patients may present with hypothyroidism. The prognosis primarily depends on the stage and histologic type of the disease. Patients with MZBL and

LYMPHOMA – DISEASE FACT SHEET Definition ៉ Primary lymphoid thyroid malignancy ៉ >90% are non-Hodgkin lymphoma

Incidence ៉ 2% of malignant thyroid neoplasms

Gender and Age Distribution ៉ Female predominance ៉ Mean onset: 65 years Risk Factor

with early stage tumors confined to the gland have a good prognosis, with a 5-year survival rate approaching 80%, whereas patient whose tumors either are of high stage or have a DLBL component have a significantly poorer prognosis.

CYTOPATHOLOGIC FEATURES The aspirates are highly cellular and comprised of atypical lymphoid cells (Fig. 2-45). The cytologic features depend on the type of lymphoma. DLBL yield cellular aspirates comprised of numerous monomorphic, large, atypical lymphoid cells with large nuclei, either cleaved or non-cleaved, displaying a vesicular chromatin pattern and conspicuous marginated nucleoli. Large, abnormal plasmacytoid lymphocytes with single macronucleoli may be seen. Extensive karyorrhexis is present in the background. MZBL aspirates are comprised of a polymorphous lymphocytic population which includes atypical small and intermediate size lymphocytes, monocytoid B cells, immunoblasts, and plasma cells. Mixed DLBL/MZBL lymphomas show features of both.

ANCILLARY STUDIES Immunocytochemical staining for leukocyte common antigen (CD45) and CD20, as well as flow cytometry and molecular studies are recommended to confirm the diagnosis.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The main differential diagnosis is Hashimoto’s thyroiditis. DLBL is usually not a diagnostic challenge

LYMPHOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ DLBL: monotonous population of large lymphoid cells ៉ MZBL: centrocytes, monocytoid B cells, immunoblasts, plasma cells ៉ Mixed DLBL/MZBL: features of DLBL and MZBL

៉ Hashimoto’s thyroiditis

Ancillary Studies

Clinical Features

៉ Flow cytometry ៉ Molecular studies ៉ Immunocytochemistry: LCA, CD20+

៉ Rapidly enlarging thyroid mass ៉ Compression symptoms due to extrathyroid extension

Differential Diagnosis and Pitfalls Prognosis ៉ Depends on stage and histologic type

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៉ Hashimoto’s thyroiditis ៉ Metastatic small cell carcinoma

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FIGURE 2-45 Diffuse large B-cell lymphoma. Cellular aspirate illustrating a monotonous population of atypical large lymphoid cells. Tingible-body macrophages are present. Diff-Quik stain, high power.

and can be easily distinguished. However, distinguishing MZBL from Hashimoto’s thyroiditis can be difficult on cytologic grounds alone. Flow cytometric analysis, immunocytochemistry, and molecular diagnostic methods are very helpful in establishing the diagnosis. Metastatic small cell carcinoma of the lung should also be considered as a differential diagnosis. Small cell carcinoma of the lung yields aspirates composed of loosely cohesive clusters of small to intermediate-sized cells with little or no cytoplasm, and nuclei displaying hyperchromasia, inconspicuous nucleoli, and prominent molding. Lymphoglandular bodies are absent from the background.

Powers CN, Frable WJ. Thyroid and parathyroid. In: Fine Needle Aspiration Biopsy of the Head and Neck, 1st ed. Boston: Butterworth-Heinemann, 1996. Hashimoto’s Thyroiditis Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 1985;312:601–604. Guarda LA, Baskin HJ. Inflammatory and lymphoid lesions of the thyroid gland. Cytopathology by fine-needle aspiration. Am J Clin Pathol 1987;87:14–22. McDonald L, Yazdi HM. Fine needle aspiration biopsy of Hashimoto’s thyroiditis. Sources of diagnostic error. Acta Cytol 1999;43:400–406. Nguyen GK, Ginsberg J, Crockford PM, Villanueva RR. Hashimoto’s thyroiditis: cytodiagnostic accuracy and pitfalls. Diagn Cytopathol 1997;16: 531–536. Nodular Goiter

SUGGESTED READINGS Introduction Cibas ES. Thyroid. In: Cibas ES, Ducatman BS, eds. Cytology: Diagnostic Principles and Clinical Correlates, 2nd ed. Philadelphia: WB Saunders, 2003. DeMay RM. Thyroid. In: The Art and Science of Cytopathology. Chicago: ASCP Press, 1996. Frost AR, Sidawy MK. Thyroid aspiration cytopathology. In: Atkinson BF, Silverman JF, eds. Atlas of Difficult Diagnoses in Cytopathology, 1st ed. Philadelphia: WB Saunders, 1998. Frost AR, Sidawy MK, Ferfelli M, Tabbara SO, Bronner N, Sherman ME. Utility of thin-layer preparations in thyroid fine-needle aspiration: diagnostic accuracy, cytomorphology, and optimal sample preparation. Cancer (Cancer Cytopathol) 1998;84:17–25. Kini SR. Thyroid. In: Kline TS, ed. Guides to Clinical Aspiration Biopsy, 2nd edn. New York: Igaku-Shoin, 1996. Merino MJ, Sidawy MK. The thyroid gland. In: Silverberg SG, DeLelllis RA, Frable WJ, eds. Principles and Practices of Surgical and Cytopathology, 3rd ed. New York: Churchill Livingstone, 1997. Miller JM, Hamburger JI, Kini SR. The impact of needle biopsy on the preoperative diagnosis of thyroid nodules. Henry Ford Hosp Med J 1980;28:145–148. The Papanicolaou Society of Cytopathology Task Force on Standards of Practice. Guidelines of the Papanicolaou Society of Cytopathology for the examination of fine-needle aspiration specimens from thyroid nodules. Mod Pathol 1996;9:710–715.

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Abbas G, Heller KS, Khoynezhad A, Dubner S, Sznyter LA. The incidence of carcinoma in cytologically benign thyroid cysts. Surgery 2001; 130:1035–1038. Caraway NP, Sneige N, Samaan NA. Diagnostic pitfall in thyroid fine needle aspiration: a review of 394 cases. Diagn Cytopathol 1993;9:345–350. Dwarakanathan AA, Staren ED, D’Amore MJ, Kluskens LF, Martirano M, Economou EG. Importance of repeat fine-needle biopsy in the management of thyroid nodules. Am J Surg 1993;166:350–352. Faquin WC, Cibas ES, Renshaw AA. ‘Atypical’ cells in fine-needle aspiration biopsy specimens of benign thyroid cysts. Cancer (Cancer Cytopathol) 2005;105:71–79. Frost AR, Sidawy MK. The effect of suppressive therapy on thyroid fine needle aspiration cytology. Acta Cytol 1995;39:402–408. Greaves TS, Olvera M, Florentine BD, et al. Follicular lesions of the thyroid: a 5-year fine-needle aspiration experience. Cancer (Cancer Cytopathol) 2000;90:335–341. Harach HR, Zusman SB, Saravia Day E. Nodular goiter: a histo-cytological study with some emphasis on pitfalls of fine-needle aspiration cytology. Diagn Cytopathol 1992;8:409–419. Nassar A, Gupta P, LiVolsi VA, Baloch Z. Histiocytic aggregates in benign nodular goiter mimicking cytologic features of papillary thyroid carcinoma. Diagn Cytopathol 2003;29:243–245. Sidawy MK, Costa M. The significance of paravacuolar granules of the thyroid. A histologic, cytologic and ultrastructural study. Acta Cytol 1989;33:929–933. Sidawy MK, Del Vecchio DM, Knoll SM. Fine needle aspiration of thyroid nodules: correlation between cytology and histology and

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70 evaluation of discrepant cases. Cancer (Cancer Cytopathol) 1997;81: 253–259. Follicular Neoplasms Baloch ZW, LiVolsi VA. Follicular-patterned lesions of the thyroid: the bane of the pathologist. Am J Clin Pathol 2002;117:143–150. Baloch ZW, LiVolsi VA. The quest for a magic tumor marker. Continuing saga in the diagnosis of the follicular lesions of the thyroid (Editorial). Am J Clin Pathol 2002;118:165–166. Cerilli LA, Mills SE, Rumpel CA, Dudley TH, Moskaluk CA. Interpretation of RET immunostaining in follicular lesions of the thyroid. Am J Clin Pathol 2002;118:186–193. DeMay RM. Follicular lesions of the thyroid. W(h)ither follicular carcinoma? Am J Clin Pathol 2000;114:681–683. Kroll TG. Molecular rearrangements and morphology in thyroid cancer. Am J Pathol 2002;160:1941–1944. LiVolsi VA, Asa SL. The demise of follicular carcinoma of the thyroid gland. Thyroid 1994;4:233–236. Segev DL, Clark DP, Zieger M, Umbricht C. Beyond the suspicious thyroid fine needle aspirate. A review. Acta Cytol 2003;47:709–722. Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 1995;118:1131–1136. Umbricht CB, Conrad GT, Clark DP, et al. Human telomerase reverse transcriptase gene expression and the surgical management of suspicious thyroid tumors. Clin Cancer Res 2004;10:5762–5768.

FINE NEEDLE ASPIRATION CYTOLOGY thyroid carcinoma in cytologic specimens. Diagn Cytopathol 2002;27: 143–148. Tabbara SO, Acoury N, Sidawy MK. The origin of multinucleated foreignbody-type giant cells in thyroid neoplasms: a cytologic, histologic and immunohistochemical study. Acta Cytol 1996;40:1184–1188. Medullary Carcinoma Bhattacharyya N. A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngol Head Neck Surg 2003;28:115–123. Bose S, Kapila K, Verma K. Medullary carcinoma of the thyroid: a cytological, immunocytochemical, and ultra-structural study. Diagn Cytopathol 1992;8:28–32. Collins BT, Cramer JM, Tabatowski K, Hearn S, Raminhos A, Lampe H. Fine needle aspiration of medullary carcinoma of the thyroid. Cytomorphology, immunocytochemistry and electron microscopy. Acta Cytol 1995;39:920–930. Forrest CH, Frost FA, de Boer WB, Spagnolo DV, Whitaker D, Sterrett BF. Medullary carcinoma of the thyroid: accuracy of diagnosis of fine-needle aspiration cytology. Cancer 1998;84:295–302. Kini SR, Miller JM, Hamburger JI, Smith MJ. Cytopathologic features of medullary carcinoma of the thyroid. Arch Pathol Lab Med 1984;108: 156–159. Insular Carcinoma

Hürthle Cell Neoplasms Chen KTK. Fine-needle aspiration cytology of papillary Hurthle-cell tumors of thyroid: a report of three cases. Diagn Cytopathol 1991;7:53–56. Gonzalez JL, Wang HH, Ducatman BS. Fine-needle aspiration of Hurthle cell lesions: a cytomorphologic approach to diagnosis. Am J Clin Pathol 1993;100:231–235. Lopez-Penabad L, Chiu AC, Hoff AO, et al. Prognostic factors in patients with Hurthle cell neoplasms of the thyroid. Cancer 2003;97:1186– 1194. McIvor NP, Freeman JL, Rosen I, Bedard YC. Value of fine-needle aspiration in the diagnosis of Hurthle cell neoplasm. Head Neck 1993;15: 335–341. Stojadinovic A, Ghossein RA, Hoos A, et al. Hurthle cell carcinoma: a critical histopathologic appraisal. J Clin Oncol 2001;19:2616–2625. Stojadinovic A, Hoos A, Ghossein RA, et al. Hurthle cell carcinoma: a 60-year experience. Ann Surg Oncol 2002;9:197–203. Papillary Carcinoma Baloch ZW, Abraham S, Roberts S, et al. Differential expression of cytokeratins in follicular variants of papillary carcinoma: an immunohistochemical study and its diagnostic utility. Hum Pathol 1999;30: 1166–1171. Chan JKC. Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 2002;117:16–18. Goellner JR, Carney JA. Cytologic features of fine-needle aspirates of hyalinizing trabecular adenoma of the thyroid. Am J Clin Pathol 1989; 91:115–119. Goodell WM, Saboorian MH, Ashfaq R. Fine-needle aspiration diagnosis of the follicular variant of papillary carcinoma. Cancer 1998;84:349–354. Lin JS, Komisar A, Opher E, Blaugrund SM. Follicular variant of papillary carcinoma: the diagnostic limitations of preoperative fine-needle aspiration and intra-operative frozen section evaluation. Laryngoscope 2000;110:1431–1436. LiVolsi VA. Unusual variants of papillary thyroid carcinoma. Adv Endocrinol Metab 1995;6:39–54. Renshaw AA. ‘Histiocytoid’ cells in fine-needle aspirations of papillary carcinoma of the thyroid: frequency and significance of an underrecognized cytologic pattern. Cancer (Cancer Cytopathol) 2002;96:240– 243. Shaha AR, Shah JP, Loree TR. Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol 1996;3: 534–538. Solomon A, Gupta PK, LiVolsi VA, Baloch ZW. Distinguishing tall cell variant of papillary thyroid carcinoma from usual variant of papillary

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Guiter GE, Auger M, Ali SZ, Allen EA, Zakowski MF. Cytopathology of insular carcinoma of the thyroid. Cancer 1999;87:196–202. Layfield LJ, Gopez EV. Insular carcinoma of the thyroid: report of a case with intact insulae and microfollicular structures. Diagn Cytopathol 2000;23:409–413. Pietribiasi F, Sapino A, Papotti M, Bussolati G. Cytologic features of poorly differentiated ‘insular’ carcinoma of the thyroid, as revealed by fineneedle aspiration biopsy. Am J Clin Pathol 1990;94:687–692. Pilotti S, Collini P, Mariani L et al. Insular carcinoma: a distinct de novo entity among follicular carcinomas of the thyroid gland. Am J Surg Pathol 1997;21:1466–1473. Sironi M, Collini P, Cantaboni A. Fine needle aspiration cytology of insular thyroid carcinoma. A report of four cases. Acta Cytol 1992;36:435–439. Anaplastic Carcinoma Berry B, MacFarlane J, Chan N. Osteoclastomalike anaplastic carcinoma of the thyroid. Diagnosis by fine needle aspiration cytology. Acta Cytol 1990;34:248–250. Brooke PK, Hameed M, Zakowski M. Fine-needle aspiration of anaplastic thyroid carcinoma with varied cytologic and histologic patterns: a case report. Diagn Cytopathol 1994;11:60–63. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer 1998;83:2638–2648. Peterson CE, Hall W, Baskin HJ. Anaplastic thyroid carcinoma: cytomorphology and clinical implications of fine-needle aspiration. Diagn Cytopathol 1991;7:63–67. Venkatesh YS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer 1990;66: 321–330. Lymphoma Das DK, Gupta SK, Francis IM, Ahmed MS. Fine-needle aspiration cytology diagnosis of non-Hodgkin lymphoma of thyroid: a report of four cases. Diagn Cytopathol 1993;9:639–645. Derringer GA, Thompson LD, Frommelt RA, Bijwaard KE, Heffess CS, Abbondanzo SL. Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases. Am J Surg Pathol 2000;24:623–639. Detweiler RE, Katz RL, Alapat C, El-Naggar A, Ordonez N. Malignant lymphoma of the thyroid: a report of two cases diagnosed by fine-needle aspiration. Diagn Cytopathol 1991;7:163–171. Skacel M, Ross CW, Hsi ED. A reassessment of primary thyroid lymphoma: high-grade MALT-type lymphoma as a distinct subtype of diffuse large B-cell lymphoma. Histopathology 2000;37:10–18.

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3

Lymph Nodes Paul E Wakely Jr

Lymph nodes (or masses suspected to represent a lymph node) rival the thyroid gland and the breast as the most frequent sites for application of fine needle aspiration (FNA) biopsy. FNA often unequivocally represents the most direct and cost-effective diagnostic path to explain an enlarged lymph node. Principal indications are to exclude or confirm a benign, malignant (primary or metastatic), or infectious process when the reason is not clinically apparent to the physician.

REACTIVE LYMPHOID HYPERPLASIA CLINICAL FEATURES Non-specific reactive lymphoid hyperplasia is a common cause of lymphadenopathy in children and young adults, but much less so in older individuals, being very infrequent beyond the fourth decade. Males and females are equally affected. Reactive lymphoid hyperplasia

manifests as a clinically enlarged lymph node that may or may not be painful upon palpation. It may be due to a variety of antigenic stimuli including organisms, foreign material (drugs, environmental pollutants, altered tissue components), altered immune status, and enlargement in the drainage pathway of a neoplasm without actually harboring neoplastic cells. In the vast majority of instances, a specific etiology remains unknown. Prognosis of reactive lymphoid hyperplasia is excellent, with most examples resolving on their own or after a course of antibiotic therapy. The utility of FNA is particularly noticeable with persistent lymphadenopathy, since the patient, parents, and clinician begin to consider a more ominous cause if an enlarged node is present for more than 3 weeks.

CYTOPATHOLOGIC FEATURES Two consistent findings in cytologic smears of lymphoid tissue regardless of a benign or malignant nature are: a) dispersion of cells predominantly as

REACTIVE LYMPHOID HYPERPLASIA – DISEASE FACT SHEET REACTIVE LYMPHOID HYPERPLASIA – PATHOLOGIC FEATURES Definition ៉ A benign proliferation of cells in the lymph node cortex, medulla, and/or paracortex caused by a variety of antigenic stimuli Incidence ៉ Very common cause of lymphadenopathy in children and young adults; much less so in adults ៉ Males = females Clinical Features ៉ Usually solitary node enlargement; less commonly produces multiple enlarged nodes ៉ Soft to palpation, non-tender, not fixed to soft tissue ៉ Typically involves cervical, axillary, or inguinal nodes; rarely supraclavicular nodes Prognosis and Treatment ៉ Completely benign and reversible ៉ Self-limited; surgical excision often occurs if node is >1 cm in

dimension and does not regress after a certain duration

Cytopathologic Findings ៉ A spectrum of lymphocytes ranging from small round forms

(7–8 μm) to transformed centrocytes and centroblasts to larger immunoblasts ៉ Dendritic/lymphocytic aggregates ៉ Follicular center fragments consisting of a syncytium of dendritic cells populated by a range of lymphocytes, tingiblebody macrophages, and short capillary segments Ancillary Studies ៉ Immunophenotyping shows a polyclonal population of B and T

lymphocytes Differential Diagnosis and Pitfalls ៉ Any ‘small cell’ non-Hodgkin lymphoma ៉ Small cell neuroendocrine carcinoma ៉ Certain benign causes of lymphadenopathy, e.g. progressive

transformation of germinal centers, Castleman disease, toxoplasma lymphadenitis, HIV lymphadenopathy

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B

C

FIGURE 3-1 Reactive lymphoid hyperplasia. A, A polymorphous population of lymphocytes is present in a dissociated (single cell) pattern. Small lymphocytes with rounded nuclei are most numerous, but large and intermediate-size lymphocytes are also present. Note the blue globular lymphoglandular bodies scattered between cells. Romanowsky stain, high power. B, A centrally placed immunoblast looms over the remaining smaller lymphocytes in this field. Note the single nucleolus and the zone of deeply basophilic staining at the immunoblast periphery. Romanowsky stain, high power. C, Three tingible-body macrophages are easily recognized because of their large size, and the presence of phagocytosed cellular debris. A heterogeneous cell mixture is seen in the background. Papanicolaou stain, high power.

non-clustered, individual forms – the so-called single cell/dissociated cell pattern; and b) presence of individual small globular or flake-like fragments of cytoplasm that have been termed lymphoglandular bodies. Lymphoglandular bodies are best seen with a Romanowsky-type stain (Giemsa, Wright-Giemsa, May-Grünwald-Giemsa, or Diff-Quik), where they stain a pale blue or blue–gray, are about the size of a red cell, and may contain small vacuoles; their size can vary somewhat. Their presence, particularly in large numbers, is assurance that lymphoid tissue has been aspirated, but it does not guarantee that the lesion on the slide is lymphoid. It merely states that a lymphoid population exists on the smear (e.g. metastatic seminoma and undifferentiated nasopharyngeal carcinoma typically contain lymphocytes as part of the neoplasm). Because little stroma exists in reactive lymphoid hyperplasia to retain lymphoid cells during the backand-forth cutting action of an aspirating needle, relatively large numbers of cells can be obtained, resulting in moderately to highly cellular smears. Degree of cellularity has no correlation with benignancy or malignancy. Even if reactive lymphoid hyperplasia is subdivided into various stages (early, mid, and late

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phases), small round lymphocytes predominate with variation in the percentage of other lymphocytes. It is important to remember that the spatial relationships visible in tissue sections of lymph node are lost in aspirates. Thus, follicular, diffuse, sinusoidal, or marginal zone architecture cannot be recognized with FNA. Since the reactive node undergoes expansion of cortical, medullary, and/or paracortical zones, the hallmark of reactive lymphoid hyperplasia is the structural polymorphism/heterogeneity typical of sampling the normal cellular elements from various parts of a normal but expanded node. These constituents include small lymphocytes, centrocytes, centroblasts, dendritic cells, tingible-body macrophages, immunoblasts, plasmacytoid monocytes, plasma cells, and, less often, capillaries, eosinophils, and endothelial cells. Small round lymphocytes prevail in aspirate smears, followed by centrocytes and centroblasts in examples of follicular reactive lymphoid hyperplasia (Fig. 3-1). Centrocytes are similar in size to or slightly larger than small lymphocytes, having slight nuclear contour irregularity. Centroblasts are non-cleaved lymphocytes (almost twice the diameter of mature lymphocytes) with coarser chromatin, slightly more cytoplasm, and may contain visible nucleoli. Plasmacytoid lymphocytes/monocytes are small to

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intermediate in size with eccentrically placed nuclei, smudged chromatin, a variable perinuclear clear zone, and a small amount of slightly basophilic cytoplasm. Immunoblasts are large cells (20–25 μm) with open fine chromatin, one or more distinct nucleoli, and moderate to abundant pale to basophilic cytoplasm. A perinuclear clear zone may be seen. Tingible-body macrophages are large cells, with rounded nuclei, finely granular chromatin, a small distinct nucleolus, and a copious debrisladen cytoplasm. Dendritic cells have oval hypochromatic nuclei, indistinct or absent nucleoli, and long cytoplasmic processes; they are commonly binucleated (Fig. 3-2). Cell processes are paradoxically better seen in Papanicolaou-stained smears. Thus, it is not so critical in reactive lymphoid hyperplasia that one tries to identify each cell on the smear, rather to recognize that a range of different lymphoid tissue cellular elements exists. An exception to the single cell pattern in a normal but reactive node is the presence of dendritic/lymphocytic aggregates and/or follicular center cell fragments. Dendritic/lymphocytic aggregates are loose collections (50–120 μm) of small lymphocytes and larger dendritic cells devoid of tingible-body macrophages or capillaries (Fig. 3-3A). The cytoplasmic processes of dendritic cells are best seen in these aggregates. Follicular center cell fragments contain the additional embellishments of branching capillaries and tingible-body macrophages, and are most often observed in examples of florid follicular reactive lymphoid hyperplasia (Fig. 3-3B).

ANCILLARY STUDIES All lymph node FNA biopsies should obtain cells in a liquid medium that preserves cells for ancillary testing.

A

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This can be accomplished either by rinsing the aspirating needle in the media after cells are expressed onto glass slides or by directly placing cells into such a medium from one of the FNA passes. The most important ancillary test for reactive lymphoid hyperplasia is immunophenotyping. Immunophenotyping should be performed on all lymph node aspirates that contain only a lymphoid population, to help assure that a non-Hodgkin lymphoma is excluded. Those aspirates

FIGURE 3-2 Reactive lymphoid hyperplasia, dendritic cells. A grouping of dendritic cells displays the web-like cytoplasmic extensions that emanate from the cell body. Cell borders are indistinct, creating a syncytium. Nuclei are hypochromatic with smooth nuclear contours and small nucleoli. Note the binucleated dendritic cell at the bottom of this group whereby the two nuclei partially overlap. Papanicolaou stain, high power.

B

FIGURE 3-3 Reactive lymphoid hyperplasia. A, Dendritic/lymphocytic aggregate. A discrete cluster of dendritic cells and heterogeneous lymphocytes is present. The former are distinguished by their larger nuclear size and abundant amphophilic cytoplasm that creates a syncytium. Note that the large number of lymphocytes partially obscures these cells. B, Follicular center cell fragment. A branching capillary traverses an aggregate of heterogeneous lymphocytes and partially hidden dendritic cells. Tingible-body macrophages are embedded within the aggregate or closely associated with it (lower center). Romanowsky stain, high power.

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74 containing a metastatic cancer do not necessarily require immunophenotyping unless the clinical circumstances dictate otherwise. For reactive lymphoid hyperplasia and all non-Hodgkin lymphomas, immunophenotyping is best accomplished using flow cytometry (FCM). FCM is the current standard for immunologic analysis of lymphoid tissue/cells. Its advantages include the ability to evaluate numerous lymphoid antigenic markers on a smaller number of cells, an objective assessment of clonality, the ability to detect small monoclonal cell populations, and a rapid turnaround time. A more time-consuming and less frequently used method is immunocytochemistry of cytospin prepared slides. With immunocytochemistry, an objective measurement of clonality is lost, it is more laborious, and fewer markers are utilized. Its major advantage is the preservation of cell morphology, but this is offset by its disadvantages, except in cases of presumptive Hodgkin lymphoma. In reactive lymphoid hyperplasia, FCM demonstrates a polyclonal population of T and B lymphocytes. The FCM result combined with the appropriate morphology, and the proper clinical context are diagnostic of reactive lymphoid hyperplasia. FCM is, however, imperfect. Some lymph node aspirates contain too few cells to evaluate, some B-cell lymphomas are immunoglobulinnegative, and some lymphomas have such a high cell turnover rate that an insufficient number of viable lymphocytes exist for immunophenotyping. In these cases, molecular studies can be employed to further identify the lesion. Molecular and genetic tests can be applied to suspended cells in a liquid medium or directly to cells smeared on a glass slide. One method uses the polymerase chain reaction (PCR) that amplifies the DNA of lymphocytes, and can determine if the heavy chain immunoglobulin genes of B cells or the T-cell receptor genes of a T-cell lymphoma have been rearranged. Another method is fluorescence in situ hybridization (FISH), whereby commercially available probes are used to label parts of a chromosome to determine whether a cytogenetically abnormal rearrangement has occurred. Specific examples are addressed under certain disease states.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Some benign lymphadenopathies have distinctive architectural features and spatial relationships in tissue sections that allow for a specific diagnosis. However, these features are not readily transferable to smears. Thus, benign lymphadenopathies such as Castleman disease, toxoplasma lymphadenitis, HIV-associated lymphadenopathy, progressive transformation of germinal centers, and some examples of dermatopathic lymphadenopathy for the most part are morphologically similar to reactive lymphoid hyperplasia smears, and are rarely distinguishable with absolute certainty by using FNA.

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The principal diagnostic pitfall is confusing reactive lymphoid hyperplasia with a small cell type of nonHodgkin lymphoma (NHL). The major morphologic feature that separates these two categories is the presence of a range of lymphocytes in the former and its relative absence in the latter. Most small cell lymphomas are composed of monotonous (or nearly monotonous) lymphocytes. Follicular lymphoma, marginal zone lymphoma, and some T-cell lymphomas, however, show a degree of cell heterogeneity that allows them to be confused with reactive lymphoid hyperplasia. Grade II follicular lymphoma in particular often has a two-cell population of small and large lymphocytes, but a true spectrum of lymphoid cells is absent. This can be difficult to appreciate. Thus, immunophenotyping is mandatory in all aspirates of presumptive reactive lymphoid hyperplasia. Small cell neuroendocrine carcinoma may be mistaken infrequently with reactive lymphoid hyperplasia. It is more apt to be confused with small cell forms of NHL, and thus is discussed in detail in that section. A cytologic diagnosis (regardless of what tissue or organ is aspirated) of reactive lymphoid hyperplasia must fit with the overall clinical context of the patient’s problem. If it does not, then the cytologic diagnosis must be validated using another method, usually surgical biopsy. In the example of an individual with a large, fixed node whose combined aspirate morphology and immunophenotyping shows reactive lymphoid hyperplasia, a cytologic diagnosis has been made that does not correlate with the clinical scenario. Partial involvement of a node by a malignant process is a potential reason why a diagnosis of reactive lymphoid hyperplasia, although technically correct, may be invalid in the overall clinical circumstance.

GRANULOMATOUS LYMPHADENOPATHY CLINICAL FEATURES Granulomatous lymphadenopathy is very common and is due to various etiologies. Most examples are secondary to infectious disease, but granulomas may appear as a consequence of placement of foreign material, immune-related disease, environmental toxins and dust, or neoplasms. Sarcoidosis is a common cause of granulomatous lymphadenopathy. In the United States, the incidence is 40 per 100,000 in black individuals, which is 8–10 times more common than in whites. All ages can be affected, but peak incidence is in the third to fi fth decade, with a female predominance (2 : 1). In addition to peripheral adenopathy, enlargement of pulmonary hilar nodes is common. Patients may also display signs and symptoms of uveitis, sinusitis, erythema nodosum, and joint lesions, along with elevated angiotensin-converting enzyme, erythrocyte sedimentation rate, and serum calcium.

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GRANULOMATOUS LYMPHADENOPATHY – DISEASE FACT SHEET Definition ៉ The presence of granulomas with or without inflammation and

necrosis in a lymph node; etiology may be infectious or non-infectious Incidence ៉ Sarcoidosis: 40 per 100,000 in black population; 8–10 times less

common in whites ៉ Infectious causes: common in children and immunosuppressed

patients Gender and Age Distribution ៉ Sarcoidosis: 20–40 years of age; women > men ៉ Infectious causes: any age, with equal male/female ratio;

dependent on immunologic status Clinical Features ៉ Enlarged node or group of nodes ៉ Usually firm to palpation in non-infectious causes ៉ May be tender to palpation with cutaneous erythema in infectious

causes Prognosis and Treatment ៉ Usually excellent prognosis ៉ Antibiotic, antifungal, antimycobacterial therapy, dependent on

etiology

Patients with fungal or mycobacterial lymphadenitis often contain granulomas within enlarged nodes. These can occur at any age, and are often associated with a deficient immune status in the host. Patients may present with non-specific lymphadenopathy, or may have the constitutional signs and symptoms of disseminated infection. Some fungal infections such as Cryptococcus and Histoplasma are endemic to certain areas of the United States. Tuberculous and non-tuberculous (M. avium and M. intracellulare) lymphadenitis are particularly common in AIDS patients and others with poor immune function, and in the under-developed world. Atypical mycobacteria lymphadenitis is often a childhood disease with enlarged cervical nodes mimicking a bacterial infection. Cat-scratch disease is a lymphadenitis secondary to Bartonella henselae. The incidence is 9 per 100,000 in the United States, and most patients are less than 20 years of age. Although a high proportion of patients are in contact with a cat, only about 50% report actually being scratched. Prognosis of patients with infectious granulomatous lymphadenitis depends on response to antimicrobials, and correction of immune status. Children with atypical mycobacteria recover fully in nearly all cases. Cat-scratch disease is self-limited in immunocompetent patients. Sarcoidosis remits spontaneously in a large percentage of cases; many are treated with steroids.

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CYTOPATHOLOGIC FEATURES Regardless of cause, the cytopathology of granulomatous lymphadenopathy is similar with minor differences. Granulomas appear in smears as either loose or tightly clustered collections of epithelioid histiocytes of variable number and size. The key feature of an epithelioid histiocyte (which allows its distinction from a macrophage or dendritic cell) is an elongated, almost elliptical or spindle-shaped nucleus. A slight smooth indentation of the nuclear contour is present on one side, producing an outline that has been variously described as ‘footprint-, boomerang-, or banana-shaped’. Not all nuclei in a collection of epithelioid histiocytes will have this shape, but enough will to allow recognition as a granuloma. These nuclei are hypochromatic and may have small nucleoli or no visible nucleoli (Fig. 3-4). Nuclei may project away from a granuloma center in a ‘starburst’ pattern. Epithelioid histiocytes have a moderate to abundant amount of finely granular, nonvacuolated cytoplasm. Multinucleated giant cells are variably present in slides of granulomatous lymphadenopathy; their presence is not necessary for the diagnosis. Infectious causes, particularly cat-scratch disease, atypical mycobacteria, and some examples of tuberculous lymphadenitis, have an added neutrophilic cellular component on the smear, and may mimic an abscess (Fig. 3-5). Mycobacterial lymphadenitis has a variety of appearances, with some cases displaying no granulomas, only necrosis with or without acute inflammation, or foamy macrophages containing cytoplasmic striations. The latter represent ingested mycobacterial organisms (Fig. 3-6).

GRANULOMATOUS LYMPHADENOPATHY – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Granulomas: syncytial clusters of epithelioid histiocytes

characterized by oval and elongated, indented nuclei in loose or tight clusters ៉ Variable number of multinucleated giant cells ៉ Variable necrosis and acute infl ammation; acute infl ammation is common in cat-scratch disease and mycobacterial infection; absent in sarcoid Ancillary Studies ៉ Histochemical stains for fungi and/or acid-fast bacilli ៉ Microbiologic testing

Differential Diagnosis and Pitfalls ៉ Dendritic/lymphocytic aggregates ៉ Suppurative lymphadenitis ៉ Spindle cell neoplasm

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FIGURE 3-4 Granulomatous lymphadenopathy: sarcoidosis. This syncytial cluster of epithelioid histiocytes forms a granuloma. Some hypochromatic nuclei are oval, but many have a markedly elongated spindled quality. Indentation of the nuclear contour varies from subtle to dramatic, particularly so in the bottom half of the image. Nucleoli are indistinct. Papanicolaou stain, high power.

FIGURE 3-6 Granulomatous lymphadenopathy: mycobacterial lymphadenitis. This smear from an immunosuppressed patient contained no granulomas, only macrophages and lymphocytes, whose nuclei are seen. The striking feature in this image is the randomly arranged and overlapping unstained lines that exist extracellularly. These represent the acid-fast bacilli whose lipid coat prevents them from taking up the stain, thus creating the so-called ‘negative’ image. Romanowsky stain, high power.

FIGURE 3-5 Granulomatous lymphadenopathy: cat-scratch disease. This well-formed granuloma has frayed edges. It is infiltrated and surrounded by numerous polymorphonuclear leukocytes that partly obscure histiocyte nuclei. All areas of the smear are covered with neutrophils. Papanicolaou stain, high power.

FIGURE 3-7 Granulomatous lymphadenopathy: mycobacterial lymphadenitis. Same case as seen in Fig. 3-6, now stained with an acid-fast stain highlighting the innumerable red rod-shaped bacilli. Culture proved to be M. avium-intracellulare. Fite stain, high power.

ANCILLARY STUDIES The primary study for any infectious cause should be microbiologic testing for an organism. Some of the aspirate can be submitted in a culture tube for fungal, bacterial, or mycobacterial testing. Direct histochemical staining of the slide for fungi and mycobacterial bacilli using conventional silver and acid-fast stains is the

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most direct path toward organism identification (Fig. 3-7). The diagnosis of sarcoidosis is based on ancillary serologic tests, and clinicoradiologic examination.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The cytologic morphology of a granuloma in a wellmade smear is so characteristic that other entities rarely

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enter into the diagnosis. Follicular dendritic cells or dendritic/lymphocytic aggregates could potentially be mistaken for granulomas; however, the round to oval nuclear shape that is universal to these cells allows their distinction from epithelioid histiocytes. A suppurative bacterial lymphadenitis may mimic cat-scratch disease because of the neutrophilic background, but will lack the granulomas that exist in the latter. Rarely, the spindle cell nature of epithelioid histiocytes is exaggerated, and mimics a spindle cell proliferation. However, not all granuloma clusters are affected, and one finds more typical granuloma morphology in other areas of the smear.

INFECTIOUS MONONUCLEOSIS CLINICAL FEATURES Infectious mononucleosis is a disease caused by the Epstein-Barr virus (EBV). It is spread through personto-person contact, and occurs most commonly in adolescents and young adults. The estimated incidence is 50 per 100,000 individuals in the United States, equally affecting males and females. The classic clinical triad includes fever, pharyngitis, and peripheral lymphadenopathy that is always bilateral in the cervical chain. Axillary and inguinal adenopathy may also occur. Occasionally, unusual features will exist that mislead the physician, resulting in delayed diagnosis. Lymph nodes are often tender upon palpation, and movable. Splenomegaly is common, and splenic rupture a poten-

INFECTIOUS MONONUCLEOSIS – DISEASE FACT SHEET

tial complication. Infectious mononucleosis is a selflimited condition lasting from 3 to 4 weeks, and supportive medical treatment is the rule. Less than 1% of affected patients develop serious complications from the viral infection resulting in death.

CYTOPATHOLOGIC FEATURES Aspiration smears typically contain many lymphocytes in a dispersed pattern. Although a range of cells is present, somewhat mimicking a reactive lymphoid hyperplasia smear, some crucial differences exist. A marked increase in the percentage of immunoblasts (a consequence of the host response to EBV), centroblasts, plasmacytoid monocytes, and plasma cells is noted along with a diminution or absence of follicular center cell fragments. This abnormal proliferation of immunoblasts results in a skewed elevated percentage of large lymphocytes that can be misinterpreted easily for a large cell lymphoma (Fig. 3-8). Immunoblasts display enlarged nuclei, finely granular chromatin, one to three nucleoli (that are indistinct in Romanowsky-stained smears), and a moderate amount of basophilic cytoplasm (Fig. 3-9). EBV also induces infected B cells to transform into plasmacytoid forms with eccentrically placed nuclei, basophilic cytoplasm, and a minimal perinuclear clear zone.

ANCILLARY STUDIES The primary role of FNA is to suggest, confirm, or exclude infectious mononucleosis in a patient who has either not undergone serologic testing or has negative serologic results. Laboratory findings include peripheral blood atypical lymphocytosis, and a positive monospot (heterophile) test. IgM heterophile antibodies are

Definition ៉ A lymphadenopathy due to Epstein-Barr viral infection

Incidence

INFECTIOUS MONONUCLEOSIS – PATHOLOGIC FEATURES

៉ About 50 per 100,000 in the US

Gender and Age Distribution ៉ Most frequent in adolescents and young adults; rare in middleaged or elderly Clinical Features Pharyngitis, fever, splenomegaly Local or generalized lymphadenopathy Peripheral blood lymphocytosis Positive heterophile antibodies

៉ ៉ ៉ ៉

Cytopathologic Findings ៉ A range of lymphocytes but with a noticeable increase in the percentage of immunoblasts, plasmacytoid lymphocytes/ monocytes, and plasma cells ៉ Few dendritic/lymphocytic aggregates and follicular center cell fragments Ancillary Studies ៉ Flow cytometry is polyclonal with a reversed T4/T8 ratio ៉ Serologic testing for heterophile antibodies

Prognosis and Treatment

Differential Diagnosis and Pitfalls

៉ Self-limited; death in <1% of cases owing to complications of

៉ Reactive lymphoid hyperplasia ៉ Large cell non-Hodgkin lymphoma ៉ Hodgkin lymphoma

EBV infection ៉ Treatment is supportive in most instances

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population, and a reversed CD4 : CD8 ratio with an increase in cytotoxic CD8 suppressor T cells.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

FIGURE 3-8 Infectious mononucleosis. A nearly monotonous population of immunoblasts mimicking a large cell lymphoma is present. These cell nuclei are enlarged with slight irregularity of their nuclear outline. Nucleoli are not particularly obvious with the Romanowsky stain. Note the two much smaller plasmacytoid lymphocytes in the center of the field and one at 9 o’clock with focal perinuclear clearing and eccentric nuclear positioning. Romanowsky stain, high power.

FIGURE 3-9 Infectious mononucleosis. A mixture of immunoblasts, plasmacytoid lymphocytes, and small lymphocytes is seen. There is marked basophilia of the immunoblast cytoplasmic periphery. The intermediate-sized plasmacytoid lymphocytes display small zones of perinuclear clearing. Romanowsky stain, high power.

the principal diagnostic serologic test for infectious mononucleosis. These are present in almost 70% of patients after the first week of symptom onset. Almost 20% of patients, however, have a negative heterophile test; this percentage is even higher in children less than 5 years of age. FCM is the principal ancillary study that should be performed from the FNA-captured cells. This will demonstrate a polyclonal lymphocyte

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Distinguishing infectious mononucleosis from reactive lymphoid hyperplasia requires recognition of the increased number of immunoblasts and plasmacytoid monocytes coupled with the clinical picture. Unlike reactive lymphoid hyperplasia, tingible-body macrophages and follicular center cell fragments are only a minor component of the infectious mononucleosis smear, if present at all. However, very early in the course of infectious mononucleosis, lymphadenopathy may demonstrate only a florid reactive lymphoid hyperplasia type of smear, without the large population of immunoblasts and centroblasts, making infectious mononucleosis indistinguishable from an early phase reactive lymph node. Other causes of nodal immunoblast proliferation such as anticonvulsant-induced lymphadenopathy, herpes simplex lymphadenitis, and drug hypersensitivity are cytologically identical to infectious mononucleosis. Clinical and serologic data combined with the cytopathology are therefore necessary to establish a specific diagnosis. Infectious mononucleosis may be confused for large cell NHL cytologically and clinically, since a small number of lymphoma patients may present with infectious mononucleosis-like clinical symptoms. Smears of large cell lymphoma exhibit greater cell monotony, do not show the range of lymphocyte types seen in infectious mononucleosis, and uncommonly possess the prominent plasmacytoid cell population. With FCM, large B-cell lymphoma will demonstrate monoclonality. Since a small number of proliferating immunoblasts in infectious mononucleosis may exhibit binucleation, Hodgkin lymphoma may enter into the differential diagnosis. True Reed-Sternberg cells have pale cytoplasm rather than the basophilic cytoplasm of B immunoblasts, and their enlarged nucleoli are much larger than those seen in the immunoblasts of infectious mononucleosis.

HODGKIN LYMPHOMA CLINICAL FEATURES Hodgkin lymphoma (HL) is considered a B-cell lymphoma defined by its unique pathologic features. The incidence is 2–4 per 100,000 in the United States, with a broad age range, peaking in the second to fourth decades. A smaller spike occurs in the elderly, but this may be artificial. HL comprises up to 35% of all lymphomas in Caucasians, but only 5–10% of all lymphomas that develop in Orientals. HL is slightly more common (1.5 : 1) in males. Clinically, patients present

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HODGKIN LYMPHOMA – DISEASE FACT SHEET Definition ៉ A lymphoma composed of cytologically abnormal cells termed

Reed-Sternberg (R-S) cells and Hodgkin cells residing in a polymorphous mixture of lymphocytes and other inflammatory cells Incidence ៉ A wide variation globally ៉ 2–4 per 100,000 in the US and western Europe; uncommon in

Asian populations

HODGKIN LYMPHOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Spectrum of lymphocytes with classic mirror-image ReedSternberg (R-S) cells or mononuclear variants ៉ R-S cell: enlarged (≥20 μm), binucleated or mononucleated, enlarged nucleus, polylobated nucleus, enlarged misshapen nucleolus, meager to moderate amount of pale cytoplasm ៉ Acute infl ammation and necrosis infrequent ៉ Small granulomas possible Ancillary Studies ៉ Classical Hodgkin lymphoma: R-S cells positive for CD15, CD30,

Gender and Age Distribution ៉ Peak age is 15–35 years with a smaller peak in the 60s; rare before 10 years in the US ៉ Slightly more common in males Clinical Features ៉ Peripheral lymphadenopathy (cervical nodes most common) with single or multiple matted nodes above or below the diaphragm and mediastinum; extranodal involvement rare ៉ Node(s) often firm to palpation ៉ Symptoms: fever, night sweats, weight loss, pruritus

and fascin; negative for CD20 ៉ Nodular lymphocyte-predominant Hodgkin lymphoma: R-S cells

positive for CD20, CD45, and EMA; negative for CD15 and CD30 Differential Diagnosis and Pitfalls ៉ Reactive lymphoid hyperplasia ៉ Large cell non-Hodgkin lymphoma ៉ Infectious mononucleosis

Prognosis and Treatment ៉ Curable in >90% with stage I–II disease ៉ Multiagent chemotherapy, radiotherapy, or both

with painless enlargement of cervical or mediastinal lymph nodes. A single node or group of nodes may be encountered. About 10% also have constitutional symptoms of fever, weight loss, pruritis, and drenching night sweats. No clinical laboratory test is specific for HL. Prognosis is related to clinical stage; overall 5-year survival is >95% for stage I and II disease with chemotherapy or radiotherapy regimens.

CYTOPATHOLOGIC FEATURES Aspirates may be hyper- or hypocellular depending on the degree of sclerosis in the affected node. Smears mimic those of reactive lymphoid hyperplasia at lowpower examination with a range of various types of lymphocytes present. Key to this diagnosis is the ability to identify Reed-Sternberg (R-S) cells. The classic binucleated R-S cell is, in most instances, not easily found. Rather, one must be able to appreciate the presence of enlarged mononuclear R-S variants in a heterogeneous lymphocytic milieu that simulates reactive hyperplasia (Fig. 3-10). These mononuclear so-called Hodgkin cells (typically readily identifiable at medium power) are markedly enlarged (20–30 μm) with rounded smooth or lobated nuclear contours and a moderate amount of pale, i.e. non-basophilic, cytoplasm. Hodgkin cells have

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single macronuclei and macronucleoli. Nucleoli are often comparable to the diameter of red cells in the same field, and are often misshapen rather than smooth and round (Fig. 3-11). Various combinations of nuclear number and appearance can be seen (Fig. 3-12). The classic R-S cell is binucleated with the same nuclear and cytoplasmic characteristics as the mononuclear form (Fig. 3-13). In some cases, only bare R-S nuclei are seen, making the diagnosis much more challenging. These abnormal cells are randomly scattered in a heterogeneous background of lymphocytes. Plasma cells and eosinophils may be increased in these smears, and necrosis is also possible. Small, poorly formed clusters of epithelioid histiocytes typical of granulomas are very infrequent. A very small number of HL cases are associated with neutrophilic inflammation. These examples of so-called suppurative HL contain R-S cells admixed with acute inflammatory cells.

ANCILLARY STUDIES FCM has no role to play in the diagnosis of HL itself, but has if one is also strongly considering large cell lymphoma in the differential diagnosis. One should attempt to collect cells for a paraffin-embedded cell block or cytospin preparation from aspirated cells, so immunostaining is possible. Classical HL, which comprises 90% of HL cases, has a completely different phenotype than nodular lymphocyte-predominant HL (Table 3-1). Without such immunophenotyping, the ability to separate HL into its two major subtypes using cytology alone is compromised.

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A

B

FIGURE 3-10 Hodgkin lymphoma, mononuclear Reed-Sternberg (R-S) cells. A, Two mononuclear R-S variants (center) are nearly hidden in this polymorphous lymphocytic focus. At this power, their recognition depends primarily on their size in relation to the lymphocytes surrounding them. Nuclear streaking is most likely secondary to the sclerosis that was present in this case of classical Hodgkin lymphoma, nodular sclerosis type. Romanowsky stain, medium power. B, This image is almost identical to (A), except for the stain. Note how much more obvious the macronucleoli appear, even though the cells are partially obscured by the smeared nuclear chromatin of small lymphocytes. Papanicolaou stain, medium power.

TABLE 3-1 Immunophenotyping of Classical and Nodular Lymphocyte-Predominant Hodgkin Lymphoma R-S cells

Classical HL

NLP HL

CD45 CD15 CD30 EMA Fascin CD20

Negative Positive/negative Positive (may be weak) Negative Positive Negative/positive

Positive Negative Negative/positive Positive/negative Negative Positive

R-S, Reed-Sternberg; HL, Hodgkin lymphoma; NLP, nodular lymphocyte-predominant; EMA, epithelial membrane antigen. FIGURE 3-11 Hodgkin lymphoma, mononuclear Reed-Sternberg (R-S) cell. A mononuclear R-S cell is just to the right of center. The macronucleus is very faintly lobated, and contains an enlarged rounded nucleolus. Note the pale cytoplasm that lacks vacuoles. Small lymphocytes predominate in this field, but an eosinophil lies directly to the left of the R-S cell, and a vacuolated histiocyte is at the lower left. Romanowsky stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of HL includes large cell lymphoma, reactive lymphoid hyperplasia, and infectious mononucleosis. Failure to capture R-S cells in the aspirate, and secondarily the inability to identify them in a polymorphous lymphocyte background are the

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principal sources of error. Since most examples of HL belong to the nodular sclerosis subtype, FNA of sclerotic nodes may lead to an absence or insufficient number of R-S cells. A way to avoid this is to aspirate not just the firm large node, but also a smaller node in the same field. The latter often will have much less sclerosis, and therefore enough R-S cells are extracted for identification. Some cases of HL will have R-S cells in clusters rather than as isolated randomly dispersed structures, thus invoking a possible diagnosis of large cell NHL. Large cell lymphoma aspirates do not exhibit the reactive lymphoid hyperplasia-type of accompanying cell types seen in HL. Rather, large cells most often populate smears, sometimes with a minor population of small lympho-

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A

B

FIGURE 3-12 Hodgkin lymphoma, Reed-Sternberg (R-S) variants. A, This enlarged cell with voluminous pale chromatin contains a dual set of mirror-image macronuclei and macronucleoli. Romanowsky stain, high power. B, Enlarged reddish nucleoli in this trinucleated R-S variant display an asymmetric rectangular shape, unlike the rounded edges in the prior image. Note the marked size difference between this R-S cell and the background lymphocytes. Papanicolaou stain, high power.

immunoblasts, dendritic cells, plasmablasts, malignant melanocytes, and, less often, the cells of a sarcoma or large cell carcinoma (Fig. 3-14).

NON-HODGKIN LYMPHOMA, SMALL CELL TYPES CLINICAL FEATURES

FIGURE 3-13 Hodgkin lymphoma, classic Reed-Sternberg (R-S) cell. Of the three R-S cells in this field, only the one on the far right shows the classic ‘owl’s eye’ binucleation with round macronucleoli. The one in the middle is a typical mononuclear so-called ‘Hodgkin cell’, and the cell at the far left is multilobated with macronucleoli that are out of the focal plane. Neutrophils are common in this field. Papanicolaou stain, high power.

cytes. The malignant cells in large cell NHL also do not typically display the marked macronucleoli typical of R-S cells. FCM can be used to demonstrate light chain restriction in large B-cell NHL or an aberrant T-cell phenotype in T-cell NHL. A binucleated cell(s) with mirror-image nucleo- and nucleolomegaly is not diagnostic of an R-S cell. This cell must exist in the proper milieu of a polymorphous lymphocyte background to be considered an R-S cell. Binucleated cells that can be confused as R-S cells include

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The major small cell types of NHL include follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, and marginal zone lymphoma (Table 3-2). Nearly all types appear in middle-age or older individuals, and are rare in children. Gender preference is dependent on NHL subtype. Men are affected more often (5 : 1) with mantle cell lymphoma, almost equal incidence occurs with follicular lymphoma and small lymphocytic lymphoma, and a slight female predominance exists with marginal zone lymphoma. With the exception of mantle cell lymphoma, these lymphomas are biologically indolent, but persistent. About 50,000 newly diagnosed patients (includes all types of NHL) in all age groups present yearly in the United States (16 per 100,000). Of these pathologic subtypes, follicular lymphoma is commonest (20–25% of cases), with mantle cell lymphoma (6%), small lymphocytic lymphoma (6%), and marginal zone lymphoma (7%) occurring less often. Most patients present with asymptomatic peripheral lymphadenopathy. Localized (stage I) disease is uncommon for this group, with the exception of marginal zone lymphoma, which is most commonly an extranodal disease (lymphoma of mucosa-associated

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A

B

C

D

FIGURE 3-14 Reed-Sternberg (R-S) cell look-alikes. A, Plasma cell myeloma. A large binucleated cell with nuclear sameness and equally sized nucleoli is surrounded by a single cell pattern of smaller cells. These smaller forms are the key to the diagnosis. They are relatively monotonous (unlike the milieu of Hodgkin lymphoma) with cytologic features of plasma cells. Papanicolaou stain, high power. B, Non-small cell carcinoma, metastatic. A binucleated cell with nucleo- and nucleolomegaly has the typical morphologic features of an R-S cell. Yet, the surrounding cells are not lymphocytes, but large epithelial cells in a single cell pattern. Papanicolaou stain, high power. C, Malignant melanoma, metastatic. An imitation R-S cell exists in the setting of monotonous cells with plasmacytoid features typical of melanoma. Note the enlarged and misshapen nucleoli in the R-S look-alike. Papanicolaou stain, high power. D, Small lymphocytic lymphoma. A binucleated immunoblast in the center of this image is surrounded by monotonous rather than polymorphic lymphocytes. Note the absence of marked nucleolomegaly in this immunoblast. Romanowsky stain, high power.

NON-HODGKIN LYMPHOMA, SMALL CELL TYPE – DISEASE FACT SHEET Definition ៉ A lymphoma composed of relatively monotonous ‘small lymphocytes’; vast majority are B-cell Incidence ៉ 16 per 100,000 in the US and Australia; much less in Asia, Africa,

and South America ៉ Follicular lymphoma, marginal zone lymphoma, small lymphocytic

Clinical Features ៉ Localized or diffuse lymphadenopathy ៉ Peripheral blood and/or bone marrow involvement possible ៉ Extranodal presentation (parotid, periorbital, thyroid) typically MALT lymphoma ៉ Node(s) rubbery or firm Prognosis and Treatment ៉ Aggressive to indolent, depending on subtype and International Prognostic Index ៉ Multiagent chemotherapy

lymphoma, and mantle cell lymphoma types are the most common Gender and Age Distribution ៉ Median age is 50–70 years ៉ Slight male predominance overall, but varies with subtype

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TABLE 3-2 WHO Classification of Lymphoid Tissue, B-Cell Neoplasms* • Precursor B-cell lymphoblastic leukemia/lymphoma • Mature B-cell neoplasms B-cell CLL/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Mantle cell lymphoma Follicular lymphoma Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type Nodal marginal zone lymphoma with or without monocytoid B-cells Splenic marginal zone B-cell lymphoma Hairy cell leukemia Diffuse large B-cell lymphoma Subtypes: mediastinal (thymic), intravascular, primary effusion Burkitt lymphoma Plasmacytoma Plasma cell myeloma *More common entities are in bold font.

lymphoid tissue, i.e. MALT lymphoma). The International Prognostic Index, which factors in patient age, performance status, serum LDH level, number of extranodal sites, and clinical stage, is commonly used to predict survival.

NON-HODGKIN LYMPHOMA, SMALL CELL TYPE – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Relatively monotonous small lymphocyte population lacking cellular heterogeneity ៉ Evenly dispersed nucleoplasm with small or indistinct nucleoli, smooth or irregular nuclear contour, sparse cytoplasm in small lymphocytes ៉ Minor population of slightly larger ‘transformed’ lymphocytes depending on subtype ៉ Dendritic/lymphocytic aggregates most common in follicular lymphoma; uncommon in other subtypes ៉ Tingible-body macrophages are uncommon Ancillary Studies ៉ Light chain restriction; surface Ig+ ៉ CD5+ = small lymphocytic lymphoma (CD23+) or mantle cell

lymphoma (CD23−) ៉ CD5− = follicular lymphoma (CD10 ±, bcl-6+) or marginal zone

lymphoma (CD10−) Differential Diagnosis and Pitfalls ៉ Distinction among various subtypes of small cell non-Hodgkin lymphoma requires ancillary studies ៉ Reactive lymphoid hyperplasia. ៉ Small cell neuroendocrine carcinoma ៉ Myeloid (granulocytic) sarcoma

typically lacking tingible-body macrophages. Dendritic cells can be particularly prominent. Some examples of follicular lymphoma show pronounced plasmacytoid differentiation. Attempts to grade follicular lymphoma by counting the percentage of large centrocytic/centroblastic cells have been made.

CYTOPATHOLOGIC FEATURES M ANTLE CELL LYMPHOMA

Except for marginal zone lymphoma, a morphologic feature common to this group is highly cellular smears with an almost monotonous population of small lymphocytes, that is, cells with small rounded or irregular nuclei, no visible nucleoli, fine or coarse nuclear chromatin, and meager, attenuated cytoplasm. A dispersed single cell pattern is the rule (with the exception of dendritic/lymphocytic aggregates), and lymphoglandular bodies are numerous. Differences are listed for each subtype.

These are highly cellular smears with almost a pure population of small to intermediate-sized rounded lymphocytes. Nuclear notches and grooves are uncommon, or at least much less exaggerated than seen in follicular lymphoma, but some cases have nuclear contour irregularity (Fig. 3-16). Plasmacytoid monocytes, tingiblebody macrophages, dendritic/lymphocytic aggregates, follicular center cell fragments, and larger lymphocytes such as centroblasts are often not seen. A blastoid variant mimics the cytologic morphology of lymphoblastic lymphoma (see below).

FOLLICULAR LYMPHOMA

Follicular lymphoma smears are composed of monotonous small lymphocytes, or a mixture of small lymphocytes and larger transformed centrocytes and centroblasts. Indentations, grooves, and small projections are markers of nuclear irregularity which is common to follicular lymphoma; some grooves/clefts appear to bisect the nucleus (Fig. 3-15). Dendritic/lymphocytic aggregates are common also in follicular lymphoma smears, as are follicular center cell fragments, but the latter are

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SMALL LYMPHOCYTIC LYMPHOMA

Small lymphocytic lymphoma is the nodal counterpart of chronic lymphocytic leukemia (CLL). The cytopathology overlaps with follicular lymphoma and mantle cell lymphoma, due to a predominance of small lymphocytes and the near exclusion of other types of lymphocytes. The nuclei of small lymphocytic lymphoma have a clumped chromatin pattern, and are smooth or minimally irregular (Fig. 3-17). A small population of large

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A

B

FIGURE 3-15 Follicular lymphoma. A, The focus of these matching small lymphocytes is the irregular shape of their nuclear membrane. In some there is only a minimal indentation (almost reniform), while others show deep clefts in the nucleus. Nucleoplasm is evenly dispersed without visible nucleoli, and only a meager amount of cytoplasm is seen. Romanowsky stain, high power. B, A two-cell population of very darkly stained small lymphocytes, and larger lymphocytes with small to intermediate amounts of cytoplasm is present. However, a true range of lymphocytes is absent. This dual population of small–intermediate-size lymphocytes is common in grades I and II follicular lymphoma. A dendritic/lymphocytic aggregate is noticeable at the lower right corner. Romanowsky stain, high power.

FIGURE 3-16 Mantle cell lymphoma. These small, almost identical lymphocytes have such a high N/C ratio that they appear to be bare nuclei, but an extremely attenuated rim of cytoplasm is present. Lymphoglandular bodies are not well seen with this stain. Note the tingible-body macrophage in the upper left corner. Papanicolaou stain, high power.

FIGURE 3-17 Small lymphocytic lymphoma. Small morphologically equivalent lymphocytes show some nuclear molding, and focal perinuclear clearing suggesting plasmacytoid differentiation. Note the abundant lymphoglandular bodies. Romanowsky stain, high power.

M ARGINAL ZONE LYMPHOMA

transformed cells corresponding to pseudofollicular growth centers is present. These large lymphocytes represent prolymphocytes and paraimmunoblasts. In smears, it is difficult to distinguish them from each other; however, it is not necessary to do so. Both are two to three times the diameter of small lymphocytes, and have a visible nucleolus and a moderate amount of pale or basophilic cytoplasm.

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Aspirates, particularly those of extranodal tissue, show variable cytomorphology. In some cases, a more or less monomorphous lymphocyte population is seen, while in others the composition is one of lymphocytic heterogeneity that imitates a reactive condition. Mixed small and large lymphocytes having round, smooth or irregular nuclei can be seen. Follicular dendritic cells, plasmacytoid monocytes, follicular center cell fragments,

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Unfortunately, lymphomas do not exhibit strict immunologic fidelity, nor are lymphocyte markers present and absent in 100% of cases. Molecular methods have been introduced recently to overcome this handicap. Mantle cell lymphoma has a t(11;14)(q13;q32) translocation in almost 75% of patients that produces an upregulation of the bcl-1(PRAD1) gene, which in turn leads to overexpression of a protein termed cyclin D1. Follicular lymphoma is characterized by a t(14;18) translocation with rearrangement of the bcl-2 gene in over 75% of cases. These cytogenetic abnormalities are currently being exploited by interphase FISH using commercially available probes to detect abnormal nuclear fusion signals from FNA specimens, thus improving diagnostic specificity.

FIGURE 3-18 Marginal zone lymphoma, nodal. These monocytoid lymphocytes contain slightly more visible cytoplasm, but their cellular sameness mimics that of other small cell forms of lymphoma. The extranodal form of marginal zone lymphoma is typically more heterogeneous. Romanowsky stain, high power.

TABLE 3-3 Immunophenotyping of Small Cell B-Cell Lymphomas Marker

SLL

MtCL

FL

MZL

CD5 CD10 CD20 CD23 FMC-7 CD43 Tdt

Pos Neg Pos/neg Pos Neg Pos Neg

Pos Neg/pos Pos Neg Pos Pos Neg

Neg Pos/neg Pos Neg/pos Pos Neg Neg

Neg Neg Pos Neg Pos Neg/pos Neg

SLL, small lymphocytic lymphoma; MtCL, mantle cell lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma; pos/neg, majority of cases are positive, small percentage negative; neg/pos, majority of cases are negative, small percentage positive.

immunoblasts, tingible-body macrophages, and plasma cells are all possible. Monocytoid lymphocytes, those having smooth rounded nuclei and a moderate amount of pale cytoplasm, are variable in number (Fig. 3-18).

ANCILLARY STUDIES Because a large degree of morphologic overlap exists among this group of NHL, it is imperative to phenotype these aspirates for specific subclassification. This is best accomplished using FCM whereby the application of various surface markers is employed (Table 3-3).

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DIFFERENTIAL DIAGNOSIS AND PITFALLS Without doubt, the most important differential decision is to accurately separate any small cell lymphoma from reactive lymphoid hyperplasia. In most cases, this is readily accomplished by light microscopy alone, due to the lymphocyte monotony of the former and heterogeneity of the latter. However, since small cell lymphoma populations are not pure, those having any variation in cell size and type can cause confusion with reactive lymphoid hyperplasia. This problem is most acute with follicular lymphoma, where a mixture of small and large lymphocytes in nearly equal numbers is possible, and not uncommon. If one looks carefully at each of these forms of small cell lymphoma (except for marginal zone lymphoma), it is rare indeed for them to show a true range of lymphocyte forms (immunoblasts, plasmacytoid monocytes, and tingible-body macrophages) as occurs in a reactive lymphoid hyperplasia smear. That said, these different cell types can be present in small cell lymphoma smears, but only as a minor population, and even more importantly it is rare for all the various cell elements to exist in similar percentages as they do in reactive lymphoid hyperplasia. Thus, immunophenotyping is currently the best protection the cytopathologist has in not confusing a small cell type of NHL for reactive lymphoid hyperplasia. Small cell neuroendocrine carcinoma consists of cells that are about three times the size of small lymphocytes, and show no range in cell types. Instead, because of their high cell turnover, a two-cell population of viable intact cells and apoptotic cells characterized by pyknotic, karyorrhectic nuclei exists (Fig. 3-19). This invariably creates smears having abundant background necrosis. Necrosis can be seen in small cell lymphomas, but is distinctly unusual. Smearing or streaking of nuclei is non-specific, since it is present in both lymphoma and carcinoma. Although small cell neuroendocrine carcinoma cells have a high nuclear to cytoplasmic (N/C) ratio and may superficially resemble small lymphocytes, they display clustering, crowding, and ‘molding’ of their nuclei into one another. This is not to say that nuclear molding is completely absent in all small cell

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A

B

FIGURE 3-19 Small cell neuroendocrine carcinoma, metastatic. A, Although a few dissociated cells are found, most are arranged in these small compressed aggregates leading to angulated distortion of nuclear shapes. Romanowsky stain, high power. B, Markedly hyperchromatic nuclei cling together loosely. Note that some of these have an angulated or spindle shape. The abundant necrosis creates numerous lymphoglandular body look-alikes, particularly with this stain. Papanicolaou stain, high power.

lymphomas, but when present is less florid than that seen in carcinoma. A search for lymphoglandular bodies in small cell neuroendocrine carcinoma will uncover cell debris fragments, but not the globular, vacuolated structures that are common to lymphoma. Myeloid (granulocytic) sarcoma is a rare tumor of myeloid precursors that can arise in extramedullary sites prior to (rare) or concurrent with acute myeloid leukemia. Skin and soft tissue are preferred sites. The blastic immature types have features of small or intermediate-size lymphoma with a single cell pattern, high N/C ratio, and minimal cytoplasm. Lymphoglandular bodies can be present. The more differentiated forms of myeloid sarcoma show a spectrum of myeloid differentiation with granulated promyelocytes, metamyelocytes, or band forms seen. Immunophenotyping shows expression of myeloid markers CD13, CD33, CD43, and myeloperoxidase.

NON-HODGKIN LYMPHOMA, LARGE CELL TYPES

NON-HODGKIN LYMPHOMA, LARGE CELL TYPES – DISEASE FACT SHEET Definition ៉ A lymphoma composed of relatively monotonous ‘large lymphocytes’; majority are B-cell, 10–12% are T-cell Incidence ៉ 30–40% of all adult lymphomas ៉ T-cell lymphomas are more common in Asians

Gender and Age Distribution ៉ Broad age range, from children to elderly; peak age in 7th decade

in adults ៉ Slightly more common in men

Clinical Features ៉ Localized or diffuse adenopathy, extranodal disease ៉ Symptoms: fever, night sweats, weight loss, pruritus ៉ Node(s) often firm to palpation

Prognosis and Treatment ៉ Aggressive, potentially curable ៉ Multiagent chemotherapy

CLINICAL FEATURES Large cell lymphomas encompass malignancies derived from B, T, or NK cells. Of these, diffuse large B-cell lymphoma is most common, constituting about 35– 40% of all adult lymphomas in Western Europe and North America (about 25,000 new cases annually) and about one-third of pediatric lymphomas. A higher incidence of large cell lymphoma exists in developing coun-

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tries and in immunosuppressed patients. In the T-cell group, anaplastic large cell lymphoma and peripheral T-cell lymphoma are most common (Table 3-4). T-cell lymphomas comprise about 10% of all NHL in North America, and about twice that percentage in Asia. The median age in adults of large cell lymphomas is 70 years, but there is a broad age range. Anaplastic large

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CYTOPATHOLOGIC FEATURES TABLE 3-4 WHO Classification of Lymphoid Tissue, T-Cell Neoplasms* • Precursor T-cell lymphoblastic leukemia/lymphoma • Mature T-cell and NK-cell neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia NK-cell leukemia Extranodal NK-/T-cell lymphoma, nasal type Mycosis fungoides Sézary syndrome Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma Adult T-cell leukemia/lymphoma (HTLV1) Systemic anaplastic large cell lymphoma (T- and null-cell types) Primary cutaneous anaplastic large cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Enteropathy-type intestinal T-cell lymphoma Hepatosplenic γ/δ T-cell lymphoma *More common entities are in bold font.

cell lymphoma and diffuse large B-cell lymphoma, for example, are the two most common forms of childhood/ young adult large cell lymphoma. Men are affected slightly more than women in diffuse large B-cell lymphoma, but there is a marked male predominance (6 : 1) for anaplastic large cell lymphoma. A rapidly enlarging mass, either nodal or extranodal, is the usual presenting complaint. Extranodal sites include the gastrointestinal tract (most common), skin, mediastinum, soft tissue, bone, central nervous system, and salivary gland. Disseminated disease at the time of diagnosis is common. The International Prognostic Index is predictive of survival. Only about 40% of patients with diffuse large B-cell lymphoma are cured with polychemotherapy. Gene expression profi ling has recently been introduced to develop molecularly distinct portraits of diffuse large B-cell lymphoma (and, parenthetically, follicular lymphoma also) to predict survival and thus target patients for various types of chemotherapy regimens. In anaplastic large cell lymphoma, a relatively homogeneous group defined by a specific cytogenetic abnormality has emerged. These patients develop systemic disease in the first three decades of life, and their lymphomas are associated with a specific translocation, t(2;5)(p23;q35), which fuses the ALK gene with the NPM gene, thereby producing a protein (anaplastic large cell lymphoma kinase) to which antibodies have been developed. These patients have a much improved prognosis (70% 5-year survival) than their anaplastic large cell lymphoma kinase-negative counterparts (30% 5-year survival).

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Common to all forms of large cell lymphoma is an aspirate smear containing a predominance of large lymphocytes. These range from two to five times the diameter of small mature lymphocytes. In some examples, large lymphocytes are the only cell type found, but in most cases there is a minor population of small lymphocytes. In diffuse large B-cell lymphoma, centroblastic-type cells are most commonly seen, with a smaller number of cases having immunoblastic features. Nuclei vary from smooth rounded structures to those with irregular contours, finely dispersed or coarse chromatin, and variable presence of nucleoli; single macronucleoli are characteristic of the immunoblastic variant of diffuse large B-cell lymphoma (Fig. 3-20). Binucleated, multinucleated, multilobated, and reniform nuclei can be seen, particularly with anaplastic large cell lymphoma (Fig. 3-21). A greater amount of cytoplasm is present when compared with the small cell lymphoma group. It is often deeply basophilic in Romanowsky-stained smears, and small cytoplasmic vacuoles are not uncommon. Tingible-body macrophages and individual cell necrosis are also more frequent in large cell lymphomas than in the small cell category; there is a paucity of follicular center cell fragments. As in all examples of lymph node aspirates, nuclear streaking and smearing are not uncommon; this is particularly evident in those large cell lymphomas associated with sclerosis. Although peripheral T-cell lymphoma aspirates are discussed in this section of large cell lymphoma, their

NON-HODGKIN LYMPHOMA, LARGE CELL TYPES – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Relatively monotonous large lymphocytes ៉ Nuclear size equal to or exceeds that of macrophage; 2–5 times larger than mature lymphocyte ៉ Nucleoli common, but not universal ៉ Nuclear pleomorphism with lobulated, indented nuclei and multiple nuclei common in anaplastic large cell lymphoma ៉ Cytoplasm moderate to abundant; can be vacuolated ៉ Variable tingible-body macrophages and necrosis Ancillary Studies ៉ Immunophenotyping best accomplished using flow cytometry ៉ B-cell: light chain restriction; positive for CD20 and CD19;

variable CD10, surface Ig, aberrant CD43 expression ៉ T-cell: aberrant phenotype with loss of CD7, CD5, or CD2;

positive for CD3, CD43, and CD30 ៉ PCR: clonally rearranged T-cell receptor genes

Differential Diagnosis and Pitfalls ៉ Infectious mononucleosis ៉ Hodgkin lymphoma ៉ Non-lymphoid large cell malignancies

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FIGURE 3-20 Diffuse large B-cell lymphoma. Large lymphocytes contain one or more nucleoli in hypochromatic vesicular nuclei. A second population of darkly stained small lymphocytes is not uncommon in large cell lymphoma. Papanicolaou stain, high power.

FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 3-22 Peripheral T-cell lymphoma, unspecified. A mixture of lymphoid cells is present, including an immunoblast (right of center), several large lymphocytes harboring visible nucleoli, plasmacytoid lymphocytes, and even an eosinophil (far left). This cytomorphology is not specific, but is typical of this lymphoma. Romanowsky stain, high power.

their absence could be a clue that one is not dealing with a normal population of lymphocytes.

ANCILLARY STUDIES

FIGURE 3-21 Anaplastic large cell lymphoma. All lymphocytes in this field are large, with some more anaplastic than others. Several nuclei have reniform configurations which are typical, but not pathognomonic, of this lymphoma. Romanowsky stain, high power.

cytomorphology is much more heterogeneous than that of diffuse large B-cell lymphoma or anaplastic large cell lymphoma. These smears may be composed of an overwhelmingly monomorphous population of large cells similar to any large cell NHL. However, many examples exhibit a mixture of small, intermediate-sized, and large lymphocytes reminiscent of reactive lymphoid hyperplasia (Fig. 3-22). A variable number of plasma cells, eosinophils, and histiocytes can be present. Follicular center cell fragments and tingible-body macrophages are uncommon to rare in peripheral T-cell lymphoma, and

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Immunophenotyping using FCM is the most efficacious method for determining light chain restriction, and thus B-cell monoclonality. Nearly all are positive for surface Ig and CD19, with variable expression of CD10, CD22, CD23, and FMC-7. For T-cell lymphomas, immunophenotyping will show an absence of B-cell markers and a variable panel of T-cell marker (CD1a, CD2, CD3, CD4, CD5, CD7, CD8) positivity. Typically, a loss of one or more of these markers, particularly CD7, or combined absence of CD4/CD8 is seen. The term anaplastic large cell lymphoma is currently restricted to CD30-positive T- and null-cell lymphomas. CD30 is typically added to an FCM panel if a large lymphocyte population is observed. PCR analysis of T-cell receptor (TCR) beta gene rearrangement is the most specific test to determine clonality of a T-cell lymphoma. This can be accomplished using PCR fragment size analysis of the FNA material, for which instruments are commercially available.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The high percentage of immunoblasts makes infectious mononucleosis a mimicker of large cell lymphoma. Close examination of the infectious mononucleosis smear will show a subpopulation of plasmacytoid

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FIGURE 3-23 Nasopharyngeal carcinoma, metastatic. A discrete tight cluster of epithelial cells to the right of center is surrounded and infiltrated by small lymphocytes. Note that epithelial cell nuclei lack discrete nucleoli, but are about three times larger than the lymphocyte population. Papanicolaou stain, high power.

FIGURE 3-24 Seminoma, metastatic. A mixture of large germ cells and smaller lymphocytes are set in a distinctive background of reticulated cytoplasm (so-called ‘tigroid background’). Some of the germ cells contain one or more visible nucleoli and a moderate amount of cytoplasm. Bare germ cell nuclei are also present (lower right). Romanowsky stain, high power.

lymphocytes, and some plasma cells. Immunophenotyping will demonstrate the polyclonality typical of infectious mononucleosis. HL has occasionally been mistaken as a large cell lymphoma also. Cells having the morphologic features of R-S cells have been seen in all forms of large cell lymphoma. The key to avoiding this trap of mistaking such cells as true R-S cells lies in examination of all components that exist in the smear. With HL, the smear background simulates that of reactive lymphoid hyperplasia, whereas in large cell lymphomas it lacks this lymphocytic heterogeneity. The two principal non-small cell carcinomas metastatic to lymph nodes, metastatic squamous cell carcinoma and adenocarcinoma, are rarely mistaken as large cell lymphoma, since they typically lack lymphoglandular bodies and nearly always display some cell aggregation. Metastatic nasopharyngeal carcinoma, undifferentiated type, however, can be misdiagnosed as lymphoma for several reasons. First, patients frequently present with an enlarged cervical node like lymphoma, bypassing the usual clinical scenario where an individual is known to have cancer and only then develops lymphadenopathy. Also, lymphocytes are a normal constituent of this tumor; therefore, lymphoglandular bodies are present. A range of lymphocytes often commingles with and can sometimes obscure the clusters of malignant epithelial cells (which may be few), and epithelial cells can be dispersed in loose aggregates. Epithelial cells have large nuclei, may or may not have visible nucleoli, and have a small amount of cytoplasm that lacks keratinization due to their undifferentiated state (Fig. 3-23). Cytokeratin staining of the smear may be necessary to fully characterize these cells. Metastatic seminoma should also be considered if the clinical setting is suggestive, such as mediastinal/hilar adenopathy or retroperitoneal lymphadenopathy in a

young adult male. A second population of lymphocytes accompanies the large germ cells. Thus, smears will contain lymphoglandular bodies. Germ cells having large rounded nuclei with enlarged nucleoli are distributed singly or in clusters, bare nuclei are common, and cell cytoplasm is smeared in a reticular pattern, or as short strips, giving the appellation ‘tigroid’ to this pattern (Fig. 3-24). It is important to remember that this pattern is not universally present, nor is it seen well in Papanicolaou- or hematoxylin and eosin (H&E)-stained smears. Malignant melanoma is probably the most frequent mimic of lymphoma since it commonly involves lymph nodes, displays a monomorphic population of cells, has a single cell pattern, is habitually amelanotic, and may present in a patient without a known primary malignancy. Smears lack lymphoglandular bodies. Characteristically, cells are often binucleated with mirror-image nuclei, have intranuclear cytoplasmic inclusions, and cell nuclei eccentrically displaced toward the cytoplasmic edge, giving them a plasma cell-like appearance (Fig. 3-25).

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PEDIATRIC NON-HODGKIN LYMPHOMAS CLINICAL FEATURES The principal lymphomas of childhood include precursor T- and B-cell lymphoblastic, Burkitt, and large cell lymphoma, comprising 30–40%, 40–50%, and 15–25% of cases, respectively. Burkitt lymphoma is rare in the

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FIGURE 3-25 Malignant melanoma, metastatic. A polymorphous population of epithelioid cells is seen. Note that two of these cells have mirror-image nuclei, and three have distinct intranuclear cytoplasmic inclusions. Eccentric nuclear placement in some gives them a plasmacytoid look. Compare the size of these to the small lymphocytes and neutrophils in the background. Papanicolaou stain, high power.

PEDIATRIC NON-HODGKIN LYMPHOMAS – DISEASE FACT SHEET Definition ៉ Lymphoblastic: lymphoma of precursor lymphocytes, 85–90% T-cell ៉ Burkitt: lymphoma of medium-size B cells with translocation involving c-myc gene Incidence ៉ Lymphoblastic lymphoma and Burkitt lymphoma each account for 30–40% of pediatric lymphomas ៉ Burkitt: endemic in equatorial Africa, sporadic in North America/ Europe Gender and Age Distribution ៉ Male to female ratio about 2 : 1 ៉ Peak in 2nd and 3rd decades of life for both

Clinical Features ៉ Lymphoblastic: cervical, supraclavicular, or axillary

lymphadenopathy, 50–80% with anterior mediastinal mass, pleural effusion, dyspnea, wheezing ៉ Burkitt: abdominal visceral disease most common in North America/Europe, head and neck masses less common; associated with EBV infection, AIDS Prognosis and Treatment ៉ 90% survival for stage I and II disease, about 70–80% for stages

III and IV

United States, with only 100–150 new cases annually, compared with in equatorial Africa, where 0.01% of children develop it. Other lymphoma subtypes are exceedingly rare in this age group. Large cell lymphomas can be B-cell, T-cell, or null-cell types; this group is discussed in the section above. In lymphoblastic lymphoma, the male to female ratio is about 2 : 1, with the majority occurring in the older child–adolescent years. Lymphoblastic lymphoma almost always presents as supra-diaphragmatic lymphadenopathy. An anterior mediastinal mass is found in up to 80% of patients. This mass may induce symptoms of bronchial asthma, persistent cough, cyanosis, syncope, or superior vena cava syndrome, and tracheal compression. Burkitt lymphoma is also a neoplasm of adolescence and young adulthood, with a male predominance (2–3 : 1). In developed countries, Burkitt lymphoma presents primarily as an intra-abdominal mass. Some individuals present with signs and symptoms of acute appendicitis. In children, precursor T-cell lymphoblastic lymphoma has a good prognosis, with 70–90% 5-year disease-free survival. The prognosis is worse in adults, with a 5-year disease-free survival of 45–55%. Burkitt lymphoma patients with localized disease or with completely resected abdominal disease can have a long-term survival rate of 90% or more.

CYTOPATHOLOGIC FEATURES Smears of lymphoblastic lymphoma are hypercellular with uniform lymphoid blasts about twice the size of small lymphocytes, having round to convoluted nuclei, finely granular so-called ‘dusty’ chromatin, inconspicuous or small nucleoli, and extremely meager, rarely vacuolated cytoplasm. Tingible-body macrophages may be present (Fig. 3-26). Aspirates of Burkitt lymphoma

PEDIATRIC NON-HODGKIN LYMPHOMAS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Lymphoblastic: monomorphic intermediate-size cells, round or convoluted nuclei, finely granular chromatin, indistinct nucleoli, infrequently vacuolated sparse cytoplasm ៉ Burkitt: monomorphic intermediate-size cells, coarse chromatin, 2–5 nucleoli, commonly vacuolated sparse cytoplasm ៉ Numerous tingible-body macrophages Ancillary Studies ៉ Lymphoblastic: Tdt-positive in both B- and T-cell types; 85–90%

express T-cell antigens ៉ Burkitt: B-cell, Tdt-negative, monoclonal light chain; positive

for surface Ig, CD10, CD19, and CD20; FISH: c-myc translocation

៉ Multiagent chemotherapy for both types

Differential Diagnosis and Pitfalls ៉ Blastoid variant of mantle cell lymphoma ៉ Myeloid (granulocytic) sarcoma ៉ Malignant small round cell tumors of childhood

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mas may be either. Lymphoblastic lymphoma is defined by the near universal presence of Tdt (terminal deoxynucleotidyl transferase), which exists in both T- and B-cell types, and can be analyzed using FCM. A consistent non-random translocation, t(8;14), that involves the c-myc gene occurs with Burkitt lymphoma.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

FIGURE 3-26 Precursor T-cell lymphoblastic lymphoma. An identical population of lymphocytic blasts display delicate, evenly dispersed chromatin without discrete nucleoli, and minimal cytoplasm. Some nuclei show slight unevenness. Smaller, more darkly stained nuclei represent apoptotic cells. Romanowsky stain, high power.

In pediatric patients, the principal diagnostic problem for either lymphoblastic lymphoma or Burkitt lymphoma is to exclude other entities that exist in the category of ‘malignant small round cell tumor’. These include rhabdomyosarcoma, Ewing sarcoma, desmoplastic small round cell tumor, and, less often, neuroblastoma or Wilms tumor. This is often accomplished merely by clinical and radiologic evaluation. The single cell pattern combined with background lymphoglandular bodies will usually suffice to allow categorization of the aspirate as a lymphoma since these two features are absent in the other lesions in this category. A potential pitfall exists if an anterior mediastinal mass is aspirated. Since benign thymocytes are Tdt-positive, one must ensure that cells have a blast morphology. The blastoid variant of mantle cell lymphoma can mimic lymphoblastic lymphoma. Clinically, these patients are not in the same age group as those with lymphoblastic lymphoma. The morphology, however, can be very similar with intermediate to large cells; immunotyping is required. All mantle cell lymphomas are B-cell and lack Tdt. Myeloid sarcoma may occur in children prior to a leukemic phase. The undifferentiated forms can mimic a blastic morphology. FCM shows lack of lymphocytic markers and expression of myeloid markers, as discussed above.

SUGGESTED READINGS Reactive Lymphoid Hyperplasia FIGURE 3-27 Burkitt lymphoma. The prominent feature in these blasts is the coarse chromatin with one to several small nucleoli. Cytoplasmic vacuoles are barely visible in this image (center cell). Mitotic figures are an expected finding in Burkitt lymphoma smears. Romanowsky stain, high power.

show nuclei with coarse chromatin, small nucleoli, and variable cytoplasmic vacuoles. Tingible-body macrophages are more frequent in Burkitt lymphoma smears, but this too is variable (Fig. 3-27).

ANCILLARY STUDIES Most lymphoblastic lymphomas are T-cell (85–90%), all Burkitt lymphomas are B-cell, and large cell lympho-

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Flanders E, Kornstein MJ, Wakely PE Jr, Kardos TF, Frable WJ. Lymphoglandular bodies in fine needle aspiration cytology. Am J Clin Pathol 1993;99:566–569. Geisinger KR, Stanley MW, Raab SS, Silverman JS, Abati A. Lymph nodes and spleen. In: Modern Cytopathology. Philadelphia: ChurchillLivingstone, 2004:643–687. Glant MD. Cytopathology of lymph nodes in nonspecific reactive hyperplasia: prognostication and differential diagnosis. Am J Clin Pathol 1997;108:S31–S55. Wakely PE Jr. Aspiration and touch preparation of lymph nodes. In: Atkinson BF, ed. Atlas of Diagnostic Cytopathology, 2nd ed. Philadelphia: Saunders, 2004:411–458. Wakely PE Jr, Cibas ES. Lymph nodes. In: Cibas ES, Ducatman BS, eds. Cytology: Diagnostic Principles and Clinical Correlates, 2nd ed. Edinburgh: Elsevier, 2003:307–344. Granulomatous Lymphadenopathy Das DK, Bhambhani S, Pant JN, et al. Superficial and deep-seated tuberculous lesions: fine-needle aspiration cytology diagnosis of 574 cases. Diagn Cytopathol 1992;8:211–215.

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92 DeMay RM. Lymph node. In: The Art and Science of Cytopathology. Chicago: ASCP Press, 1996:779–846. Ellison E, Lapuerta P, Martin SE. Fine needle aspiration diagnosis of mycobacterial lymphadenitis. Sensitivity and predictive value in the United States. Acta Cytol 1999;43:153–157. Stanley MW, Horwitz CA, Burton LG, Weisser JA. Negative images of bacilli and mycobacterial infection: a study of fine-needle aspiration smears from lymph nodes in patients with AIDS. Diagn Cytopathol 1990;6: 118–121. Stastny JF, Wakely PE Jr, Frable WJ. Cytologic features of necrotizing granulomatous inflammation consistent with cat scratch disease. Diagn Cytopathol 1996;15:108–115.

Infectious Mononucleosis Kardos TF, Kornstein MJ, Frable WJ. Cytology and immunocytology of infectious mononucleosis in fine needle aspirates of lymph nodes. Acta Cytol 1988;32:722–726. Stanley MW, Steeper TA, Horwitz CA, Burton LG, Strickler JG, Borken S. Fine needle aspiration of lymph nodes in patients with acute infectious mononucleosis. Diagn Cytopathol 1990;6:323–329. Wakely PE Jr. Aspiration and touch preparation of lymph nodes. In: Atkinson BF, ed. Atlas of Diagnostic Cytopathology, 2nd ed. Philadelphia: Saunders, 2004:411–458.

Hodgkin Lymphoma Chhieng DC, Cangiarella JF, Symmans WF, Cohen J-M. Fine-needle aspiration cytology of Hodgkin disease. A study of 89 cases with emphasis on the false-negative cases. Cancer (Cancer Cytopathol) 2001;93:52– 59. Fulciniti F, Vetrani A, Zeppa P, et al. Hodgkin’s disease: diagnostic accuracy of fine needle aspiration; a report based on 62 consecutive cases. Cytopathology 1994;5:226–233. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. Kardos TF, Vinson JH, Behm FG, Frable WJ, O’Dowd GJ. Hodgkin’s disease: diagnosis by fine needle aspiration biopsy. Analysis of cytologic criteria from a selected series. Am J Clin Pathol 1986;86:286–291. Tani E, Ersoz C, Svedmyr E, et al. Fine needle aspiration cytology and immunocytochemistry of Hodgkin’s disease – suppurative type. Diagn Cytopathol 1998;18:437–440.

Non-Hodgkin Lymphoma, Small Cell Types Caraway NP, Gu J, Lin P, et al. The utility of interphase fluorescence in situ hybridization for the detection of the translocation t(11;14)(q13;32) in the diagnosis of mantle cell lymphoma on fine-needle aspiration specimens. Cancer (Cancer Cytopathol) 2005;105:110–118. Chhieng DC, Cohen J-M, Cangiarella JF. Cytology and immunophenotyping of low- and intermediate-grade B-cell non-Hodgkin’s lymphomas with a predominant small-cell component: a study of 56 cases. Diagn Cytopathol 2001;24:90–97. Crapanzano JP, Lin O. Cytologic findings of marginal zone lymphoma. A study of 14 specimens. Cancer (Cancer Cytopathol) 2003;99:301–309.

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FINE NEEDLE ASPIRATION CYTOLOGY Meda BA, Buss DH, Woodruff RD, et al. Diagnosis and subclassification of primary and recurrent lymphomas. The usefulness and limitations of combined fine needle aspiration cytomorphology and flow cytometry. Am J Clin Pathol 2000;113:688–699. Rassidakis GZ, Tani E, Svedmyr E, Porwit A, Skoog L. Diagnosis and subclassification of follicle center and mantle cell lymphomas on fineneedle aspirates. A cytology and immunocytochemical approach based on the revised European-American lymphoma (REAL) classification. Cancer (Cancer Cytopathol) 1999;87:216–223. Suh YK, Shin HJ. Fine-needle aspiration biopsy of granulocytic sarcoma: a clinicopathologic study of 27 cases. Cancer (Cancer Cytopathol) 2000; 90:364–372. Young NA, Al-Saleem T. Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European-American classification of lymphoid neoplasms. Cancer (Cancer Cytopathol) 1999;87:325–345. Zeppa P, Marino G, Troncone G, et al. Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer (Cancer Cytopathol) 2004;102:55–65. Non-Hodgkin Lymphoma, Large Cell Types Al Shanqeety O, Mourad WA. Diagnosis of peripheral T-cell lymphoma by fine-needle aspiration biopsy: a cytomorphologic and immunophenotypic approach. Diagn Cytopathol 2000;23:375–379. Dong HY, Harris NL, Preffer FI, Pitman MB. Fine-needle aspiration biopsy in the diagnosis and classification of primary and recurrent lymphoma: a retrospective analysis of the utility of cytomorphology and flow cytometry. Mod Pathol 2001;14:472–481. Ng W-K, Ip P, Choy C, Collins RJ. Cytologic and immunocytochemical findings of anaplastic large cell lymphoma. Analysis of ten fine-needle aspiration specimens over a 9-year period. Cancer (Cancer Cytopathol) 2003;99:33–43. van Heerde P. Lymph nodes. In: Orell SR, Sterrett GF, Walters MN-I, Whitaker D, eds. Manual and Atlas of Fine Needle Aspiration Biopsy. London: Churchill-Livingstone, 1999:74–108. Yao JL, Cangiarella JF, Cohen J-M, Chhieng DC. Fine-needle aspiration biopsy of peripheral T-cell lymphomas. A cytologic and immunophenotypic study of 33 cases. Cancer (Cancer Cytopathol) 2001;93:151– 159. Pediatric Non-Hodgkin Lymphomas Geisinger KR, Silverman JF, Wakely PE Jr. Pediatric Cytopathology. Chicago: ASCP Press, 1994:201–228. Jacobs JC, Katz RL, Shabb N, et al. Fine needle aspiration of lymphoblastic lymphoma. A multiparameter diagnostic approach. Acta Cytol 1992;36: 887–894. Stastny JF, Almeida MM, Wakely PE Jr, Kornstein MJ, Frable WJ. Fine needle aspiration biopsy and imprint cytology of small non-cleaved cell (Burkitt’s) lymphoma. Diagn Cytopathol 1995;12:201–207. Tani E, Maeda S, Frostad B, et al. Aspiration cytology with phenotyping and clinical presentation of childhood lymphomas. Diagn Oncol 1993;3:294–301. Wakely PE Jr, Kornstein MJ. Aspiration cytopathology of lymphoblastic lymphoma and leukemia: the MCV experience. Pediatr Pathol Lab Med 1996;16:243–252.

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Soft Tissue

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Marlo M Nicolas Ritu Nayar Fadi W Abdul-Karim

INTRODUCTION Fine needle aspiration biopsy (FNAB) is a safe and reliable method for the assessment of soft tissue tumors and tumor-like lesions. Many of these entities have distinctive clinical attributes such as specific age ranges and predilection for certain body sites, so that a limited list of differential diagnoses or a definitive diagnosis can be rendered after cytologic evaluation and clinical correlation. The line of communication between the cytopathologist, radiologist, and clinician should always be open to assure an optimal interpretation of the available material. Familiarity with the various spectra of the histopathologic features of soft tissue lesions is important for interpretation of the FNAB specimens. The cytomorphology of these lesions often reflects the histologic features by which most of these entities are defined. An accompanying cell block (CB) may prove useful in some instances due to the approximation to the native histologic architecture of the lesion. A needle core biopsy (NCB) can establish the histologic specific subtype of a lesion, especially when a diagnosis of sarcoma, not otherwise specified is rendered from FNAB materials. Nevertheless, surgeons are often satisfied with the diagnosis of a low- or high-grade sarcoma, and further subclassification may not be necessary in the immediate management. NCBs are most effective in establishing the diagnosis of soft tissue lesions when employed in instances where the FNAB is unsatisfactory. In the setting of a non-diagnostic NCB or FNAB, an open or excisional biopsy should be obtained for further evaluation. Performance of the FNAB by an experienced pathologist with immediate assessment of adequacy will reduce the number of unsatisfactory specimens and results in better material for interpretation. The pathologist can also, following rapid assessment, triage the specimens for ancillary studies such as DNA ploidy, cytogenetics, and electron microscopy (EM). In selected cases, the judicious application of immunohistochemical stains done on the CB or NCB will aid in narrowing down the differential diagnosis. FNAB is most useful for documenting recurrence or metastases in a patient previously diagnosed with sarcoma. Recurrent and metastatic sarcomas, however, may show significant variations in cell morphology

•

when compared to the primary tumor. Radiation and chemotherapy can induce changes that mimic recurrent disease. In addition, many non-neoplastic, rapidly proliferating or exuberant reactive lesions can have cytologic atypia that approximates that seen in higher-grade sarcomas. Awareness of these changes helps avoid overdiagnosis. This chapter focuses on the cytologic features of soft tissue tumors and tumor-like lesions that are most commonly encountered in the practice of cytopathology.

ADIPOSE TISSUE TUMORS LIPOMA CLINICAL FEATURES Lipomas are composed of mature adipose tissue and are the most common benign soft tissue tumors. They usually occur in older adults and have a male predilection. Lipomas present as a painless mass in the head and neck region, shoulder, back, and extremities. Complete excision is usually curative. The admixture of other mesenchymal elements results in several variants: spindle cells (spindle cell lipoma), capillaries (angiomyolipoma), smooth muscle (myolipoma), and giant ‘floret’ cells (pleomorphic lipoma). In addition to subcutaneous tissue, lipomas may arise in skeletal muscle (muscular lipoma) and synovial connective tissue (lipoma arborescens).

LIPOMAS – DISEASE FACT SHEET Incidence and Location ៉ Most common soft tissue tumor ៉ Trunk, proximal extremities, and head and neck

Gender, Race and Age Distribution ៉ Male predominance ៉ No racial predilection ៉ Adult (more than 40–60 years)

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PATHOLOGIC FEATURES Histologically, lipomas are typically composed of mature adipose tissue indistinguishable from nonneoplastic fatty tissue. FNAB of lipomas consists of mature adipocytes, usually as tissue fragments and rarely as singly dispersed cells (Fig. 4-1). The adipocytes are round or ovoid and have a dominant cytoplasmic vacuole that does not indent the eccentrically located nucleus. Capillaries may be seen separating clusters of adipocytes. In addition to the mature adipose tissue, spindle cells and large multinucleated tumor cells are seen in aspirates of spindle cell and pleomorphic lipomas, respectively. FNAB of intramuscular lipomas and angiolipomas can yield other mesenchymal elements, such as skeletal muscle and excessive amounts of capillaries, respectively.

ANCILLARY STUDIES The tumor cells of lipomas are positive for vimentin and S-100 protein. Up to 75% of lipomas can have an abnormal karyotype, the most common of which involves the long arm of chromosome 12.

LIPOMAS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Aspirated material consists of fatty droplets when extruded on to the slide; fairly cellular to hypocellular smears; mature adipose cells have a dominant cytoplasmic vacuole, nuclei are small and eccentrically placed ៉ Spindle cell lipomas: spindle cells admixed with mature adipose cells ៉ Pleomorphic lipomas: multinucleated cells and mature adipose cells ៉ Other variants may consist of other types of mesenchymal tissue admixed with mature adipose cells: skeletal muscle (intramuscular lipoma), chondroid matrix (chondrolipoma), bone marrow elements (myelolipoma), and smooth muscle (myolipoma)

FIGURE 4-1 Lipoma: FNAB. The aspirated adipocytes are cohesively clustered. The cells have abundant cytoplasm and peripherally located small nuclei. Papanicolaou stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The cytologic features of lipomas may be indistinguishable from those of atypical lipomatous tumor (ALT)/ well-differentiated liposarcoma (WDLS), which may consist predominantly of mature adipose tissue. Lipoblasts and atypical adipocytes are expectedly rare in these aspirates and are often difficult to recognize. Cytogenetic studies may assist in recognizing these tumors. The cells of lipomas are identical to those of nonneoplastic subcutaneous fat. The possibility of sampling the subcutaneous fat should be entertained when the aspirates yield mature adipocytes, especially if detailed clinical information is not provided or the FNAB is performed by health professionals other than the cytopathologist interpreting the case.

LIPOSARCOMA CLINICAL FEATURES

Immunohistochemistry ៉ Adipocytes are positive for vimentin and S-100 protein; spindle

cells of spindle cell lipomas are positive for CD34 ៉ Tumor cells are negative for epithelial, smooth muscle, skeletal muscle, and neuroendocrine markers Genetics ៉ Approximately 55–75% have an abnormal karyotype; 66% involve

12q13–15 Differential Diagnosis and Pitfalls ៉ Atypical lipomatous tumor/well-differentiated liposarcoma ៉ Normal subcutaneous adipose tissue (adjacent normal adipose

tissue is sampled and needle missed the lesion)

Liposarcomas are malignant mesenchymal tumors with fatty differentiation. Four histologic types are recognized: atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLS), dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS)/round cell liposarcoma (RCLS), and pleomorphic liposarcoma (PLS). Liposarcomas are tumors of adults and infrequently occur in children. More than 90% of the liposarcomas are ALTs/WDLSs and MLSs/RCLSs. PLSs and DDLSs account for less than 10% of liposarcomas. PLSs are quite rare. ALTs and WDLSs are composed of mature adipose tissue with scattered atypical cells. Superficial tumors of

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LIPOSARCOMA – DISEASE FACT SHEET Incidence ៉ Atypical lipomatous tumor(ALT)/well-differentiated liposarcoma (WDLS): 50% of liposarcomas ៉ Myxoid liposarcoma (MLS)/round cell liposarcoma (RCLS): 30–40% of liposarcomas ៉ Dedifferentiated liposarcoma (DDLS): 5% of liposarcomas ៉ Pleomorphic liposarcoma (PLS): <5% of liposarcomas Location ៉ ALT: superficial trunk and extremities ៉ WDLS: deep soft tissue of thigh, retroperitoneum, paratesticular area, and mediastinum ៉ MLS/RCLS: lower extremities (70% in thigh) ៉ DDLS: Retroperitoneum, mediastinum, and paratesticular region ៉ PLS: lower extremities, less often retroperitoneum and mediastinum

LIPOSARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Atypical lipomatous tumor(ALT)/well-differentiated liposarcoma (WDLS): variably cellular smears of mature adipose tissue indistinguishable from non-neoplastic fat; scattered atypical cells; lipoblasts are scarce ៉ Myxoid liposarcoma (MLS)/round cell liposarcoma (RCLS): uniform round or oval cells; myxoid matrix appears as purple or magenta in Romanowsky-stained smears; branching capillary network; signet-ring lipoblasts ៉ Dedifferentiated liposarcoma (DDLS): clusters of spindle or pleomorphic cells without intervening mature adipose tissue; no lipoblasts; may have cells similar to ALT/WDLS ៉ Pleomorphic liposarcoma (PLS): highly cellular aspirate with pleomorphic or bizarre-appearing tumor cells; pleomorphic (mulberry) lipoblasts Immunohistochemistry

Gender, Race, and Age Distribution No sex or race predilection ALT/WDLS: middle-aged adults (peak – 6th decade) MLS/RCLS: young and middle-aged adults (peak – 4th decade) DDLS: middle-aged adults PLS: elderly patients (>50 years)

៉ ៉ ៉ ៉ ៉

the trunk or extremities are designated as ALTs, while WDLSs apply to similar tumors in deep-seated locations such as the retroperitoneum, paratesticular region, and mediastinum. A liposarcoma is categorized as a dedifferentiated type when an area of non-lipogenic sarcoma is present in a newly diagnosed ALT/WDLS (de novo), in a local recurrence of an ALT/WDLS, or in a distant metastasis following or with a concurrent diagnosis of ALT/WDL. DDLSs have a significant potential for metastasis. MLSs and RCLSs have identical cytogenetic abnormalities. Histopathologically, RCLSs are considered a less differentiated type of MLSs. The presence of an RCLS component imparts a more aggressive behavior. PLSs are highly malignant tumors characterized by an early onset of metastasis and a high mortality rate.

PATHOLOGIC FEATURES Histologically, ALTs/WDLSs are composed mainly of mature adipose tissue with fibrous septae containing atypical cells. Lipoblasts may be present. The foci of DDLSs are usually high grade and are indistinguishable from other sarcomas. MLSs/RCLSs have characteristic branching capillaries and uniform tumor cells. RCLSs are considerably more cellular than MLSs. PLSs are characterized by extremely atypical cells and lipoblasts of the pleomorphic (mulberry) type. Smears of ALTs/WDLSs consist predominantly of mature adipose tissue indistinguishable from nonneoplastic fatty tissue and lipoma. The atypical cells may be sparse and difficult to recognize. Multivacuolated

៉ ALT/WDLS: atypical cells are positive for S-100 protein ៉ MLS/RCLS: tumor cells are positive for vimentin and S-100

protein ៉ DDLS: dedifferentiated areas usually express antibodies

expected of the morphology; residual ALT/WDLS is positive for S-100 protein ៉ PLS: tumor cells are positive for vimentin and S-100 protein; epithelioid variant may be positive for cytokeratin Genetics ៉ ALT/WDLS: supernumerary ring and giant marker chromosomes; amplified sequences of 12q14–15 and, less frequently, 12q21–22 and 1q21–25 ៉ MLS/RCLS: t(12;16)(q13;p11) in 90% of cases; t(12;22)(q13;q12) in 10% of cases ៉ DDLS: supernumerary ring and giant marker chromosomes; amplified sequences of 12q14–15 and, less frequently, 12q21–22 and 1q21–25 ៉ PLS: complex cytogenetic aberrations Differential Diagnosis and Pitfalls ៉ ALT/WDLS: lipoma, fat necrosis, and non-neoplastic fat ៉ MLS/RCLS: extraskeletal myxoid chondrosarcoma and low-grade fibromyxoid sarcoma; small round cell tumors in pure or predominantly RCLS ៉ DDLS: may be indistinguishable from other sarcomas including malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, and leiomyosarcoma if ALT/WDLS areas are not sampled ៉ PLS: malignant fibrous histiocytoma, other pleomorphic sarcomas and carcinomas

lipoblasts are rarely present. The diagnosis of ALT/ WDLS usually necessitates a biopsy. DDLSs are recognized by the presence of a high-grade non-lipomatous component in a background of ALT/WDL (Fig. 4-2). MLSs/RCLSs consist mainly of uniform round or ovoid tumor cells with a high nuclear to cytoplasmic (N/C) ratio and occasionally signet-ring lipoblasts in a background of abundant myxoid matrix (Figs 4-3 & 4-4). Branching capillaries are conspicuously present. Bizarre tumor cells and a variable number of pleomorphic lipoblasts typify PLSs (Fig. 4-5).

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FIGURE 4-2 Dedifferentiated liposarcoma: touch preparation. The dedifferentiated foci are cellular and usually densely aggregated. These tumor cells are indistinguishable from other high-grade sarcomas. Demonstration of such cells in a patient with a previous or concurrent diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma suggests transformation of the tumor to dedifferentiated liposarcoma. Diff-Quik stain, high-power.

FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 4-4 Myxoid liposarcoma: needle core biopsy. Signet-ring lipoblasts are randomly scattered. Note the relative uniformity of the lesional cells without unusually large or bizarre tumor cells. H&E stain, medium power.

ALTs/WDLSs and DDLSs have similar genetic abnormalities. Both tumors have supernumerary ring and giant cell marker chromosomes mostly derived from the 12q14–15 karyotypic abnormality. The majority of MLSs/RCLSs have t(12;16)(q13;p11) and about 10% of these tumors show t(12;22)(q13;q12). PLSs do not show a specific genetic aberration, and the cytogenetic makeup of these tumors is complex.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

FIGURE 4-3 Myxoid liposarcoma: FNAB. The aspirate is moderately cellular. The tumor cells are round or oval and of uniform size. The stromal background is myxoid. Prominent branching capillaries are present in the middle of the tumor clusters. Diff-Quik stain, medium power.

ANCILLARY STUDIES The mature adipocytes and lipoblasts are positive for vimentin and S-100 protein. With the exception of some epithelioid variants of PLSs, all types of liposarcomas are negative for cytokeratins (CK). Dedifferentiated foci other than malignant fibrous histiocytoma are reactive to antibodies expected for the morphology, e.g. rhabdomyosarcomatous areas are MyoD1- and myogenin-positive.

ALTs/WDLSs may consist predominantly of mature adipose tissue and can be indistinguishable from normal fat or lipoma. Aspirates of mature-appearing adipose tissue in deep-seated locations should be examined carefully for any atypical fibroblast-like cells. In general, a biopsy is necessary to establish this diagnosis. Necrotic non-neoplastic fat may harbor histiocytes with large nuclei which simulate the atypical cells of ALTs/WDLSs. DDLS components are indistinguishable from those of high-grade sarcomas such as malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, and leiomyosarcoma. The diagnosis of DDLS can only be established when foci of ALT/WDLS are demonstrated in the current specimen or a previous history of ALT/WDLS is elicited. The presence of vascular channels and limited atypia of tumor cells, in a myxoid background is not unique for MLS/RCLS and may be observed in other neoplasms such as low-grade fibromyxoid sarcoma and extraskeletal chondromyxoid sarcoma. A biopsy is necessary to discriminate these lesions. In the absence of mulberry-type lipoblasts, PLSs are indistinguishable from other poorly differentiated mesenchymal and epithelial malignancies.

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A

B

FIGURE 4-5 Pleomorphic liposarcoma: touch preparation. Pleomorphic cells and lipoblasts are shown here. The cytoplasmic vacuoles indent the peripherally displaced nuclei. Due to variable numbers of lipoblasts, these may not be demonstrated in FNAB. Diff-Quik stain, high power.

FIBROBLASTIC AND FIBROHISTIOCYTIC TUMORS

NODULAR FASCIITIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirate; the mildly atypical tumor cells are spindle or

NODULAR FASCIITIS CLINICAL FEATURES Nodular fasciitis (NDF) usually arises in the subcutaneous tissue of the extremities, head and neck, or trunk regions. The mass lesion often abuts the underlying adjacent fascia. NDF may develop within blood vessels (intravascular NDF), skeletal muscle (intramuscular NDF), skull (cranial NDF), and, rarely, in visceral organs. The typical presentation is that of a rapidly growing painful mass in a young adult. A history of antecedent trauma is often reported.

plump cells; stellate or ganglion-like cells may be present; small but sometimes prominent nucleoli; infl ammatory infiltrates and mitotic figures are variably present ៉ Myxoid or collagenous stroma ៉ Depending on the site of lesion, degenerated tissue such as fat necrosis or skeletal muscle may accompany the lesional cells Immunocytochemistry ៉ Positive for vimentin, smooth muscle actin, and muscle-specific

actin, and rarely for desmin ៉ Negative for S-100 protein, CD34, bcl-2, and cytokeratin

Genetics ៉ Diploid by DNA ploidy analysis ៉ t(15;15)(q13;q22 or q25) was described in three cases Differential Diagnosis and Pitfalls

PATHOLOGIC FEATURES Histologically, NDF is composed of spindly and wavy cells haphazardly arranged or in short fascicles (tissue

NODULAR FASCIITIS – DISEASE FACT SHEET Incidence and Location ៉ Not uncommon ៉ Upper and lower extremities, head and neck, and trunk; rarely

within skeletal muscle, vessels, and skull/scalp Gender, Race, and Age Distribution ៉ No sex or race predilection ៉ Peak incidence between 2nd and 5th decades

៉ Benign and malignant spindle cell and myxoid tumors including

solitary fibrous tumor, low-grade fibromyxoid sarcoma, fibrosarcoma, malignant peripheral nerve sheath tumor, and leiomyosarcoma ៉ Spindle cell carcinoma

culture pattern). The stromal background is characteristically myxoid and patchy in distribution. Mitotic figures can be readily found. Older lesions are less mitotically active with more fibrocollagenous stroma. The FNAB smears of NDF are cellular and composed of tightly clustered and singly scattered spindle, polygonal, or stellate cells in a myxoid background (Fig. 4-6). The tumor cells are relatively uniform round or spindled with a smooth outline. They have cytoplasmic processes, and centrally located nucleoli reminiscent of a ganglion cell are sometimes identified (proliferative

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A

B

FIGURE 4-6 Nodular fasciitis: FNAB. The aspirated materials are often cellular. The lesional cells are spindle or stellate with a moderate N/C ratio, inconspicuous nucleoli, and abundant cytoplasm. Myxoid stroma often predominates. A few fragments of skeletal muscle are also present. Papanicolaou stain, medium power.

fasciitis). A variable number of inflammatory cells including neutrophils, eosinophils, and mononuclear cells may be seen. Mitotic figures are usually present.

ANCILLARY STUDIES The tumor cells are usually positive for vimentin, smooth muscle actin (SMA), and muscle-specific actin (MSA). Desmin may also be focally expressed. There is no immunoreactivity with S-100 protein, melanoma markers (HMB-45 and Melan A), CK, CD34, or bcl-2. The tumor cells are diploid by flow cytometry. Cytogenetic analysis performed on a few reported cases showed t(15;15)(q13;q22 or q25).

DIFFERENTIAL DIAGNOSIS AND PITFALLS NDFs are perhaps the most common benign tumors to be mistaken for malignancy on FNAB. An important clue to their diagnosis is the clinical information of a rapidly growing mass. Cytologically, several benign and malignant spindle cell neoplasms can have similar features to those of the cells of NDFs. Oftentimes, a definitive diagnosis can not be made on smear preparations, and biopsy or excision is necessary for definitive diagnosis.

FIBROMATOSIS CLINICAL FEATURES Fibromatoses (FMs) are locally infi ltrative tumors composed of spindle cells with fibroblastic and myo-

FIBROMATOSIS – DISEASE FACT SHEET Incidence ៉ Superficial: common among those of northern and eastern European descent; 20% of 65 years or older ៉ Desmoid-type (aggressive): 2–4 per million population per year Location ៉ Superficial: palmar and plantar regions ៉ Desmoid-type (aggressive): abdominal wall, retroperitoneum, trunk,

shoulder and proximal extremities Gender, Race, and Age Distribution ៉ Superficial: ៉ Palmar fibromatosis: 3–4 times more common in men,

particularly those of northern or eastern European descent; rare in non-Caucasians ៉ Plantar fibromatosis: slight male predilection; 35% of cases are 35 years or younger ៉ Desmoid-type (aggressive): ៉ Children: no sex or race predilection; extra-abdominal location is more common ៉ Child-bearing age: female predilection; abdominal location is more common ៉ Older age: no sex predilection; equal distribution (abdominal and extra-abdominal locations)

fibroblastic differentiation. They are usually divided based on their location into superficial (palmar or Dupuytren FM, and plantar or Ledderhose disease) and desmoid types (aggressive FM). Palmar FMs often present as subcutaneous nodules with flexion contractures of the fingers. The overlying skin of the palm and fingers may be dimpled. In most instances, the subcutaneous nodules of plantar FMs are asymptomatic. Pain on pressure from standing or

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A

B

FIGURE 4-7 Fibromatosis: FNAB. (A) The aspirates are usually paucicellular in tumors with collagenous stroma. The tumor cells are spindle-shaped. Groups of tumor cells (B) are held by fibrocollagenous stroma. Singly scattered nuclei are often devoid of their cytoplasm. Papanicolaou stain, medium power.

walking may be the initial presentation. These lesions are usually clinically diagnosed and not subject to FNAB. Desmoid-type FMs are further subdivided into abdominal, intra-abdominal, and extra-abdominal types. These tumors have a tendency for local recurrence, either from multicentricity or residual tumor. Although they do not have the capacity for distant spread, significant morbidity through local destructive invasion may result. Abdominal FMs often present as asymptomatic abdominal wall mass lesions following previous surgery such as caesarian section. Owing to their location, intra-abdominal FMs are symptomatic if vital structures are compromised. Extra-abdominal FMs present as palpable masses in the neck, shoulder, trunk, and pelvic girdle.

FIBROMATOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellularity depends on the stroma: myxoid lesions tend to

aspirate better than collagenous lesions ៉ Clusters or singly scattered cells; tumor cells have ovoid or

round nuclei with a smooth nuclear membrane and fine chromatin material; elongated cytoplasm Immunohistochemistry ៉ Positive for vimentin, smooth muscle actin, muscle-specific

actin, and β-catenin; may be positive for desmin

៉ Negative for S-100 protein, CD34, and cytokeratin

Genetics ៉ No specific karyotypic abnormality ៉ No specific genetic abnormality ៉ Patients with familial polyposis and, rarely, sporadic

fibromatosis may have APC gene inactivation

PATHOLOGIC FEATURES Histologically, the bland-appearing spindle cells are arranged in longitudinal fascicles with a collagenous or myxoid background. The superficial FMs have a typical clinical presentation and are excised without preoperative cytologic evaluation. Desmoid-type FMs are clinically indistinguishable from other soft tissue tumors, and FNAB may be performed as part of the initial evaluation. The collagenous stroma may lead to paucicellular aspirates with only singly scattered spindle cells often stripped of their cytoplasm (Fig. 4-7). Clusters of these bland-appearing spindle cells are commonly seen. The tumor cells have oval and uniform nuclei with a smooth outline, and a moderate amount of cytoplasm. If present, the myxocollagenous stroma is characteristically metachromatic on Romanowsky-based stains.

Differential Diagnosis and Pitfalls ៉ Benign and malignant spindle cell tumors such as

myofibroblastoma, neurofibroma, solitary fibrous tumor, leiomyoma, benign fibrous histiocytoma, dermatofibrosarcoma protuberans, and low-grade fibromyxoid sarcoma

ANCILLARY STUDIES The tumor cells are immunoreactive for vimentin, SMA, MSA, and β-catenin. Rarely, desmin is also expressed. The tumor cells are usually negative for S-100, CD34, and CK. There are no known genetic aberrations in FMs, although patients with familial polyposis (FP) may have APC gene inactivation.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS On FNAB, the spindle cells of FMs are morphologically indistinguishable from many spindle cell lesions including myofibroblastoma, neurofibroma, solitary fibrous tumor, benign fibrous histiocytoma, dermatofibrosarcoma protuberans, and low-grade fibromyxoid sarcoma. More aggressive tumors such as desmoplastic melanoma and spindle cell carcinoma may also have a similar appearance. Immunohistochemical work-up can assist in the differential. The diagnosis of FM is usually strongly suspected on clinical and radiologic grounds. NCB or excisional biopsy may be necessary for a definitive diagnosis.

DERMATOFIBROSARCOMA PROTUBERANS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Fairly cellular aspirates composed of tightly clustered spindle cells and scattered single cells devoid of cytoplasm; tumor cells are spindly with ovoid, smooth-outlined nuclei, inconspicuous nucleoli, and bipolar cytoplasmic processes ៉ Myxocollagenous stroma Immunohistochemistry ៉ Positive for vimentin and CD34 ៉ Negative for S-100 protein, actins, desmin, cytokeratin, and

epithelial membrane antigen Genetics

DERMATOFIBROSARCOMA PROTUBERANS

៉ Ring chromosomes from chromosome 17 and 22 ៉ t(17;22)(q22;q13) resulting in COL1A–PDGFB fusion transcript

Differential Diagnosis and Pitfalls

CLINICAL FEATURES Dermatofibrosarcoma protuberans (DFSP) presents as a slow-growing, pink or erythematous skin plaque or as a subcutaneous mass. The tumors occur most frequently in the trunk and proximal extremities in middle-aged patients without sex predilection. DFSPs are locally aggressive tumors with a high recurrence rate following excision. Transformation to fibrosarcoma is rare but well-documented. Rare cases of metastatic DFSPs have been reported, typically following multiple recurrence and prolonged follow-up.

PATHOLOGIC FEATURES Histologically, DFSPs are composed of spindle cells arranged in short interlacing fascicles forming a storiform or cartwheel pattern. The neoplastic cells are relatively uniform and show minimal pleomorphism. Infi ltrative tumor cells in the deep subcutaneous tissue often surround individual or groups of fat cells. The aspirated material is usually cellular. The tumor cells are either individually dispersed or in small

៉ Benign and malignant spindle cell tumors such as

myofibroblastoma, neurofibroma, benign fibrous histiocytoma, fibromatosis, low-grade fibromyxoid sarcoma, and fibrosarcoma

aggregates with ill-defined boundaries (Fig. 4-8). The spindled tumor cells have elongated or ovoid nuclei with fine chromatin and inconspicuous nucleoli. Their cytoplasm may demonstrate bipolar cytoplasmic processes. The background stroma may be myxoid, collagenous, or fibrillary, and exhibits metachromasia with Romanowsky-based stains. Mast cells and Touton-type giant cells may be seen. Aspirated fragments of DFSPs may display the characteristic storiform pattern. Transformation to a higher-grade sarcoma (e.g. fibrosarcoma) may not be possible to establish on FNAB specimens due to lack of distinctive cytologic features unless frankly atypical tumor cells are present.

DERMATOFIBROSARCOMA PROTUBERANS – DISEASE FACT SHEET Incidence and Location ៉ 1.8% of soft tissue tumors ៉ Trunk, proximal portion of the extremities, and head and neck

Gender, Race, and Age Distribution ៉ No sex or race predilection ៉ Peak incidence: young and middle-aged adults

FIGURE 4-8 Dermatofibrosarcoma protuberans: touch preparation. The tumor cells have fine chromatin and are devoid of nucleoli. Significant pleomorphism of tumor cells is not demonstrated. Diff-Quik stain, high power.

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ANCILLARY STUDIES The tumor cells of DFSPs are positive for vimentin and CD34, and negative for S-100 protein, SMA, MSA, desmin, CK, and epithelial membrane antigen (EMA). The main reported cytogenetic abnormality in DFSPs is a ring chromosome derived from chromosomes 17 and 22. This translocation, t(17;22)(q22;q13), results in a chimeric transcript, COL1A-PDGFB (collagen type 1–platelet-derived growth factor beta), which can be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH). The same genetic abnormality is seen in giant cell fibroblastoma, a closely related entity.

FIBROSARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirate; uniform spindle tumor cells; considerable cellular atypia in poorly differentiated tumors ៉ Myxocollagenous stroma Immunohistochemistry ៉ Positive for vimentin; may be focally positive for smooth

muscle actin; fibrosarcoma arising from dermatofibrosarcoma protuberans is positive for CD34 ៉ Negative for epithelial markers (cytokeratin and epithelial membrane antigen), muscle markers (MyoD1, myogenin, and calponin), and neural/melanoma markers (S-100, HMB-45, Melan A) Genetics

DIFFERENTIAL DIAGNOSIS AND PITFALLS The spindle cell lesions listed under fibromatosis are included in the differential diagnosis of DFSP. The typical immunophenotype of DFSP, however, is not observed in these entities. The presence of areas that are negative for CD34 together with the appropriate cellular morphology suggests transformation to FS. When available, molecular studies can assist in the diagnosis of DFSPs.

FIBROSARCOMA CLINICAL FEATURES Fibrosarcomas most often arise in the upper trunk, proximal extremities, and head and neck region of adults. They tend to be slow growing, and may be associated with pain or paresthesia secondary to mass effect. A preceding diagnosis of DFSP may be extracted from the history.

៉ Complex karyotype

Differential Diagnosis and Pitfalls ៉ Benign and malignant spindle cell tumors such as

myofibroblastoma, neurofibroma, benign fibrous histiocytoma, fibromatosis, low-grade fibromyxoid sarcoma, and leiomyosarcoma ៉ Pleomorphic areas of fibrosarcoma are indistinguishable from other high-grade sarcomas

fascicles that pull towards opposite directions (herringbone pattern). A collagenous background is variably present. Fibrosarcomas have become a diagnosis of exclusion after entities (e.g. synovial sarcoma) of overlapping histology are classified under separate categories. The aspirated material is often cellular. Tissue fragments often show fibrocollagenous stroma in which tumor cells are embedded (Fig. 4-9). Individually scattered neoplastic cells are spindle-shaped and often devoid of cytoplasm. When intact, the cytoplasmic processes are elongated at both ends of the cell. Considerable pleomorphism may be appreciated in tumors with less differentiated components.

PATHOLOGIC FEATURES The characteristic feature of fibrosarcomas is the presence of spindly tumor cells forming long sweeping

FIBROSARCOMA – DISEASE FACT SHEET

ANCILLARY STUDIES FSs express vimentin but none of the more specific antibodies. Epithelial, neural, and melanoma markers are negative. At present, a specific genetic abnormality has not been described.

Incidence and Location ៉ Rare tumors (other histologically similar tumors should be ruled

out) ៉ Deep soft tissue of lower extremities, trunk, head and neck

Gender, Race, and Age Distribution ៉ No sex or race predilection ៉ Middle-aged and older adults

DIFFERENTIAL DIAGNOSIS AND PITFALLS The entities in the differential diagnosis of fibrosarcomas are similar to those listed under fibromatoses. A more pleomorphic fibrosarcoma is difficult to distinguish from high-grade sarcomas. A more definitive

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A

B

FIGURE 4-9 Fibrosarcoma: FNAB. FNAB often yields cellular material. Tumors cells are spindled and show variable, moderate pleomorphism. The stroma may be prominent or entirely non-existent. Component cells are indistinguishable from those in other spindle cell tumors such as synovial sarcomas. Papanicolaou stain, high power.

diagnosis requires NCB or open biopsy. Expression of an antibody or set of antibodies known to more or less define an entity should exclude fibrosarcoma from consideration.

MALIGNANT FIBROUS HISTIOCYTOMA CLINICAL FEATURES Two types of malignant fibrous histiocytomas (MFHs) are considered here: pleomorphic MFH (PMFH), and myxoid MFH (MMFH) or myxofibrosarcoma. PMFHs usually present as a rapidly growing deep-seated mass. The common locations are the proximal extremities, trunk. and retroperitoneum. Pain, swelling, and loss of

MALIGNANT FIBROUS HISTIOCYTOMA – DISEASE FACT SHEET Incidence ៉ Pleomorphic MFH: 1–2 cases per 100,000 per year ៉ Myxoid MFH: common sarcoma in elderly patients

Location ៉ Pleomorphic MFH: lower extremity and trunk (deep or cutaneous) ៉ Myxoid MFH: lower and upper extremities (proximal part)

Gender, Race, and Age Distribution ៉ Slight male predilection ៉ No race predilection ៉ Pleomorphic MSH: most common sarcoma in persons aged 40 years

or older ៉ Myxoid MSH: most common in elderly patients

function are secondary to mass effect or tumor infi ltration. Metastasis to the lungs may be present at the time of diagnosis. MMFHs are slow-growing subcutaneous tumors that frequently arise from the extremities; ulceration of the overlying skin from tumor infi ltration may be present. Lower-grade MMFHs may have an indolent behavior.

PATHOLOGIC FEATURES Malignant fibrous histiocytomas (MFHs) are malignant soft tissue tumors composed of tumor cells without definitive morphologic, immunohistochemical, and ultrastructural evidence of specific tissue differentiation. The tumor cells are closely related to fibroblasts/myofibroblasts. Histologically, PMFHs are hypercellular with markedly atypical tumor cells and brisk mitotic activity. An admixture of spindle and polygonal cells is common and a storiform pattern is typically present. MMFHs have variable cellularity composed of spindle cells with few scattered pleomorphic cells in a myxoid background. Relatively thick-walled vessels associated with fibrosis are usually recognized. FNAB of PMFHs consists of a pleomorphic population of spindle, polygonal, and multinucleated cells (Fig. 4-10). The tumor cells may cling to vascular structures, giving a pseudopapillary appearance. Erythrophagocytosis can be identified. The neoplastic cells do not show cytomorphologic evidence of specific tissue differentiation. Mitoses are easily recognized. FNAB of MMFHs shows hypocellular or moderately cellular aspirates composed of a relatively less pleomorphic population of tumor cells (usually spindly) with randomly interspersed bizarre cells (Fig. 4-11). A copious myxoid stroma is characteristic.

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A

B

FIGURE 4-10 Malignant fibrous histiocytoma, pleomorphic type: FNAB. The hypercellular aspirates are composed of pleomorphic tumor cells without specific cytomorphologic differentiation. Mitotic figures are easy to find. Diff-Quik stain, high power.

MALIGNANT FIBROUS HISTIOCYTOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Pleomorphic MFH: cellular aspirates, bizarre tumor cells, mitotic

figures abound; fibrocollagenous or myxoid stroma ៉ Myxoid MFH: moderately cellular aspirates, spindle and polygonal

tumor cells, nuclear to cytoplasmic ratio is lower than in pleomorphic MFH; prominent myxoid stroma Immunohistochemistry ៉ Pleomorphic MFH: positive for vimentin; rare cells positive for

epithelial (cytokeratin and epithelial membrane antigen), muscle (actin, desmin, MyoD1, and myogenin), and other markers of specific tissue differentiation ៉ Myxoid MFH: positive for vimentin; rare cells positive for epithelial (cytokeratin and epithelial membrane antigen), muscle (actin, desmin, MyoD1, and myogenin), and other markers of specific tissue differentiation Genetics ៉ Complex karyotype ៉ No specific genetic abnormality

Differential Diagnosis and Pitfalls ៉ Pleomorphic MFH: pleomorphic variants of other sarcomas including liposarcoma, rhabdomyosarcoma, and leiomyosarcoma ៉ Myxoid MFH: malignant myxoid tumors (low-grade fibromyxoid sarcoma, myxoid malignant peripheral nerve sheath tumor, and myxoid liposarcoma)

ANCILLARY STUDIES MFH does not exhibit a specific immunophenotype. Rare scattered tumor cells may express epithelial and muscle markers, and S-100 protein. The cytogenetic abnormality is complex.

FIGURE 4-11 Malignant fibrous histiocytoma, myxoid type: FNAB. The tumor cells are spindle, stellate, or polygonal cells and less pleomorphic compared with the pleomorphic type of MFH. The tumor cells are usually drawn toward the immediate periphery of the vascular channels. Note the prominent myxoid stroma. Diff-Quik stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS FNAB of high-grade sarcomas including liposarcoma, rhabdomyosarcoma, and leiomyosarcoma, and poorly differentiated carcinomas can be morphologically indistinguishable from PMFHs. Similarly, aspirates of MMFHs may resemble myxoid malignant peripheral nerve sheath tumor and myxoid liposarcoma. Diligent search for isolated cells or clusters of cells that demonstrate specific differentiation (lipoblasts, rhabdomyoblasts, keratinization, and mucin production) can exclude the diagnosis of MFH.

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NEURAL TUMORS

NEURAL TUMORS – PATHOLOGIC FEATURES Cytopathologic Findings

NEUROFIBROMA AND SCHWANNOMA (NEURILEMMONA) CLINICAL FEATURES NEUROFIBROMA

Peripheral neurofibromas often present as visible and palpable subcutaneous nodules. Neurofibromas of the spinal roots may be incidentally discovered or manifest symptoms from neural impingement. Neurofibromas occur in two settings, either as a sporadic case or in a background of neurofibromatosis type 1 (NF1). Patients with NF1 usually have other stigmata of the syndrome, including café-au-lait spots, skin freckling (usually in the axillary and inguinal areas), iris hamartomas (Lisch nodules), and other neoplasms (somatostatinoma, pheochromocytoma). An increased incidence of transformation to malignant peripheral nerve sheath tumor (MPNST) is seen in the setting of NF1.

៉ Neurofibroma: hypocellular to fairly cellular aspirates; spindle

tumor cells; fibrocollagenous or myxoid stroma ៉ Schwannoma: fairly cellular aspirates; spindle tumor cells, tight

clusters sometimes predominate; atypical cells representing degenerative changes may be prominent; fibrocollagenous or myxoid stroma Immunohistochemistry ៉ Neurofibroma: positive for S-100 (less staining intensity

compared with schwannoma); negative for cytokeratin and epithelial membrane antigen ៉ Schwannoma: positive for S-100 (strong and diffuse); negative for cytokeratin and epithelial membrane antigen Electron Microscopy ៉ Neurofibroma: admixture of Schwann cells and fibroblasts ៉ Schwannoma: Luse bodies (compact fibrous long spacing

collagen), long cytoplasmic processes and basal lamina surrounding Schwann cells Genetics ៉ Neurofibroma: neurofibromatosis type 1 (NF1) syndrome; loss of

wild-type NF1 allele ៉ Schwannoma: loss of chromosome 22; loss of wild-type NF2

SCHWANNOMA

The distribution of schwannomas is similar to that of neurofibromas, with few exceptions, including intracranial locations and the propensity to arise from the 8th cranial nerve. The tumors are asymptomatic unless there is impingement on a nerve, and compression of the spinal cord or other vital structures.

PATHOLOGIC FEATURES Histologically, neurofibromas show spindle tumor cells with buckled nuclei in a variably myxoid and collage-

NEURAL TUMORS – DISEASE FACT SHEET Incidence ៉ Neurofibroma: common tumors ៉ Schwannoma: common tumors; may be multiple in

neurofibromatosis type 2 Location ៉ Neurofibroma: skin and subcutaneous tissue, spinal and peripheral

nerves but not cranial nerves ៉ Schwannoma: peripheral nerves, spinal and cranial nerves,

particularly 8th cranial nerve Gender, Race, and Age Distribution ៉ No sex or racial predilection ៉ Neurofibroma: affects all ages ៉ Schwannoma: affects all ages (peak – 4th to 6th decades)

allele Differential Diagnosis and Pitfalls ៉ Benign and malignant spindle cell tumors such as

myofibroblastoma, neurofibroma, benign fibrous histiocytoma, fibromatosis, low-grade fibromyxoid sarcoma, and dermatofibrosarcoma protuberans

nous stroma. The histology of NF1-associated neurofibromas is similar to that of sporadic cases. Plexiform neurofibromas, seen almost exclusively in NF1 patients, consist of thickened nerve trunks and branches. Schwannomas are encapsulated tumors. Alternating cellular (Antoni A) and hypocellular (Antoni B) foci are usually identified. The nuclei of schwannoma cells may line up, forming a palisading pattern referred to as Verocay bodies. The intratumoral blood vessels typically have thick and hyalinized walls. In both neurofibromas and schwannomas, a sharp pain or a tingling sensation extending to the immediate distribution of the involved nerve may be felt by the patient during the FNAB procedure. The cytomorphologic features of neurofibromas and schwannomas are generally similar (Figs 4-12–4-14). Aspirates from both tumors are variably cellular. The tumor cells are arranged in clusters and rarely are individually scattered. The tumor cells are spindle-shaped or, rarely, epithelioid. The nuclei are uniformly wavy and devoid of nucleoli. When tissue fragments are obtained, tumor cells of schwannomas lie in a homogeneous or fibrillary myxocollagenous stroma. Occasionally, palisades of cellular nuclei (Verocay bodies) may be appreciated in schwannomas. The patchy areas of hypercellularity and rarity of single cells also suggest a

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FIGURE 4-12 Neurofibroma: FNAB. FNAB yield is variably cellular. The spindle tumor cells are often held together by fibromyxoid stroma. Diff-Quik stain, high power.

A

B

FIGURE 4-13 Neurofibroma: needle core biopsy. The tumor cells display tapered and buckled nuclei and ample cytoplasm with abundant intervening fibrocollagenous or fibromyxoid stroma. The tumor cells express S-100 protein (B). A, H&E stain, high-power. B, S-100 protein, high power.

A B

FIGURE 4-14 Schwannoma: FNAB. The aspirates are variably cellular. Tumors with a thick fibrocollagenous background may yield only a few cell clusters. Tumor cells have a plump or epithelioid appearance. A, Diff-Quik stain, high power. B, Papanicolaou stain, high power.

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diagnosis of a schwannoma rather than a neurofibroma. Ancient schwannomas may have a few large atypical cells which represent degenerative atypia and do not necessarily signify transformation to malignancy. These atypical cells are not mitotically active.

trunk, breast, and aerodigestive tract. The clinical manifestations of GCTs are site-dependent. In the skin and aerodigestive tract, the tumor is often discovered as an asymptomatic subcutaneous or submucosal slowgrowing nodule, usually mistaken for a more serious lesion. GCTs can be multicentric.

ANCILLARY STUDIES PATHOLOGIC FEATURES Immunohistochemically, anti-S-100 protein stains neurofibromas in a patchy distribution and schwannomas in a diffuse and relatively strong manner.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Neurofibromas and schwannomas may be mistaken for other benign spindle cell tumors and low-grade spindle cell sarcomas, particularly in small samples. S-100 protein expression is very helpful in confirming a diagnosis of neurofibromas and schwannomas. Immunohistochemical staining for CD34 and smooth muscle markers can assist in excluding solitary fibrous tumor and smooth muscle and fibroblast/myofibroblast-derived neoplasms such as fibromatosis, low-grade fibromyxoid sarcoma, and dermatofibrosarcoma protuberans. A recent increase in the size of a pre-existing nerve sheath tumor warrants a careful assessment for the presence of atypical cells that may signify transformation to MPNST.

Histologically, the tumor cells are polygonal or spindleshaped with abundant granular cytoplasm and small round nuclei. The cell borders are usually distinct. Infi ltration into adjacent tissue is common and not indicative of a more aggressive behavior. Typically, S100 protein and CD68 are positive, and smooth muscle markers are negative. FNAB of GCTs is usually cellular and composed of clusters and dispersed tumor cells with abundant granular cytoplasm (Figs 4-15 & 4-16). Fragmentation of the granular cytoplasm may impart a hazy background on low magnification. The cells have centrally located round nuclei. Naked round or oval nuclei with a smooth outline and devoid of prominent nucleoli may be observed. Pseudonuclear inclusions may be present. Cytologic atypia including hyperchromasia, pleomorphism and prominent nucleoli, necrosis, and mitotic activity are not identified in clinically benign GCTs.

GRANULAR CELL TUMOR – PATHOLOGIC FEATURES

GRANULAR CELL TUMOR CLINICAL FEATURES Granular cell tumors (GCTs) arise commonly in the tongue, subcutaneous tissue of the extremities and

Cytopathologic Findings ៉ Aspirates are usually cellular; tumor cells have abundant and granular cytoplasm ៉ Disintegrated cytoplasm may impart a necrotic background; closer examination will show fragments of granular cytoplasm ៉ Naked nuclei are round and uniform with small but sometimes prominent nucleoli Immunohistochemistry ៉ Positive for vimentin, S-100 protein, CD68, laminin, and myelin

proteins ៉ Negative for cytokeratin, smooth muscle actin, neurofilament,

GRANULAR CELL TUMOR – DISEASE FACT SHEET Incidence and Location ៉ Relatively common ៉ Usual location is the subcutis of the extremities, breast and trunk, and submucosa of the aerodigestive tract; rarely, the lesion(s) may be multiple

and glial fibrillary acidic protein Electron Microscopy ៉ Numerous lysosomes

Genetics ៉ No specific karyotypic abnormality ៉ No specific genetic abnormality

Gender, Race, and Age Distribution ៉ Slight female predilection ៉ More common in Blacks ៉ Any age bracket; rare in children <5 years; peak – 4th to 6th

decades

Differential Diagnosis and Pitfalls ៉ Oncocytic neoplasms and paraganglioma ៉ Alveolar soft part sarcoma, renal cell carcinoma, and rhabdomyosarcoma

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A

B

FIGURE 4-15 Granular cell tumor: FNAB. The aspirates are moderately cellular. The tumor cells are spindle or polygonal with round nuclei and ample, granular cytoplasm. A, Papanicolaou stain, medium power. B, Diff-Quik stain, high power.

A

B

FIGURE 4-16 Granular cell tumor: cell block. The tumor cells typically have granular cytoplasm and a low N/C ratio. The tumor cells are strongly positive for S-100 protein (B). Note the absence of staining in gastric epithelial cells. A, H&E stain, low power. B, S-100 protein, low power.

ANCILLARY STUDIES GCTs stain with S-100 protein (Fig. 4-16B), CD68, and myelin proteins. GCTs do not stain for CK, SMA, neural fi lament, and glial fibrillary acidic protein (GFAP). Similar to neurofibroma and schwannoma, GCTs can also express laminin. The cytoplasm is fi lled with numerous lysosomes on EM.

DIFFERENTIAL DIAGNOSIS AND PITFALLS GCTs may be mistaken for oncocytic neoplasms that are known to arise in several organs, including the salivary gland, thyroid, and kidney. Immunohisto-

chemistry readily differentiates GCT from these neoplasms, GCT being positive for S-100 protein and CD68, and negative for epithelial markers. Ultrastructural studies demonstrate the abundance of lysosomes in GCTs and mitochondria in oncocytic neoplasms. Paragangliomas may resemble GCTs. The absence of cytoplasmic granularity and expression of CK and neuroendocrine markers are more in keeping with paraganglioma. In rare instances, alveolar soft part sarcoma, renal cell carcinoma (RCC), and rhabdomyosarcoma (RMS) may be difficult to separate from GCTs, particularly in small biopsies. The immunophenotypes of GCTs, RCCs, and RMSs should be relied upon in such instances. Gingival GCTs of the newborn, although morphologically similar to GCTs of other sites, do not express S-100 protein and the immunohistochemical profile suggests a smooth muscle differentiation.

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MALIGNANT PERIPHERAL NERVE SHEATH TUMORS CLINICAL FEATURES Malignant peripheral nerve sheath tumors (MPNSTs) present as an enlarging mass with pain or with symptoms from neural impingement. MPNSTs are most commonly located in the proximal extremities and paraspinal region. Approximately 50% of MPNSTs arise in NF1 patients. Progressive enlargement of an existing neurofibroma may herald transformation to malignancy.

MALIGNANT PERIPHERAL NERVE SHEATH TUMORS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirates; tumor cells are spindle and polygonal cells; less frequently, epithelioid cells or pleomorphic cells may be present ៉ Cellular atypia and mitotic figures are readily appreciated: hyperchromasia, coarse chromatin, pleomorphism, and prominence of nucleoli ៉ Myxocollagenous stroma Immunohistochemistry ៉ Positive for vimentin; foci of rhabdomyosarcomatous

differentiation are positive for muscle markers ៉ Epithelioid MPNST and epithelial components are positive for

cytokeratin

PATHOLOGIC FEATURES Histologically, MPNSTs are hypercellular. Most tumors are composed of spindle cells with buckled nuclei. A transition to a rounded or epithelioid tumor cell population is noted in a minority of tumors. Malignant glandular (glandular MPNST) and rhabdomyosarcomatous (malignant Triton tumor) elements may be present. The aspirates are usually very cellular with predominance of spindle cells in tight clusters and myxocollagenous stroma (Figs 4-17 & 4-18). The tumor cells may also be epithelioid, glandular, or rhabdoid forms. Cellular evidence of malignancy including hyperchromasia, pleomorphism, nucleolar prominence, and brisk mitotic activity are usually evident. Sampling of MPNSTs arising in a background of neurofibromas might yield benignappearing spindle tumor cells typical of neurofibromas.

ANCILLARY STUDIES

៉ 50–70% are positive for S-100 protein (faint/patchy) ៉ Negative for CD34, HMB-45, and tyrosinase

Genetics ៉ Complex karyotype ៉ May have deletion of the INKA/CDK2A gene (9p)

Differential Diagnosis and Pitfalls ៉ Spindle cell MPNSTs: fibrosarcoma, synovial sarcoma,

gastrointestinal stromal tumor, and desmoplastic melanoma ៉ Glandular MPNSTs: biphasic synovial sarcoma and carcinosarcoma ៉ Epithelioid MPNSTs: carcinoma, epithelioid sarcoma, and

melanoma

and schwannomas, which are strongly reactive. MPNSTs with epithelioid morphology may be positive for epithelial markers. The glandular epithelial components (glandular MPNST) are expectedly CK-positive. Foci of rhabdomyosarcomatous differentiation (Triton tumors) are immunoreactive to skeletal muscle markers (MyoD1 and myogenin).

MPNSTs typically express S-100 protein in a patchy and faint distribution, in contrast to neurofibromas

DIFFERENTIAL DIAGNOSIS AND PITFALLS MALIGNANT PERIPHERAL NERVE SHEATH TUMORS – DISEASE FACT SHEET Incidence ៉ 5% of soft tissue tumors ៉ 66% arise from neurofibromas of NF1 patients and less frequently in sporadic neurofibromas Location ៉ Large nerve trunk of the proximal extremities and spinal nerve

roots Gender, Race, and Age Distribution ៉ Slight predilection for females ៉ No race predilection ៉ Peak at 3rd to 6th decades

Spindle cell MPNSTs may be indistinguishable from other spindle cell tumors. Remnants of neurofibroma or schwannoma in the sampled material may indicate origin of the malignancy. The stromal cells of synovial sarcoma (SS) are spindle and uniform, in contrast to the more pleomorphic mesenchymal components of MPNSTs. The glandular MPNSTs may be mistaken for biphasic SS. The epithelial components of glandular MPNSTs are bland-appearing compared to their counterpart in biphasic SSs. The malignant epithelial components of carcinosarcoma are considerably more pleomorphic than the glandular elements of MPNSTs. Epithelioid MPNSTs may have components that are morphologically similar with carcinoma, melanoma, and other sarcomas with epithelioid/epithelial components, including epithelioid sarcoma.

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A

B

FIGURE 4-17 Malignant peripheral nerve sheath tumor: touch preparation. The tumor is hypercellular and composed of spindle and epithelioid cells. Considerable cytologic atypia is usually demonstrated. Note the prominent nucleoli. Diff-Quik stain, high power.

RHABDOMYOSARCOMA – DISEASE FACT SHEET Incidence ៉ Embryonal rhabdomyosarcoma (ERMS): most common sarcoma in children ៉ Alveolar rhabdomyosarcoma (ARMS): less common than ERMS ៉ Pleomorphic rhabdomyosarcoma (PRMS): rare Location ៉ ERMS: most common sites are the head and neck, and

FIGURE 4-18 Malignant peripheral nerve sheath tumor: FNAB. The tumor cells are predominantly spindled with elongated cytoplasmic processes. Note the presence of necrotic debris in the background. Papanicolaou stain, high power.

SKELETAL MUSCLE TUMORS

genitourinary tract; spindle cell variant arises in scrotal area, and head and neck; botryoid variant arises in the urinary bladder, biliary tract, and pharynx ៉ ARMS: most common in the extremities, perineum, paraspinal area, and paranasal sinuses ៉ PRMS: most common in the lower extremities Gender, Race, and Age Distribution ៉ ERMS: slight male predilection; incidence is higher in Caucasians;

most common variant of rhabdomyosarcoma in children less than 15 years of age (45% occur in those less than 5 years of age) ៉ ARMS: no sex predilection; no racial predilection; more common in adolescent and young adults ៉ PRMS: male predilection; no race predilection; adult population (6th decade); very rare in children

RHABDOMYOSARCOMA CLINICAL FEATURES Rhabdomyosarcomas (RMSs) are generally divided into three types: embryonal (ERMS), alveolar (ARMS), and pleomorphic (PRMS). RMSs are rapidly growing tumors and present with symptoms secondary to mass effect. ERMSs are the most common RMS in children. They occur predominantly in the head and neck (50%), followed by the genitourinary tract (30%) and the

extremities (10%), and less commonly in other sites (10%). Head and neck ERMSs usually present as proptosis, diplopia, or hearing loss. Botryoid ERMSs represent a distinct subtype arising in a submucosal location, mostly from the urinary bladder, vagina, and bile ducts. In these organs, the patients may present with hematuria, obstructive uropathy, or jaundice. ARMSs occur more frequently in the extremities or paranasal sinuses of adolescents and young adults and may have similar manifestation as ERMSs. On occasion, widespread dissemination of the tumor is noted at the time of diagnosis.

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The rare PRMSs arise from the lower extremities of adults.

PATHOLOGIC FEATURES Histologically, rhabdomyoblasts range from round to stellate and are usually identified in either paucicellular myxoid foci or densely populated aggregates of primitive cells. Botryoid ERMSs are characterized by the presence of a cambium layer which is a cellular band of neoplastic cells beneath the mucosal surface. ARMSs are composed of relatively small round cells devoid of prominent nucleoli, aggregating as nests separated by thin vascularized septae. The cellular nests may undergo degenerative changes and fixation artifact resulting in the formation of a central ‘cavity’ filled with detached tumor cells. The solid variants of ARMSs have a nested pattern of tumor cells separated by fibrocollagenous septa. PRMSs are high-grade pleomorphic sarcomas composed of bizarre tumor cells showing morphologic or immunohistochemical evidence of skeletal muscle differentiation. FNAB of RMSs is usually markedly cellular, consisting of tissue fragments and dissociated cells. ERMSs (Fig. 4-19) tend to have an admixture of primitiveappearing round cells and variable forms of rhabdomyoblasts including ‘spider’ cells or ‘strap’/‘tadpole’ cells with occasional demonstrable striations. The latter cells are also seen in PRMSs and, to a lesser extent, in ARMSs. A myxoid and collagenous stroma may be exceptionally abundant in any of the RMS subtypes. Uniform round cells with pink cytoplasm and eccentrically located nuclei are the typical findings in ARMSs (Fig. 4-20). The presence of such cells helps to distinguish ARMSs from other differential diagnostic considerations of small round cell tumors. Spindle ERMSs consist principally of elongated slender cells, some with

A

RHABDOMYOSARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Embryonal rhabdomyosarcoma (ERMS): admixture of round cells and rhabdomyoblasts (spider cells, tennis-racket cells, or strap cells) with demonstrable striations; elongated cells are common in the spindle cell variant ៉ Alveolar rhabdomyosarcoma (ARMS): relatively monomorphic population of round cells with eccentrically located nuclei; cytoplasmic vacuoles may be present ៉ Pleomorphic rhabdomyosarcoma (PRMS): bizarre tumor cells with demonstrable striations in some cells; mitotic figures are easy to find Immunohistochemistry ៉ ERMS: positive for vimentin, MyoD1, myogenin, desmin, actin,

and myoglobin; rare expression of cytokeratin, S-100, Leu7, neuron-specific enolase, neurofilament, CD99, and B-cell markers (CD20) ៉ ARMS: same immunophenotype; may be negative for myogenin ៉ PRMS: same immunophenotype Genetics ៉ ERMS: complex karyotype; allelic loss in chromosomal region

11p15 ៉ ARMS: about 90% of cases, t(2;13)(q35;q14); less common,

t(1;13)(p36;q14); PAX3/FKHR and PAX7/FKHR fusion transcripts ៉ PRMS: complex karyotype

Differential Diagnosis and Pitfalls ៉ ERMS: carcinoma, melanoma, ARMS, and epithelioid sarcoma ៉ Spindle ERMS: spindle cell tumors including fibrosarcoma,

synovial sarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, and melanoma ៉ ARMS: alveolar soft part sarcoma, renal cell carcinoma, epithelioid sarcoma, and melanoma ៉ PRMS: pleomorphic sarcomas, and carcinomas

B

FIGURE 4-19 Rhabdomyosarcoma, embryonal type: FNAB. Aspirates are usually cellular. The tumor cells are predominantly round cells with a high N/C ratio. Tumor cells may have eccentrically placed nuclei and a scant eosinophilic cytoplasm. Papanicolaou stain, high power.

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A

B

FIGURE 4-20 Rhabdomyosarcoma, alveolar type: FNAB. The tumor cells are round and uniform in size, indistinguishable from other entities under the ‘small round blue cell tumor’ category. Cells with more abundant cytoplasm (B, arrow) are rare, but, when present, they suggest a skeletal muscle differentiation. Papanicolaou stain, high power.

demonstrable striations. The tumor cells of PRMSs are expectedly large with great variation in size and shape.

ANCILLARY STUDIES All variants of RMSs share a similar immunophenotype. MyoD1 and myogenin (nuclear stain) are highly specific for skeletal muscle differentiation, and about 90% of RMSs express these antibodies. Myoglobin is not commonly used due to high background staining and may not stain less differentiated RMSs. RMSs also stain with desmin and actins (SMA and MSA). Ultrastructural studies may reveal diagnostic features including thick and thin fi laments and rudimentary sarcomeres. Of the three histologic types, ARMSs have the most consistent cytogenetic abnormality: t(2;13)(q35;q14) and t(1;13)(p36;q14). Usually, these translocations are part of a more complex karyotype. The fusion transcripts (PAX3/FKHR and PAX7/FKHR) act as transcriptional activators and can be demonstrated by RT-PCR. It has been reported that allelic loss in chromosomal region 11p15 is common among ERMSs. The karyotype of both ERMSs and PRMSs is often complex.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of ARMSs encompasses other small round cell tumors including lymphoma,

Ewing/peripheral nerve sheath tumor (PNET), neuroblastoma, and desmoplastic small round cell tumor. Pulmonary small cell carcinoma, poorly differentiated squamous cell carcinoma, and Merkel cell carcinoma are also included in the cytologic differentials; however, these neoplasms are only encountered in adults. When an alveolar pattern is prominent, alveolar soft part sarcoma may be difficult to discriminate from ARMSs in small tissue biopsies; desmin may be positive in both tumors, further compounding the dilemma. Additional tumors with a prominent alveolar pattern such as renal cell carcinoma, epithelioid sarcoma, and melanoma may resemble ARMSs. Other spindle cell tumors such as synovial sarcoma, rhabdomyoma, and even reactive conditions (postoperative spindle cell nodules) should be differentiated from ERMSs in the urinary bladder and scrotal area. Poorly differentiated variants of other sarcomas and carcinomas are indistinguishable from PRMSs except for the presence of scattered rhabdomyoblasts. In all three types of RMSs, demonstration of rhabdomyoblasts is supportive of the diagnosis. Antibodies against skeletal muscle differentiation (MyoD1 and myogenin) are quite specific and often essential for diagnosis. Triton tumors have true rhabdomyoblastic differentiation and have to be taken into consideration in the evaluation. Prudence should be exercised not to mistake entrapped and regenerating non-neoplastic skeletal muscle fibers as rhabdomyoblasts. Other antibodies including epithelial, smooth muscle, hematolymphoid, and other markers directed to the entities in the differential diagnosis may be necessary. When adequate tissue is available, samples for cytogenetic, molecular, and ultrastructural examinations should be submitted to assist in problematic cases.

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SMOOTH MUSCLE TUMORS LEIOMYOSARCOMA CLINICAL FEATURES The common sites of leiomyosarcomas (LMSs) are the uterus, deep large vessels (pulmonary vessels, inferior vena cava, and vessels of the extremities), and dermis. The latter tend to have a more indolent behavior. Symptoms secondary to obstruction of large vessels, such as Budd–Chiari syndrome, superior vena cava syndrome, renal hypertension, or leg edema, may be the initial manifestation of the deep-seated LMSs.

LEIOMYOSARCOMA – DISEASE FACT SHEET Incidence and Location ៉ Most common in the uterus ៉ In the soft tissue, leiomyosarcomas (LMSs) account for 10–15% of soft tissue tumors; most common in the retroperitoneum Gender, Race, and Age Distribution ៉ Soft tissue LMSs: female predilection for retroperitoneal and

inferior vena cava LMS; other sites including large vessel or dermal LMS, no sex predilection; most common in middle-aged but also affects children ៉ Uterine LMSs: more common in black women; more common in middle-aged or elderly patients (median age, 50–55 years)

PATHOLOGIC FEATURES Histologically, LMSs are composed of spindle-shaped tumor cells forming short fascicles that intersect at right angles. The tumor cells have rounded ends, and, occasionally, epithelioid variants may be encountered. Mitotic activity may be brisk. The stroma is usually fibrocollagenous. The histologic criteria applied for the diagnosis of LMSs may differ according to the site of origin. Uterine LMSs are not sampled by fine needle aspiration. Primary LMSs of the large vessels and, less commonly, dermal LMSs may be aspirated. Most aspirated LMSs are from tumors metastatic to the lungs or other visceral organs. The aspirates of LMSs are usually cellular and consist of cohesive spindle-shaped tumor cells arranged in fascicles (Figs 4-21 & 4-22). The cytoplasm may have fine granules. The spindle cells typically have cigar-shaped (blunt-ended) nuclei. Less differentiated forms of LMSs may consist of atypical poorly cohesive polygonal cells. Bizarre pleomorphic tumor cells may be present. Epithelioid LMSs consist predominantly of uniform or markedly pleomorphic tumor cells with hyperchromasia, pleomorphism, mitotic figures, and prominent nucleoli. Necrosis may be present. The stroma in all types of LMSs can be fibrocollagenous or myxoid.

ANCILLARY STUDIES LMSs are invariably positive for SMA (Fig. 4-22B) and MSA, and less frequently for desmin, particularly in poorly differentiated types. Caldesmon and calponin are two other antibodies expressed by smooth musclederived neoplasms. LMSs may be positive for CK and

A B

FIGURE 4-21 Leiomyosarcoma: FNAB. The aspirated materials are usually cellular. The tumor cells are typically spindled with cigar-shaped nuclei. A fascicular arrangement may be suggested by tight cohesion of cells (B). A, Diff-Quik stain, high power. B, Papanicolaou stain, high power.

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B

A

FIGURE 4-22 Leiomyosarcoma: needle core biopsy. A, The tumor cells form short fascicles characteristically intersecting at right angles. H&E stain, low-power. B, Smooth muscle actin is invariably expressed. Smooth muscle actin, low power.

LEIOMYOSARCOMA – PATHOLOGIC FEATURES

There is no specific karyotypic aberration, and chromosomal analysis usually shows multiple and complex abnormalities.

Cytopathologic Findings ៉ Fairly cellular aspirates composed of predominantly spindle

cells; cigar-shaped nuclei; occasionally, epithelioid cells and pleomorphic cells predominate ៉ Spindle tumor cells have elongated cytoplasm ៉ Stroma is myxocollagenous Immunohistochemistry ៉ Positive for smooth muscle actin, caldesmon, desmin, and

calponin ៉ May be positive for cytokeratin and epithelial membrane

antigen ៉ Negative for CD34, S-100, CD117, and β-catenin

Electron Microscopy ៉ Actin filaments with focal densities, cell junctions, pinocytotic vesicles, and basement membrane Genetics ៉ Complex karyotype ៉ RB1 gene abnormality may be detected

Differential Diagnosis and Pitfalls ៉ Spindle cell sarcomas including dermatofibrosarcoma protuberans, fibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and angiosarcoma ៉ Gastrointestinal stromal tumors (GIST), mesenteric fibromatosis ៉ Presence of pleomorphic cells broadens the differential diagnosis

EMA in up to 30% of cases. LMSs do not express S-100 and CD117, and rarely CD34. Whereas uterine LMSs are positive for estrogen and progesterone receptors, LMSs from other organs are negative. Ultrastructurally, presence of actin fi laments with focal densities in the cytoplasm, suggestive of smooth muscle differentiation, may be demonstrated.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Other spindle cell tumors such as dermatofibrosarcoma protuberans (DFSP), fibrosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma (SS), angiosarcoma, gastrointestinal stromal tumors (GIST), and mesenteric fibromatosis enter the differential diagnosis. Tumors originating from a vessel wall suggest a smooth muscle origin. Expression of muscle markers (SMA, MSA, caldesmon, calponin, and desmin) supports the diagnosis of LMSs. The immunohistochemical panel should include S-100 protein, CD34, CD117, and β-catenin to assist in the differential diagnosis. Rarely, cytogenetic and ultrastructural studies are resorted to in the confirmation of the diagnosis. Although there is no specific cytogenetic abnormality of LMSs, entities with specific aberrations, including SS and DFSP, can be detected by genetic analysis.

VASCULAR TUMORS ANGIOSARCOMA CLINICAL FEATURES Angiosarcomas (ASs) may arise sporadically, associated with syndromes (neurofibromatosis, Klippel–Trenaunay syndrome, and Maffucci syndrome), or related to exposure to chemicals including therapeutic and diagnostic

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ANGIOSARCOMA – DISEASE FACT SHEET Incidence ៉ Rare tumor Location ៉ Sporadic angiosarcoma: deep soft tissue of extremities, head and neck, trunk, and visceral organs ៉ Postradiation angiosarcoma: chest wall and breast tissue, and any tissue in the field of exposure

ANGIOSARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity; predominantly spindle cells, rarely

epithelioid (polygonal) and plasmacytoid cells; intracytoplasmic lumen containing red blood cells may be seen ៉ Hemorrhagic background Immunohistochemistry ៉ Positive for vimentin, CD31, CD34, and factor VIII-related

antigen Gender and Age Distribution ៉ Sporadic angiosarcoma: more common in elderly patients, without sex predilection ៉ Postradiation angiosarcoma: middle-aged to elderly women

៉ 50% are positive for cytokeratin and epithelial membrane

antigen Electron Microscopy ៉ Weibel-Palade bodies are definitive for angiosarcomas but rarely

demonstrated

agents (radiation, Thorotrast, foreign body implants, arsenic-containing insecticides, and vinyl chloride). The common locations for sporadic AS are the scalp and deep soft tissue. Postradiation ASs, most commonly seen in patients treated for breast carcinoma, often arise in the chest wall and breast tissue. ASs may present as cutaneous plaques, subcutaneous nodules, or soft tissue mass lesions. Non-specific symptoms related to visceral organ involvement, such as gastrointestinal bleeding or obstruction, may precede the discovery of visceral AS. Epithelioid and poorly differentiated ASs are aggressive tumors and may rapidly metastasize.

PATHOLOGIC FEATURES Histologically, the spectrum of ASs varies from welldifferentiated innocuous vessel-forming lesion to high-grade malignant tumor that mimics carcinoma. A

Genetics ៉ Complex karyotype ៉ No specific genetic defect

Differential Diagnosis and Pitfalls ៉ Spindle angiosarcomas: other vascular tumors including hemangioma and Kaposi sarcoma, and other spindle cell sarcomas including fibrosarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor ៉ Epithelioid angiosarcomas: epithelioid hemangioendothelioma, carcinoma, and epithelioid mesenchymal tumors (epithelioid sarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor)

helpful clue to the correct diagnosis is the presence of intracytoplasmic lumina containing red blood cells. Aspirates from ASs are often bloody with a variable number of tumor cells (Fig. 4-23). The tumor cells may be spindle-shaped, polygonal (epithelioid), or plasma-

B A

FIGURE 4-23 Angiosarcoma: FNAB. The aspirates are variably cellular, often in a hemorrhagic background. High-grade angiosarcomas usually exhibit an epithelioid cytomorphology. Intracytoplasmic lumina are not regularly demonstrated. Note prominent nucleoli in (B). A, Papanicolaou stain, high power. B, Diff-Quik stain, high power.

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cytoid cells. Epithelioid AS may mimic carcinoma or other mesenchymal lesions with epithelioid features. Sheets of pleomorphic tumor cells are seen in poorly differentiated ASs. Mitoses may be frequent, and intracytoplasmic hemosiderin pigment may be seen. Identification of intracytoplasmic lumina with red blood cells is an important feature of ASs; however, this feature may be more difficult to appreciate in cytologic preparations.

ANCILLARY STUDIES Most ASs express commonly used endothelial markers (CD31, CD34, and factor VIII-related antigen). Some ASs, particularly the epithelioid variants, are also immunoreactive to CK and EMA. EM can demonstrate Weibel-Palade bodies, which are regarded as specific organelles for endothelial cells; however, these are rarely identified in proven cases of ASs. The karyotype of ASs is usually complex and without specific genetic abnormalities.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis depends on the degree of differentiation of an AS. Well-differentiated ASs can be mistaken for hemangioma or Kaposi sarcoma. Less differentiated ASs may present with solid sheets of spindle cells that may be indistinguishable from other spindle cell sarcomas such as fibrosarcoma, malignant fibrous histiocytoma, and leiomyosarcoma. Epithelioid variants of AS can resemble any epithelial/epithelioid neoplasms. CK and EMA expression of ASs can further add to the difficulty in the differential diagnosis. In general, unusually bloody aspirates should suggest possibility of a vascular lesion. Cytologically, the presence of cytoplasmic lumina with red blood cells, and intracytoplasmic hemosiderin are also suggestive of endothelial differentiation. In the right clinical background and cell morphology, expression of CD31, CD34, and/or factor VIII-related antigen confirms the diagnosis of ASs.

GASTROINTESTINAL STROMAL TUMOR CLINICAL FEATURES

GASTROINTESTINAL STROMAL TUMOR – DISEASE FACT SHEET Incidence ៉ 7–14.5 per million population per year

Location Stomach – 51% Small intestine – 36% Colon and rectum – 12% Esophagus – 1% Mesentery, omentum, and extra-abdominal sites – rare

៉ ៉ ៉ ៉ ៉

Gender, Race, and Age Distribution ៉ Slight male predilection ៉ Black women are affected six times more frequently than white

women ៉ Mean age – 63 years

mass effect. However, in some instances, the fi rst presentation is a metastasis, usually within the peritoneal cavity, liver, or mesentery. The diagnosis of GIST is usually established by endoscopic ultrasound-guided or percutaneous FNAB.

PATHOLOGIC FEATURES The histology of GISTs ranges from spindle cells in fascicles to nested epithelioid cells to patternless clustering of pleomorphic cells.

GASTROINTESTINAL STROMAL TUMOR – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirates; admixture of clustered or singly scattered

tumor cells; tumor cells form three-dimensional clusters ៉ Myxocollagenous stroma

Immunohistochemistry ៉ Positive for CD117 (almost all cases), CD34 (60–70%), smooth

muscle actin (30–40%), and, rarely, desmin and S-100 protein (<5%) ៉ CD117 negative cases are positive for PDGFRA mutation Genetics ៉ Common losses in chromosomes 14 and 22 ៉ Mutation in exons 11, 9, or 13 of c-kit gene ៉ Mutation of PDGFR in c-kit-negative GISTs

Differential Diagnosis and Pitfalls ៉ Spindle GISTs: smooth muscle tumors, infl ammatory fibroid

Gastrointestinal stromal tumors (GISTs) arise from the wall of the GI tract and occasionally in adjacent tissues such as the omentum and mesentery. The stomach is most frequently affected, followed in order of frequency by the small intestine, colon, and esophagus. A common presentation is mucosal ulceration which may lead to hemorrhage, intestinal obstruction or perforation, and other non-specific abdominal symptoms secondary to

polyp, infl ammatory myofibroblastic tumor, fibromatosis, solitary fibrous tumor, dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, spindle cell carcinoma, melanoma, and reactive nodular fibrous pseudotumor ៉ Epithelioid GISTs: carcinoma and melanoma ៉ Pleomorphic GISTs: malignant fibrous histiocytoma, carcinoma, and pleomorphic sarcomas

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A

B

FIGURES 4-24 Gastrointestinal stromal tumor: FNAB. The aspirates are usually cellular. The component cells may have spindle (A), oval/round (B), epithelioid, or pleomorphic cytology, and usually with abundant myxocollagenous stroma. A, Diff-Quik stain, low power. B, Diff-Quik stain, high power.

A

B

FIGURE 4-25 Gastrointestinal stromal tumor: cell block. A, The spindle tumor cells are arranged in short fascicles with moderate fibrocollagenous stroma. H&E stain, medium power. B, The tumor cells are strongly positive for CD117. Note the adjacent gastric epithelium. CD117, medium power.

FNAB smears are usually cellular (Fig. 4-24). Cell block preparation may exhibit typical fascicular arrangement of cells (Fig. 4-25). The tumor cells appear as clusters, often in three-dimensional forms or palisades admixed with single cells. The individually scattered cells are often devoid of their cytoplasm. Where intact cells are demonstrated, the cytoplasmic processes are often delicate. Generally, the nuclei are relatively uniform, ovoid to spindled, and often wavy with blunt or tapered ends. Nuclear grooves and intranuclear inclusions have been reported, particularly in epithelioid variants. A combination of spindle and epithelioid lesional cells may be encountered. The background usually consists of myxocollagenous stroma.

ANCILLARY STUDIES Approximately 95% of GISTs express c-kit (CD117) by immunohistochemistry (Fig. 4-25B). The c-kit negative GISTs have been shown to be immunoreactive for PDGFRA (platet-derived growth factor receptor-α). Up to 90% of these neoplasms also react with CD34, which appears to be influenced by the site of the tumor. Esophageal and rectal GISTs are known to have a higher incidence of CD34 expression compared with gastric and small intestine GISTs. Less than one-third of GISTs are SMA-positive and much less frequently (5%) desmin-positive. GISTs often express caldesmon.

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The genetics of GISTs have been extensively studied. There is a gain-of-function mutation of c-kit, a growth factor transmembrane receptor, leading to activation of proteins in the signal transduction pathway and resulting in cell proliferation. C-kit mutations often involve exons 11 and 9. Some of the c-kit-negative GISTs have been shown to have mutation of PDGFRA, another tyrosine kinase receptor. Common cytogenetic abnormalities include loss of chromosomes 14, 15, and 22.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

MYXOMA – DISEASE FACT SHEET Incidence ៉ Intramuscular myxoma (IM): relatively common tumor ៉ Juxta-articular myxoma (JM): rare ៉ Cutaneous myxoma (CM) or superficial angiomyxoma: rare;

association with Carney syndrome Location ៉ IM: thigh, buttocks, shoulder, and trunk ៉ JM: near knee, shoulder, elbow, and ankle joints ៉ CM: trunk, thigh, and head and neck

Gender, Race, and Age Distribution

There is a long list of entities that cytologically resemble GISTs. These include true smooth muscle tumors of the GI tract, inflammatory myofibroblastic tumor, inflammatory fibroid polyp, fibromatosis, solitary fibrous tumor, dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, carcinoma, and metastatic melanoma. Pleomorphic GISTs are indistinguishable from other pleomorphic tumors of both epithelial and mesenchymal origin. The importance of accurate diagnosis lies in the good response of GISTs to imatinib mesylate (Gleevae), a selective inhibitor of tyrosine kinases including c-kit and PDGFRA. Melanoma may express CD117, so other antibodies (S-100 protein, HMB-45, and Melan A) should be included in the laboratory work-up if melanoma is suspected. Although some of the neoplasms listed above are CD34-positive, none consistently express CD117. Carcinomas with small cell component may be positive for CD117, but CK expression is rarely observed in GISTs. More problematic cases are the CD117-negative GIST. PDGFRA may be of help in some of these tumors. Mutational analysis in most of these cases will show c-kit or PDGFRA mutations. In the right histomorphology and site of origin (most c-kit-negative GISTs arise from the peritoneum and omentum), these tumors should be considered as GISTs. A recently described lesion, reactive nodular fibrous pseudotumor, is CD117-positive and may be difficult to discriminate from GISTs without the benefit of clinical history and ancillary studies.

៉ IM: female predilection; no race predilection; middle-aged to

elderly patients ៉ JM: male predilection; no race predilection; middle-aged patients ៉ CM: no sex predilection; no race predilection; young and middle-

aged patients

the knee joint, but can occur in the shoulder or elbow. CMs may be multiple and are distributed in the trunk, head and neck, and extremities. When CMs are multiple, Carney complex (familial myxoma syndrome) should be suspected.

PATHOLOGIC FEATURES Histologically, the tumor cells are usually scant with abundant myxoid stroma. The tumor vascularity is often minimal to non-existent in IMs and JMs, but CMs may have focally prominent capillaries.

MYXOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Low cellularity and abundant myxoid stroma; tumor cells are

spindle-shaped with a low N/C ratio; cytoplasm is bipolar with elongated processes; absence of vascular channels Immunohistochemistry

TUMORS OF UNCERTAIN HISTOGENESIS

៉ Positive for vimentin ៉ May be positive for CD34, desmin, and smooth muscle actin ៉ Negative for S-100 protein

Genetics

MYXOMA

៉ Intramuscular myxoma: mutation in GNAS1 gene ៉ Juxta-articular myxoma: no specific genetic abnormality; GNAS1

gene mutation is absent

CLINICAL FEATURES Myxomas are subclassified into three clinicopathologic types: intramuscular myxomas (IMs), juxta-articular myxomas ( JMs), and cutaneous myxomas (CMs) or superficial angiomyxomas. IMs often arise in the thigh muscles as a painless, soft and fluctuant mass. JMs are usually located close to a large joint, most commonly

៉ Cutaneous myxoma: association with Carney complex; mutation

in 17q22–24 locus (PRKAR1A gene) Differential Diagnosis and Pitfalls ៉ Scar, and benign and malignant tumors with myxoid stroma

(benign fibrous histiocytoma, fibromatosis, dermatofibrosarcoma protuberans, myxoid liposarcoma, low-grade fibromyxoid sarcoma, and myxoid malignant fibrous histiocytoma)

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A

B

FIGURE 4-26 Myxoma: touch preparation. The tumor is often hypocellular and composed mainly of thin myxoid stroma. The bland-appearing tumor cells are elongated with long cytoplasmic processes. Vascular channels are usually not identified. Diff-Quik stain, high power.

Aspirates from these tumors yield clear viscous fluid. The smears are generally paucicellular with profuse myxoid material in the background (Fig. 4-26). The tumor cells are elongated and bland with long cytoplasmic processes. The N/C ratio is low and nucleoli are not conspicuous. Aspirated capillary channels are quite rare. Other entrapped or surrounding mesenchymal elements such as skeletal muscle, fat, or fibrocollagenous tissue may be present in the aspirates.

myxoid stroma invariably contain markedly atypical cells and, in most occasions, moderate amount of vascular channels. Immunohistochemistry is of limited use in myxoma owing to the absence of specific antibody associated with the tumor; however, absence of expression of antibodies known to be positive in other tumors (e.g. S-100 protein expression of myxoid liposarcoma) assists in the differential diagnosis. Mutational analysis directed to GNAS1 (for IMs) and PRKAR1A (for CMs) genes may help establish the diagnosis.

ANCILLARY STUDIES The lesional cells of myxoma may be positive for CD34, desmin, and SMA. S-100 protein is not expressed. Point mutation of the GNAS1 gene appears to be a consistent abnormality of IMs but not JMs and CMs. CMs associated with Carney complex may have mutation of the suppressor gene – protein kinase A type I-α (PRKAR1A) gene.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Several sarcomas may have spindle cells and myxoid stroma, including malignant fibrous histiocytoma, lowgrade fibromyxoid sarcoma, and liposarcoma, particularly the myxoid variant. Other benign and low-grade sarcomas with myxoid component in the differential diagnosis are fibromatosis, benign fibrous histiocytoma, and dermatofibrosarcoma protuberans. The presence of bland-appearing spindle cells with elongated cytoplasmic processes and absent or minimal vascular channels in the aspirate support the diagnosis of myxoma and exclude most of the entities listed in the differential diagnosis. The malignant neoplasms with

EPITHELIOID SARCOMA CLINICAL FEATURES Epithelioid sarcomas commonly affect young and middle-aged male patients. The distal types often

EPITHELIOID SARCOMA – DISEASE FACT SHEET Incidence and Location ៉ Rare tumors ៉ Associated with tendons and aponeurosis of the distal extremities

(distal type) and deep soft tissue of the proximal extremities (proximal type) Gender, Race, and Age Distribution ៉ Male predilection ៉ No race predilection ៉ Young and middle aged adults for distal type; older age for

proximal type

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present as slow-growing subcutaneous nodules in the fingers, palm, and wrist. The proximal types often arise from the buttocks or thigh as deep-seated mass lesions. The mode of spread is through regional lymph nodes. Frequently, the tumor tracks along the tendon and aponeurosis before reaching the lymph nodes. Distant metastases are usually to the lungs.

PATHOLOGIC FEATURES

EPITHELIOID SARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Spindle and polygonal cells with moderately pleomorphic nuclei and variable nucleolar prominence; necrosis may be present; palisading of aspirated tumor cells and necrosis may resemble granulomas ៉ Proximal-type epithelioid sarcomas appear more undifferentiated with a high N/C ratio and round or polygonal tumor cells Immunohistochemistry ៉ Positive for cytokeratin, epithelial membrane antigen, and V-

Histologically, the tumor cells form nests separated by fibrocollagenous stroma. The most characteristic feature of epithelioid sarcomas is the presence of central necrosis surrounded by palisading tumor cells. The tumor cells are spindle or polygonal with eosinophilic cytoplasm, moderately pleomorphic nuclei, and small nucleoli. The aspirated material is usually highly cellular (Fig. 4-27). Due to the fibrocollagenous elements of some tumors, occasional paucicellular aspirates can be expected. The tumor cells are usually round or polygonal. Infrequently, spindle-shaped cells may predominate. The neoplastic cells may also assume a rhabdoid or plasmacytoid appearance. Moderate to severe atypia, abundant mitotic figures, necrosis, and prominent nucleoli are common in the proximal types of epithelioid sarcomas. Loosely cohesive clusters of polygonal and epithelioid cells and a background of necrosis may recapitulate a granulomatous histology.

ANCILLARY STUDIES Aside from vimentin, epithelioid sarcomas also consistently express CK and EMA. Approximately 50%

cadherin; 50% are positive for CD34; variable expression of desmin, muscle-specific actin (HHF-35), and smooth muscle actin ៉ Negative for E-cadherin and S-100 Genetics ៉ No consistent karyotypic abnormality Differential Diagnosis and Pitfalls ៉ Granuloma annulare, carcinoma, melanoma, rhabdomyosarcoma,

alveolar soft part sarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and epithelioid angiosarcoma

are positive for CD34. Epithelioid sarcomas may stain with muscle markers including desmin, MSA (HHF-35), and SMA. The tumor is consistently negative for S-100 protein, but may occasionally express HMB-45. The ultrastructural features of tumor cells range from epithelial to fibroblast-like mesenchymal cells. There is no specific chromosomal or genetic abnormality identified so far.

A B

FIGURE 4-27 Epithelioid sarcoma: FNAB. FNAB materials are often cellular. The tumor cells are round or polygonal and indistinguishable from other epithelial malignancies. Necrosis may be apparent on the aspirated material (A). A, Papanicolaou stain, medium power. B, Diff-Quik stain, high power.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS Epithelioid sarcomas can mimic granuloma annulare (GA), carcinoma, and other epithelioid-appearing sarcomas including alveolar soft part sarcoma (ASPS), synovial sarcoma (SS), and epithelioid angiosarcoma (AS). The frequent location of the tumor on the hand and the presence of prominent central necrosis may be interpreted as representing GA. Attention to the cytologic atypia in the surrounding cells should prompt a consideration of epithelioid sarcoma. The typical location of the tumor, pure epithelioid lesional cells, and expression of epithelial markers substantiate the diagnosis. Immunohistochemical stains are usually necessary mainly to rule out other entities in the differential diagnosis: expression of CD31 and factor VIII-related antigen for AS, CD68 for GA. Other ancillary studies are intended to exclude other entities with specific ultrastructural or genetic features, such as rhomboid crystals and t(X;17) of ASPS, Weibel-Palade bodies of AS, or t(X;18) of SS.

ALVEOLAR SOFT PART SARCOMA CLINICAL FEATURES Alveolar soft part sarcomas (ASPSs) are rare neoplasms that present as slow-growing deep-seated tumors in the lower extremities, particularly the thigh, usually in young males. Other reported sites for ASPSs are the orbit and tongue in children. ASPSs may also present as metastatic lesions, particularly in the lungs, bone, and brain.

A

ALVEOLAR SOFT PART SARCOMA – DISEASE FACT SHEET Incidence and Location ៉ Rare tumor: 0.5–0.9% of soft tissue tumors ៉ Lower extremities (41% in thigh or buttocks); orbit and tongue in children Gender, Race, and Age Distribution ៉ Female predilection before age of 30 years; slight male

predilection after 30 years ៉ No race predilection

PATHOLOGIC FEATURES The characteristic histology of ASPSs is that of a nested pattern of tumor cells forming a central cavity partially fi lled with dissociated tumor cells and thin septae separating each nest. The tumor cells are polygonal with ample eosinophilic cytoplasm and eccentrically placed nuclei. The aspirated material is cellular and composed of tight aggregates or singly dispersed tumor cells (Fig. 4-28). The lesional cells are composed of relatively large round cells with a low N/C ratio. Binucleation and multinucleation are frequently seen with the nuclei exhibiting conspicuous nucleoli. The nuclei are round with smooth outline, and of variable size. The abundant cytoplasm is finely granular. Due to the fragility of the cytoplasm, scattered naked nuclei are often prominent in the background. Branching capillaries may be associated with clusters of tumor cells. Myxocollagenous stroma is rarely prominent.

B

FIGURE 4-28 Alveolar soft part sarcoma: touch preparation. The tumor is usually cellular and composed of round or polygonal cells with abundant finely granular cytoplasm, imparting a deceptively low N/C ratio. The nuclei, some devoid of cytoplasm, are round and smooth-outlined. Diff-Quik stain, high power.

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ALVEOLAR SOFT PART SARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirates; relatively large round cells with eosinophilic and granular cytoplasm; nuclei are round and nucleoli are small; mitotic figures are rare ៉ Stroma is usually scant Immunohistochemistry ៉ No specific immunophenotype ៉ May be positive for desmin and S-100 ៉ Negative for synaptophysin, chromogranin, cytokeratin, and

epithelial membrane antigen Electron Microscopy ៉ Rhomboid crystals, free or membrane-bound

Genetics ៉ der(17) t(X;17) (p11.2;q25) ៉ ASPL/TFE3 fusion product

tumors. It is prudent to submit a portion of the tumor, when adequate material is available, for EM, cytogenetic, and/or molecular studies.

SYNOVIAL SARCOMA CLINICAL FEATURES The majority of synovial sarcomas (SSs) are usually slow-growing tumors which arise from soft tissue of the extremities, often in the thigh. Less common sites include the upper extremities, trunk, and head and neck region. Patients may complain of pain, numbness, paresthesia, or some loss of function of the involved extremity. Incompletely excised tumor may locally recur. Metastasis is usually to the lungs.

Differential Diagnosis and Pitfalls ៉ Paraganglioma, epithelioid sarcoma, renal cell carcinoma,

PATHOLOGIC FEATURES

alveolar rhabdomyosarcoma, and melanoma

ANCILLARY STUDIES The only antibody that ASPSs consistently express is vimentin. ASPSs are variably reactive to desmin, and occasionally reactive to SMA, MSA, and S-100 protein. The tumor is non-reactive to MyoD1 and myogenin. Epithelial and neuroendocrine markers are negative. The characteristic intracytoplasmic crystals can be appreciated as periodic acid–Schiff (PAS)-positive needle-shaped crystals in tumor cells. These membranebound or free rhomboid crystals can be demonstrated by EM. A non-balanced translocation, t(X;17)(p11;q25), resulting in fusion of TFE3 (Xp11) with ASPL (17q25) appear to be specific for ASPS. The fusion product (TFE3/ASPL) can be demonstrated by PCR analysis.

Histologically, three types are currently recognized: biphasic type, monophasic type, and poorly differentiated type. The biphasic SSs consist of spindle cells and epithelial cells often with glandular differentiation. The monophasic SSs are composed purely of spindle cells or plump cells with foci of cellular evidence of epithelial differentiation manifested immunohistochemically by expression of CK. Poorly differentiated SSs (PDSSs) are composed of rather round or oval cells that are indistinguishable from other small round cell tumors. Immunohistochemical stains and molecular studies are necessary to establish the diagnosis of PDSSs. FNAB of SSs is usually hypercellular (Figs 4-29 & 4-30). Singly dispersed lesional cells and tumor tissue fragments, sometimes branched, are frequently obtained. Myxofibrous stroma accompanies aggregates of spindle cells or chunks of tumor. Singly dispersed neoplastic cells are often stripped of their cytoplasm. The tumor cell nuclei have fine chromatin and inconspicuous nucleoli. The cytoplasm is elongated with bipolar processes. Spindle-shaped tumor cells

DIFFERENTIAL DIAGNOSIS AND PITFALLS The distinctive alveolar pattern of ASPSs and its moderate, sometimes clear cytoplasm are shared by other tumors including alveolar rhabdomyosarcoma (ARMS), paraganglioma, renal cell carcinoma (RCC), and granular cell tumor (GCT). Immunohistochemistry is often performed to exclude other tumors in the differential diagnosis. ARMSs are consistently positive for MyoD1 and myogenin; paraganglioma, for neuroendocrine markers; RCC, for CK and vimentin; and GCT, for S-100 protein and CD68. On occasions, ASPSs may express desmin and S-100 protein, so a complete panel of antibodies should be run to effectively exclude other

SYNOVIAL SARCOMA – DISEASE FACT SHEET Incidence and Location ៉ ∼10% of soft tissue tumors ៉ Extremities, trunk, and neck and head regions

Gender, Race, and Age Distribution ៉ Slight male predilection ៉ No race predilection ៉ Young adults and children (median age, 30–35 years)

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SYNOVIAL SARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Biphasic SS: cellular aspirates; spindle cells predominate; scant or absent epithelial cells; myxocollagenous stroma ៉ Monophasic SS: cellular aspirates; spindle cells with commashaped nuclei; myxocollagenous stroma ៉ Poorly differentiated SS: cellular aspirates; oval or round cells; spindle and epithelial cells may be present; myxocollagenous stroma

predominate even in biphasic SSs. Epithelial elements of biphasic SSs may stand out as three-dimensional clusters or gland-forming cuboidal or polygonal cells associated with mucinous material. Squamous epithelial elements are infrequent. The neoplastic cells of monophasic SSs appear as ‘comma’-shaped cells and are indistinguishable from spindle cells of biphasic SSs. The tumor cells of PDSSs are round or oval, and relatively small sized, with a high N/C ratio. In all three variants of SSs, markedly pleomorphic cells are uncommon.

Immunohistochemistry ៉ Biphasic SS: ៉ Epithelial cells: positive for cytokeratin (CK), epithelial

membrane antigen (EMA), vimentin, HBME1 and calretinin, and, less frequently, CD99; negative for bcl-2 ៉ Stromal cells: positive for vimentin and bcl-2, CD99 (60%), S-100 protein (30%); negative for desmin and smooth muscle actin; scattered CK-positive cells ៉ Monophasic SS: phenotype is similar to the stromal cells of biphasic SS; patchy areas are positive for CK, EMA, CD99, and calretinin ៉ Poorly differentiated SS: phenotype is similar to the stromal cells of biphasic SS; negative for WT1; patchy areas are positive for CK, EMA, CD99, and calretinin Genetics ៉ t(X;18)(p11.2;q11.2) ៉ SYT/SSX fusion transcript

Differential Diagnosis and Pitfalls ៉ Biphasic SS: malignant peripheral nerve sheath tumor (MPNST)

with glandular component and carcinosarcoma ៉ Monophasic SS: neurofibroma, fibromatosis, solitary fibrous

tumor, fibrosarcoma, low-grade fibromyxoid sarcoma, MPNST, leiomyosarcoma and other spindle cell soft tissue tumors, and carcinoma ៉ Poorly differentiated SS: small round cell tumors (Ewing sarcoma/ primitive neuroectodermal tumor, rhabdomyosarcoma, nonHodgkin lymphoma, desmoplastic small round cell tumor, and other small round cell tumors in children; small cell carcinoma, Merkel cell carcinoma, and non-Hodgkin lymphoma in adults)

A

ANCILLARY STUDIES CK (Fig. 4-30B), EMA, and, less frequently, mesothelial markers (HBME1 and calretinin) highlight the epithelial cells of biphasic SSs, and some areas of monophasic SSs and PDSSs. The stromal cells of biphasic SSs, and the majority of lesional cells of monophasic SSs and PDSSs are positive for vimentin, bcl-2, and CD99. CKand EMA-positive foci of PDSSs may be minimal. PDSSs are negative for WT1. SSs occasionally express S-100 protein. All variants of SSs exhibit t(X;18)(p11.2;q11.2), a genetic abnormality not seen in other tumors. The chimeric transcript (SYT/SSX) results from fusion of the SYT gene in chromosome 18 and SSX1, SSX2, or SSX4 in the X chromosome. The translocation can be demonstrated by karyotyping, FISH, and RT-PCR. The epithelial cells have ultrastructural characteristics of glandular cells: desmosomal junctions and short microvilli. Spindle cells have non-specific ultrastructural features. There is no transition from epithelial to mesenchymal cells.

B

FIGURE 4-29 Synovial sarcoma: FNAB. FNAB usually yields cellular smears. The tumor cells are spindled or round (poorly differentiated type), with a variable amount of stroma. The epithelial component of the biphasic type is infrequently recognized in aspirates. A, Diff-Quik stain, low power. B, Diff-Quik stain, high power.

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A

B

FIGURE 4-30 Synovial sarcoma: cell block. Spindled stromal cells and strips of epithelial cells are identified in this cell block preparation. The epithelial cells may be morphologically indistinguishable from the stromal cells, but are readily highlighted by cytokeratin stain (B). A, H&E stain, low power. B, Cytokeratin stain, low power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The spindle cells in biphasic SSs predominate and the list of differential diagnoses is similar to that of monophasic SS, including benign and malignant spindle cell mesenchymal neoplasms such as neurofibroma, fibromatosis, fibrosarcoma, and glandular MPNST. When the epithelial component of biphasic SS is represented in the aspirated material, other biphasic tumors including MPNST and carcinosarcoma may be considered. The main cytomorphologic feature that favors SS is the uniformity of the malignant stromal cells. In contrast, the sarcomatous elements of MPNST and carcinosarcoma are more pleomorphic. PDSSs fall under the category of small round cell tumors and the set of differential diagnoses vary with the patient’s age. Neuroblastoma, non-Hodgkin lymphoma (NHL), Ewing sarcoma/primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, and desmoplastic small round cell tumor should be considered in children. NHL, small cell carcinoma, and Merkel cell carcinoma are the most frequently encountered small round cell tumors in adults. Immunohistochemistry, flow cytometry, cytogenetic and/or molecular studies are essential in arriving at a definitive diagnosis. SUGGESTED READINGS General Soft Tissue Tumors Enzinger FM, Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue Tumors, 4th ed. St Louis, Mosby, 2001. Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumors. Pathology and Genetics. Tumors of Soft Tissue and Bone. Lyon, France: IARC Press, 2002. Miettinen M. Diagnostic Soft Tissue Pathology. Philadelphia, Churchill Livingstone, 2003.

Cytology of Soft Tissue Abdul-Karim FW, Rader AE. Fine needle aspiration of soft-tissue lesions. Clin Lab Med 1998;18:507–540. Bennert KW, Abdul-Karim FW. Fine needle aspiration cytology vs. needle core biopsy of soft tissue tumors. A comparison. Acta Cytol 1994;38: 381–384. Das K, Hameed M, Heller D, et al. Liquid-based vs. conventional smears in fine needle aspiration of bone and soft tissue tumors. Acta Cytol 2003;47:197–201. Gonzalez-Campora R. Fine needle aspiration cytology of soft tissue tumors. Acta Cytol 2000;44:337–343. Gonzalez-Campora R. Cytoarchitectural findings in the diagnosis of primary soft tissue tumors. Acta Cytol 2001;45:115–146. Guiter GE, Gatscha RM, Zakowski MF. ThinPrep vs. conventional smears in fine-needle aspirations of sarcomas: a morphological and immunocytochemical study. Diagn Cytopathol 1999;21:351–354. Jones C, Liu K, Hirschowitz S, et al. Concordance of histopathologic and cytologic grading in musculoskeletal sarcomas: can grades obtained from analysis of the fine-needle aspirates serve as the basis for therapeutic decisions? Cancer 2002;96:83–91. Kilpatrick SE, Cappellari JO, Bos GD, et al. Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? Experience with 140 patients. Am J Clin Pathol 2001;115: 59–68. Kilpatrick SE, Geisinger KR. Soft tissue sarcomas: the usefulness and limitations of fine-needle aspiration biopsy. Am J Clin Pathol 1998;110: 50–68. Kilpatrick SE, Ward WG, Cappellari JO, Bos GD. Fine-needle aspiration biopsy of soft tissue sarcomas. A cytomorphologic analysis with emphasis on histologic subtyping, grading, and therapeutic significance. Am J Clin Pathol 1999;112:179–188. Kilpatrick SE, Ward WG, Chauvenet AR, Pettenati MJ. The role of fineneedle aspiration biopsy in the initial diagnosis of pediatric bone and soft tissue tumors: an institutional experience. Mod Pathol 1998;11: 923–928. Maitra A, Ashfaq R, Saboorian MH, et al. The role of fine-needle aspiration biopsy in the primary diagnosis of mesenchymal lesions: a community hospital-based experience. Cancer 2000;90:178–185. Mathur S, Kapila K, Verma K. Accuracy of cytological grading of spindlecell sarcomas. Diagn Cytopathol 2003;29:79–83. Nagira K, Yamamoto T, Akisue T, et al. Reliability of fine-needle aspiration biopsy in the initial diagnosis of soft-tissue lesions. Diagn Cytopathol 2002;27:354–361. Palmer HE, Mukunyadzi P, Culbreth W, Thomas JR. Subgrouping and grading of soft-tissue sarcomas by fine-needle aspiration cytology: a histopathologic correlation study. Diagn Cytopathol. 2001;24:307– 316.

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Dermatofibrosarcoma Protuberans

Lipoma and Liposarcoma

Malignant Fibrous Histiocytoma

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Nodular Fasciitis Aydin O, Oztuna V, Polat A. Three cases of nodular fasciitis: primary diagnoses by fine needle aspiration cytology. Cytopathology 2001;12: 346–347. Dahl I, Akerman M. Nodular fasciitis a correlative cytologic and histologic study of 13 cases. Acta Cytol 1981;25:215–223. Dodd LG, Martinez S. Fine-needle aspiration cytology of pseudosarcomatous lesions of soft tissue. Diagn Cytopathol 2001;24:28–35. Kong CS, Cha I. Nodular fasciitis: diagnosis by fine needle aspiration biopsy. Acta Cytol 2004;48:473–477. Plaza JA, Mayerson J, Wakely PE. Nodular fasciitis of the hand. A potential diagnostic pitfall in fine-needle aspiration cytopathology. Am J Clin Pathol 2005;123:388–393. Willen H, Akerman M. Fine needle aspiration of nodular fasciitis – no need for surgery. Acta Orthop Scand Suppl 1995;265:54–55.

Domanski HA, Gustafson P. Cytologic features of primary, recurrent, and metastatic dermatofibrosarcoma protuberans. Cancer 2002;96:351– 361. Klijanienko J, Caillaud JM, Lagace R. Fine-needle aspiration of primary and recurrent dermatofibrosarcoma protuberans. Diagn Cytopathol 2004;30:261–265. Klijanienko J, Caillaud JM, Lagace R. Fine-needle aspiration of primary and recurrent benign fibrous histiocytoma: classic, aneurysmal, and myxoid variants. Diagn Cytopathol 2004;31:387–391. Mendenhall WM, Zlotecki RA, Scarborough MT. Dermatofibrosarcoma protuberans. Cancer 2004;101:2503–2508.

Neurofibroma and Schwannoma Dahl I, Hagmar B, Idvall I. Benign solitary neurilemoma (schwannoma). A correlative cytological and histological study of 28 cases. Acta Pathol Microbiol Immunol Scand [A] 1984;92:91–101. Ferretti M, Gusella PM, Mancini AM, et al. Progressive approach to the cytologic diagnosis of retroperitoneal spindle cell tumors. Acta Cytol 1997;41:450–460. Kong CS, Cha I. Nodular fasciitis: diagnosis by fine needle aspiration biopsy. Acta Cytol 2004;48:473–477. Mooney EE, Layfield LJ, Dodd LG. Fine-needle aspiration of neural lesions. Diagn Cytopathol 1999;20:1–5. Resnick JM, Fanning CV, Caraway NP, et al. Percutaneous needle biopsy diagnosis of benign neurogenic neoplasms. Diagn Cytopathol 1997;16: 17–25. Slagel DD, Powers CN, Melaragno MJ, et al. Spindle-cell lesions of the mediastinum: diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 1997;17:167–176. Stelow EB, Lai R, Bardales RH, et al. Endoscopic ultrasound-guided fineneedle aspiration cytology of peripheral nerve-sheath tumors. Diagn Cytopathol 2004;30:172–177.

Granular Cell Tumor Husain M, Nguyen GK. Cytopathology of granular-cell tumor of the lung. Diagn Cytopathol 2000;23:294–295. Liu K, Madden JF, Olatidoye BA, Dodd LG. Features of benign granular cell tumor on fine needle aspiration. Acta Cytol 1999;43:552–557. Liu Z, Mira JL, Vu H. Diagnosis of malignant granular cell tumor by fine needle aspiration cytology: Acta Cytol 2001;45:1011–1021. Wieczorek TJ, Krane JF, Domanski HA, et al. Cytologic findings in granular cell tumors, with emphasis on the diagnosis of malignant granular cell tumor by fine-needle aspiration biopsy. Cancer 2001;93:398–408.

Fibromatosis Hayry P, Reitamo JJ, Totterman S, et al. The desmoid tumor. II. Analysis of factors possibly contributing to the etiology and growth behavior. Am J Clin Pathol 1982;77:674–680. Raab SS, Silverman JF, McLeod DL, et al. Fine needle aspiration biopsy of fibromatoses. Acta Cytol 1993;37:323–328. Reitamo JJ, Scheinin TM, Hayry P. The desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor. Am J Surg 1986;151:230–237. Zaharopoulos P, Wong JY. Fine-needle aspiration cytology in fibromatoses. Diagn Cytopathol 1992;8:73–78.

Malignant Peripheral Nerve Sheath Tumor Ferretti M, Gusella PM, Mancini AM, et al. Progressive approach to the cytologic diagnosis of retroperitoneal spindle cell tumors. Acta Cytol 1997;41:450–460. Klijanienko J, Caillaud JM, Lagace R, Vielh P. Cytohistologic correlations of 24 malignant peripheral nerve sheath tumor (MPNST) in 17 patients: the Institut Curie experience. Diagn Cytopathol 2002;27:103–108. Mooney EE, Layfield LJ, Dodd LG. Fine-needle aspiration of neural lesions. Diagn Cytopathol 1997;16:17–25.

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Soft Tissue

Resnick JM, Fanning CV, Caraway NP, et al. Percutaneous needle biopsy diagnosis of benign neurogenic neoplasms. Diagn Cytopathol 1997;16: 17–25. Vendraminelli R, Cavazzana AO, Poletti A, et al. Fine-needle aspiration cytology of malignant nerve sheath tumors. Diagn Cytopathol 1992;8: 559–562.

Liu K, Layfield LJ. Cytomorphologic features of angiosarcoma on fine needle aspiration biopsy. Acta Cytol 1999;43:407–415. Mullick SS, Mody DR, Schwartz MR. Angiosarcoma at unusual sites. A report of two cases with aspiration cytology and diagnostic pitfalls. Acta Cytol 1997;41:839–844. Wakely PE Jr, Frable WJ, Kneisl JS. Aspiration cytopathology of epithelioid angiosarcoma. Cancer. 2000;90:245–251.

Rhabdomyosarcoma Brahmi U, Rajwanshi A, Joshi K, et al. Role of immunocytochemistry and DNA flow cytometry in the fine-needle aspiration diagnosis of malignant small round-cell tumors. Diagn Cytopathol 2001;24:233–239. de Jong AS, van Kessel-van Vark M, van Heerde P. Fine needle aspiration biopsy diagnosis of rhabdomyosarcoma. An immunocytochemical study. Acta Cytol 1987;31:573–577. Lussier C, Klijanienko J, Vielh P. Fine-needle aspiration of metastatic nonlymphomatous tumors to the major salivary glands: a clinicopathologic study of 40 cases cytologically diagnosed and histologically correlated. Cancer 2000;90:350–356. Pohar-Marinsek Z, Anzic J, Jereb B. Topical topic: value of fine needle aspiration biopsy in childhood rhabdomyosarcoma: twenty-six years of experience in Slovenia. Med Pediatr Oncol 2002;38:416–420. Pohar-Marinsek Z, Bracko M. Rhabdomyosarcoma. Cytomorphology, subtyping and differential diagnostic dilemmas. Acta Cytol 2000;44: 524–532. Seidal T, Walaas L, Kindblom LG, Angervall L. Cytology of embryonal rhabdomyosarcoma: a cytologic, light microscopic, electron microscopic, and immunohistochemical study of seven cases. Diagn Cytopathol 1988;4:292–299. Valencerina Gopez E, Dauterman J, Layfield LJ. Fine-needle aspiration biopsy of alveolar rhabdomyosarcoma of the parotid: a case report and review of the literature. Diagn Cytopathol 2001;24:249–252.

Gastrointestinal Stromal Tumor Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33:459– 465. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 2002;33:484–495. Rader AE, Avery A, Wait CL, et al. Fine-needle aspiration biopsy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutational analysis of c-kit. Cancer 2001;93:269–275. Rossi G, Valli R, Bertolini F, et al. PDGFRA expression in differential diagnosis between KIT negative gastrointestinal stromal tumours and other primary soft-tissue tumours of the gastrointestinal tract. Histopathology 2005;46:522–531. Wieczorek TJ, Faquin WC, Rubin BP, Cibas ES. Cytologic diagnosis of gastrointestinal stromal tumor with emphasis on the differential diagnosis with leiomyosarcoma. Cancer 2001;93:276–287. Yantiss RK, Nielsen GP, Lauwers GY, Rosenberg AE. Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases. Am J Surg Pathol 2003;27: 532–540. Myxoma

Leiomyosarcoma Barbazza R, Chiarelli S, Quintarelli GF, Manconi R. Role of fine-needle aspiration cytology in the preoperative evaluation of smooth muscle tumors. Diagn Cytopathol 1997;16:326–330. Ferretti M, Gusella PM, Mancini AM, et al. Progressive approach to the cytologic diagnosis of retroperitoneal spindle cell tumors. Acta Cytol 1997;41:450–460. Giuntoli RL II, Metzinger DS, DiMarco CS, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol 2003;89: 460–469. Hornick JL, Fletcher CD. Criteria for malignancy in nonvisceral smooth muscle tumors. Ann Diagn Pathol 2003;7:60–66. Hummel P, Cangiarella JF, Cohen JM, et al. Transthoracic fine-needle aspiration biopsy of pulmonary spindle cell and mesenchymal lesions: a study of 61 cases. Cancer 2001;93:187–198. Ito E, Saito T, Suzuki T, et al. Cytology of vaginal and uterine sarcomas. Acta Cytol 2004;48:601–607. Klijanienko J, Caillaud JM, Lagace R, Vielh P. Fine-needle aspiration of leiomyosarcoma: a correlative cytohistopathological study of 96 tumors in 68 patients. Diagn Cytopathol 2003;28:119–125. Lin O, Olgac S, Zakowski M. Cytological features of epithelioid mesenchymal neoplasms: a study of 21 cases. Diagn Cytopathol 2005;32: 5–10. Otano-Joos M, Mechtersheimer G, Ohl S, et al. Detection of chromosomal imbalances in leiomyosarcoma by comparative genomic hybridization and interphase cytogenetics. Cytogenet Cell Genet 2000;90:86–92. Tao LC, Davidson DD. Aspiration biopsy cytology of smooth muscle tumors. A cytologic approach to the differentiation between leiomyosarcoma and leiomyoma. Acta Cytol 1993;37:300–308. Angiosarcoma Boucher LD, Swanson PE, Stanley MW, et al. Cytology of angiosarcoma. Findings in fourteen fine-needle aspiration biopsy specimens and one pleural fluid specimen. Am J Clin Pathol 2000;114:210–219. Klijanienko J, Caillaud JM, Lagace R, Vielh P. Cytohistologic correlations in angiosarcoma including classic and epithelioid variants: Institut Curie’s experience. Diagn Cytopathol 2003;29:140–145. Lin O, Olgac S, Zakowski M. Cytological features of epithelioid mesenchymal neoplasms: a study of 21 cases. Diagn Cytopathol 2005;32:5–10.

Akerman M, Rydholm A. Aspiration cytology of intramuscular myxoma. A comparative clinical, cytologic and histologic study of ten cases. Acta Cytol 1983;27:505–510. Caraway NP, Staerkel GA, Fanning CV, et al. Diagnosing intramuscular myxoma by fine-needle aspiration: a multidisciplinary approach. Diagn Cytopathol 1994;11:255–261. Fornage BD, Romsdahl MM. Intramuscular myxoma: sonographic appearance and sonographically guided needle biopsy. J Ultrasound Med 1994;13:91–94. Gonzalez-Campora R, Otal-Salaverri C, Hevia-Vazquez A, et al. Fine needle aspiration in myxoid tumors of the soft tissues. Acta Cytol 1990;34: 179–191. Silver WP, Harrelson JM, Scully SP. Intramuscular myxoma: a clinicopathologic study of 17 patients. Clin Orthop Relat Res 2002;(403): 191–197. Wakely PE Jr, Geisinger KR, Cappellari JO, et al. Fine-needle aspiration cytopathology of soft tissue: chondromyxoid and myxoid lesions. Diagn Cytopathol 1995;12:101–105. Epithelioid Sarcoma Cardillo M, Zakowski MF, Lin O. Fine-needle aspiration of epithelioid sarcoma: cytology findings in nine cases. Cancer 2001;93:246–251. Gonzalez-Peramato P, Jimenez-Heffernan JA, Cuevas J. Fine-needle aspiration cytology of ‘proximal-type’ epithelioid sarcoma. Diagn Cytopathol 2001;25:122–125. Kitagawa Y, Ito H, Sawaizumi T, et al. Fine needle aspiration cytology of primary epithelioid sarcoma. A report of 2 cases. Acta Cytol 2004;48: 391–396. Lin O, Olgac S, Zakowski M. Cytological features of epithelioid mesenchymal neoplasms: a study of 21 cases. Diagn Cytopathol 2005;32:5–10. Zeppa P, Errico ME, Palombini L. Epithelioid sarcoma: report of two cases diagnosed by fine-needle aspiration biopsy with immunocytochemical correlation. Diagn Cytopathol 1999;21:405–408. Alveolar Soft Part Sarcoma Lopez-Ferrer P, Jimenez-Heffernan JA, Vicandi B, et al. Cytologic features of alveolar soft part sarcoma: report of three cases. Diagn Cytopathol 2002;27:115–119.

126 Shabb N, Sneige N, Fanning CV, Dekmezian R. Fine-needle aspiration cytology of alveolar soft-part sarcoma. Diagn Cytopathol 1991;7:293– 298. Synovial Sarcoma Akerman M, Ryd W, Skytting B; Scandinavian Sarcoma Group. Fine-needle aspiration of synovial sarcoma: criteria for diagnosis: retrospective

FINE NEEDLE ASPIRATION CYTOLOGY reexamination of 37 cases, including ancillary diagnostics. A Scandinavian Sarcoma Group study. Diagn Cytopathol 2003;28:232–238. Ewing CA, Zakowski MF, Lin O. Monophasic synovial sarcoma: a cytologic spectrum. Diagn Cytopathol 2004;30:19–23. Klijanienko J, Caillaud JM, Lagace R, Vielh P. Cytohistologic correlations in 56 synovial sarcomas in 36 patients: the Institut Curie experience. Diagn Cytopathol 2002;27:96–102.

5

Breast Shahla Masood

MASTITIS, ABSCESS, AND FAT NECROSIS Inflammation of the breast as the result of lactation, infection, or trauma often presents as a palpable breast lesion with varying degrees of pain and tenderness. Acute supportive mastitis is typically seen in 1% to 3% of lactating women in the postpartum period. The most common organisms are staphylococci and streptococci. When inflammation localizes, acute mastitis often results in an abscess and rarely leads to chronic mastitis with periductal inflammation, duct ectasia, fibrohistiocytic reaction, and mononuclear chronic inflammatory infi ltrate. Cytologically, smears are cellular and contain abundant numbers of inflammatory infiltrates, histiocytes with evidence of cytophagocytosis and nuclear debris. Isolated and clusters of epithelial cells with reactive atypia are also present (Fig. 5-1). The differential diagnosis includes subareolar abscess, granulomatous mastitis, and fat necrosis with organized hematoma. Subareolar abscess is a specific clinicopathologic entity, which was first described by Zuka et al as a lowgrade infection in the lactiferous duct or sinus with subsequent abscess formation, chronic recurrent infection, and fistula formation at the base of the nipple. Suggestion has been made that squamous metaplasia of columnar epithelial cells of the lactiferous ducts is the cause of this lesion. The breast aspirate shows rich cellularity with abundant inflammatory cells and many anucleated squamous cells, and keratinous material (Fig. 5-2).

MASTITIS, ABSCESS, AND FAT NECROSIS – DISEASE FACT SHEET Clinical Features ៉ Inflammatory conditions of the breast account for 5–10% of all

breast diseases ៉ Primary causes of inflammatory conditions of the breast are

lactation, infection, and trauma ៉ Approximately 70% of abscesses are non-lactational and only 30%

are related to puerperium ៉ Clinically, they present as a generalized cellulitis or a localized

mass which may be associated with pain and tenderness ៉ Clinically and mammographically, they may mimic carcinoma ៉ FNAB may serve as a diagnostic and therapeutic procedure

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MASTITIS, ABSCESS, AND FAT NECROSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirates ៉ Abundant infl ammatory cells ៉ Cytophagocytosis and granular debris in the background ៉ Epithelial cells with nuclear enlargement and prominent nucleoli ៉ Occasional multinucleated cells ៉ Macrophages Ancillary Studies ៉ Microbiologic examination ៉ Culture and sensitivity

Differential Diagnosis and Pitfalls ៉ Subareolar abscess: cellular aspirate; abundant acute infl ammatory cells; anucleated squamous cells and keratinous material; macrophages and foreign body type giant cells ៉ Granulomatous mastitis: cellular aspirate; abundant chronic infl ammatory cells, mostly lymphocytes and plasma cells; granulomatous reaction and giant cells; fibroblasts and reactive atypical epithelial cells ៉ Fat necrosis and organized hematoma: cellular aspirate; necrotic background with granular debris; lipid and hemosiderincontaining macrophages; multinucleated giant cells; mononuclear infl ammatory cells; small, newly formed vessels; reactive atypical epithelial cells; cholesterol crystals

Granulomatous mastitis is characterized by the presence of granulomatous reaction and giant cell formation. This entity is an inflammatory lesion of an unknown etiology or may be the result of tuberculosis, fungal infection, epidermal inclusion cyst, or foreign body reaction such as suture and leakage from silicone implants (Fig. 5-3). Fat necrosis and organized hematoma are traumainduced inflammatory conditions that predominantly present with foamy or hemosiderin-containing macrophages, lymphocytes, plasma cells, fibroblasts, fragments of fibrous tissue, and newly formed vessels (Fig. 5-4). Reactive epithelial atypia associated with fat necrosis has resulted in false positive diagnosis of cancer. Mammographically, fat necrosis with subsequent calcification may also mimic a neoplastic process. In the above-mentioned inflammatory conditions, surgery can be avoided by the use of fine needle 127

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FIGURE 5-1 Direct smear of breast abscess: cellular aspirate containing abundant acute infl ammatory infiltrate and a few isolated and clusters of epithelial cells with infl ammatory atypia.

FIGURE 5-2 Direct smear of subareolar abscess: cellular aspirate with abundant acute infl ammatory cells and squamous and anucleated cells.

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FIGURE 5-3 Direct smear of a granulomatous infl ammation: non-caseating granuloma with epithelioid cells, mononuclear infl ammatory cells, and giant cells.

FIGURE 5-4 Direct smear of fat necrosis: cellular aspirate with amorphous material in the background, acute infl ammatory cells, abundant macrophages, and newly formed vessels.

aspiration biopsy (FNAB). In conjunction with microbiologic studies of the aspirated material, FNAB can provide valuable information about the etiology of an inflammatory condition of the breast. It can also serve as a therapeutic modality. TREATMENT-INDUCED CHANGES – DISEASE FACT SHEET

TREATMENT-INDUCED CHANGES Recent interest in breast cancer conservative therapy and neoadjuvant chemotherapy has brought a new diagnostic challenge for pathologists/cytopathologists. The distinction between recurrent breast carcinoma

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Clinical Features ៉ Patients often present with thickening and/or a skin nodule at the site of previous operation or following radiation therapy ៉ Cytologic distinction between a reactive process and a recurrent tumor is critical in further management ៉ Radiation-induced angiosarcoma can also present as a nodule following conservation therapy

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FIGURE 5-5 Direct smear of recurrent breast carcinoma following radiation therapy, characterized by isolated and clusters of highly pleomorphic epithelial cells, macrophages, and necrosis in the background.

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FIGURE 5-6 Direct smear of recurrent breast carcinoma following radiation therapy: higher magnification of the case seen in Fig. 5-5, highlighting necrosis and macronucleoli of neoplastic cells.

TREATMENT-INDUCED CHANGES – PATHOLOGIC FEATURES Cytopathologic Findings Poor cellularity Granulation tissue Fat necrosis Epithelial atypia Granulatomous reaction Fibroblastic/spindle cell reaction Lymphoplasmacytic infiltration

៉ ៉ ៉ ៉ ៉ ៉ ៉

Ancillary Studies ៉ Positive immunostaining reaction with endothelial cell markers

Differential Diagnosis and Pitfalls ៉ Recurrent tumor: rich cellularity; similar cytonuclear features to

the original tumor; conspicuous anisonucleosis with distinct cell borders ៉ Angiosarcoma: moderate to rich cell yield; epithelioid and spindle cell pattern; various-sized nuclei with multiple nucleoli; arborizing vessels and rosette-like structures

and treatment-induced atypia is a difficult task, since these entities present with overlapping features. It is suggested that radiation-induced changes in the breast exhibit three different patterns in FNAB smears. These include epithelial atypia, fat necrosis, and poor cellularity. In contrast, malignancy in an irradiated breast presents with a cellular aspirate featuring loss of cellular cohesion, arrangement of cells in small clusters, anisonucleosis, conspicuous nucleoli, an irregular nuclear membrane, and necrosis (Figs 5-5 & 5-6). In our own experience, the most important feature in distinction between a radiation-induced change and recurrent malignancy is the rich cellularity of the aspirate. It may be advisable to refrain from making a

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FIGURE 5-7 Direct smear of radiation-induced angiosarcoma: isolated, clustered, and neoplastic spindle cells.

diagnosis of recurrent carcinoma in a sparsely cellular aspirate from an irradiated breast. Radiation-induced angiosarcoma may also present as a skin or subcutaneous nodule. This entity can easily be mistaken for a recurrent carcinoma. Typically, patients present with a discrete skin nodule several years after breast conservation therapy. Cytologically, breast aspirates yield moderate to high cellularity with a variable cell pattern. Tumor cells are spindly and show positive reaction for endothelial markers by immunocytochemistry. Often, a network of thin, arborizing vessels is seen in the background. Tumor cells may form pseudorosettes and have large nuclei with multiple nucleoli (Figs 5-7 & 5-8). A high index of clinical suspicion is the key factor in rendering an accurate diagnosis of angiosarcoma by FNAB.

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FIGURE 5-8 Cell block preparation of same case as Fig. 5-7, a radiation-induced angiosarcoma. Positive immunostaining with factor VIII.

FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 5-10 Direct smear of treatment-induced changes following surgery, showing an ill-defined granuloma characterized by epithelioid cells, infl ammatory cells, and granular fibers.

Lack of cytologic similarity to the primary tumor and predominance of spindle cells are important diagnostic clues to exclude a recurrent tumor. Therefore it is critical to review the original pathology slides of each patient for comparison.

HORMONAL CHANGES: SECRETORY, PREGNANCY, AND LACTATIONAL CHANGES

FIGURE 5-9 Direct smear of treatment-induced changes following surgery, characterized by the granulation tissue, new vessel formation, abundant infl ammatory cells, and giant cell reaction.

Preoperative chemotherapy in locally advanced breast carcinomas may also produce tissue reaction with and without residual tumor. These tissue reactions are similar to those with other forms of therapy, such as granulomatous reaction, necrosis, and epithelial atypia. In addition, the presence of a lymphoplasmacytic reaction may be conspicuous. Surgery-induced fibrosis and suture granulomas also present with reactive inflammatory atypia that should be separated from recurrent cancer. The typical form of suture granuloma is characterized by the presence of granulation tissue, granulomatous inflammation, histiocytes, mononuclear inflammatory cells, blood vessels, and giant cells (Figs 5-9 & 5-10). Occasionally, retractable suture material can also be seen. However, excessive amount of granulation tissue, atypical fat necrosis, and atypical immature fibroblasts in surgery-induced changes may be misinterpreted as a malignant tumor.

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The recognition of the spectrum of changes that reflect the biologic attractions in normal mammary epithelial cells is essential for the accurate interpretation of various entities in breast pathology. The breast is a hormone-dependent organ which undergoes puberty, pregnancy, lactation, and involution and is influenced by exogenous hormone effect. These changes may introduce cytonuclear alterations that may be confused with real disease process. The normal breast is a glandular tissue with various amount of mammary adipose tissue. During prepubertal and involutionary phases, the aspirates are often hypocellular with a few ductal

HORMONAL CHANGES: SECRETORY, PREGNANCY, AND LACTATIONAL CHANGES – DISEASE FACT SHEET Clinical Features ៉ Pregnancy-associated lesions may present as galactocele, lactating adenoma, and fibroderma ៉ The distinction between pregnancy in cancer and pregnancyassociated changes is critical in evaluation of pregnant patients with a palpable breast lesion

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FIGURE 5-11 Direct smear of a pregnancy-associated change: cellular aspirate with bubbly background, dispersed cell pattern, and a few macrophages.

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FIGURE 5-12 Direct smear of a pregnancy-associated change: dispersed cell pattern with enlarged cells, prominent nucleoli, granular debris in the background, and fraying of cytoplasmic borders.

HORMONAL CHANGES: SECRETORY, PREGNANCY, AND LACTATIONAL CHANGES – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirate ៉ Proteinaceous background with bubbly appearance ៉ Dispersed cells and loosely arranged cell clusters ៉ Large epithelial cells with uniform nuclei and prominent nucleoli ៉ Cytoplasmic vacuolization with fraying of cytoplasmic borders ៉ Bipolar naked nuclei, foamy macrophages, and occasional multinucleated giant cells Ancillary Studies ៉ Immunostain for myoepithelial cell markers

Differential Diagnosis and Pitfalls ៉ Cancer in pregnancy: high cellular yield; dispersed cell pattern with intact cell borders; marked anisonucleosis and prominent nucleoli; proteinaceous background

epithelial cells and fragments of fibroadipose tissue. Secretory changes in mammary epithelial cells occur in normal breast or in association with other entities such as fibroderma, proliferative breast disease and in association with a neoplastic process. Pregnancy results in an increased number of acini per lobule, with accumulation of secretory material in the lobular epithelial cells. These changes occur de novo, as a lactating adenoma or due to the enlargement of pre-existing tumors such as tubular adenoma and fibroadenomas. Fine needle aspirates of pregnancy and lactational changes are rich in cellularity with a bubbly appearance and proteinaceous background. The cells contain several secretory vacuoles with fraying of cytoplasmic borders (Figs 5-11 & 5-12). Pregnancy-

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FIGURE 5-13 Direct smear of a galactocele characterized by a cluster of epithelial cells surrounded by abundant lipid-laden macrophages.

associated changes present as galactocele, lactating adenoma, or fibroderma. Galactoceles often present as a discrete and mobile mass, which may increase in size during breastfeeding. The mass regresses following FNAB. The smears show low to moderate cellularity with numerous foamy cells, proteinaceous background, and a few epithelial cells with vacuolated cytoplasm (Fig. 5-13). Lactating adenomas are initially noticed during pregnancy. Aspirates from lactating adenomas are cellular and show grape-like clusters of epithelial cells similar to expanded acini, attached to terminal ductules. The cells and the background have all the features of hormoneinduced changes. Fibrodermas become more conspicuous in size during pregnancy. The cytologic features are similar to those of lactating adenoma. In fibroadenomas there are bipolar stripped nuclei, more stromal fragments, less

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FIBROADENOMAS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Highly cellular aspirate ៉ Biphasic pattern of stromal component and epithelial/ myoepithelial cells ៉ Sheets of monolayered ductal epithelial cells forming antler horns ៉ Bipolar naked nuclei ៉ Occasional apocrine cells ៉ Rare multinucleated cells Ancillary Studies ៉ Immunostain for myoepithelials cell markers

Differential Diagnosis and Pitfalls ៉ Proliferative breast disease: lack of stromal component; lack of

FIGURE 5-14 Direct smear of primary breast cancer in pregnancy: isolated and clusters of neoplastic epithelial cells with an intact cell membrane.

antler-horn pattern; lack of naked nuclei in the background ៉ Papillary lesions: presence of fibrovascular core; abundance of

macrophages; conspicuous columnar cell differentiation ៉ Low-grade carcinoma: absence of naked nuclei in the

proteinaceous material, and lipid droplets in the background. They may contain a few giant cells. Pregnancy and lactational changes often present with loosely cohesive cellular aspirates with enlarged cells with conspicuous nucleoli. Those features mimic primary breast carcinoma. This distinction is a diagnostic challenge, particularly since pregnancy-associated changes can also be seen in non-lactating women. Primary breast carcinoma occurs in 1 out of 1000 pregnancies. Aside from anisonucleosis and chromatin clumping, the most important cytologic feature in favor of carcinoma is the presence of intact cell membrane in the aspirated smears (Fig. 5-14). FNAB is an effective initial tool in the evaluation of pregnant women with a palpable mass. This approach reduces the delay in the diagnosis of cancer in pregnant and lactating women. Further follow-up and management of a pregnant breast cancer patient depend on the stage of pregnancy and the choice of the patient.

FIBROADENOMAS Fibroadenomas are slow-growing tumors that are under the influence of unopposed estrogen. They are the most common tumor in young women and often present as

FIBROADENOMAS – DISEASE FACT SHEET Clinical Features ៉ Most common benign tumor of the breast ៉ Often presents as a mobile breast mass ៉ Mammographically presents as a well-defined lesion

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background; absence of discrete stromal components; absence of myoepithelial cells ៉ Phyllodes tumor: cellular stromal component; variable degree of atypicality and mitosis

a small, solitary and painless nodule. Mammographically, they appear as well-defined lesions, and in 7% to 16% of cases, they may show evidence of multiplicity. Carcinoma, often of lobular type, rarely occurs in fibroadenomas. Giant fibroadenomas are rapidly growing fibroadenomas that occur in adolescent girls and they may become as large as 19 cm. Cytologically, fibroadenomas yield cellular aspirates showing a biphasic pattern of epithelial and stromal elements. The cell population displays two cell types: epithelial and myoepithelial. The epithelial component forms sheets of monolayered epithelial cells with clusters forming antler-horn projections. Myoepithelial cells are smaller and darker, and often spindly in appearance. These cells appear in the background with bipolar and naked nuclei and are admixed with epithelial cells (Fig. 5-15). Classical-pattern fibroadenomas are easy to diagnose; however, when they are associated with proliferative breast disease, undergo metaplastic change, or are affected by hormones, they become atypical and cellular. Loose edematous stroma occasionally displays myxoid features mimicking mucinous carcinoma (Figs 5-15–5-20). Cellular fibroadenomas are the most common cause of false positive diagnosis in breast FNAB. Differential diagnoses include proliferative breast disease, papillary lesions, and low-grade carcinomas such as tubular carcinoma. In addition, distinction between fibroadenoma and benign phyllodes tumor is difficult. High cellularity, presence of a stromal component that is distinctly separated from the epithelial component, naked nuclei in the background, as well as antlerhorn cell clusters are the features that differentiate between proliferative breast disease and fibroadenomas.

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FIGURE 5-15 Direct smear of a fibroadenoma characterized by a biphasic pattern, showing isolated and clusters of epithelial/myoepithelial cells and the associated stromal components. Note the presence of myoepithelial cells as naked nuclei in the background.

FIGURE 5-16 Direct smear of a cellular fibroadenoma characterized by a cellular aspirate with isolated and clusters of epithelial/myoepithelial cells with numerous naked nuclei in the background. The clusters show overriding of the nuclei commonly seen in proliferative breast disease.

FIGURE 5-17 Direct smear of a cellular fibroadenoma, showing higher magnification of the same features as in Fig. 5-14.

FIGURE 5-18 Direct smear of a cellular fibroadenoma associated with proliferative breast disease. Another view of the same case as in Fig. 5-16, showing the presence of a biphasic pattern commonly seen in fibroadenoma.

FIGURE 5-19 Direct smear of a fibroadenoma with loose myxoid background, simulating mucoid carcinoma. The presence of myoepithelial cells in the background substantiates the diagnosis of fibroadenoma.

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FIGURE 5-20 Direct smear of the fibroadenoma with myxoid stroma as seen in Fig. 5-17 and the associated antler-horn pattern seen in the same case.

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FIGURE 5-21 Direct smear of a benign phyllodes tumor characterized by a biphasic pattern of epithelial/myoepithelial cells and the associated cellular stroma.

Papillary lesions may also resemble a fibroadenoma. Key features in favor of papillary lesions are high cellularity and three-dimensional architecture of branched epithelial clusters, the presence of fibrovascular cores, various numbers of macrophages, apocrine cells, and columnar epithelial cell clusters. Distinction between tubular adenoma and fibroadenoma is usually not possible because of overlapping features. However, this distinction has no clinical implication. Fibroadenomas are known to simulate carcinoma. Extensive search for stromal elements and the presence of myoepithelial cells are the features favoring a fibroadenoma. The myoepithelial origin of spindle cells can be demonstrated by expression of myoepithelial cell markers by immunocytochemistry. The distinction between fibroadenoma and phyllodes tumor in an aspirate is based on higher cellularity of stromal elements seen in phyllodes tumors. These cases should be checked for the presence of abnormal mitosis and pleomorphism to exclude the possibility of a malignant phyllodes tumor (Figs 5-21 & 5-22). It is important to note that phyllodes tumors often occur in an older age than fibroadenomas and present with a larger palpable mass of over 4 cm. A follow-up surgical excision of fibroadenomas with atypical features is the current procedure.

FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 5-22 Direct smear of a benign phyllodes tumor: higher view of case shown in Fig. 5-21, exhibiting cellular stroma characteristic of a phyllodes tumor.

PAPILLARY BREAST LESIONS – DISEASE FACT SHEET Clinical Features ៉ Uncommon tumors of the breast ៉ Occur in postmenopausal women ៉ Presenting symptoms are nipple discharge, nipple retraction, and association with a palpable mass ៉ Complete removal of the lesion is the recommended procedure

PAPILLARY BREAST LESIONS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Intraductal papilloma: cellular aspirate; proteinaceous or bloody

background; three-dimensional papillary cell clusters; foamy or hemosiderin-laden macrophages; myoepithelial cells; tall columnar cells ៉ Papillary carcinoma: cellular aspirate; bloody background; hemosiderin-laden macrophages; occasional necrotic debris; papillary clusters of atypical cells enriched by a fibrovascular core; large atypical nuclei; tall columnar cells; absence of myoepithelial cells ៉ Intercystic papillary carcinoma: cellular aspirate; hemosiderinladen macrophages; monomorphic cell population; anisonucleosis and pleomorphism; absence of myoepithelial cells; papillary and/or cribriform pattern Ancillary Studies

PAPILLARY BREAST LESIONS Papillary lesions of the breast constitute a spectrum of pathologic entities ranging from intraductal papillomas to papillary carcinomas. Intraductal papillomas, the benign forms of papillary lesions, are solitary lesions of the major ducts, commonly based in the subareolar region. Papillomas often occur in postmenopausal

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៉ Immunostains for myoepithelial cell markers

women and are frequently seen in the male breast. Nipple discharge, nipple retraction, and a subareolar mass are the pre-existing symptoms. Cytologic diagnosis of intraductal papillomas can be made by nipple fluid cytology or by the examination of the breast FNAB. Cytologically, the aspirates are cellu-

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FIGURE 5-23 Direct smear of an intraductal papilloma characterized by cellular aspirate showing proliferating epithelial cells with myoepithelial cells in the background.

FIGURE 5-24 Direct smear of an intraductal papilloma showing proliferating cells forming various architectural patterns.

lar and contain a proteinaceous background and conspicuous numbers of macrophages. Three-dimensional cell balls, tall columnar cells, apocrine cells, and myoepithelial cells are also present (Figs 5-23–5-26). Distinction between an intraductal papilloma and well-differentiated papillary carcinoma may be somewhat difficult. These entities share common cytologic features. However, papillary carcinomas often present with a monomorphic and uniform-appearing cell population with no evidence of myoepithelial cell differentiation. There are also no apocrine cells (Figs 5-27–5-29). Papillary carcinomas account for 1% to 2% of breast cancers and are associated with a good prognosis. Bloody discharge is the most common presenting symptom, and in 90% of cases, a mass can be palpated. There is also

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135

FIGURE 5-25 Direct smear of an intraductal papilloma exhibiting a cell ball or threedimensional structure.

FIGURE 5-26 Direct smear of an intraductal papilloma showing clusters of apocrine cells, columnar cells, and histiocytes in the background.

evidence of skin dimpling and nipple retraction. The neoplastic cells may display a variety of patterns such as cribriform and micropapillary. The absence of a myoepithelial cell layer is one of the most important characteristics of papillary carcinoma (Fig. 5-30). Another focus of papillary lesions of the breast is an intracystic carcinoma. This is a rare breast tumor accounting for 0.7% of all breast carcinomas. It frequently occurs in black and obese women, with bloody nipple discharge as the first presenting symptom. Breast imaging shows a well-circumscribed cystic mass that persists following FNAB. Cytologically, they mimic the features seen in papillary carcinoma. The diagnosis of papillary lesions of the breast by FNAB requires complete excision of the lesion with a rim of normal breast tissue. It is advisable to refrain from attempting to do frozen section because of

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FIGURE 5-27 Direct smear of a papillary carcinoma characterized by highly cellular aspirate of clusters of epithelial cells forming different architectural patterns.

FIGURE 5-28 Direct smear of a papillary carcinoma showing isolated and clusters of a monomorphic population of tumor cells with columnar cell differentiation surrounding a fibrovascular core. No apocrine cells are seen.

FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 5-29 Direct smear of a papillary carcinoma showing a higher magnification of a monomorphic cell population with columnar cell differentiation.

FIGURE 5-30 Immunostained slide: cell block preparation of a papillary carcinoma with no evidence of myoepithelial cell differentiation.

experiencing the same difficulty in rendering a definite diagnosis as in cytology. FIBROCYSTIC CHANGE – DISEASE FACT SHEET

FIBROCYSTIC CHANGE Fibrocystic change represents a spectrum of changes ranging from normal physiologic alterations to highrisk proliferative breast disease. Cyst formation, apocrine neoplasia, stromal fibrosis, sclerosing adenosis, and various degrees of epithelial hyperplasia are the features of fibrocystic change. The association between these morphologic changes and the subsequent

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Clinical Features ៉ The most common breast lesions ៉ Present as a non-palpable breast lesion or as a palpable mass ៉ Asystematic density, mass effect, and calcification are the common features in breast imaging ៉ The degree of proliferation correlates positively with the incidence of subsequent development of breast cancer ៉ As a morphologic risk factor, recognition of atypical ductal hyperplasia helps to stratify patients for risk-reduction modalities

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FIBROCYSTIC CHANGE – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Non-proliferative breast disease: low to moderate cellularity; fragments of stroma and adipose tissue; monolayered cell population with honeycomb pattern; histiocytes, apocrine cells, and myoepithelial cells ៉ Proliferative breast disease without atypia: moderate to high cellularity; abundant clusters of two-cell population of epithelial/myoepithelial cells; conspicuous overriding of the nuclei; occasional nucleoli and focal loss of polarity; apocrine cells, histiocytes, and occasional calcified particles ៉ Proliferative breast disease with atypia (atypical ductal hyperplasia): high cellularity; clustering of epithelial/ myoepithelial cells; marked crowding of nuclei forming slit-like openings and loss of polarity; nuclear enlargement and macronucleoli; chromatin clumping; occasional apocrine cells and microcalcified particles

Cytologically, a semiquantitative score, the ‘Masood Cytology Index’, has been developed. This cytologic grading system is based on the comparison of cytomorphology of mammographically detected breast fine needle aspirates and their corresponding needle localization excisional biopsies. Attempts have been made to incorporate cellular arrangement with the traditional nucleocytologic features and presence or absence of myoepithelial cells (Tables 5-1 & 5-2). Controversy regarding the use of this cytologic grading system in clinical practice continues. However, this index has been used as a morphologic risk factor in chemoprevention trials (Fig. 5-31). Recently, an association between the degree of morphologic abnormality defined by this index and the frequency of expression of retinoic acid receptor-β2 promoter methylation has been reported (Fig. 5-32).

Ancillary Studies ៉ Immunostain for myoepithelial cell markers Differential Diagnosis and Pitfalls ៉ Papillary lesions: tall columnar cells; hemosiderin-containing macrophages; fibrovascular core ៉ Fibroadenoma: distinct stromal component; naked nuclei in the background; antler-horn pattern ៉ Low nuclear grade ductal carcinoma in situ: monotonous cell population; lack of myoepithelial cells

24 P<0.0001

16 Total high risk cohort (N=480)

8 3.9% at 45 months

development of breast cancer is now well established. In addition, the new terminology of non-proliferative breast disease, proliferative breast disease without atypia and proliferative breast disease with atypia (atypical hyperplasia), have replaced the commonly used term fibrocystic disease.

No FNA atypia (N=378)

0 0

12

24

36

48

60

72

84

96

108

Time from entry on study (months) FIGURE 5-31 The relationship between cellular atypia in fine needle aspiration biopsy and increased risk for breast cancer.

TABLE 5-1 Masood Cytology Index Cellular arrangement

Cellular pleomorphism

Myoepithelial cells

Anisonucleosis

Nucleoli

Chromatin clumping

Score

Monolayer Nuclear overlapping Clustering

Absent Mild Moderate

Many Moderate Few

Absent Mild Moderate

Absent Rare Occasional

1 2 3

Loss of cohesion

Conspicuous

Absent

Conspicuous

Absent Micronucleoli Micro- and/or rare macronucleoli Predominately macronucleoli

Frequent

4

Sum of scores:

6–10 Normal 11–14 Proliferative 15–18 Atypia ≥19 Suspicious for cancer

Modified from Masood S, Frykberg ER, McLellan GL, et al. Prospective evaluation of radiologically directed fine-needle aspiration biopsy of nonpalpable breast lesions. Cancer 1990;66:1480–1487.

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138

FINE NEEDLE ASPIRATION CYTOLOGY Methylation present

Methylation absent

12 M3 RARbeta P2 methylation Number RPFNA

10 8

FIGURE 5-32 The association between Masood Cytology Index score and the expression of retinoic acid receptor-β2 promoter methylation in random periareolar fine needle aspiration.

6 4 2 0 10

11

12

13

14

15

>15

Masood cytology index

TABLE 5-2 Concordance Between Cytologic Evaluation and Histologic Diagnosis in 100 Mammographically Guided Fine Needle Aspirates Diagnosis Non-proliferative breast disease Proliferative breast disease without atypia Proliferative breast disease with atypia Cancer

No. of cases

Concordance %

29/34

85

15/17

88

21/23

91

17/20

85

Modified from Masood S, Frykberg ER, McLellan GL, et al. Cytologic differentiation between proliferative and nonproliferative breast tissue in mammographically guided fine-needle aspirates. Diagn Cytopathol 1991;7:581–590.

NON-PROLIFERATIVE BREAST DISEASE Non-proliferative breast disease may present as a cystic lesion. This is a common condition which is often the subject of FNAB. Cysts produce fluids that vary in appearance from clear to opaque, dark brown, yellow– green to bloody. Benign cysts are acellular with granular debris. Occasionally, a few epithelial cells/apocrine cells may be present. If associated with duct ectasia or chronic cystic mastitis, the smears are more cellular and may contain inflammatory cells. Bloody cysts are also often associated with papillary lesions. Rarely, medullary carcinomas may become cystic and contain atypical malignant cells. Since more than 99% of cysts are benign, there is controversy regarding the need for cytologic examination of clear cysts. It may be more cost effective to limit cytologic analysis to the cysts that are associated with a turbid or bloody appearance. In non-cystic lesions, aspirates from a non-proliferative breast disease are characterized by scant or moderate cellularity. The uniform ductal cells are arranged in

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FIGURE 5-33 Direct smear of non-proliferative breast disease characterized by a monolayered cluster of epithelial/myoepithelial cells, a cluster of apocrine cells, stromal fragments, and a few histiocytes.

monolayered sheets with a honeycomb pattern. Foam cells, apocrine cells, and myoepithelial cells are present (Figs 5-33 & 5-34).

PROLIFERATIVE BREAST DISEASE WITHOUT ATYPIA FNAB of proliferative breast disease without atypia presents with a higher cell yield and unique cellular arrangement. The honeycomb monolayered arrangement is changed to clusters of epithelial/myoepithelial cells that show overriding of the nuclei, occasional loss of polarity, and some variability in nuclear size. Micronuclei are occasionally seen. Cytologic atypia is inconspicuous. Apocrine cells, histiocytes, and occasional naked nuclei are seen in the background (Figs 5-35 & 5-36). Differential diagnosis includes fibroadenoma and papillary lesions. These conditions have overlapping features. The presence of well-demarcated stroma,

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FIGURE 5-34 Direct smear of non-proliferative breast disease: a cluster of reactive apocrine cells with micronucleoli.

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FIGURE 5-36 Direct smear of proliferative breast disease without atypia: higher magnification of the same case as in Fig. 5-35. Note the conspicuous crowding of nuclei, with large, oval and pale epithelial cells intermixed with small, dark and slender myoepithelial cells.

FIGURE 5-35 Direct smear of proliferative breast disease without atypia, characterized by clusters of proliferating epithelial/myoepithelial cells with overriding of the nuclei and loss of honeycomb pattern.

various naked nuclei, and an antler-horn pattern are the features of fibroadenoma. In papillary lesions, hemosiderin-containing macrophages and polymorphic populations of tall columnar cells forming papillae are the differentiating features.

PROLIFERATIVE BREAST DISEASE WITH ATYPIA (ATYPICAL HYPERPLASIA) Breast aspirates of lesions with atypical hyperplasia are characterized by rich cellularity composed of several clusters of epithelial cells with conspicuous crowding of the nuclei. The degree of overriding of nuclei forms different-sized slits and openings with some loss of

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FIGURE 5-37 Direct smear of proliferative breast disease with atypia (atypical ductal hyperplasia) characterized by a loosely cohesive cluster of proliferating epithelial/myoepithelial cells with crowding of the nuclei and loss of polarity forming various-sized slits and openings.

polarity of the contour of ductal elements. Nuclei display a coarse chromatin pattern and there are some variations in the cell nuclei. Intermingled with epithelial cells are myoepithelial cells. Rare apocrine cells and macrophages may also be present (Figs 5-37– 5-40). The differential diagnosis includes a low-grade ductal carcinoma in situ. A monotonous cell arrangement and the absence of myoepithelial cells are the key differentiating features. Immunostaining for myoepithelial cell markers is an important ancillary study.

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FIGURE 5-38 Direct smear of proliferative breast disease with atypia: higher magnification, highlighting the presence of micronucleoli, nuclear atypia, intermixed myoepithelial cells, and various-sized cribriform-type pattern of proliferation.

FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 5-40 Direct smear of proliferative breast disease with atypia, showing an isolated cluster of atypical epithelial cells. Note the persistence of accompanying myoepithelial cells.

DUCTAL CARCINOMA IN SITU – DISEASE FACT SHEET Clinical Features ៉ Increased emphasis in breast cancer screening has resulted in an

increased frequency of detection of in-situ lesions ៉ Microcalcification is the most common mammographic feature of

in-situ lesions ៉ Distinction between an in-situ lesion and an invasive process may

have clinical significance

DUCTAL CARCINOMA IN SITU – PATHOLOGIC FEATURES

FIGURE 5-39 Direct smear of proliferative breast disease with atypia: high magnification of another view, displaying nuclear features, architectural change, and hyperchromasia.

Cytopathologic Findings ៉ Low nuclear grade: variable cellularity; monomorphic pattern of cells forming cribriform, solid, and micropapillary patterns; small to medium-sized cells with uniform nuclei; absence of myoepithelial cells ៉ High nuclear grade: variable cellularity in a necrotic background; pleomorphic population of highly anaplastic epithelial cells with individual cell necrosis and mitosis; absence of myoepithelial cells

DUCTAL CARCINOMA IN SITU LOW NUCLEAR GRADE DUCTAL CARCINOMA IN SITU (NON-COMEDO TYPE) Distinction between atypical ductal hyperplasia and low nuclear grade ductal carcinoma has remained a diagnostic challenge in breast pathology. This difficulty is compounded in interpretation of minimally invasive specimens such as core needle biopsy and FNAB. It is generally agreed that the diagnosis of atypical ductal hyperplasia by any of these minimally invasive proce-

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dures requires a follow-up surgical biopsy to exclude the possibility of a more severe lesion. However, the diagnosis of atypical ductal hyperplasia by FNAB has the benefit of identifying high-risk individuals for breast cancer who may benefit from chemoprevention and the available risk-reduction modalities. In recent years, breast cancer awareness and screening programs have resulted in an increased detection of borderline breast disease and ductal carcinoma in situ. Clustered microcalcification is the most frequent feature in breast imaging.

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FIGURE 5-41 Direct smear of low nuclear grade ductal carcinoma in situ demonstrating clusters of a monomorphic cells forming a cribriform pattern. Myoepithelial cells are seen only at the periphery of cell clusters.

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FIGURE 5-43 Direct smear of high nuclear grade ductal carcinoma in situ: pleomorphic population of neoplastic cells with necrosis in the background.

FIGURE 5-44 Direct smear of high nuclear grade ductal carcinoma in situ: pleomorphic cell population with individualized cell necrosis. FIGURE 5-42 Direct smear of low nuclear grade ductal carcinoma in situ: higher view of the same case as in Fig. 5-41 with similar features.

Breast aspirates from non-comedo-type ductal carcinoma in situ is characterized by moderate to high cellularity. Cell population is monomorphic and uniform. No myoepithelial cells are present. The cell clusters may form cribriform, solid, and micropapillary patterns. Microcalcified particles may also be present (Figs 5-41 & 5-42).

HIGH NUCLEAR GRADE DUCTAL CARCINOMA IN SITU (COMEDO TYPE) High nuclear grade ductal carcinoma in situ is known to have a higher rate of local recurrence compared to

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the low nuclear grade ductal carcinoma in situ. It is associated with a higher rate of microinvasion, expression of HER-2/neu oncogene, and hormone receptor negativity. Fine needle aspirates of high nuclear grade ductal carcinoma in situ are often cellular and display highly neoplastic epithelial cells with individual cell necrosis. Extreme pleomorphism with anisonucleosis occasionally is associated with the microcalcified particles. Large irregularly shaped nucleoli are also present (Figs 5-43 & 5-44). The distinction between high and low nuclear grade is important since high nuclear grade lesions require more aggressive therapy and better respond to chemotherapy. Assessment of the status of invasion may be critical for treatment planning. Attempts have been made to cytologically differentiate between an insitu versus an invasive breast cancer. However, controversy remains regarding the reliability of cytologic features to make this distinction. In these circumstances,

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142 it is best to consider an open biopsy to determine the presence or absence of an invasive process.

PRIMARY BREAST CARCINOMA FNAB is one of the most cost-effective procedures for the initial diagnosis of primary breast carcinoma in palpable breast lesions. Associated with integration of clinical presentation and breast imaging, in experienced hands FNAB provides a diagnostic accuracy similar to that of surgical biopsy. Diagnosis of malignancy in breast cytopathology is based on the combination of architectural pattern and the nuclear features. Aside from familiarity with subtle diagnostic pitfalls associated with various forms of breast carcinoma, recognition of the limitation of this procedure is the key to an accurate diagnosis. It is critically important to study the spectrum of morphologic features of benign and borderline breast disease that may present with atypia. To achieve this goal, attempts should be made to refrain from the casual use of the term atypia. Similarly, recognition of breast malignancies that are associated with insignificant atypia, such as lobular, tubular, and mucinous lesions, is important. Based on the guidelines proposed in the National Cancer Institute (NCI)-sponsored workshop, rendering the diagnosis of malignancy in a breast FNAB is sufficient for patient management. However, typing of breast carcinoma whenever possible is strongly encouraged.

INFILTRATING DUCT CELL CARCINOMA, NOT OTHERWISE SPECIFIED (NOS) Based on data from the Surveillance, Epidemiology, and End Results (SEER) programs registry of the NCI, the most common primary carcinoma of the breast is infi ltrating duct carcinoma, not otherwise specified (NOS). This form of primary breast cancer accounts for 68% of all breast carcinomas. Infi ltrating duct cell carcinoma can present as an image-detected abnormal-

INFILTRATING DUCT CELL CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ Most common type of primary breast carcinoma ៉ Clinically presents with a palpable mass with or without skin

changes ៉ Mammographically presents as a poorly defined spiculated mass

with or without microcalcifications ៉ Characterized by a hypoechoic mass with irregular borders and an

uneven echo texture by ultrasound

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FINE NEEDLE ASPIRATION CYTOLOGY

INFILTRATING DUCT CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular aspirate ៉ Conspicuous loss of cell cohesion ៉ Variable cell pattern in a clean or necrotic background ៉ Variable nuclear atypia and cellular pleomorphism ៉ Rare multinucleated tumor giant cells ៉ Occasionally, small cells with plasmacytoid appearance ៉ Absence of myoepithelial cells Histopathologic Findings ៉ Infiltrating duct cell carcinoma NOS varies based on the degree

of differentiation Ancillary Studies ៉ Immunostain for epithelial versus melanoma specific markers

Differential Diagnosis and Pitfalls ៉ Infl ammatory/reactive/hyperplasia: presence of myoepithelial

cells; preservation of cellular cohesion; polymorphic cell pattern ៉ Infiltrating lobular carcinoma: more uniformity of the nuclei; less hyperchromasia; occasional Indian filing; occasional signetring cells; presence of intracytoplasmic mucin vacuoles ៉ Amelanotic melanoma: presence of intranuclear vacuoles; frequent binucleation; prominent, often cherry red, nucleoli

ity or as a hard mass with or without skin changes. The more common variety is the stellate lesion, which is characterized by extensive fibrosis, also known as scirrhous carcinoma. Mammographically, the vast majority of these malignancies present with a poorly defined spiculated mass with or without microcalcifications. Sonographically, the most common features of malignancy are those of a hypoechoic mass with irregular borders and an uneven texture. Histologically, infi ltrating duct cell carcinoma is characterized by a spectrum of changes that vary accordingly to atypia and differentiation such as the degree tubule formation, nuclear pleomorphism, and mitotic activity. Cytologically, variable patterns reflecting the diverse histology are seen. Breast aspirates of infiltrating duct cell carcinoma are cellular and often show conspicuous loss of cell cohesion. Scattered individual tumor cells and aggregates of various-sized cells demonstrate threedimensional clustering, syncytial groups or, occasionally, gland-like arrangements. Tumor cells are often large and pleomorphic with prominent nucleoli. The background may be clear or contain red blood cells and necrotic debris. Occasionally, multinucleated giant cells can also be observed. The above-mentioned morphologic features are characteristic of poorly differentiated infiltrating duct cell carcinoma/grade III tumors. Grade I and grade II will exhibit sheets of monomorphic cells with round and bland-appearing nuclei with single inconspicuous nucleoli (Figs 5-45–5-47).

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Breast

FIGURE 5-45 Direct smear of an infiltrating duct cell carcinoma yielding a cellular aspirate with conspicuous loss of cell cohesion.

FIGURE 5-47 Direct smear of an infiltrating duct cell carcinoma, high nuclear grade, demonstrating various-sized nucleoli with clumped chromatin and conspicuous nucleoli.

FIGURE 5-46 Direct smear of an infiltrating duct cell carcinoma, low nuclear grade, characterized by uniform small nuclei with inconspicuous nucleoli. FIGURE 5-48 Direct smear of an infiltrating duct cell carcinoma, small cell variant, showing numerous small cells with eccentric nuclei.

Another variant of duct cell carcinoma, which may be difficult to diagnose cytologically, is the small cell variant. Breast aspirate of this entity is characterized by numerous isolated and clusters of small cells with eccentric round nucleoli and a moderate amount of cytoplasm exhibiting a ‘plasmacytic’ pattern. This entity should be differentiated from the rare plasmacytomas of the breast and from a metastatic amelanotic malignant melanoma. Immunostaining for epithelial markers aids in making an accurate diagnosis of the small cell variant of infiltrating duct cell carcinoma, which commonly occurs in older women. This tumor also shares a similar pattern with infiltrating lobular carcinoma. Higher cellularity and increased hyperchromasia of the nuclei are the features more commonly seen in this variant (Fig. 5-48). Infiltrating duct cell carcinoma should be differentiated from borderline and atypical benign lesions.

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Absence of myoepithelial cells is the key to making the distinction.

TUBULAR CARCINOMA Tubular carcinoma, a previously rare breast tumor, now accounts for up to 20% of all carcinomas detected through mammographic screening. It occurs in a younger age group than the classic type of infi ltrating duct cell carcinoma and is associated with a higher incidence of bilaterality and multiplicity. Because of their small size and infrequent lymph node involvement, tubular carcinomas are associated with a good

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TUBULAR CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ Accounts for up to 20% of mammographically detected

carcinomas ៉ Mammographically, it shares similar features with radial scar ៉ Associated with a low incidence of axillary lymph node metastasis

and a favorable prognosis ៉ Suitable for conservative therapy

TUBULAR CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity ៉ Presence of epithelial cells forming angulated tubular structures ៉ Uniform nuclei with occasional nuclear grooving ៉ Cytoplasmic vacuoles

FIGURE 5-49 Direct smear of tubular carcinoma characterized by isolated and clusters of epithelial cells with tubular structures and cell balls.

Ancillary Studies ៉ Immunostain for myoepithelial cell markers

Differential Diagnosis and Pitfalls ៉ Radial scar: low to moderate cellularity; admixed myoepithelial cells with epithelial cells; absence of nuclear grooves and intracytoplasmic vacuoles ៉ Microglandular adenosis: low cellularity; absence of angulated tubules; cell balls; myoepithelial cells ៉ Fibroadenoma: complex branching of ductal epithelial cells; myoepithelial cells within the clusters of epithelial cells and in the background; absence of nuclear grooving and intracytoplasmic vacuoles

prognosis and are most suitable for conservative therapy. Mammographically, tubular carcinomas present as a spiculated mass, similar to that of a radical scar, which may require surgical excision. Grossly, tubular carcinomas present as stellate or scirrhous areas of gray–white discoloration with induration and retroaction. Histologically, the tumor consists of elongated round tubular structures lined by a single layer of cells, some of which may exhibit apocrine snouts. Cytologically, the aspirates are moderately cellular, containing bland-appearing tumor cells which form angular branching and three-dimensional tubular structures. Tumor cells are uniform with a finely granular chromatin and small nucleoli. Groved nuclei and solitary intracytoplasmic vacuoles are often features of tubular carcinomas (Figs 5-49–5-51). The differential diagnosis includes radial scar, fibroadenoma, and microglandular adenosis. There are overlapping features between tubular carcinoma and radial scar. Radial scars, however, present with lower cellularity and show the presence of myoepithelial cells within the cell clusters and have inconspicuous nucleoli. If radial scar is associated with proliferative breast disease with atypia, the higher

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FIGURE 5-50 Direct smear of tubular carcinoma showing an angulated tubular structure with no myoepithelial cells within the cluster of epithelial cells.

FIGURE 5-51 Direct smear of tubular carcinoma showing a uniform population of cells with uniform nuclei and no myoepithelial cells.

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cellularity, loss of polarity, and some degree of anisonucleosis may mimic a neoplastic process. Immunostaining for myoepithelial cell markers is an effective tool in making the distinction. Similarly, tubular carcinomas may mimic fibroadenomas. However, fibroadenomas often present with complex branching of ductal epithelial cells admixed with myoepithelial cells. Tubular carcinomas may occasionally lead to false negative diagnosis, particularly if the aspirate is not cellular. When in doubt, it is reasonable to recommend total surgical excision of the lesion.

MUCINOUS CARCINOMA

145 are well-circumscribed lesions; on ultrasound, they are solid and hypoechoic. Histologically, they present as pure or mixed type, with two prognostically different behaviors. Pure forms present with a welldefined gelatinous mass and show small epithelial islands floating in abundant extracellular mucin. Pure mucinous carcinomas are associated with a favorable prognosis. Cytologically, the aspirates contain thick mucinous material on smears, and show abundant mucin in the background. Clusters of relatively small and uniform epithelial cells with bland-appearing cytologic features are often seen within the mucinous background. Tumor cells may appear in three-dimensional clusters, monolayered sheets, or as dissociated isolated cells. The epithelial cells are relatively uniform with wispy cytoplasm and a vesicular chromatin pattern (Figs 5-52 & 5-53).

Mucinous carcinomas represent approximately 2% of breast cancers. It is also known as colloid, mucoid, gelatinous, and mucin-producing carcinoma. These tumors generally occur in older women. Clinically, they present as a soft mobile mass. Mammographically, they

MUCINOUS CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ A rare breast tumor that occurs in an older age group ៉ Clinically, it presents as a soft mobile mass ៉ Breast imaging shows a well-defined lesion ៉ Prognosis in pure mucinous carcinomas is favorable ៉ Mixed variety of mucinous carcinoma is associated with the same prognosis as an infiltrating duct cell carcinoma FIGURE 5-52 Direct smear of mucinous carcinoma characterized by abundant mucin in the background and clusters of epithelial cells. MUCINOUS CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity ៉ Mucinous background ៉ Cohesive clustering of small aggregates of epithelial cells with minimal nuclear atypia ៉ Fragments of stroma and newly formed small vessels Ancillary Studies ៉ Immunostain for myoepithelial cell markers

Differential Diagnosis and Pitfalls ៉ Mucocele-like tumor: occurs in younger women; associated with proliferative and premalignant breast disease; contains both epithelial and myoepithelial cell components ៉ Myxoid fibroadenoma: occurs in younger women; demonstrates stromal and mixed epithelial components; presence of antlerhorn pattern ៉ Signet-ring cell carcinoma: abundance of signet-ring cells with intracellular mucin production

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FIGURE 5-53 Direct smear of mucinous carcinoma showing the same features in higher magnification. The epithelial cells are uniform and there are no myoepithelial cells.

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The cellularity varies based on the amount of extracellular mucin. In hypocellular aspirates, the bland appearance of tumor cells may lead to false negative diagnosis. The mixed form of mucinous carcinoma is an infiltrating duct cell carcinoma with mucinous differentiation. The prognosis of this variant is the same as for the classical form of infiltrative duct cell carcinoma. In the mixed form, cellular pleomorphism is more conspicuous with occasional necrosis and a smaller amount of mucin in the background. Regardless of the cellularity and the presence of mucinous material, it is best to classify these lesions as ‘breast carcinoma with a mucinous component’ by FNAB. Mucinous carcinomas must be distinguished from ‘mucocele-like lesions’ and myxoid fibroadenomas. Mucocele-like tumors of the breast are benign entities that are associated with a variety of metaplastic and hyperplastic conditions. They occur in young and in premenopausal women, in contrast to mucinous carcinoma, which is a tumor of old age. Aside from age, the aspirates from mucoceles display the presence of both epithelial and myoepithelial cells, which can be supported by immunostains for myoepithelial cell markers. Another entity which should be differentiated from mucinous carcinoma is fibroadenoma with myxoid stroma. Clues to the correct diagnosis are young age of the patient and the presence of stroma and epithelial/ myoepithelial components. Immunostain for myoepithelial cell markers will provide the supporting evidence. Signet-ring cell carcinoma of the breast may also mimic mucinous carcinoma. However, in this tumor, the majority of cells show evidence of intracytoplasmic mucin.

FIGURE 5-54 Direct smear of signet-ring cell carcinoma characterized by isolated and clusters of neoplastic epithelial cells with a signet-ring pattern.

SIGNET-RING CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Moderate to high cellularity ៉ Abundance of small to medium-sized cells with crescent-shaped

nuclei and intracellular mucin Ancillary Studies ៉ Special stains ៉ Electron microscopy ៉ Panel of immunostains for organ-specific antibodies

Differential Diagnosis and Pitfalls ៉ Metastatic adenoma: pertinent clinical history; review of the

original pathology slides; use of ancillary studies

SIGNET-RING CELL CARCINOMA

៉ Infiltrating lobular carcinoma: presence of other forms of

neoplastic epithelial cells; Indian file pattern ៉ Secretory carcinoma: numerous branching sheets of neoplastic

Signet-ring cell carcinomas are rare breast tumors that are associated with an unfavorable prognosis. This lesion occurs in the mid to late fifties. The origin of this as a variant of mucinous carcinoma versus an infi ltrating lobular carcinoma remains controversial. Cytologically, signet-ring cell carcinomas present with moderate to rich cellularity. The cells are arranged singly or in

SIGNET-RING CELL CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ A rare breast tumor with an unfavorable prognosis ៉ May mimic other forms of malignancies ៉ Distinction from metastatic tumors is important and requires clinical information, review of the original tumor, and ancillary studies

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cells with cytoplasmic vacuoles and extracellular lumina; red blood cells, cellular debris with tumor diathesis in the background; multiple intracytoplasmic vacuoles ៉ Lipid-rich carcinoma: moderate cellular yield, loose cohesive cell arrangement; atypical, indented nuclei with nuclear vacuoles; abundant intracytoplasmic lipid material, which can be demonstrated on air-dried smears and by the use of oil res O staining

small loose clusters. The cells are small with crescentshaped nuclei compressed to the cell periphery by mucin (Figs 5-54 & 5-55). The differential diagnosis includes metastatic carcinoma (especially from gastrointestinal tumors), infiltrating lobular carcinomas, secretory carcinomas, and lipid-secreting carcinomas. The clinical history, review of the original pathology slides, and use of ancillary studies such as special stains, electron microscopy, and

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FIGURE 5-55 Direct smear of signet-ring cell carcinoma: higher magnification of the same case as in Fig. 5-54, showing signet-ring cells with mucin droplets.

FIGURE 5-57 Direct smear of secretory carcinoma: higher magnification of the same case as in Fig. 5-56, showing multiple vacuoles in the cytoplasm.

MEDULLARY CARCINOMA

FIGURE 5-56 Direct smear of secretory carcinoma characterized by clusters of neoplastic epithelial cells with abundant vacuolated cytoplasm.

a panel of immunostains for organ-specific antibodies are the tools to differentiate between a signet-ring cell carcinoma and a metastatic tumor. The distinction between signet-ring cell carcinomas and other tumors requires special attention to subtle morphologic differences. Infiltrating lobular carcinomas often show other characteristics of this tumor, including the presence of Indian file pattern. Secretory carcinomas present with several prominent intracytoplasmic vacuoles (Figs 5-56 & 5-57). Lipid-rich carcinomas contain small cytoplasmic vacuoles that present in different forms. The vacuoles are often seen in the perinuclear area, and nuclei are indented. Special stain demonstrates the presence of fat droplets in the cytoplasm of tumor cells.

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Medullary carcinomas of the breast are rare tumors, accounting for 5% to 7% of all breast cancers, and are associated with a good prognosis. Medullary carcinomas occur in patients aged between 21 and 95 years, with a mean age of 50 years. In young patients, medullary carcinomas may be associated with genetically mutated cancer in high-risk individuals. Medullary carcinomas present as a well-defined lesion, both clinically and mammographically. On histology, typical medullary carcinomas are characterized by sharp circumscription and a syncytial growth pattern of highly pleomorphic epithelial cells with no glandular pattern and surrounded by a lymphocytic infiltration. Tumors that exhibit any or few of these criteria are called atypical medullary carcinomas. The behavior and prognosis of these tumors are similar to those seen in the usual forum of infiltrating duct cell carcinoma. Therefore, the designation of ‘ductal carcinoma with medullary features’ is more appropriate for cytologic diagnosis of medullary carcinoma. Cytologically, the aspirates from a medullary carcinoma are hypercellular with a background showing lymphocytes and plasma cells. The neoplastic epithelial cells show an extreme degree of pleomorphism,

MEDULLARY CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ A rare breast tumor that occurs in all age groups ៉ In young patients, may be associated with breast cancer genes ៉ A well-circumscribed lesion, both clinically and mammographically ៉ Associated with a good prognosis

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FIGURE 5-58 Direct smear of medullary carcinoma characterized by clusters of epithelial cells surrounded by lymphocytes.

FIGURE 5-59 Direct smear of medullary carcinoma showing syncytial growth pattern.

APOCRINE CARCINOMA MEDULLARY CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ High cell yield ៉ Pleomorphic cell population forming syncytial growth pattern ៉ Pronounced lymphoplasmacytic infiltration ៉ Necrotic background Ancillary Studies

Apocrine carcinoma, a rare breast tumor, occurs in an older age group. The apocrine features and biomarker findings may suggest a difference in steroid metabolism, particularly a higher frequency of androgen receptor positivity compared to the ductal carcinoma not otherwise specified. It has been suggested that patients

៉ Immunophenotyping by immunocytochemistry and/or fl ow

cytometry Differential Diagnosis and Pitfalls ៉ Malignant lymphoma: monotonous cell population; absence of epithelial cells; evidence of monoclonality by immunocytochemistry or flow cytometry ៉ Infiltrating duct cell carcinoma with lymphocytic pattern: absence of syncytial growth pattern; lesser degree of anisonucleosis and pleomorphism

APOCRINE CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ A rare breast tumor that occurs in an older age group ៉ May have a different pathway of steroid metabolism

APOCRINE CARCINOMA – PATHOLOGIC FEATURES

anisonucleosis, a high mitotic rate and arrangement in syncytial sheets (Figs 5-58 & 5-59). Medullary carcinomas rarely present as a cystic lesion. They are frequently hormone receptor-negative and have an abnormal DNA pattern. The differential diagnosis includes poorly differentiated infiltrating duct cell carcinoma with lymphocytic infiltrate and malignant lymphoma. Ductal cell carcinoma with lymphocytic pattern does not present with a syncytial growth pattern. Malignant lymphomas are characterized by a monotonous cell population with no evidence of epithelial differentiation. Immunophenotyping by immunocytochemistry or flow cytometry will aid in making the differentiation.

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Cytopathologic Findings ៉ Cellular aspirate ៉ Pleomorphic population of cells with abundant granular cytoplasm ៉ Marked anisonucleosis with large nuclei and prominent nucleoli Differential Diagnosis and Pitfalls ៉ Hyperplastic/metaplastic apocrine cells: presence of

accompanying proliferating epithelial cells; lack of significant anisonucleosis and hyperchromasia ៉ Secretory carcinoma: neoplastic cells with prominent intracellular spaces; cytoplasmic vacuoles; signet-ring formation ៉ Lipid-rich carcinoma: abundant multivacuolated cells with a more uniform nuclear appearance; lack of multiple nucleoli

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INFILTRATING LOBULAR CARCINOMA

FIGURE 5-60 Direct smear of apocrine carcinoma characterized by a population of neoplastic epithelial cells with granular cytoplasm and conspicuous nucleoli.

Infi ltrating lobular carcinoma accounts for approximately 6.3% of primary breast carcinomas. It occurs in wide range of age groups, ranging from 26 to 86 years old. Clinical presentation is similar to that of other primary breast carcinomas. However, it is not associated with Paget’s disease and occasionally it may present as an indurated area without any discrete mass. Infi ltrating lobular carcinomas have a different pattern of metastatic presentations and tend to involve skeletal, visceral, serosal, and meningeal areas. Similarly, ovary, bone, and uterus are the common sites of metastasis from this tumor. Mammographically, it can present as an asymmetric density with no clearly delineated margin with no or little architectural distortion. Multifocal infiltrating lobular carcinoma may present with minimal distortion with no significant mass or increased density or microcalcification. These subtle mammographic features warrant careful examination of the breast and sampling of any suspicious area. Infiltrating lobular carcinoma is often bilateral and shows evidence of multiplicity. On histology, infiltrating lobular carcinomas are characterized by diffuse infiltration of mammary stroma

INFILTRATING LOBULAR CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ Variable clinical and mammographic presentations ៉ Associated with bilaterality and multiplicity ៉ Has a different pattern of metastasis from tumors of ductal origin

FIGURE 5-61 Direct smear of apocrine carcinoma showing multinucleation and prominent nucleoli.

with apocrine carcinoma may experience a longer survival. Cytologically, the aspirates are often cellular and show pleomorphic tumor cells with abundant granular cytoplasm. The nuclei are large, vesicular and are centrally or eccentrically located. The nucleoli are prominent and multinucleation is common (Figs 5-60 & 5-61). Apocrine carcinomas should be distinguished from atypical changes seen in proliferative and metaplastic apocrine cells. The clues are the presence of an accompanying polymorphous cell population commonly seen in proliferative breast disease. Absence of anisonucleosis and significant hyperchromasia are also other features seen in atypical apocrine lesions. Other lesions included in the differential diagnosis are lipid-rich and secretory carcinomas.

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INFILTRATING LOBULAR CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity ៉ Monomorphic cell population of small cells with insignificant atypia ៉ Eccentrically located nuclei ៉ Cells with intracytoplasmic lumina ៉ Indian file pattern ៉ No myoepithelial cells Ancillary Studies ៉ Immunostain for myoepithelial cell markers and E-cadherin

Differential Diagnosis and Pitfalls ៉ Fibrocystic change: presence of polymorphic cell pattern; presence of myoepithelial cells ៉ Low nuclear grade ductal carcinoma: positive immunostain for E-cadherin ៉ Atypical lobular hyperplasia and lobular carcinoma in situ: less cellularity; more cohesive cell pattern

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FIGURE 5-62 Direct smear of an infiltrating lobular carcinoma characterized by isolated and a cluster of epithelial cells with uniform nuclei and intracytoplasmic lumina.

FIGURE 5-63 Direct smear of an infiltrating lobular cell carcinoma showing clusters of epithelial cells with no myoepithelial cells.

and ductal structures with neoplastic cells in a pagetoid growth pattern. An area of carcinoma in situ is commonly seen. Infiltrating lobular carcinoma may present in a variety of patterns with similar prognostic behavior, except for the pleomorphic variant, which is associated with a more unfavorable outcome. Cytologically, infiltrating lobular carcinomas present with variable cellularity. The cells are small and uniform with small nucleoli, and present as cell balls or with Indian file appearance. Tumor cells present with eccentric nuclei, occasional intracytoplasmic lumina with mucin droplets, and rare signet-ring cells (Figs 5-62– 5-64). The pleomorphic variant features more pleomorphism and nuclear atypia (Figs 5-65 & 5-66). Infiltrating lobular carcinomas are one of the main reasons for false negative diagnosis in breast FNAB. This is often due to

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FIGURE 5-64 Direct smear of an infiltrating lobular cell carcinoma exhibiting an Indian file pattern.

FIGURE 5-65 Direct smear of an infiltrating lobular carcinoma, pleomorphic variant, characterized by a cellular aspirate showing an isolated population of epithelial cells with eccentric nuclei, anisonucleosis. and hyperchromasia.

insignificant atypia associated with this entity. The presence of a monomorphic pattern of small cells arranged in single cells, cords, or clusters with no recognizable myoepithelial cells is the key feature to differentiate infiltrating lobular carcinoma from benign breast lesions. Differentiation between infiltrating lobular carcinoma and other entities may be difficult. With a hypocellular specimen, it is best to consider surgical excision for further characterization of suspicious cells for lobular carcinoma. There are overlapping features between atypical lobular hyperplasia, lobular carcinoma in situ, and an infiltrating lobular carcinoma. These entities are collectively called lobular neoplasia if the distinction is not possible. Higher cellularity and a higher proportion

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FIGURE 5-66 Direct smear of an infiltrating duct cell carcinoma, pleomorphic variant, showing intracytoplasmic lumina with mucin droplets.

FIGURE 5-68 Direct smear of lobular carcinoma in situ showing acini and clustering of uniform-appearing epithelial cells.

FIGURE 5-67 Direct smear of lobular carcinoma in situ characterized by clusters of small uniform-appearing epithelial cells with no myoepithelial cells.

of dissociated cells are commonly seen in an infiltrating lobular carcinoma (Figs 5-67–5-70). The differential diagnosis also includes low nuclear grade carcinoma of ductal origin. Immunostain for E-cadherin can differentiate between these two entities.

FIGURE 5-69 Direct smear of atypical lobular hyperplasia characterized by proliferation of small cells simulating acini.

METASTASES TO THE BREAST METASTASES TO THE BREAST – DISEASE FACT SHEET

The breast is not a common site for metastases from other primary malignancies. The distinction between a primary breast carcinoma and a metastasis is critically important because of different therapeutic implications and the differences in outcome. Clinically, the presentation of the two entities may be similar; however, nipple discharge and retraction are not seen in metastatic tumors. Metastatic tumors have a variety of mammographic features, ranging from features similar

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Clinical Features ៉ Rare ៉ Clinical and mammographic features may be similar to those of primary breast carcinoma ៉ Cytologic distinction is important for the management and clinical outcome ៉ Clinical history, review of the original pathology slides, and ancillary studies are essential to make an accurate diagnosis

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FIGURE 5-70 Direct smear of atypical lobular hyperplasia: higher magnification of the same case as shown in Fig. 5-69.

FIGURE 5-71 Direct smear of metastatic squamous cell carcinoma showing isolated and clusters of neoplastic epithelial cells with evidence of keratinization.

METASTASES TO THE BREAST – PATHOLOGIC FEATURES Cytopathologic Findings ៉ High cellularity ៉ Dispersed cell pattern of various types and shapes, dissimilar to the classic types of breast cancer ៉ Variable cytomorphology similar to the primary site of origin Ancillary Studies Special stains Electron microscopy Panel of immunostains Flow cytometry

៉ ៉ ៉ ៉

Differential Diagnosis and Pitfalls ៉ Primary breast carcinoma: clinical history; classic pattern of

cytomorphology for primary breast cancer

to those of proliferative breast disease, cyst, or fibroadenoma to those of a malignant lesion such as medullary carcinoma. Microcalcification is not frequent except in rare cases of psammoma bodies in metastatic tumors from the ovary. Patients with metastatic breast lesions experience a poor outcome and about 80% of them die within a year. The differentiation between a primary breast tumor and a metastasis may not be always possible. The most important step is the recognition of a cytologic pattern not commonly seen in a primary breast carcinoma. This should alert the pathologist to explore the possibility of a metastasis. Review of the clinical history and the pathology slides of the primary tumor associated with special stains and often ancillary studies such as EM and/or organ-specific immunohistochemical stains usually resolves the quandary. This process can be completed by the use of special stains and ancillary studies such as electron microscopy and of immunostaining for a panel of specific antibodies.

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FIGURE 5-72 Direct smear of mucin-producing metastatic adenocarcinoma characterized by isolated epithelial cells with centrally located nuclei and abundant cytoplasm and intracellular mucin.

Cytologically, metastatic tumors present with rich cellularity. Based on the site of the origin, the aspirates present with various cell types, sizes, and cellular arrangements. Malignant melanomas, squamous cell carcinoma, various adenocarcinomas, Hodgkin disease, large cell lymphoma, and pleomorphic sarcomas exhibit pleomorphic large cells. Melanomas, lymphomas, leukemias, and poorly differentiated carcinomas present with a dispersed cell pattern. Malignant melanoma cells may contain pigment, intranuclear inclusions and binucleation (Figs 5-71–5-78). Neuroendocrine tumors and small cell carcinoma of the lung often present with small-sized tumor cells. Spindle cell tumors often represent various types of sarcomas. The most common metastatic tumors to the breast are lung and malignant melanoma. Metastasis from other sites have also been reported. In men,

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FIGURE 5-73 Direct smear of non-Hodgkin lymphoma characterized by dispersed cell pattern and various-sized malignant lymphoid cells.

FIGURE 5-74 Direct smear of Hodgkin lymphoma characterized by atypical lymphoid elements and classic Reed-Sternberg cell.

FIGURE 5-75 Direct smear of malignant melanoma: dispersed cell pattern with binucleation and intracytoplasmic vacuoles.

FIGURE 5-76 Immunostained cell block showing expression of HMB-45 (same case as Fig. 5-75).

FIGURE 5-77 Direct smear of metastatic prostate carcinoma characterized by uniformappearing epithelial cells.

FIGURE 5-78 Metastatic prostate carcinoma: immunostained cell block showing expression of prostate-specific antigen.

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prostate cancer is the most common form of metastatic tumor to the breast. Lymphoma including Hodgkin disease of the breast is commonly seen as a manifestation of a known generalized lymphoma and presents no difficulty in rendering a diagnosis. However, rarely they may occur as the primary breast carcinoma. Immunophenotyping with immunocytochemistry or flow cytometry can establish the diagnosis. Sarcomas can also occur as a primary breast carcinoma or as metastasis from other sites. The aspirate of sarcomas is cellular with a spindle cell pattern. Electron microscopy and immunostaining for mesenchymal markers are helpful in establishing the diagnosis of a sarcomatous lesion.

MISCELLANEOUS CONDITIONS

FIGURE 5-79 Direct smear of granular cell tumor characterized by uniform-appearing tumor cells with conspicuous granular cytoplasm.

GRANULAR CELL TUMOR Granular cell tumors are examples of stromal tumors of the breast, which are rare and present as a palpable mass. These tumors may resemble breast carcinomas, both clinically and mammographically, and FNAB is quite helpful to provide an accurate diagnosis. Cytologically, the aspirates show moderately cellular smears with isolated and clusters of cells with granular and foamy cytoplasm. The nuclei are uniform and the chromatin is fine. Immunostain for S-100 and electron microscopy are often used to substantiate the diagnosis of granular cell tumor (Figs 5-79 & 5-80). Malignant

GRANULAR CELL TUMOR – DISEASE FACT SHEET Clinical Features

FIGURE 5-80 Granular cell tumor: immunostained cell block showing expression of S-100 protein.

៉ Rare form of stromal tumors of the breast ៉ Clinically and mammographically, may mimic primary breast

carcinoma

GRANULAR CELL TUMOR – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity ៉ Isolated and clusters of cells with uniform nuclei, conspicuous

nucleoli, and fine chromatin pattern ៉ Tumor cells with granular cytoplasm

Differential Diagnosis and Pitfalls ៉ Malignant granular cell tumor: pronounced cellular

pleomorphism; abundant mitosis

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granular cell tumors show extensive pleomorphism with a high degree of mitotic activity.

GYNECOMASTIA Gynecomastia refers to unilateral or bilateral enlargement of the male breast. This condition may be due to hormonal changes, testicular or hepatic tumors, Klinefelter’s syndrome, drug therapy, liver or renal disease. Cytologically, gynecomastias present with a cellular aspirate that shows tightly cohesive groups of epithelial cells and stromal components, features seen in fibroadenomas in the female breast. Apocrine metaplasia, histiocytes, fragments with cribriform or micropapillary

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FIGURE 5-81 Direct smear of gynecomastia characterized by uniform-appearing epithelial/myoepithelial cells with stromal fragments.

GYNECOMASTIA – DISEASE FACT SHEET Clinical Features ៉ Most frequent breast lesion in men ៉ Commonly caused by hormone-induced conditions ៉ FNAB is most effective in establishment of diagnosis

GYNECOMASTIA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity ៉ Uniform population of small groups of epithelial/myoepithelial

cells ៉ Tall columnar cells ៉ Stromal fragments

Differential Diagnosis and Pitfalls ៉ Primary and metastatic breast cancer: obvious evidence of

morphologic features of malignancy; history of other primary carcinomas

arrangements, and cystic changes may be associated with gynecomastia (Figs 5-81 & 5-82). Occasionally, the cellular patterns, presence of small groups and isolated cells, and columnar cell differentiation may cause diagnostic difficulty. However, a diagnosis of malignancy should be considered only if the aspirate presents obvious features of malignancy. Primary breast cancers in men are similar to those in women. Intracystic papillary carcinomas are frequent in men. In addition, there is relatively equal frequency of primary and metastatic lesions in the male breast, with

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FIGURE 5-82 Direct smear of gynecomastia: a cluster of epithelial/myoepithelial cells with an architectural pattern similar to a fibroadenoma.

lung cancer, prostrate cancer, and lymphoma being common metastatic tumors.

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Masood S, Lu L, Assaf Munasifi N, McCaulley K. Application of immunostaining for muscle specific actin for detection of myoepithelial cells in breast fine needle aspirates. Diagn Cytopathol 1995;13: 71–74. Masood S, Rasty G. Potential value of cytology in the detection of breast cancer precursors by fine needle aspiration biopsy: ‘The future Pap smear for breast cancer.’ Acta Cytol 1999;43:890. Shiels LA, Mulford D, Dawson AG. Cytomorphology of proliferative breast disease [abstract]. Acta Cytol 1993;37:768. Sidawy M, Stoler M, Frable W, et al. Interobserver variability in the classification of proliferative breast lesions by fine-needle aspiration: results of the Papanicolaou Society of Cytopathology Study. Diagn Cytopathol 1998;18:150–165. Silverman J, Masood S, Ducatman BS, et al. Can FNA biopsy separate atypical hyperplasia, carcinoma in situ and invasive carcinoma of the breast? Cytomorphic criteria and limitations in diagnosis. Diagn Cytopathol 1993; 9:713–728. Sneige N, Staerkel GA. Fine needle aspiration cytology of ductal hyperplasia with and without atypia and ductal carcinoma in situ. Hum Pathol 1994;25:485–492. Stanley MA, Henry-Stanley MJ, Zera R. Prospective study of high-risk proliferative lesions of breast duct epithelium by fine needle aspiration [abstract]. Acta Cytol 1991;35:611. Ductal Carcinoma In Situ Frable WJ. Fine needle aspiration biopsy: a review. Hum Pathol 1983;14: 9–28. Frykberg ER, Masood S, Copeland EM, et al. Ductal carcinoma in situ of the breast. Surg Gynecol Obstet 1993;177:425–440. Klijanienko J, Katsahian S, Vielh P, Masood S. Stromal infiltration as a predictor of tumor invasion in breast fine needle aspiration biopsy. Diagn Ctyopathol 2004;30:182–186. Lagios MD, Westdahl PR, Margopin FR, et al. Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multiplicity, lymph node metastasis and short-term treatment failures. Cancer 1982;50:1309–1314. Lilleng R, Hagmar B. The comedo subtype of intraductal carcinoma. Cytologic characteristics. Acta Cytol 1992;36:345–352. Malamud YR, Ducatman BS, Wang HH. Comparative features of comedo and noncomedo ductal carcinoma in situ of the breast on fine needle aspiration biopsy. Diagn Cytopathol 1991;8:571–576. Wang HH, Ducatman BS, Eick D. Comparative features of ductal carcinoma in situ and infiltrating ductal carcinoma of the breast on fine needle aspiration biopsy. Am J Clin Pathol 1989;92:736–740. Primary Breast Carcinoma Abendroth CS, Wang HH, Ducatman BS. Comparative features of carcinoma in situ and atypical ductal hyperplasia of the breast on fine needle aspiration biopsy. Am J Clin Pathol 1991;96:654–659. Ductaman BS, Emery ST, Wang HH. Correlation of histologic grade of breast carcinoma with cytologic features on fine needle aspiration of the breast. Mod Pathol 1993;6:539–543. Patel JJ, Gartel PC, Smallwood JA, et al. Fine needle aspiration cytology of breast masses: an evaluation of its accuracy and reasons for diagnostic failure. Ann R Coll Surg Engl 1987;69:156–159. Tubular Carcinoma Bondeson L, Lindholm K. Aspiration cytology of tubular breast carcinoma. Acta Cytol 1990;34:15–20. Cleary PMG, Mayze JD. Recognition of tubular breast carcinoma on fine needle aspiration cytology [abstract]. Acta Cytol 1992;36:773. de la Torre M, Lindholm K, Lindgren A. Fine needle aspiration cytology of tubular breast carcinoma and radial scar. Acta Cytol 1994;38:884– 890. Dei Tos AP, Della-Giustina D, Martin VD, et al. Aspiration biopsy cytology of tubular carcinoma of the breast. Diagn Cytopathol 1994;11:146– 150. Evans AT, Hussein KA. A microglandular adenosis-like lesion simulating tubular adenocarcinoma of the breast. A case report with cytological and histological appearances. Cytopathology 1990;1:311–316.

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Fisher ER, Gregorio R, Redmond C, Fisher B. Tubulolobular invasive breast cancer: a variant of lobular invasive cancer. Hum Pathol 1977;8:679– 683. Frierson JF Jr, Iezzoni J, Covell JL. Stereotaxic fine needle aspiration cytology of radial scars [abstract]. Acta Cytol 1993;37:814. Gupta RK, Dowle C. Fine needle aspiration cytology of tubular carcinoma of the breast in a young woman. Diagn Cytopathol 1991;7:72–74. Silverman JF. Breast. In: Bibbo M, ed. Comprehensive Cytopathology. Philadelphia: WB Saunders, 1991:703–770. Mucinous Carcinoma Duane GB, Kanter MH, Branigan T, Chang C. A morphologic and morphometric study of cells from colloid carcinoma of the breast obtained by fine needle aspiration. Distinction from other breast lesions. Acta Cytol 1987;31:742–750. Fisher CJ, Millis RR. A mucocele-like tumour of the breast associated with both atypical ductal hyperplasia and mucoid carcinoma. Histopathology 1992;21:69–71. Ro JY, Sneige N, Sahin AA, Silva EG, Del Junco GW, Ayala AG. Mucocele like tumor of the breast associated with atypical ductal hyperplasia or mucinous carcinoma. A clinicopathologic study of seven cases. Arch Pathol Lab Med 1991;115:137–140. Stanley MW, Tani EM, Skoog L. Mucinous breast carcinoma and mixed mucinous-infiltrating ductal carcinoma: a comparative cytologic study. Diagn Cytopathol 1989;5:134–138. Weaver MG, Abdul Karim FW, al Kaisi N. Mucinous lesions of the breast. A pathological continuum. Pathol Res Pract 1993;189(8):873–876. Signet-Ring Cell Carcinoma Craig JP. Secretory carcinoma of the breast in an adult. Correlation of aspiration cytology and histology on the biopsy specimen. Acta Cytol 1985;29:589–592. Fisher ER, Gregoriao R, Kim WS, et al. Lipid invasive cancer of the breast. Am J Clin Pathol 1977;68:558–561. Insabato L, Russo R, Cascone AM, et al. Fine needle aspiration cytology of lipid-secreting breast carcinoma. A case report. Acta Cytol 1993;37:752–755. Merino MY, Livolsi VA. Signet ring carcinoma of the female breast. Cancer 1981;48:1830–1837. Nguyen GK, Neifer R. Aspiration biopsy cytology of secretory carcinoma of the breast. Diagn Cytopathol 1987;3:234–237. Ramos CV, Taylor HB. Lipid-rich carcinoma of the breast. A clinicopathologic analysis of 13 examples. Cancer 1974;33:812–819. Shinagawa T, Tadokoro M, Kitamura H, et al. Secretory carcinoma of the breast: correlation of aspiration cytology and histology. Acta Cytol 1994;38:909–914. Shinagawa T, Tadokoro M, Takeuchi E, et al. Aspiration biopsy cytology of secretory carcinoma of the breast. A case report. Acta Cytol 1992;36: 189–193. Medullary Carcinoma Howell LP, Kline TS. Medullary carcinoma of the breast. A rare cytologic finding in cyst fluid aspirate. Cancer 1990;65:277–282. Meyer JE, Amin E, Lindfors KK, Lipman JC, Stomper PC, Genest D. Medullary carcinoma of the breast: mammographic and US appearance. Radiology 1989;179(1 Pt 1):79–82. Moore OSJ, Foote FWJ. The relatively favourable prognosis of medullary carcinoma of the breast. Cancer 1949;2:635–642. Pedersen L, Schiodt T, Holck S, Zedeler K. The prognostic importance of syncytial growth pattern in medullary carcinoma of the breast. APMIS 1990;98:921–926. Pedersen L, Zedeler K, Holck S, Schiodt T, Mouridsen HT. Medullary carcinoma of the breast, proposal for a new simplified histopathological definition. Based on prognostic observations and observations on interand intraobserver variability of 11 histopathological characteristics in 131 breast carcinomas with medullary features. Br J Cancer 1991;63: 591–595. Ridolfi RF, Rosen PP, Post A, Kinne T, Mike V. Medullary carcinoma of the breast. A clinicopathologic study with 10 year follow-up. Cancer 1977; 40:1365–1385.

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158 Wargotz ES, Silverberg SG. Medullary carcinoma of the breast: a clinicopathologic study with appraisal of current diagnostic criteria. Hum Pathol 1988;19:1340–1346.

Apocrine Carcinoma Abati AD, Kimmel M, Rosen PP. Apocrine mammary carcinoma. A clinicopathologic study of 72 cases. Am J Clin Pathol 1990;94:371–377. Bryant J. Male breast cancer: a case of apocrine carcinoma with psammoma bodies. Hum Pathol 1981;12:751–753. Frable WJ, Kay S. Carcinoma of the breast. Histologic and clinical features of apocrine tumors. Cancer 1968;21:756–763. Gupta RK, McHutchison AG, Simpson JS, Dowle CS. Fine needle aspiration cytodiagnosis of apocrine carcinoma of the breast. Cytopathology 1992;3:321–326. Ito F, Avai, Suzuki M, et al. Apocrine carcinoma of the breast with cytologic, histologic and electron microscopic findings: a case report [abstract]. Acta Cytol 1992;36:792. Japaze H, Emina J, Diaz C, et al. Pure invasive apocrine carcinoma of the breast: a new clinicopathological entity? Breast 2005;14:3–10. Makunura CN, Curling OM, Yeomans P, Perry N, Wells CA. Apocrine adenosis within a radial scar: a case of false positive breast cytodiagnosis. Cytopathology 1994;5:123–128. Page DL, Anderson TJ. Miscellaneous features of carcinoma. In: Diagnostic Histopathology of the Breast. Edinburgh: Churchill Livingstone, 1987: 294–295. Simpson JF, Page DL, Dupont WD. Apocrine adenosis – a mimic of mammary carcinoma. Surg Pathol 1990;3:289–299. Zajdela A, Ghossein NA, Pilleran JP, et al. The experience of aspiration cytology in the diagnosis of breast cancer. Experience at the Foundation Curie. Cancer 1975;35:499–506.

Infiltrating Lobular Carcinoma Dixon JM, Anderson TJ, Page DL, et al. Infiltrating lobular carcinoma of the breast: an evaluation of the incidence and consequence of bilateral disease. Br J Surg 1983;70:513–516. Ermier WJ, Gaffey TA, Welch JS, et al. Linitis plastica caused by metastatic lobular carcinoma of the breast. Mayo Clin Proc 1980;55:747–753. Eusebi V, Maghales F, Azzopardi JG. Pleomorphic lobular carcinoma of the breast. An aggressive tumor showing apocrine differentiation. Hum Pathol 1992;23:655–662. Fechner RE. Histologic variants of infiltrating lobular carcinoma of the breast. Hum Pathol 1975;6:373–378. Kline TS. Handbook of Fine Needle Aspiration Biopsy Cytology. St. Louis, MO: CV Mosby, 1988:199–252. Kline TS, Joshi LP, Neal HS. Fine needle aspiration of the breast: diagnostic pitfalls. Cancer 1979;4:1458–1464. Koss LG, Woyke J, Olszewski W. Cytologic Interpretation and Histologic Bases. New York: Igaku-Shoin, 1984. Rajesh L, Dey P, Joshin K. Fine needle aspiration cytology of lobular breast carcinoma. Comparison with other breast lesions. Acyta Cytol 2003;47: 177–182. Salhany KE, Page DL. Fine needle aspiration of mammary lobular carcinoma in situ and atypical lobular hyperplasia. Am J Clin Pathol 1989; 92:22–26. Smith DB, Howell A, Harris M, et al. Carcinomatous meningitis associated with infiltrating lobular carcinoma of the breast. Eur J Surg Oncol 1985;11:33–36.

Metastases to the Breast Gorczyca W, Olszewski W, Tuziak T, et al. Fine needle aspiration biopsy of rare malignant tumors of the breast. Acta Cytol 1992;36:918–926. Gorczyca W, Wlodzimierz O, Tuziak T, Kram A, Woyke S, Ucinski M. Fine needle aspiration cytology of rare malignant tumors of the breast. Acta Cytol 1992;36:918–926.

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FINE NEEDLE ASPIRATION CYTOLOGY Levine PH, Zamuco R, Yee HT. Role of fine-needle aspiration cytology in breast lymphoma. Diagn Cytopathol 2004;30:332–340. Mattia AR, Ferry JA, Harris JA. Breast lymphoma: a B-cell spectrum including the low grade B-cell lymphoma of mucosa associated lymphoid tissue. Am J Surg Pathol 1993;17:574–587. Miura H, Konaka C, Kamate N, et al. Fine needle aspiration cytology of metastatic breast tumor originating from leukemia. Diagn Cytopathol 1992;8:605–608. Nielsen M, Andersen JA, Henriksen FW, et al. Metastases to the breast from extramammary carcinomas. Acta Pathol Microbiol Scand [A] 1981;89:251–256. Pettinato G, Manivel JC, Petrella G, De Chiara A. Primary multilobated T-cell lymphoma of the breast diagnosed by fine needle aspiration cytology and immunocytochemistry. Acta Cytol 1991;35:294–299. Silverman JF, Feldman PS, Covell JL, Frable WJ. Fine needle aspiration cytology of neoplasms metastatic to the breast. Acta Cytol 1987;31: 291–300. Sneige N, Zachariah S, Fanning TV, Dekmezian RH, Ordonez NG. Fine needle aspiration cytology of metastatic neoplasms in the breast. Am J Clin Pathol 1989;92:26–35. Granular Cell Tumor Adeniran A, Al-Ahmadie H, Mahone M, Robinson-Smith T. Granular cell tumor of the breast: a series of 17 cases and review of the literature. Breast J 2004;19:528–531. DeMay RM, Kay S. Granular cell tumor of the breast. Pathol Annu 1984;19:121–148. Geisinger KR, Kawamoto EH, Marshall EB, et al. Aspiration and exfoliative cytology, including ultrastructure of a malignant granular cell tumor. Acta Cytol 1985;29:593–597. Ingram DL, Mossler JA, Snowwhite I, et al. Granular cell tumors of the breast. Steroid receptor analysis and localization of carcinoembryonic antigen, myoglobin, and S-100 protein. Arch Pathol Lab Med 1984;108: 897–901. Lowhagen T, Rubio CA. The cytology of the granular cell myoblastoma of the breast. Report of a case. Acta Cytol 1977;21:314–315. Strobel SL, Shah NT, Lucas JG, et al. Granular cell tumor of the breast: a cytologic immunohistochemical and ultrastructural study of two cases. Acta Cytol 1985;29:598–601. Gynecomastia Gorczyca W, Olszewski W, Tuziak T, et al. Fine needle aspiration biopsy of rare malignant tumors of the breast. Acta Cytol 1992;36:918–926. Hajdu SI, Espinosa MH, Robbins GF. Recurrent cystosarcoma phyllodes. A clinicopathologic study of 32 cases. Cancer 1976;38:1402–1406. Hoeven KV, Hibbard C, Jones J, et al. Fine needle aspiration diagnosis of tumors metastatic to the breast. Acta Cytol 1991;35:613. Koss LG, Woyke S, Olszewski W. Aspiration Biopsy: Cytologic Interpretation and Histologic Bases. New York: Igaku-Shoin, 1984. London G, Senige N, Ordonez NG, et al. Carcinoid metastatic to breast diagnosed by fine needle aspiration biopsy. Diagn Cytopathol 1987;3: 230–233. Martinez-Onsurbe P, Fuentes-Vaamonde E, Gonzalez-Estecha A, Hernandez-Ortiz MJ, Ruiz-Villaespesa A. Neurilemmoma of the breast in a man. A case report. Acta Cytol 1992;36:511–513. Miura H, Konaka C, Kamate N, et al. Fine needle aspiration cytology of metastatic breast tumor originating from leukemia. Diagn Cytopathol 1992;8:605–608. Rao CR, Narasimhamurthy NK, Jaganathan K, Mukherjee G, Hazarika D. Cystosarcoma phyllodes. Diagnosis by fine needle aspiration cytology. Acta Cytol 1992;36:203–207. Simi U, Moretti D, Iacconi P, et al. Fine needle aspiration cytopathology of phyllodes tumor. Differential diagnosis with fibroadenoma [see comments]. Acta Cytol 1988;32:63–66. Toker C, Tang CK, Whitely JF, Verkheiser SW, Rachman R. Benign spindle cell breast tumour. Cancer 1981;48:1615–1622.

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6

Lung Ema A Berbescu Celeste N Powers

INTRODUCTION Fine needle aspiration (FNA) of the lung has increased in popularity and frequency over the last two decades. It is often the preferred method for sampling solid lesions and can be performed safely and accurately via transbronchial (during fiberoptic bronchoscopy) or transthoracic (radiology-guided) methods; however, these methods are not useful for sampling diffuse pulmonary infiltrates. Tables 6-1 and 6-2 summarize the indications for transbronchial and transthoracic lung FNA. Transbronchial FNA uses a retractable needle (Wang needle) attached at the tip of a flexible catheter that is inserted into the flexible bronchoscope. Transthoracic FNA is performed under radiologic guidance using computed tomography (CT), fluoroscopy, or ultrasonography. The needle types more commonly used are Chiba and Franseen, with needle gauges ranging from 18G to 25G. Selection of the size, gauge, and type of needle is based on location and predicted consistency of any given lesion, as well as experience and personal preference. Many radiologists tend to select large diameter needles (18–20G) for these procedures; however, when these needles are used, this procedure should not be termed fine needle aspiration biopsy. FNA uses 22G or smaller-sized needles (23G, 25G) and has much less risk of complications, such as hemorrhage and/or pneumothorax, which are associated with the use of largediameter biopsy needles. Complications of lung FNA are presented in Table 6-3; contraindications of lung FNA are summarized in Table 6-4.

NORMAL CONSTITUENTS Normal cellular constituents that may be encountered in lung FNA comprise bronchial cells, alveolar macrophages, pneumocytes, and mesothelial cells (in transthoracic FNA). Bronchial cells are usually columnar or cuboidal and ciliated (Fig. 6-1A). They have basal nuclei with small nucleoli. Cilia and terminal bars are usually visible at the apical poles. The presence of cilia in a cell group is a major clue to its benign nature.

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• Michael O Idowu •

Alveolar macrophages (Fig. 6-1B) have a similar morphology to macrophages elsewhere in the body. They have round, oval, or bean-shaped eccentric nuclei. They usually have abundant cytoplasm and are typically laden with dust, carbon, and other particulate matters. Hemosiderin-laden macrophages usually indicate prior hemorrhage or infarction; however, this diagnosis can be overlooked if the pigment is attributed to the normal ‘dust burden’. Alveolar pneumocytes. Type I pneumocytes are not usually encountered in aspirate specimens. Type II pneumocytes are relatively small with finely vacuolated cytoplasm and centrally placed small nuclei. They may be difficult to distinguish from macrophages unless the latter have pigment-laden cytoplasm. Type II pneumocytes can increase in number in reparative states and in response to chronic injury such as pneumonia, diffuse alveolar damage, drugs, radiotherapy, etc. In such cases, they may be in three-dimensional clusters or singly with a high nuclear to cytoplasmic (N/C) ratio, coarse chromatin, and prominent nucleoli – and may resemble adenocarcinoma, so much so, that the history of pneumonia becomes very important. Mesothelial cells may be seen in the lung FNA, especially in transthoracic FNA. This is due to the transfer of the pleural mesothelial lining by the aspiration needle, often when the FNA target is a peripheral mass. The morphology of the mesothelial cells in this case is similar to that of the mesothelial cells covering visceral organs. Mesothelial cells on FNA present as honeycomb sheets of evenly spaced, uniform cells with abundant cytoplasm, narrow gaps or ‘windows’ (due to the interaction of the microvilli), and small, discrete nucleoli (Fig. 6-2).

NON-NEOPLASTIC CONDITIONS SARCOIDOSIS CLINICAL FEATURES Sarcoidosis is a multisystem granulomatous disease of unknown etiology. It affects predominantly the lungs (90% of patients), but can also involve extrapulmonary 159

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B

A

FIGURE 6-1 Normal cellular constituents. A, Bronchial cells are columnar cells with small, round–oval, basally located nuclei. Note the presence of cilia and terminal bars. Identifying cilia in a group of cells indicates their benign nature. Bronchial cells are frequently seen in transbronchial FNA materials. Papanicolaou stain, medium power. B, Alveolar macrophages have abundant, somewhat vacuolated cytoplasm and a small, round nucleus. Characteristically, macrophages hold on their cytoplasm during slide preparation. Diff-Quik stain, high power.

TABLE 6-1

TABLE 6-3

Indications for Transbronchial FNA

Complications of Lung FNA

• Centrally located lesions: • beneath the bronchial mucosa • intrabronchial polypoid lesions • Mediastinal adenopathy (sarcoidosis, lymphoma, staging of patients with lung cancer)

1. Pneumothorax • Most common complication (its incidence increases with the number of aspirations) • Most are clinically insignificant • 5% of them require chest tube 2. Hemorrhage 3. Air embolism

TABLE 6-2 Indications for Transthoracic FNA • Peripherally located nodules that cannot be sampled by bronchoscopy • Evaluation for metastasis in a patient with multiple lung nodules • Confirm the diagnosis of lung cancer in an inoperable patient • Confirm the diagnosis of small cell carcinoma and avoid unnecessary surgery

sites such as eye, skin, heart, liver, spleen, salivary glands, and central nervous system. Between 30% and 50% of patients are asymptomatic and are diagnosed on routine chest radiographs. One-third of patients have non-specific symptoms, such as fever, fatigue, weight loss, malaise, and respiratory symptoms (dry cough, dyspnea, chest discomfort). Pulmonary sarcoidosis has an unpredictable course that may result in spontaneous remission or lead to progressive loss of lung function with fibrosis.

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TABLE 6-4 Contraindications of Lung FNA • • • •

Bleeding diathesis and coagulation abnormalities Pulmonary hypertension (increased risk of bleeding) Severe respiratory distress Severe emphysema with bullae (risk of pneumothorax)

The diagnosis of sarcoidosis includes compatible clinicoradiologic features, pathologic evidence of noncaseating epithelioid granulomas, and exclusion of similar diseases. The pathologic proof of epithelioid granulomas is obtained most commonly by transbronchial lung biopsy, but also lymph node or skin biopsy can be helpful. Bronchoscopy with transbronchial lung biopsy is non-diagnostic in 30% of patients with suspected sarcoidosis and has a risk of pneumothorax and hemoptysis. Recently, endoscopic ultrasound-guided

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FIGURE 6-2 Mesothelial cells. They present as fl at, two-dimensional sheets of evenly spaced, bland cells. Mesothelial cells can be sampled during transthoracic FNA and usually they are sparsely present within a given specimen. It is very important not to confuse them with the cells aspirated from a bronchioloalveolar carcinoma. Clues to the origin of these cells are sparse cellularity and lack of single, discohesive cells. Diff-Quik stain, low power.

SARCOIDOSIS – DISEASE FACT SHEET

particularly methotrexate (Rheumatrex) and azathioprine (Imuran).

Definition ៉ Granulomatous disease of unknown etiology

R ADIOLOGIC FEATURES

Gender, Race, and Age Distribution ៉ More common in women than in men (incidence of 6.3 cases and

5.9 cases per 100,000 person-year, respectively) ៉ Affects all races and ages, but more common in patients younger than 40 years and more prevalent in US Blacks, Swedes, and Danes Clinical Features ៉ 30–50% of patients are asymptomatic ៉ One-third of patients have non-specific symptoms

Radiologic Features

Chest X-ray findings are classified in four stages. Stage 0 refers to an apparently normal chest radiograph; stage I consists of bilateral hilar adenopathy without parenchymal changes; stage II refers to hilar adenopathy and parenchymal involvement; stage III consists of only parenchymal involvement; and stage IV refers to advanced fibrosis with bullae formation.

CYTOPATHOLOGIC FEATURES

៉ Four stages

Prognosis and Treatment ៉ Unpredictable clinical course ៉ Corticotherapy, cytotoxic agents

FNA of enlarged hilar lymph nodes has been performed in patients with suspected sarcoidosis, with 95% sensitivity and specificity. Oral corticosteroids are the mainstay therapy for pulmonary sarcoidosis. Patients who do not respond to corticosteroids may benefit from cytotoxic agents,

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The characteristic feature of sarcoidosis is tight, noncaseating epithelioid granulomas (Fig. 6-3). In general, in the FNA material from hilar lymph nodes, the epithelioid granulomas are numerous, in a background of lymphocytes. The characteristic cell is the epithelioid histiocyte, which is a large, polygonal cell with abundant eosinophilic cytoplasm and indistinct cell borders. The nucleus is elliptical, slightly curved (‘footprint’) and pale, with fine chromatin and one or two small nucleoli. Admixed with the epithelioid histiocytes are multinucleated giant cells. In general, caseous necrosis is absent, but occasionally a small focus of necrosis can be seen in large granulomas.

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FIGURE 6-3 Sarcoidosis. The characteristic feature of sarcoidosis is the presence of non-caseating epithelioid granulomas. They consist of tight clusters of epithelioid histiocytes admixed with lymphocytes. The inset shows the characteristic features of epithelioid histiocytes: abundant eosinophilic cytoplasm with indistinct cell borders and a slightly curved (‘footprint’) nucleus with fine nuclear chromatin. Diff-Quik stain, low power (inset: Diff-Quik stain, high power).

SARCOIDOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Tight, non-caseating epithelioid granulomas ៉ Epithelioid histiocyte is a large cell with abundant eosinophilic

cytoplasm, indistinct cell borders, and a slightly curved (‘footprint’) nucleus ៉ Multinucleated giant cells can be present ៉ It is a diagnosis of exclusion Ancillary Studies ៉ Special stains (Ziehl-Neelsen, GMS) ៉ Cultures

Differential Diagnosis and Pitfalls ៉ Mycobacterial infections ៉ Histoplasmosis ៉ Granulomas accompanying malignancy

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ANCILLARY STUDIES Sarcoidosis is a diagnosis of exclusion. Infectious and non-infectious etiologies need to be excluded before making the diagnosis of sarcoidosis. Special stains for microorganisms (Ziehl-Neelsen, Gomori methenamine silver [GMS]) need to be performed on the cytology material. Cultures can be obtained at the time of FNA. Foreign material (talc, beryllium, etc.) can be identified by light microscopy using polarized light or by laser mass spectrometric analysis.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Non-caseating granulomas are not specific for sarcoidosis and they can be seen in a variety of other

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conditions. The differential diagnosis for epithelioid granulomas in the hilar lymph nodes includes mycobacterial infection (including atypical mycobacteria), histoplasmosis, and non-specific granulomas accompanying malignancy (T-cell lymphomas, Hodgkin lymphoma, seminomas).

R ADIOLOGIC FEATURES Typically, tuberculosis involves the apical and posterior segments of upper lobes, but any lung segment can be affected. The chest X-ray shows hazy infi ltrates that progress to cavitation and fibrosis.

TUBERCULOSIS CYTOPATHOLOGIC FEATURES CLINICAL FEATURES Worldwide it is estimated that 1 billion people are infected with Mycobacterium tuberculosis. In the United States, the annual tuberculosis case rate is estimated to be 9.5 per 100,000 persons. Forty percent of tuberculosis cases in the United States occur in foreign-born persons. Tuberculosis is the result of infection with Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis), transmitted by infected aerosols, by direct personto-person contact (M. tuberculosis), or by ingestion of contaminated food (milk; M. bovis). After the initial infection (primary tuberculosis), the disease is latent for a variable period of time and reactivates when the immune system is weakened (secondary tuberculosis). Non-tuberculous mycobacterial infections (M. aviumintracellulare complex) cannot be distinguished on clinical and radiologic grounds from M. tuberculosis complex infections. This distinction is made only by cultures with biochemical tests or using polymerase chain reaction (PCR) techniques. Treatment is characterized by using multiple drugs for a long period of time to prevent resistance. Major antituberculous drugs used are isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin.

The aspirated material shows granulomas, plump histiocytes, and/or necrosis (Figs 6-4 & 6-5). Routine cytologic stains do not stain the actual bacilli; however, there may be significant clues that suggest their presence. Mycobacteria cannot be identified on Papanicolaou stain. While the Diff-Quik stain does not stain the individual organisms per se, it does outline them. The unstained bacilli appear as slender, straight or slightly curved, colorless rods highlighted against a dirty blue– grey background. Thus, the terms ‘negative images’ or ‘ghost bacilli’ are used as descriptors. This characteristic ‘negative image’ is presumably the result of hydrophobic interactions of the water-based Diff-Quik stain with the lipid within the cell walls of the bacilli (Fig. 6-6). The identification of these negative images within histiocytes and in the background is virtually pathognomonic for mycobacteria. Lowering the substage condenser often increases the refractivity of the bacilli and enhances their identification when they are scattered in the smear background. In FNA material from mediastinal lymph nodes, the presence of numerous organisms both within distended histiocytes and scattered in the background tends to be from atypical mycobacterial infections rather than from tuberculosis.

TUBERCULOSIS – PATHOLOGIC FEATURES TUBERCULOSIS – DISEASE FACT SHEET Definition ៉ Infectious disease caused by Mycobacterium tuberculosis Clinical Features ៉ Pathogenic non-tuberculous mycobacteria species (such as M. avium-intracellulare complex) produce similar clinical and radiologic findings; distinction made only by cultures or PCR ៉ In the US, certain populations are at increased risk: foreign-born individuals, HIV-positive individuals, nursing home residents, and prison inmates Radiologic Features ៉ More commonly involves the apical and posterior segments of

upper lobes ៉ Hazy infiltrates that progress to cavitation and fibrosis

Treatment ៉ Multiple antituberculous drugs over a long period of time

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Cytopathologic Findings ៉ Necrotizing granulomatous infl ammation ៉ Routine cytologic stains do not stain the bacilli ៉ ‘Negative images’ or ‘ghost bacilli’ can be seen on Diff-Quik

stain (unstained bacilli as colorless slender rods against a dirty-blue background) Ancillary Studies ៉ Acid-fast (Ziehl-Neelsen) or auramine rhodamine stains, or

culture are necessary for confirmation ៉ Material can be obtained for rapid detection of Mycobacterium

tuberculosis by PCR techniques Differential Diagnosis and Pitfalls ៉ Other conditions associated with granulomatous infl ammation (sarcoidosis, fungal infections, etc.) ៉ Clofazimine crystals within macrophages can mimic ‘negative images’ ៉ Nocardia species can appear as acid-fast, beaded filamentous organisms

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FIGURE 6-4 Tuberculosis. The FNA yields abundant necrosis and scattered granulomas, characteristic findings in any necrotizing granulomatous process. The inset shows a Ziehl-Neelsen stain performed on the cell block material that reveals scattered acid-fast bacilli. Diff-Quik stain, low power (inset: Ziehl-Neelsen stain, high power).

FIGURE 6-5 Tuberculosis. The granulomas in tuberculosis are loosely formed, with admixed necrosis and infl ammatory cells. Contrast this with the tight granulomas and clean background seen in sarcoidosis. Papanicolaou stain, high power.

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FIGURE 6-6 Atypical mycobacteria. The FNA yields a dirty-grey background in which the unstained bacilli appear as slender, straight or slightly curved colorless rods (‘negative images’). Ziehl-Neelsen stain performed on an alcohol-fixed slide confirms the presence of numerous acid-fast bacilli (inset). DiffQuik stain, low power (inset: Ziehl-Neelsen stain, high power).

Acid-fast stain (Ziehl-Neelsen) can be performed on smears, cytospins, and cell block sections and should be used for confirmation. The organisms appear as thin, slender, red beaded bacilli.

ANCILLARY STUDIES The diagnosis of tuberculosis is confirmed by identifying acid-fast bacilli in respiratory specimens or cultures. In many instances, when the patient is known to be immunocompromised or has had prior infections, the index of suspicion for infection is high and additional specimens are obtained for culture or fluorescence microscopy. PCR can now be used for rapid detection of M. tuberculosis.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Sarcoidosis, fungal infections, and reaction to an adjacent neoplasm (such as Hodgkin lymphoma, seminoma, T-cell lymphomas) also present with granulomatous

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inflammation with or without necrosis. The presence of M. tuberculosis or atypical mycobacteria should be suspected in every case of granulomatous inflammation, especially when the patient is immunosuppressed, and confirmed with acid-fast (Ziehl-Neelsen) or auramine rhodamine stains, cultures, or PCR. ‘Negative images’ are not specific. Patients treated with clofazimine show crystal formation within macrophages that mimic negative images. Nocardia species can appear beaded on acid-fast stain; however, they are slender fi laments, branching at acute angles, and are larger in diameter than mycobacteria.

FUNGAL INFECTIONS Pulmonary infections with dimorphic fungi (hyphae at room temperature and yeasts at body temperature) are increasing in importance as causes for opportunistic infections in immunocompromised patients, especially those with AIDS. The three dimorphic fungi discussed in this chapter are Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis. Other important fungi involved in pulmonary infections in

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immunocompromised individuals that will be discussed in this chapter are Cryptococcus neoformans, Aspergillus fumigatus, and fungi belonging to Zygomycetes class (Rhizopus, Absidia, and Mucor species).

HISTOPLASMOSIS CLINICAL FEATURES Histoplasmosis is produced by inhalation of microconidia of Histoplasma capsulatum or by reactivation of latent infection in individuals with past histoplasmosis who become immunosuppressed. H. capsulatum can be found throughout the world. In the United States, H. capsulatum is endemic in the Mississippi and Ohio river valleys. Bird and bat excrement enhance growth of the organism in the soil. In endemic areas, 50–80% of young adults are infected with H. capsulatum and are asymptomatic. After low-level exposure, less than 5% of individuals develop symptomatic disease. After high-level exposure (work or recreational activities in contaminated sites), more than 75% of individuals develop symptoms. There are several clinical manifestations of infection with H. capsulatum: acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis, granulomatous mediastinitis, disseminated histoplasmosis, and fibrosing mediastinitis.

HISTOPLASMOSIS – DISEASE FACT SHEET Definition ៉ Infection resulting from inhalation of Histoplasma capsulatum or

reactivation of latent infection Incidence and Geographic Distribution ៉ Annual incidence: 5/100,000 ៉ Endemic in Mississippi and Ohio river valleys

Clinical Features ៉ 50–80% of infected young adults are asymptomatic ៉ Several clinical manifestations: acute pulmonary histoplasmosis

(mimics flu); chronic histoplasmosis (mimics tuberculosis); granulomatous mediastinitis (less than 10% of patients); disseminated histoplasmosis and fibrosing mediastinitis

Acute histoplasmosis is characterized by flu-like symptoms (fever, chills, myalgia, headache, cough) and chest X-ray abnormalities. Chronic pulmonary histoplasmosis develops in patients with emphysema exposed to H. capsulatum. They present with cough, dyspnea, fatigue, fever, and sweats, mimicking tuberculosis. Granulomatous mediastinitis produces obstruction of mediastinal structures (airways, superior vena cava, pulmonary vessels, esophagus). The mediastinal lymph nodes are enlarged, forming cystic masses with central necrosis and surrounded by granulomatous inflammation and encased in a fibrous capsule. Disseminated histoplasmosis occurs in 1 in 2000 acute infections. It is rare in immunocompetent individuals and more common in immunosuppressed individuals (in particular, AIDS). The infection spreads to extrapulmonary sites (liver, spleen, bone marrow, skin, gastrointestinal tract, adrenal glands). Fibrosing mediastinitis is an excessive fibrotic response to past infection. This is a rare complication (less than 1 in 5000 infections); 80% of cases occur in individuals between the ages of 20 and 40 years. Antifungal therapy (triazole agents and liposomal formulations of amphotericin B) is indicated in patients with symptomatic acute pulmonary histoplasmosis, granulomatous mediastinitis, chronic pulmonary histoplasmosis, and in disseminated disease. Antifungal therapy is not indicated in acute, self-limited forms of pulmonary histoplasmosis or in fibrosing mediastinitis.

R ADIOLOGIC FEATURES Chest X-ray in symptomatic acute pulmonary histoplasmosis shows enlarged hilar and mediastinal lymph nodes with focal patchy or nodular pulmonary infi ltrates. In granulomatous mediastinitis, radiologic studies show enlarged, often cystic, mediastinal lymph nodes (measuring up to 10 cm). Chest X-ray in fibrosing mediastinitis shows subcarinal and mediastinal widening, but high-resolution chest CT with contrast is required to delineate the mediastinal abnormalities.

CYTOPATHOLOGIC FEATURES

Radiologic Features ៉ Acute form: hilar and mediastinal adenopathy with pulmonary

infiltrates ៉ Granulomatous mediastinitis: enlarged, cystic mediastinal lymph nodes ៉ Fibrosing mediastinitis: mediastinal widening Treatment ៉ Antifungal therapy in symptomatic patients ៉ Antifungal therapy not indicated for self-limited forms of acute

disease or for fibrosing mediastinitis

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Material can be obtained by FNA from enlarged mediastinal lymph nodes and cavitary lesions. H. capsulatum is one of the smallest dimorphic fungi (3 to 5 μm). It is predominantly intracellular, as foamy or vacuolated oval structures within the cytoplasm of histiocytes (Fig. 6-7). Yeast forms of H. capsulatum are easiest to identify when they are within macrophages; their engulfment results in a vacuolated or foamy cytoplasm with small halos surrounding each organism (due to retraction from the wall creating the appearance of a pseudocapsule). Macrophages with engulfed organisms

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ANCILLARY STUDIES PCR studies can be done in cases in which the morphology of the yeasts identified in tissue specimens is inconclusive. Detection of Histoplasma antigen in body fluids (blood, urine, bronchoalveolar lavage) allows a rapid diagnosis (24 to 48 hours) in patients with severe disease. Cultures are also useful, particularly in the disseminated form. The highest yield is from blood and bone marrow specimens.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

FIGURE 6-7 Histoplasmosis. The yeast forms of Histoplasma capsulatum appear as foamy or vacuolated oval structures within the cytoplasm of histiocytes. The small halos surrounding each organism are the result of wall retraction. This artifact can mimic the Cryptococcus neoformans capsule. Diff-Quik stain, high power.

GMS stain must be interpreted carefully, as other organisms (Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, Toxoplasma gondii, Leishmania species, Pneumocystis carinii) or staining artifacts can be misinterpreted as H. capsulatum. When the organism retracts from its wall, it creates a clear space that mimics the capsule of C. neoformans. If the differential diagnosis includes leishmaniasis, recognition of a nucleus and kinetoplast and the absence of budding will exclude H. capsulatum.

HISTOPLASMOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Histoplasma capsulatum is a small yeast (3 to 5 μm), with narrow-based budding ៉ Usually intracellular (engulfed by macrophages) ៉ Vacuolated cytoplasm with small halos surrounding the organism (appearance of pseudocapsule) ៉ On Papanicolaou stain, it is difficult to visualize ៉ On Diff-Quik stain: dark-purple organisms

BLASTOMYCOSIS CLINICAL FEATURES Blastomycosis is the result of inhalation of spores of Blastomyces dermatitidis. In the United States, the

Ancillary Studies ៉ Confirmatory stain: GMS ៉ PCR performed when morphology is inconclusive ៉ Histoplasma antigen detection and cultures in severe cases,

particularly in disseminated disease

BLASTOMYCOSIS – DISEASE FACT SHEET Definition ៉ Infection caused by inhalation of Blastomyces dermatitidis

Differential Diagnosis and Pitfalls ៉ Other organisms (Candida species, Cryptococcus neoformans,

Blastomyces dermatitidis, Toxoplasma gondii, Leishmania species, Pneumocystis carinii) ៉ Staining artifacts

Incidence and Geographic Distribution ៉ Annual incidence: 0.5/100,000 ៉ Endemic areas in the US are Central, South-central, and Southeastern ៉ Endemic area overlaps with that of histoplasmosis Clinical Features

are typically present in a background of granulomatous inflammation that can also include necrosis, acute inflammatory cells, and lymphocytes. Yeast forms of H. capsulatum demonstrate narrow-based (teardrop) budding. If present in small numbers, H. capsulatum can be very difficult to visualize on Papanicolaou stain. The Diff-Quik stain is useful because it stains these organisms a dark purple that is usually in stark contrast to the pale-staining cytoplasm. Confirmatory stain (GMS) should be performed when this organism is presumptively identified.

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៉ Primary infection in the lung with subsequent dissemination to

skin and bone Radiologic Features ៉ Variable: round densities, consolidations, mass-like infiltrates,

etc. Treatment ៉ Itraconazole (in sporadic cases) and amphotericin B (in severely

ill and immunosuppressed patients)

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endemic areas are Central, South-central, and Southeastern, with the highest incidence along the Mississippi and Ohio river valleys and the western shore of Lake Michigan. The endemic area overlaps with the endemic area for histoplasmosis. The annual incidence is roughly 0.5/100,000. Clinically, patients can be asymptomatic or can present with life-threatening pulmonary and disseminated disease. The majority of patients with sporadic pulmonary blastomycosis do well with itraconazole therapy, which is safe, highly effective, and non-toxic. Severely ill patients require amphotericin B therapy. Immunosuppressed patients (on prednisone or organ transplant recipients) require sequential therapy of amphotericin B until improved clinically, followed by 6–12 months of itraconazole. HIV-infected patients require a similar sequential therapy, but they are not permanently cured and lifelong therapy with itraconazole is necessary to maintain control.

multinucleated giant cells. The organisms will be found in this non-specific background. Only the yeast forms are identified in vivo. Yeast forms of B. dermatitidis are large (8–15 μm), spherical, and double-contoured. They have a rigid, refractile cell wall with a centrally retracted cytoplasm (Fig. 6-8). The yeast forms are generally larger than those of Cryptococcus neoformans. Because of their double-contoured rigid cell wall, they often appear slightly out of the plane of focus, making detection difficult on routine screening. Characteristically, they have a broad-based budding. Broad-based budding is a useful criterion to differentiate B. dermatitidis from the other dimorphic fungi. The yeast forms appear blue–green on Papanicolaou stain and blue on DiffQuik stain. Although most often identified extracellularly, these organisms can also be engulfed by macrophages. Special stain (GMS) can be performed to highlight the yeast forms. Cytomorphology is usually sufficient for diagnosis. This is the easiest and fastest way to make a diagnosis. Culture identification takes usually several weeks.

R ADIOLOGIC FEATURES Radiologic findings are variable and include single or multiple round densities scattered throughout, segmental/lobar consolidation, mass-like perihilar infi ltrates, and diffuse nodular, interstitial, or alveolar infi ltrates.

CYTOPATHOLOGIC FEATURES B. dermatitidis produces a granulomatous suppurative inflammatory reaction. FNA cytology aspirate shows acute suppurative inflammation, necrotic debris, and clusters of epithelioid histiocytes, macrophages, and

DIFFERENTIAL DIAGNOSIS AND PITFALLS B. dermatitidis yeasts can be confused with the immature spherules of Coccidioides immitis. The endospores of C. immitis are not visible in the immature spherules. This, combined with the thick wall of C. immitis, results in an erroneous identification as B. dermatitidis. Another potential problem is that the pathologist may overlook these yeast forms. Although larger, yeast forms of B. dermatitidis are very difficult to identify on cytologic preparations, chiefly because they are not numerous and are often out of the plane of focus. The latter problem is due to their rigid cell walls, which resist compression by a coverslip.

BLASTOMYCOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Blastomyces dermatitidis is a large yeast (8–15 μm), spherical, double-contoured with broad-based budding ៉ Has a rigid, refractile cell wall appearing slightly out of plane of focus ៉ Background shows acute suppurative infl ammation, necrosis, and macrophages ៉ Yeast forms can be extracellular or engulfed by macrophages ៉ In Papanicolaou stain, appears blue–green ៉ In Diff-Quik stain, appears blue Ancillary Studies ៉ GMS highlights the yeast forms ៉ Culture takes several weeks

Differential Diagnosis and Pitfalls ៉ Immature spherules of Coccidioides immitis ៉ Can be completely overlooked because is out of plane of focus

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COCCIDIOIDOMYCOSIS CLINICAL FEATURES Coccidioidomycosis is produced by inhalation of arthroconidia of Coccidioides immitis. This is a dimorphic fungus limited to the Western hemisphere, from California to Argentina. Endemic areas in the United States are Southwest desert regions (Arizona, California, Nevada, Utah, New Mexico, and Texas). Patients with impaired cell-mediated immunity (HIV infection, prolonged corticotherapy, organ transplant recipients, patients under chemotherapy, pregnant women) are most susceptible to C. immitis infection. Between 60% and 70% of individuals exposed to C. immitis are completely asymptomatic. The rest of patients develop signs and symptoms of primary pulmonary coccidioidomycosis. A small group of patients can

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FIGURE 6-8 Blastomycosis. Yeast forms of Blastomyces dermatitidis are spherical, double-contoured with a rigid, refractile wall. They appear blue on Diff-Quik stain. The inset shows several yeasts of B. dermatitidis engulfed by a macrophage. Note the broad-based budding. Diff-Quik stain, high power (inset: GMS stain, high power).

COCCIDIOIDOMYCOSIS – DISEASE FACT SHEET Definition ៉ Fungal disease caused by inhalation of Coccidioides immitis Distribution ៉ Endemic in Southwest desert regions ៉ Most susceptible are HIV-positive individuals, organ transplant

recipients, patients under chemotherapy or prolonged corticotherapy, and pregnant women Clinical Features

develop disseminated disease, with predilection for skin, bones, soft tissues, meninges, and disseminated pulmonary disease. The sequelae of pulmonary disease are nodules and cavities that are single, asymptomatic, less than 5 cm, and can persist for a long period of time. Cavities can be complicated by infection (bacteria from upper respiratory tract or Aspergillus species), hemoptysis or rupture into the pleural space with pyopneumothorax. The antifungal therapy (with amphotericin B and azoles) is reserved for immunocompromised patients with pulmonary or disseminated disease and for immunocompetent patients whose symptoms have persisted for more than 6 weeks.

៉ 60–70% of patients are asymptomatic

Radiologic Features ៉ Alveolar infiltrates that progress to cavities

Prognosis and Treatment ៉ Pulmonary sequelae: cavities that can get infected or rupture

within pleural space ៉ Antifungal therapy for immunocompromised individuals or

patients with prolonged symptoms

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R ADIOLOGIC FEATURES In primary pulmonary coccidioidomycosis, the chest X-ray shows segmental or lobar alveolar infi ltrates with occasional hilar and mediastinal adenopathy. The cavities are thin-walled, and, when infected, they will appear with air–fluid level, opacified, and surrounded by parenchymal infi ltration (Fig. 6-9).

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FIGURE 6-10 Coccidioidomycosis. The thick-walled spherules of Coccidioides immitis are identified engulfed by macrophages. They appear orangeophilic in Papanicolaou stain, being easy to identify. Papanicolaou stain, high power.

FIGURE 6-9 Cavitary lesion: radiologic findings. An isolated cavitary lesion with air–fluid level is seen in the left lower lobe. The differential diagnosis includes infectious process (abscess; tuberculosis; fungal infection, especially coccidioidomycosis, aspergillosis, and zygomycosis) versus malignant neoplasm (especially squamous cell carcinoma).

CYTOPATHOLOGIC FEATURES C. immitis is one of the largest of the dimorphic fungi. The organism can be identified extracellularly within a background of acute fibrinopurulent exudate and granulomatous inflammation or engulfed by macro-

COCCIDIOIDOMYCOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Coccidioides immitis is the largest of the dimorphic fungi ៉ Presents as endospores within thick-walled spherules; the

endospores are expelled and the empty spherule appears folded and fractured ៉ The spherules are extracellular or engulfed by macrophages Ancillary Studies

phages (Figs 6-10 & 6-11A). This organism presents as endospores within thick-walled spherules that can vary tremendously in size. Endospores are not visible in immature spherules; as the spherules mature, they will contain numerous small (2–5 μm) endospores. The endospores are expelled from the spherule, creating an acute inflammatory reaction. The now-empty spherule will appear fractured and folded (Fig. 6-11B). This organism occasionally stains orangeophilic by Papanicolaou stain, making it easy to detect (Fig. 6-11C). The spherules stain lightly or not at all with the Diff-Quik stain, although, with experience, this lack of staining is a useful clue. Periodic acid–Schiff (PAS) stain after diastase digestion with a light-green counterstain is a very useful confirmatory stain, since the spherules stain a vivid magenta against a pale-green background (Fig. 6-11D). Rarely, the cavities may be exposed to air, resulting in the development of mycelial forms with barrel-shaped arthroconidia (5% of cases).

ANCILLARY STUDIES Direct examination of respiratory specimens is negative in approximately 60% of patients with culturepositive pulmonary coccidioidomycosis. Fungal culture is a sensitive method of diagnosis. The organism grows rapidly (3 to 5 days), at 35ºC, on a variety of media. It should be remembered that in the culture C. immitis grows as a mold and is highly infectious.

៉ Fungal culture is sensitive (C. immitis in culture grows as a mold

and is highly infectious) Differential Diagnosis and Pitfalls Other fungi (Blastomyces dermatitidis, Histoplasma capsulatum) Pollen grains Inorganic contaminants Helpful clue: look for older, folded and fractured spherules

៉ ៉ ៉ ៉

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DIFFERENTIAL DIAGNOSIS AND PITFALLS C. immitis can resemble a variety of other fungi, pollen grains, and even inorganic contaminants. Endospores are not visible in immature spherules; combined with the thick wall of C. immitis, this often results in an

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A

B

C

D

FIGURE 6-11 Coccioidomycosis: FNA findings. A, The spherules of Coccidioides immitis are scattered in an acute fibrinopurulent background. They stain very light with Diff-Quik, and this lack of staining can be a useful clue. Diff-Quik stain, low power. B, After the endospores are expelled, the empty spherule of C. immitis appears fractured and folded. Diff-Quik stain, high power. C, A mature spherule of C. immitis containing numerous endospores is engulfed by a macrophage. Note the orangeophilic staining. Papanicolaou stain, high power. D, Three spherules of C. immitis are engulfed by a macrophage. They appear vivid magenta colored against a pale-green background. PAS stain after diastase digestion with light-green counterstain, high power.

erroneous identification as Blastomyces dermatitidis. Once the endospores are separated from the spherule, they may resemble Histoplasma capsulatum and even Toxoplasma gondii, and a careful search for older, folded and fractured spherules is necessary. Conversely, when these older spherules are seen without intact, mature spherules, they may be overlooked as inorganic contaminants.

CRYPTOCOCCOSIS – DISEASE FACT SHEET Definition ៉ Infection caused by inhalation of Cryptococcus neoformans

Incidence ៉ Most common fungal infection in immunosuppressed individuals ៉ Isolated pulmonary cryptococcosis is rare Clinical Features ៉ Affects brain, lung, skin, and bone

CRYPTOCOCCOSIS Radiologic Features ៉ Pulmonary infiltrates, mimicking neoplasm or other infections

CLINICAL FEATURES Treatment

Cryptococcosis is an infection caused by inhalation from the environment of Cryptococcus neoformans,

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៉ Amphotericin B with 5-fluorocytosine

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172 which is spread worldwide. The infection affects the brain, lung, skin, or bone, both in immunocompetent and in immunosuppressed patients. C. neoformans is the most common fungal infection complicating HIV infection. Meningitis is the most common form of disease. Isolated pulmonary cryptococcosis is very rare. The majority of patients clear the pulmonary infection but later develop meningitis, while 90% of patients with cryptococcal meningitis (excluding AIDS patients) have a clear chest X-ray and no history of pneumonia. Treatment of cryptococcal infection in immunosuppressed patients includes amphotericin B with 5-fluorocytosine; when clinical improvement is obtained, then the treatment is switched to fluconazole for life.

RADIOGRAPHIC FEATURES The chest radiographic fi lms show pulmonary infi ltrates, single or multiple, mimicking other pulmonary infections or neoplasms. Occasionally, patients can develop large, round masses up to 10 cm in diameter.

FINE NEEDLE ASPIRATION CYTOLOGY

CYTOPATHOLOGIC FEATURES C. neoformans is a round or oval encapsulated yeast (5 to 10 μm in diameter). The capsule measures from 1 to 30 μm in thickness and is made of polysaccharides. Due to its large capsule, C. neoformans resists phagocytosis. T-cell-mediated immunity with granuloma formation is necessary to stop the infection. In patients with impaired T-cell-mediated immunity (HIV-positive, organ transplant recipients), granuloma formation does not occur and the growth continues, producing large gelatinous masses of cryptococci with no tissue reaction. In FNA material, this organism is usually abundant, being found individually or as clusters of organisms with accentuated capsular halos (Fig. 6-12). In DiffQuik-stained preparations, the purple yeasts with accentuated clear halos against the deep-purple background give the smear a punched-out appearance (Fig. 6-13). A useful feature is the appearance of teardrop, narrowbased budding. At times, the daughter bud will not detach and repetition of budding yields small chains of daughter progeny. Occasionally, the yeast can be engulfed by histiocytes.

FIGURE 6-12 Cryptococcosis. In the FNA material, the organisms are abundant, single or in small clusters. The inset shows the characteristic ‘teardrop’, narrowbased budding. Diff-Quik stain, low power (inset: GMS stain, high power).

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based budding is a distinctive, helpful feature to identify C. neoformans.

ASPERGILLOSIS CLINICAL FEATURES

FIGURE 6-13 Cryptococcosis. The yeast forms of Cryptococcus neoformans have a large polysaccharide capsule. They appear as purple yeasts with accentuated clear halos giving the smear a punched-out appearance. Diff-Quik stain, high power.

CRYPTOCOCCOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cryptococcus neoformans is a round to oval yeast (5 to 10 μm) with a polysaccharide capsule ៉ Teardrop, narrow-based budding ៉ In Diff-Quik stain: purple yeasts with accentuated clear halos against a deep-purple background Ancillary Studies ៉ Special stains: GMS (stains the organism), PAS, mucicarmine,

Alcian blue (stain the capsule)

Aspergillosis refers to infection, through inhalation, with molds of the genus Aspergillus. The most common pathogen encountered in lung infections is A. fumigatus (which is the most pathogenic of all species). Pulmonary manifestations are numerous and include allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, asthma, aspergilloma, and invasive pulmonary aspergillosis. From all these manifestations, invasive pulmonary aspergillosis and aspergilloma present most commonly as a distinct mass on radiologic studies and can be sampled by FNA. Invasive pulmonary aspergillosis is a progressive and usually fatal disease (mortality rate is 80%). Immunosuppression predisposes to invasive pulmonary aspergillosis. Risk factors are prolonged neutropenia, corticosteroid therapy, advanced HIV infection, bone marrow and solid-organ transplant, and chronic granulomatous disease. The incidence of invasive aspergillosis is 0.7% in renal transplant recipients, 6.4% in bone marrow transplant recipients, 8.4% in lung transplant recipients, and 5–24% in patients with chemotherapyinduced neutropenia. Clinical manifestations of invasive aspergillosis are fever, non-productive cough,

Differential Diagnosis and Pitfalls ៉ Histoplasma capsulatum

Diagnosis of C. neoformans still rests primarily on its cytomorphology, with confirmation, as necessary, by special stains. Silver stains (GMS) stain the organism itself, while mucicarmine, PAS, and Alcian blue stain the mucopolysaccharide capsule.

ASPERGILLOSIS – DISEASE FACT SHEET Definition ៉ Infection caused by inhalation of molds of the genus Aspergillus Clinical Features ៉ Most common in lung infections is Aspergillus fumigatus ៉ Invasive pulmonary aspergillosis and aspergilloma present as

masses ៉ Risk factors for invasive aspergillosis (80% mortality rate):

ANCILLARY STUDIES The capsule is the target of serologic tests both in serum and in cerebrospinal fluid (CSF). The best single test for cryptococcal meningitis is the cryptococcal antigen assay.

DIFFERENTIAL DIAGNOSIS AND PITFALLS When the yeasts are engulfed by histiocytes, they can be mistaken for Histoplasma capsulatum. Narrow-

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neutropenia, HIV infection, bone marrow and solid organ transplant, chronic granulomatous disease, corticosteroid therapy ៉ Aspergilloma: hyphae of Aspergillus species growing within a pre-existing cavity Radiologic Features ៉ Invasive aspergillosis: non-specific lung infiltrate that rapidly progresses to a cavitary mass or infarct ៉ Aspergilloma: cavitary mass with fungus ball (moves with the position) Treatment ៉ Invasive aspergillosis: intravenous amphotericin B ៉ Aspergilloma: surgical excision

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174 dyspnea, and hemoptysis, which can be life-threatening (due to the ability of A. fumigatus to invade blood vessels). An aspergilloma consists of Aspergillus species hyphae growth within a pre-existing cavity that communicates with the bronchial tree. The etiology of such a cavity includes neoplasm, tuberculosis, healed abscess, cystic fibrosis, congenital cysts, and bullous emphysema. The standard therapy in invasive pulmonary aspergillosis is intravenous amphotericin. Resection of the localized consolidated mass has been performed with good results. Granulocyte–monocyte colony-stimulating factor may improve the outcome and should be considered in neutropenic patients. The treatment of choice for aspergilloma is surgical excision. In patients with compromised lung function, in whom surgical excision is not a viable solution, intracavitary instillation of amphotericin can be tried.

R ADIOLOGIC FEATURES In invasive pulmonary aspergillosis, the initial radiologic studies can appear normal or show a non-specific,

FINE NEEDLE ASPIRATION CYTOLOGY

vague lung infi ltrate. This infi ltrate will progress in the course of days to a classic wedge-shaped infarct or a consolidated mass with cavitation. Chest radiography in aspergilloma shows a cavitary mass, usually in the upper lobes. The fungus ball will move with the position (when standing and decubitus films are compared).

CYTOPATHOLOGIC FEATURES The FNA will show the organisms commonly present as tangled clusters of branched hyphae that are accompanied by acute inflammation, necrosis, and cellular debris. When a cytologic specimen contains hyphal structures that are relatively large (3–6 μm in diameter), septate, with regular, progressive dichotomous branching at 45-degree angles, Aspergillus species should be immediately suspected (Fig. 6-14). Aspergillus species stain fairly well by Papanicolaou and hematoxylin–eosin (H&E) stains, which clearly delineate the hyphal septations. The organisms also stain with Diff-Quik; however, many times the staining is extreme, i.e. either too dark to distinguish internal structure or too light such that the fungus blends into the dirty

FIGURE 6-14 Aspergillosis. The FNA material contains tangled clusters of branched hyphae, acute infl ammation, necrosis, and debris. The inset shows septate hyphae of Aspergillus species with characteristic progressive, dichotomous, 45-degree branching. Papanicolaou stain, low power (inset: Diff-Quik stain, high power).

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ASPERGILLOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Septate hyphae with regular, progressive, dichotomous

ZYGOMYCOSES CLINICAL FEATURES

branching at 45-degree angle ៉ Background shows abundant necrosis with reactive atypical

squamous cells ៉ When fungus cavity exposed to air: fruiting bodies with conidia ៉ Rosettes of needle-like calcium oxalate crystals Differential Diagnosis and Pitfalls ៉ The scattered atypical squamous cells within a necrotic

background can be interpreted as necrotic squamous cell carcinoma ៉ Clue: low cellularity should preclude a diagnosis of malignancy; look for septate hyphae ៉ Other fungi (Fusarium species, Pseudoallescheria boydii)

background. Septations are often colorless, creating a negative image that contrasts with the darkly stained hyphae. Occasionally, when the fungus cavity is exposed to air, fruiting bodies with conidia can be detected in cytologic specimens; their presence helps confirm the presence of Aspergillus species and can be used in further classification. Sheaves or rosettes of needle-like, birefringent crystals, representing calcium oxalate, may be identified.

Zygomycoses are an infrequent, often fatal, group of infections caused by fungal organisms from the class of Zygomycetes (Rhizopus, Absidia, and Mucor species). The most common pathogen is Rhizopus species. Pulmonary zygomycosis is most common in patients with hematologic malignancies (leukemia or lymphoma) with severe neutropenia. The incidence of zygomycosis in patients with hematologic malignancies is approximately 1%. Other risk factors are uncontrolled diabetic ketoacidosis, corticosteroid therapy, neutropenia, burns, HIV infection, and desferrioxamine therapy. Patients will present with fever and pulmonary infiltrates. The organism has a propensity for angioinvasion, with thrombosis and tissue infarction. This can lead to massive, life-threatening hemorrhage. The infection can extend to invade the chest wall, diaphragm, pericardium, etc. A definite diagnosis is made by histologic examination and cultures. A negative culture result does not exclude the possibility of infection, and the most important is direct histopathologic examination. Pulmonary zygomycosis in immunosuppressed patients is a progressive disease, usually fatal within a few days or weeks. Successful treatment requires a high index of suspicion, with diagnosis made early, and aggressive therapy with amphotericin B, surgical excision of infarcted tissues, and decrease of immunosuppression.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Since infection with Aspergillus species can cause a necrotizing pneumonitis, which presents radiologically as a cavitary lesion, the immediate concern is the possibility that this mass may represent a squamous cell carcinoma with central necrosis. Although malignant squamous cells do not resemble fungal hyphae, active infection by Aspergillus species can cause the surrounding lung parenchyma to become quite atypical. Severely reactive squamous cells may mimic carcinoma – this can result in a false positive diagnosis, with potentially serious consequences for the patient. Unlike most FNAs that attempt to sample the center of a mass in order to maximize recovery of material, FNAs of cavitary lesions are directed away from the presumed necrotic center in favor of the peripheral viable lesional tissue. In aspergillomas, this is precisely where viable fungus will be located. Recognition of these branched structures can still be difficult if necrotic debris and inflammation are also present. Even if close scrutiny reveals no organisms, in the absence of a positive diagnosis of carcinoma, silver stains are recommended to completely exclude the possibility of an infectious agent. A diagnosis of Aspergillus species is sometimes used as a wastebasket for all morphologically similar fungi, such as Fusarium species and Pseudoallescheria boydii.

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R ADIOLOGIC FEATURES Pulmonary zygomycosis presents on CT scan as a segmental or lobar consolidation with central cavitation.

ZYGOMYCOSIS – DISEASE FACT SHEET Clinical Features ៉ Most common pathogen in lung infections is Rhizopus species ៉ Risk factors: neutropenia, hematologic malignancies, burns, HIV infection, uncontrolled diabetic ketoacidosis, desferrioxamine therapy ៉ Propensity for angioinvasion with thrombosis, infarction, and hemorrhage Radiologic Features ៉ Segmental/lobar consolidation with cavitation

Prognosis and Treatment ៉ Progressive disease, fatal in a few days in immunosuppressed

patients ៉ Amphotericin B, excision of infarcted tissues, decrease of

immunosuppression

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CYTOPATHOLOGIC FEATURES Zygomycetes are characterized by their wide (3–25 μm), waxy, ribbon-like hyphae that branch irregularly and are pauci-septate. Side branches are short and at 90degree angle (Fig. 6-15). Usually associated with prominent acute inflammation and necrosis, these organisms can be overlooked on Diff-Quik stain and are best seen on Papanicolaou or H&E stains, while silver stains (GMS) may be used for confirmation.

ACTINOMYCOSIS CLINICAL FEATURES Actinomyces species are normal constituents of oral cavity flora. The most common is A. israelii, but several other species are seen in humans. There are three distinctive syndromes associated with A. israelii: cervicofacial, pulmonary and abdominal actinomycosis.

ZYGOMYCOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Zygomycetes class (Rhizopus, Absidia, and Mucor species) ៉ Wide (3–25 μm), waxy, ribbon-like, pauci-septate hyphae with 90-degree branching ៉ Side branches are short ៉ Background shows marked acute infl ammation and necrosis ៉ Can be overlooked on Diff-Quik stain ៉ Best seen on Papanicolaou stain

ACTINOMYCOSIS – DISEASE FACT SHEET Clinical Features ៉ Risk factors: dental caries and periodontal disease ៉ Actinomyces species are normal constituents of oral flora

Radiologic Features ៉ Dense, nodular infiltrates (mimic lung cancer)

Treatment Ancillary Studies ៉ GMS used for confirmation

៉ Penicillin for long period of time ៉ Surgery to drain the abscess

FIGURE 6-15 Zygomycosis. The Zygomycetes are wide, waxy, ribbon-like hyphae embedded within a prominent acute fibrinopurulent exudate. The inset shows the pauci-septate hyphae with 90-degree branching. Papanicolaou stain, low power (inset: Papanicolaou stain, high power).

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Pulmonary actinomycosis occurs after aspiration of infective material. Individuals with dental caries or periodontal disease are predisposed to pulmonary actinomycosis. The incidence is not precisely known; the disease is uncommon, but not rare. Diagnosis is established by transbronchial biopsy, open lung biopsy, or radiologyguided FNA of the nodular cavities. Evaluation of the upper respiratory specimens or samples obtained by bronchoscopy is of limited value because they may be contaminated by upper respiratory flora, which normally contains Actinomyces species. The treatment of choice for actinomycosis is penicillin, given for a long period of time (6 to 12 months). Shorter treatment is associated with relapses. Surgery is necessary to drain abscesses. If the disease is recognized early and treated appropriately, the prognosis is very good.

RADIOGRAPHIC FEATURES Chest radiograph fi lms show a dense, nodular infiltrate that mimics lung cancer. Half of the patients can have also nodular cavities.

CYTOPATHOLOGIC FEATURES Actinomyces species are Gram-positive bacteria, nonacid-fast, non-motile, strict or facultative anaerobes. In tissues, they grow in microcolonies that appear as yellow granules in the drainage from actinomycotic lesions. They are called sulfur granules because of the yellow color, but their content in sulfur is actually low. In cytology specimens, the organisms present as

ACTINOMYCOSIS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Gram-positive bacteria, non-acid-fast, non-motile, strict or

facultative anaerobes ៉ Fragments of slender, delicate, beaded filaments with acute-

angle branching ៉ Background shows suppurative infl ammation

Ancillary Studies ៉ Special stains: Gram, PAS, GMS ៉ Modified acid-fast (Fite’s) stain is negative

Differential Diagnosis and Pitfalls ៉ Nocardia species (but Nocardia is acid-fast with Fite’s stain)

fragments and tangles of slender, delicate, beaded fi laments with acute-angle branching, usually in a background of suppurative inflammation (Fig. 6-16). The equivalent of sulfur granules is accumulations of these organisms with a very dark granular center with peripherally radiating fi laments. Splendore-Hoeppli reaction consists of elongated, club-like structures radiating centrifugally from a dense band at the periphery of the granules. Necrosis and abscess formation may also accompany these infections.

DIFFERENTIAL DIAGNOSIS AND PITFALLS A bacteria morphologically similar to Actinomyces species is Nocardia species; however, Actinomyces

FIGURE 6-16 Actinomycosis. The FNA shows clusters of delicate, slender filamentous organisms. Papanicolaou stain, low power.

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species organisms are slightly larger (1–1.5 μm in diameter, 20–70 μm in length) than Nocardia species and branch at acute angles. Most cytologic and histologic stains, including silver stains, can be used to identify Actinomyces species; however, unlike Nocardia species, Actinomyces species are not acid-fast when stained with a modified acid-fast (Fite’s) stain. Other useful ‘special stains’ include PAS and a modified Gram stain.

BENIGN NEOPLASMS HAMARTOMA CLINICAL FEATURES Patients are usually asymptomatic and the condition is discovered incidentally on radiologic images. The common type is usually in the periphery of the lung. In the rare endobronchial variant, the patients present with symptoms of airway obstruction, such as cough and dyspnea. There is a wide age range, with the peak age of incidence in the sixth decade. It is relatively rare in children.

R ADIOLOGIC FEATURES Hamartoma appears as a well-circumscribed, discrete (‘coin’) lesion (Fig. 6-17). The characteristic ‘popcorn’ calcification can be detected in about 15–30% of cases on plain radiographs.

PULMONARY HAMARTOMA – DISEASE FACT SHEET Incidence ៉ Uncommon, benign ៉ Peak age of incidence is the 6th decade Clinical Features ៉ Usually asymptomatic and discovered incidentally ៉ Rarely presents with symptoms of airway obstruction

Radiologic Features ៉ Well-circumscribed ‘coin’ lesion ៉ May have ‘popcorn’ calcifications

Treatment ៉ Surgical excision

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FIGURE 6-17 Hamartoma: radiologic findings. A well-circumscribed, discrete, ‘coin’ lesion is present in the right upper lobe. This is usually an incidental finding. This presentation is characteristic for benign pulmonary neoplasms such as hamartoma, clear cell (sugar) tumor, granular cell tumor, and sclerosing hemangioma.

CYTOPATHOLOGIC FEATURES Pulmonary hamartoma is a tumor-like malformation composed of both an epithelial and a mesenchymal component. There is usually a mixture of cartilage, adipose tissue and some cellular fibrous tissue (mesenchymal component), and a non-specific epithelial component (usually entrapped lung epithelium) (Fig. 6-18). The cartilage may be predominant with a chondroid matrix and recognizable chondrocytes. When the epithelial component predominates, a diagnosis of malignancy may be considered (Fig. 6-19). Careful search for the mesenchymal component resolves the dilemma. The aspirate smears have variable cellularity, with metachromatic chondromyxoid stroma on Diff-Quik stain and fibrillar-myxoid connective tissue with bland, oval, or spindle nuclei embedded within the stroma, similar to benign mixed tumors of the salivary gland. This matrix may be the only indication of a cartilage component of the tumor. The chondromyxoid matrix is less characteristic on Papanicolaou stain and may stain a pale blue, making it difficult to distinguish it from other extracellular elements (Fig. 6-20). In any case, the presence of adipose tissue and cartilage in a lung aspirate should alert one to the possibility of pulmonary hamartoma.

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FIGURE 6-18 Hamartoma. The FNA yields a mixture of fibrillary metachromatic chondromyxoid stroma and adipose tissue. Diff-Quik stain, low power.

FIGURE 6-19 Hamartoma: FNA findings. The epithelial component of a hamartoma consists usually of fl at, honeycomb groups of cytologically bland cells. These cells can be confused with mesothelial cells or with a malignant process, such as bronchioloalveolar carcinoma. Diff-Quik stain, medium power.

FIGURE 6-20 Hamartoma. The mesenchymal component with bland, spindle-shaped nuclei appears very pale with Papanicolaou stain and can be overlooked. Papanicolaou stain, high power.

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PULMONARY HAMARTOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity with epithelial and mesenchymal

CLEAR CELL (SUGAR) TUMOR – DISEASE FACT SHEET Definition ៉ Benign tumor of uncertain origin

components ៉ Metachromatic chondromyxoid stroma with embedded bland,

Gender and Age Distribution

oval or spindle nuclei (best seen on Diff-Quik stain) ៉ Occasionally adipose tissue

៉ Equal incidence in males and females ៉ Wide age range, mean age is 49 years

Differential Diagnosis and Pitfalls

Clinical Features

៉ Carcinoid tumor, bronchioloalveolar carcinoma, small cell

៉ Usually asymptomatic, discovered incidentally

carcinoma ៉ Predominance of epithelial cells may lead to a diagnosis of

carcinoma; careful search for the mesenchymal component is necessary

Radiologic Features ៉ Well-circumscribed ‘coin’ lesion

Treatment ៉ Surgical excision

DIFFERENTIAL DIAGNOSIS AND PITFALLS Evaluation of the accuracy of FNA biopsy of pulmonary hamartoma by the College of American Pathologists (CAP) revealed that FNA has a specificity of 78% with a false positive rate of 22%. The usual false positive diagnoses are carcinoid tumor, adenocarcinoma, and small cell carcinoma. Contributing factors to erroneous diagnoses are the fact that the cartilaginous and the fibromyxoid components may not be easily identified in Papanicolaou-stained preparations and the fact that the reactive bronchial cells (the epithelial component) may look worrisome with large nuclei, prominent nucleoli, intranuclear invaginations, and multinucleation. Careful search for the mesenchymal component helps avoiding diagnostic pitfalls.

CYTOPATHOLOGIC FEATURES The aspirate is cellular, composed of small irregular clusters or individual, single, polygonal and spindleshaped cells. The neoplastic cells are cytologically bland. They have abundant clear cytoplasm with ill-defined borders. The cytoplasm can be occasionally vacuolated or granular. The tumor cells are easily stripped of their abundant vacuolated (glycogen-rich) cytoplasm, resulting in a very granular, foamy background. The nuclei show minimal pleomorphism, with fine, evenly distributed chromatin and inconspicuous nucleoli. The nuclei are round–oval or may be only slightly indented, resembling histiocytes. Naked (stripped) nuclei are usually present in the background, as the cells lose their cytoplasm during smearing (Fig. 6-21). Mitoses and necrosis are usually absent.

CLEAR CELL (SUGAR) TUMOR CLINICAL FEATURES This is a rare benign tumor of uncertain nature, which is usually asymptomatic and found incidentally. There is an equal occurrence in males and females. There is a wide age range, from 8 to 73 years, with a mean age of 49 years. The tumor is usually in the lung periphery, and circumscribed but not encapsulated. There is usually no obvious connection with major airways, blood vessels, or pleura.

CLEAR CELL (SUGAR) TUMOR – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable cellularity with large irregular clusters of polygonal and spindle-shaped bland cells ៉ Cytoplasm is usually clear with indistinct cell borders; may be vacuolated or granular ៉ Bland round, oval, or spindle-shaped nuclei ៉ Naked nuclei in the background Ancillary Studies ៉ Positive for HMB-45 and PAS

R ADIOLOGIC FEATURES The tumor presents as a circumscribed, ‘coin’ lesion.

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Differential Diagnosis and Pitfalls Metastatic renal cell carcinoma Carcinoid tumor, clear cell variant Granular cell tumor Metastatic clear cell sarcoma

៉ ៉ ៉ ៉

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FIGURE 6-21 Clear cell (sugar) tumor. The FNA yields groups of bland-appearing cells with round–oval nuclei with finely distributed chromatin. The cytoplasm is fine, with indistinct cell borders, and is frequently detached from the nucleus during slide preparation. Note naked, stripped nuclei in the background. Diff-Quik stain, high power.

ANCILLARY STUDIES Immunohistochemical studies are usually necessary to confirm the diagnosis. Although the histogenesis of the ‘sugar’ tumor is still unclear, the tumor cells are positive for HMB-45 (similar to angiomyolipoma and lymphangioleiomyomatosis), leading to the speculation that they may have the same histogenesis. The clear cells are positive for PAS (due to glycogen content). Clear cell tumor is negative for epithelial markers.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Differential diagnosis includes metastatic renal cell carcinoma, clear cell variant of carcinoid tumor, granular cell tumor, and metastatic clear cell sarcoma. It may be extremely difficult to differentiate these entities by cytomorphology alone. Ancillary studies are often needed to reach the correct diagnosis. Clear (‘sugar’) cell tumor of lung and metastatic renal cell carcinoma are both positive for PAS, but renal cell carcinoma is positive for epithelial markers and negative for HMB45, while clear (‘sugar’) cell tumor has the opposite staining pattern. Granular cell tumor is distinguished by S-100 protein reactivity and negative results with PAS. Clear cell variant of carcinoid is negative for HMB-45 and positive for neuroendocrine markers (synaptophysin, chromogranin).

squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, and pleomorphic carcinoma. From a practical point of view, based on specific cytologic criteria, lung carcinoma can be divided in two main categories: small cell (20% of lung cancer cases) and non-small cell carcinoma (NSCLC) (80%). This distinction has clinical and prognostic significance. There is no age difference between the patients with small cell carcinoma and those with NSCLC. The average age at presentation is 66 years, but there is a wide age distribution, ranging from younger than 40 years to older than 80 years. Small cell carcinoma is a rapidly growing and widely metastatic tumor that is treated primarily with chemotherapy. NSCLC is treated with surgery, radiotherapy, and chemotherapy, depending on clinical stage.

SQUAMOUS CELL CARCINOMA CLINICAL FEATURES Squamous cell carcinoma is the most common histologic type of lung cancer, with an incidence of 35%. It is the most common type of lung cancer in smokers.

SQUAMOUS CELL CARCINOMA – DISEASE FACT SHEET Incidence ៉ Most common histologic type of lung cancer (35% of all cases) ៉ Most common histologic type in smokers

PRIMARY MALIGNANT TUMORS

Radiologic Features ៉ Presents commonly as a central, cavitary, submucosal lesion

Lung cancer is the leading type of cancer worldwide and is the leading cause of mortality from cancer in both men and women. According to the World Health Organization’s international histologic classification, there are five major histologic types of lung cancers:

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Prognosis and Treatment ៉ Dependent on stage ៉ Surgery, radiotherapy, and chemotherapy

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R ADIOLOGIC FEATURES Squamous cell carcinoma usually presents as a central, cavitary, submucosal lesion (two-thirds of cases). Rarely, it can present as a peripheral lesion (one-third).

CYTOPATHOLOGIC FEATURES Squamous cell carcinoma is a malignant neoplasm that, by definition, has features of squamous differentiation. In cytology, squamous differentiation translates as keratin pearls, twisted keratin strands (Herxheimer spirals), partial or complete cytoplasmic rings, and bizarre-shaped cells with bright orangeophilic cytoplasm on Papanicolaou stain. In well-differentiated neoplasms, all or almost all of these features can be seen, while in poorly differentiated cases, they can be completely absent. Such cases can be diagnosed as poorly differentiated non-small cell carcinomas. KERATINIZING (WELL- DIFFERENTIATED) SQUAMOUS CELL C ARCINOMA

FNA of a well-differentiated squamous cell carcinoma usually yields a cellular aspirate characterized by cohesive sheets, aggregates, or single malignant cells with evidence of keratinization (Fig. 6-22). There is usually little nuclear overlapping. The neoplastic cells can have bizarre shapes (fiber, strap, tadpole cells) (Fig. 6-23). They have variable amounts of dense, waxy, ‘hard’ cytoplasm with clearly defined cytoplasmic borders. The N/C ratios range from low to high. The nuclei are pleomorphic, hyperchromatic, with irregular

FINE NEEDLE ASPIRATION CYTOLOGY

KERATINIZING (WELL-DIFFERENTIATED) SQUAMOUS CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cohesive sheets and single cells with evidence of keratinization ៉ N/C ratios range from low to high ៉ Dense, waxy, ‘hard’ orangeophilic cytoplasm with clearly defined borders ៉ Cells with bizarre forms: fiber, strap, tadpole ៉ Nuclei hyperchromatic with inconspicuous nucleoli or pyknotic (ink dot-like) ៉ Background: necrosis, debris, and ghost cells Differential Diagnosis and Pitfalls ៉ Pulmonary infarct, pneumonia, mycetoma ៉ Metastatic urothelial carcinoma ៉ Metastatic squamous cell carcinoma from other sites (in

particular, head and neck areas)

nuclear contours, obscured chromatin details, and often inconspicuous nucleoli. The nuclei can undergo degeneration and become pyknotic (ink dot-like). Frequently, squamous cell carcinoma undergoes central necrosis and cavitation; hence, the background can show necrosis and debris, ghost cells, multinucleated cells, and inflammation. NON-KERATINIZING (MODERATELY TO POORLY DIFFERENTIATED) SQUAMOUS CELL C ARCINOMA

FNA of a non-keratinizing, moderately to poorly differentiated squamous cell carcinoma also yields a cellular specimen with abundant single, discohesive cells or syncytial groups with no cytologic evidence of keratinization (Fig. 6-24). The neoplastic cells are usually

FIGURE 6-22 Well-differentiated (keratinizing) squamous cell carcinoma. The FNA yields a cellular material with malignant squamous cells with dark, hyperchromatic, irregular nuclei and variable amounts of dense, bright orangeophilic or cyanophilic cytoplasm. Note the background containing ghost cells and pyknotic, degenerating nuclei. Papanicolaou stain, medium power.

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FIGURE 6-23 Well-differentiated (keratinizing) squamous cell carcinoma. The malignant squamous cells can have bizarre shapes (strap cells). Note the dense eosinophilic cytoplasm. Papanicolaou stain, high power.

NON-KERATINIZING (MODERATELY TO POORLY DIFFERENTIATED) SQUAMOUS CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Single, discohesive groups of cells with no or very little

evidence of keratinization ៉ High N/C ratio ៉ Hyperchromatic nuclei with visible nucleoli ៉ Scant to moderate, often vacuolated, cytoplasm

Differential Diagnosis and Pitfalls ៉ Adenocarcinoma ៉ Large cell carcinoma

FIGURE 6-24 Poorly differentiated (non-keratinizing) squamous cell carcinoma. The FNA shows syncytial groups of cells with a moderate amount of cyanophilic cytoplasm. The nuclei are hyperchromatic and pleomorphic, with small nucleoli. Papanicolaou stain, high power.

smaller, with high N/C ratios, moderate to scant cyanophilic cytoplasm, and irregular, pleomorphic nuclei with irregular, granular chromatin and visible, prominent nucleoli (Fig. 6-25) (in contrast to a well-differentiated squamous cell carcinoma, which has dense nuclear chromatin, inconspicuous nucleoli or pyknotic nuclei). Since the cytologic features of keratinization are absent in these cases, it is difficult to distinguish them from

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adenocarcinoma. More, squamous cell carcinoma may have a finely vacuolated cytoplasm. This feature combined with prominent nucleoli may lead to confusion with adenocarcinoma. From a practical standpoint, this distinction is not of critical importance because these cases can be classified as moderately to poorly differentiated non-small cell carcinomas.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Well-differentiated squamous cell carcinoma needs to be differentiated primarily from: 1) reactive, inflammatory and infectious processes; 2) metastatic low-grade urothelial carcinoma; and 3) metastatic squamous cell

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FIGURE 6-25 Poorly differentiated (nonkeratinizing) squamous cell carcinoma. In this aspirate, the cells have high N/C ratios, with scant, hard cytoplasm and large, hyperchromatic nuclei with prominent nucleoli. The presence of nucleoli may suggest the diagnosis of adenocarcinoma. Such cases can be diagnosed generically as non-small cell carcinoma. Diff-Quik stain, high power.

carcinoma from other sites, particularly head and neck primary. Because of central necrosis and cavitation, a welldifferentiated squamous cell carcinoma can be confused with reactive, inflammatory and infectious processes associated with necrosis, such as granulomatous inflammation (fungal [mycetoma], rheumatoid arthritis), pneumonia, and pulmonary infarct. Several generalities can be made concerning these benign conditions: 1) fewer cells are present when compared to carcinoma; 2) the nuclear details are not so distinct or, if so, they are combined with a relatively normal N/C ratio; and 3) degeneration is often greater in these conditions than in carcinomas. Other helpful features are subtle palisading in granulomatous inflammation and identification of hyphae. A good rule of thumb is to avoid making a diagnosis of malignancy in cases with few, degenerated and poorly visualized cells. Pulmonary infarct with subsequent repair atypia can be a source of false positive diagnoses. Pulmonary infarct may be asymptomatic. It can mimic a lung neoplasm radiographically. The FNA material shows twodimensional sheets of metaplastic squamous cells and numerous hemosiderin-laden macrophages. The metaplastic squamous cells show features of regeneration and atypia characterized by enlarged nuclei with pale, vesicular chromatin and a prominent chromocenter or small nucleolus. The presence of atypical squamous cells on aspiration smears may result in overdiagnosis, unless the

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cytologic features are correlated with clinical and radiologic findings. Many of these specimens will have limited numbers of cells to evaluate. However, cellularity and cell debris may vary greatly, depending upon the age of the infarction. Recent infarctions may show only hemosiderophages and necrotic cellular debris, a potential source of diagnostic error if confused with a tumor diathesis. A diagnosis of malignancy in a low cellularity specimen should be made with extreme caution. Rarely, metastatic urothelial carcinoma may mimic squamous cell carcinoma, particularly the low-grade urothelial neoplasms. In FNA specimens, metastatic urothelial carcinoma tends to occur as flat sheets with accompanying individual cells that look as if they have been pulled from these sheets. These single cells and the cells at the periphery of the fragments have elongated unipolar cytoplasmic processes with bland hyperchromatic nuclei at the apical cytoplasmic pole. These cells have been termed cercariform cells because of their resemblance to parasitic cercariform larvae. Primary lung keratinizing squamous cell carcinoma is morphologically similar to primary head and neck squamous cell carcinoma metastatic to the lung. Comparison with previous histologic or cytologic material, clinical presentation, and radiologic findings are necessary in such cases. Moderately to poorly differentiated squamous cell carcinoma may be difficult to distinguish from poorly differentiated adenocarcinoma and, to a lesser extent, large cell carcinoma.

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ADENOCARCINOMA CLINICAL FEATURES This is the most common type of lung cancer in women and non-smokers. Most adenocarcinomas arise at the periphery of the lungs. Central adenocarcinomas, though uncommon, may be seen. Many peripheral tumors reach a substantial size and may actually metastasize before they cause any symptoms, because major airways are not affected.

CYTOPATHOLOGIC FEATURES Adenocarcinoma is a malignant neoplasm with glandular differentiation. In cytology, this translates as cellular smears with cohesive clusters of cells and acinar groups. The cell clusters are tridimensional and exhibit depth of focus. There is an increased N/C ratio. The neoplastic cells have round to oval, enlarged nuclei with irregular nuclear membranes, granular chromatin (finely or coarsely distributed), and prominent nucleoli (which can be multiple). The cytoplasm is scant to

R ADIOLOGIC FEATURES Adenocarcinoma usually presents as a discrete lung mass of variable sizes with infiltrative edges (Fig. 6-26).

ADENOCARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cohesive sheets or clusters of cells with depth of focus (three-

dimensional) ៉ Columnar, cuboidal, or polygonal cells with scant/moderate

ADENOCARCINOMA – DISEASE FACT SHEET Incidence ៉ Most common lung carcinoma in females and non-smokers

Radiologic Features ៉ Discrete lung mass with infiltrative edges

Prognosis and Treatment ៉ Prognosis depends on the stage of the tumor ៉ Resection and/or chemotherapy

cytoplasm with vacuolization ៉ Enlarged nuclei with prominent nucleoli ៉ Mitoses and necrosis may be present

Ancillary Studies ៉ Positive for CK, EMA, CEA, CD15, CK7, and TTF-1; negative for

CK20 Differential Diagnosis and Pitfalls ៉ Metastatic adenocarcinoma (breast, stomach, colon, pancreas,

gynecologic tract, etc.)

FIGURE 6-26 Adenocarcinoma: radiologic findings. There is an infiltrative mass with indistinct edges in the right lower lobe. Surgical follow-up showed this mass to be an adenocarcinoma.

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A

B

FIGURE 6-27 Adenocarcinoma. A, The FNA yields a cellular aspirate with tridimensional clusters of malignant cells with scant cytoplasm and large, hyperchromatic nuclei with prominent nucleoli. B, Abundant tumor cell necrosis can be seen. Papanicolaou stain, high power.

moderate with coarse to fine vacuolization; occasionally, it may be clear. Mitoses and necrosis may also be seen (Figs 6-27 & 6-28).

ANCILLARY STUDIES Immunohistochemical studies are necessary to distinguish primary lung adenocarcinoma from metastatic adenocarcinoma. In addition to being positive for cytokeratin markers, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), and CD15, primary adenocarcinoma of the lung is usually positive for cytokeratin 7 (CK7) and thyroid transcription factor-1 (TTF-1), and negative for cytokeratin 20 (CK20).

DIFFERENTIAL DIAGNOSIS AND PITFALLS Primary lung adenocarcinomas need to be differentiated from adenocarcinomas from other sites that have metastasized to the lung, i.e. breast, gastro intestinal tract (stomach, colon), pancreato-biliary tract, gynecologic tract, etc. If there is a history of a previous neoplasm, comparing the current specimen with previous material may help in determining whether the lung mass is primary or metastatic. In addition, immunohistochemical stains can be performed on cell block material or alcohol-fi xed slides.

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FIGURE 6-28 Adenocarcinoma. In this aspirate, note the hyperchromatic nuclei with irregularly distributed, coarse nuclear chromatin and visible nucleoli. There is marked nuclear pleomorphism. The cytoplasm is almost absent and the nuclei are crowded together. Compare with normal bronchial cells in the upper left. This case can be diagnosed generically as nonsmall cell carcinoma. Attention to nuclear details helps in distinguishing non-small cell carcinoma from small cell carcinoma at the time of preliminary interpretation in the radiology suite. Diff-Quik stain, medium power.

BRONCHIOLOALVEOLAR CARCINOMA (BAC) This is an uncommon variant of adenocarcinoma (about 2% of all lung malignancies), which, by definition, has a pure bronchioloalveolar growth pattern

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BRONCHIOLOALVEOLAR CARCINOMA – DISEASE FACT SHEET Incidence ៉ Uncommon; approximately 2% of all lung malignancies

Radiologic Features ៉ Discrete nodule, multiple nodules, or pneumonic infiltrate

Prognosis and Treatment ៉ Better prognosis than bronchogenic adenocarcinoma ៉ Non-mucinous variant has better prognosis that mucinous variant ៉ Treatment: surgical (if discrete nodule), chemotherapy (if multiple nodules, pneumonic infiltrate)

BRONCHIOLOALVEOLAR CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Non-mucinous and mucinous variants ៉ Highly cellular aspirate with bland cuboidal to columnar neoplastic cells in papillary clusters or fl at sheets ៉ Nuclear pseudoinclusions and psammoma bodies ៉ Abundant intracellular/extracellular mucin (in the mucinous variant) Histopathologic Findings ៉ Tumor cells grow along the alveolar septa, with no stromal,

vascular, or pleural invasion Differential Diagnosis and Pitfalls ៉ Reactive pneumocytes, mesothelial cells, or bronchial cells ៉ Clues: high cellularity, lack of terminal bars and/or cilia

with no evidence of stromal, vascular, or pleural invasion. BAC presents radiologically as a single nodule, multiple nodules, or as a diffuse ‘pneumonic’ infi ltrate.

CYTOPATHOLOGIC FEATURES BAC can have either a mucinous or non-mucinous appearance. The non-mucinous type is more common and may be difficult to differentiate from bronchogenic adenocarcinoma. Aspirate smears are highly cellular and composed of bland neoplastic cells (cuboidal or columnar), usually in clusters. No terminal bars or cilia are identified on these cells. Since BAC’s predominant pattern of growth is along the alveolar septa, the FNA

material will result in flat sheets, acinar arrays, and/or papillary fragments with depth of focus. The neoplastic cells may resemble alveolar pneumocytes, mesothelial cells, or even bronchial cells (Fig. 6-29). The nuclei are usually enlarged and there is an increase in N/C ratio, and the nuclear membrane may be slightly irregular (Fig. 6-30). Nuclear pseudoinclusions and psammoma bodies may be seen. The mucinous variant of BAC consists of bland columnar cells with basally oriented nuclei and abundant apical cytoplasmic mucin (Fig. 6-31). Mucinous BAC is often multicentric and usually has a worse prognosis than the non-mucinous variant.

FIGURE 6-29 Bronchioloalveolar carcinoma. The FNA yields a highly cellular aspirate with fl at groups of cytologically bland cells. These cells can be confused with alveolar pneumocytes or mesothelial cells. The high cellularity is a very helpful clue for a malignant diagnosis. Avoid making a diagnosis of malignancy from specimens with scant cellularity. Papanicolaou stain, medium power.

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FIGURE 6-30 Bronchioloalveolar carcinoma. Careful evaluation of the nuclei identifies slight nuclear variability and irregular nuclear contours with occasional nuclear grooves. Note also slight depth of focus of this group of malignant cells. Papanicolaou stain, high power.

FIGURE 6-31 Bronchioloalveolar carcinoma. In the mucinous variant of bronchioloalveolar carcinoma, the neoplastic cells have moderate to abundant, vacuolated, mucinous cytoplasm. Extracellular mucin can be present in the background. The nuclei are round–oval and uniform. Diff-Quik stain, high power.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS The chief mimics of BAC are reactive pneumocytes, mesothelial cells, and bronchial cells. Carcinoma should never be diagnosed in aspirate materials with atypical cells that have terminal bars and/or cilia. A very important clue to the right diagnosis is high cellularity, with neoplastic cells arranged in flat sheets and/or papillary fragments. Supportive clinical and radiologic findings are usually necessary for a definitive diagnosis of BAC.

SMALL CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Highly cellular aspirate ៉ High N/C ratio, very little cytoplasm, and large hyperchromatic nuclei with finely granular chromatin and inconspicuous nucleoli ៉ Spectrum of viability ៉ Nuclear molding, crush artifact ៉ Individual cell necrosis and tumor diathesis Ancillary Studies ៉ pan-CK, EMA, CK7, TTF-1 (positive in 90% cases);

neuroendocrine markers (positive in 50% of cases); CK20 (negative)

SMALL CELL CARCINOMA CYTOPATHOLOGIC FEATURES The aspirate smear is very cellular, composed of viable and degenerating cells dispersed singly or in loose clusters. These tumor cells are very fragile and as such are often encountered as single cells or stripped hyperchromatic nuclei. The cells have an increased N/C ratio with large, round to oval, hyperchromatic nuclei and very scant cytoplasm (Fig. 6-32). The nuclear chromatin is hyperchromatic and finely granular, and nucleoli are inconspicuous. Nuclear molding, crush artifact, and mitotic figures are commonly seen (Fig. 6-33). While in effusion specimens the malignant cells are small, 1–1.5 times the size of a lymphocyte, in FNA material they may be up to three times the size of a lymphocyte. This rather dramatic size difference is attributed to the sampling of viable tumor without degeneration or necrosis. Nuclear detail, including the presence of small distinct nucleoli, is easier to visualize in these larger cells. While tumor cells will be round with slight nuclear irregularities in the majority of cases, occasionally the cells will be small and oval or spindleshaped, hence the term ‘oat’ cell carcinoma.

Differential Diagnosis and Pitfalls ៉ Carcinoid tumor ៉ Lymphoma ៉ Poorly-differentiated non-small cell carcinoma

In addition, small cell carcinoma shows a spectrum of viability that is very characteristic: viable cells with intact chromatin, smaller more degenerated cells, pyknotic nuclei and ghost nuclei (individual cell necrosis). The process of smearing aspirated material often shears the scant, delicate cytoplasm from the tumor cells. This, combined with cell necrosis, creates a very granular background often with tingible-body macrophages. This particular background helps to exclude carcinoid from the differential diagnosis.

SMALL CELL CARCINOMA – DISEASE FACT SHEET Incidence and Distribution ៉ 20% of lung carcinomas ៉ Adult smokers; median age of 66 years ៉ More common in men

Radiologic Features ៉ Discrete central mass ៉ May have extensive pulmonary and extrapulmonary metastases at

diagnosis Prognosis and Treatment ៉ Prognosis poor ៉ Chemotherapy and radiotherapy

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FIGURE 6-32 Small cell carcinoma. The FNA yields a very cellular aspirate; the malignant cells have large, round–oval nuclei with very scant cytoplasm. Note the characteristic nuclear features: hyperchromatic, speckled chromatin with inconspicuous nucleoli and prominent nuclear molding. Apoptotic cells are noted in the background (range of viability) as well as tingible-body macrophages. The cell size is not an important diagnostic criterion, as the small cell carcinoma cells reach quite large sizes in the FNA material. Diff-Quik stain, medium power.

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FIGURE 6-33 Small cell carcinoma. The Papanicolaou stain highlights the characteristic nuclear features. Note the crush artifact and the apoptotic cells. Papanicolaou stain, high power.

ANCILLARY STUDIES Small cell carcinomas of the lung are positive for cytokeratins (pan-cytokeratin, low molecular weight cytokeratin, EMA, CK7) and TTF-1 (90% of cases). CD56 is positive in more than 90% of cases. Neuroendocrine markers (chromogranin A, synaptophysin) are positive in half of cases.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Small cell carcinoma can be confused with carcinoid tumor, lymphoma, or a poorly differentiated non-small cell carcinoma. Attention to cytologic features, in particular identifying the spectrum of viability and the characteristic background with necrosis, debris, and mitoses, helps in excluding carcinoid tumor. The nuclear chromatin quality (hyperchromatic, finely granular, small or inconspicuous nucleolus) and the presence of nuclear molding are key features to exclude a poorly differentiated carcinoma. The absence of lymphoglandular bodies excludes a lymphoid process. In difficult cases, immunohistochemical stains on the cell block can be performed.

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LARGE CELL CARCINOMA AND PLEOMORPHIC CARCINOMA These are rare variants of non-small cell carcinoma. They share similar cytologic features that help to separate them from small cell carcinoma, and will be discussed together.

LARGE CELL CARCINOMA AND PLEOMORPHIC CARCINOMA – DISEASE FACT SHEET Incidence ៉ Large cell carcinoma: 9% of all lung cancers Radiologic Features ៉ Large cell carcinoma: often found at lung periphery; large necrotic

tumors ៉ Pleomorphic carcinoma: large, peripheral tumors that often invade

the chest wall Prognosis ៉ Poor

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LARGE CELL CARCINOMA AND PLEOMORPHIC CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Large cell carcinoma: ៉ Undifferentiated malignant tumor ៉ It is a diagnosis of exclusion ៉ Discohesive, large malignant cells with large nuclei and moderate amount of cytoplasm ៉ Variant: large cell neuroendocrine carcinoma ៉ Pleomorphic carcinoma: ៉ Poorly differentiated non-small cell carcinoma with giant cells and/or spindle cells ៉ Giant cells are often multinucleated ៉ Emperipolesis of neutrophils Histopathologic Findings ៉ Pleomorphic carcinoma: should have at least 10% component of spindle or giant cells

Large cell carcinoma is an undifferentiated malignant tumor that lacks the characteristic cytologic features of squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. It is a diagnosis of exclusion. The aspirate is cellular, consisting of discohesive large malignant cells with large nuclei and a moderate amount of cytoplasm. The nuclei have irregular contours, unevenly distributed, coarse chromatin, and prominent nucleoli (Fig. 6-34). A variant of this tumor is large cell neuroendocrine carcinoma, in which neuroendocrine differentiation can be demonstrated by immunochemistry or electron microscopy. The cell block material may show

FIGURE 6-34 Large cell carcinoma. Large malignant cells with pleomorphic nuclei with irregular, folded nuclear membranes and irregular chromatin. Mitotic figures are easily identified. Papanicolaou stain, high power.

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an organoid arrangement. However, cytologically, this tumor has the features of a non-small cell carcinoma and is not confused with a small cell carcinoma. Specifically, this tumor has visible nucleoli, a moderate amount of cytoplasm, and an abundant necrotic background with frequent mitoses. Pleomorphic carcinoma is a poorly differentiated non-small cell carcinoma that contains giant cells and/ or spindle cells. The giant cells are large, often multinucleated, and discohesive with emperipolesis of neutrophils (Fig. 6-35).

CARCINOID TUMOR CLINICAL FEATURES Carcinoid tumor is a rare lung neoplasm, with an incidence of 0.4–3%. It has now been recognized that even a typical carcinoid has the ability to metastasize. For this reason, this tumor is classified as a malignant neoplasm. The median age at presentation is 47 years, younger than the median age for lung cancer. There are no known risk factors associated with the development of carcinoid tumor. Symptoms at presentation depend on the location. A centrally located carcinoid tumor will present with hemoptysis, cough, dyspnea, pain, or recurrent pneumonia. A peripherally located lesion is usually asymptomatic, discovered incidentally. This tumor is treated by surgical excision.

FIGURE 6-35 Pleomorphic carcinoma. Very cellular aspirate with a discohesive population of large, multinucleated malignant cells. Some of the cells have engulfed neutrophils in their cytoplasm, characteristic finding in pleomorphic carcinoma. Diff-Quik stain, low power.

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CARCINOID TUMOR – DISEASE FACT SHEET Incidence ៉ 0.4% to 3%

Clinical Features ៉ Symptomatic if centrally located (cough, dyspnea, hemoptysis,

recurrent pneumonia) ៉ Asymptomatic if peripheral

Radiologic Features ៉ Peripheral mass (25%), central tumor (30%), atelectasis (40%) ៉ Normal chest X-ray (5%)

Treatment ៉ Surgical excision

CARCINOID TUMOR – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Uniform population of cells with moderate, finely granular cytoplasm ៉ Round–oval nuclei, with smooth nuclear contours, stippled chromatin, and a small, distinct nucleolus ៉ Cells can be spindle-shaped (spindle cell carcinoid) ៉ Background is clean, with occasional naked nuclei (but no necrosis or mitotic figures) ៉ Atypical carcinoid (difficult diagnosis to make on FNA material) can be suggested if focal necrosis and rare mitoses are seen Histopathologic Findings ៉ Atypical carcinoid: 2–10 mitoses/10 HPF or a focus of necrosis

Ancillary Studies ៉ Positive for neuroendocrine markers ៉ Positive for CK7 and TTF-1; negative for CK20

CYTOPATHOLOGIC FEATURES The aspirate consists of uniform cells arranged in loose groups, larger tissue fragments, or dispersed as single cells. The larger tissue fragments have a distinctive architecture, reminiscent of the trabecular or festooning patterns seen histologically. When the cells are dispersed individually, they tend to form small linear arrays (similar to the single cell filing seen in lobular carcinoma of the breast), rosettes, or acini. It is very characteristic for carcinoid tumor to have uniform, small cells with very little pleomorphism. These cells

Differential Diagnosis and Pitfalls Lymphoma Adenocarcinoma Other spindle cell lesions Sclerosing hemangioma

៉ ៉ ៉ ៉

have scant to moderate, finely granular cytoplasm with poorly defined borders (Fig. 6-36). However, it is not uncommon that the cytoplasm is stripped from the nuclei, resulting in single, dispersed bare nuclei. At low power, these naked, dispersed nuclei can be confused

FIGURE 6-36 Carcinoid tumor. The FNA yields a cellular aspirate composed of uniform cells arranged in loose groups or dispersed as single cells. They have round nuclei and scant, fine cytoplasm with indistinct cell borders. The nuclei have smooth contours, ‘salt and pepper’ chromatin, and a small nucleolus. Note the acinar arrangement, which can be misinterpreted as glandular differentiation. Papanicolaou stain, medium power.

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ANCILLARY STUDIES

FIGURE 6-37 Spindle cell carcinoid tumor. Cellular aspirate consisting of uniform, discohesive spindle-shaped cells with oval nuclei and small amounts of cytoplasm. Note the finely granular, ‘salt and pepper’ chromatin. Papanicolaou stain, medium power.

with inflammatory cells. The nuclei are small, round to oval, with smooth nuclear contours, stippled, ‘salt and pepper’ chromatin (due to uniform dispersion of the nuclear chromatin), and a small, distinct nucleolus. Occasionally, variable numbers of small, spindle tumor cells can be seen. In some cases, the spindle cells are the only component (spindle cell carcinoid). The cytoplasm and nuclear characteristics of spindle cell carcinoid are similar to those of typical carcinoid tumor (Fig. 6-37). Smears have a clean background because the cytoplasm of these cells, more abundant than in small cell carcinoma, remains intact during the smearing process and there is no necrosis, apoptotic bodies, or mitoses. Atypical carcinoid tumor is defined as a tumor with a recognizable carcinoid pattern that has 2–10 mitoses/ 10 high-power fields or a focus of necrosis. Since these features may be focal, sampling is critical in correct classification of this tumor. For this reason, a specific distinction on FNA between typical and atypical carcinoid may not be always possible. The morphology of atypical carcinoid tumor is intermediate between typical carcinoid and small cell carcinoma. The tumor cells show greater cellular pleomorphism, the nuclei can have modest membrane irregularities, but the nuclear chromatin remains finely distributed with small nucleoli. A diagnosis of atypical carcinoid can be suggested on FNA material if one sees mitotic activity and necrosis in an otherwise typical carcinoid tumor.

R ADIOLOGIC FEATURES Carcinoid tumor can present as a peripheral mass (25%), as a centrally located tumor (30%), or as atelectasis (40%); in 5% of patients, the chest radiograph is normal.

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To confirm the diagnosis, immunohistochemical studies using neuroendocrine markers (chromogranin A, synaptophysin, neuron-specific enolase) can be performed on the cell block. In addition, a combination of CK7, CK20, and TTF-1 helps to differentiate between pulmonary carcinoid, gastrointestinal carcinoid, and pancreatic endocrine tumors. Pulmonary carcinoid tumors are negative for CK20 and have a variable expression of CK7 and TTF-1. A profi le of CK7+/CK20−/TTF-1+ has high specificity (100%) and moderate sensitivity (50%) for pulmonary carcinoid tumors. TTF-1 expression is highly specific for pulmonary carcinoid but is negative in one-third of cases. Gastrointestinal tract carcinoid and pancreatic endocrine tumors are negative for TTF-1. Sixty-seven percent of gastrointestinal carcinoid tumors are CK7−/CK20− and 20% of them are CK7−/CK20+. Thirty-three percent of pancreatic endocrine tumors are CK7+/CK20−, 33% are CK7−/CK20−, and the rest are equally divided between CK7−/CK20+ and CK7+/CK20+ profi les.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Lymphoma, especially a low-grade type, enters in the differential diagnosis in cases with abundant stripped, naked nuclei that at low power are misinterpreted as lymphocytes. Lack of lymphoglandular bodies, presence of cohesive groups of epithelial cells with moderate wispy cytoplasm, and nuclear characteristics favor a carcinoid tumor. Immunohistochemical stains on the cell block for leukocyte common antigen (CD45) and neuroendocrine markers will also help the distinction. In addition, the rosette formation can be misinterpreted as evidence of glandular differentiation, resulting in an erroneous diagnosis of adenocarcinoma. Spindle cell carcinoid can be confused with rare spindle cell lesions (leiomyoma, leiomyosarcoma, neurofibroma) that occur in the lung. Low cellularity specimens may be underdiagnosed as ‘negative’ when the typical, uniform carcinoid cells are confused with benign bronchial cells. The lack of terminal bars and cilia should alert the pathologist that these bland cells are not bronchial cells. Sclerosing hemangioma shows also bland, monotonous, round to polygonal cells. The cell uniformity and bland cytology can mimic perfectly a typical carcinoid tumor. Immunohistochemical studies for neuroendocrine markers performed on the cell block will help in difficult cases.

METASTASES The lung is a very common site for metastases, because the entire blood supply must circulate through the lungs. Pulmonary metastases can be diagnosed using

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METASTASES – DISEASE FACT SHEET

METASTASES – PATHOLOGIC FEATURES

Clinical Features

Cytopathologic Findings

៉ Lung is a very common site for metastases ៉ 14–25% of lung FNAs identify metastases ៉ Most common metastases to the lung are adenocarcinomas

៉ In general, a metastatic adenocarcinoma to the lung has

(breast, colon, kidney) and malignant melanoma ៉ Although rare, sarcomas can also metastasize to the lung; most

common sarcomas encountered in lung FNA are synovial sarcoma, chondrosarcoma, osteosarcoma, and alveolar soft part sarcoma

FNA; indeed, between 14% and 25% of aspirates identify metastatic disease. The most common metastases to the lung identified by FNA are adenocarcinomas (breast, colon, and kidney) and malignant melanoma, although different series may vary the order of frequency for metastasis. The cytomorphology of a metastatic adenocarcinoma overlaps significantly with that of a primary lung adenocarcinoma. However, in certain types of tumors, specific

cytologic features similar to those of primary lung adenocarcinoma ៉ Clues to a specific diagnosis include the following: ៉ Cells with abundant vacuolated cytoplasm suggest renal cell carcinoma ៉ Cells with elongated, hyperchromatic, ‘picket-fence’ nuclei suggest colonic adenocarcinoma ៉ Cercariform cells suggest urothelial carcinoma ៉ Discohesive, epithelioid or spindle cells with prominent nucleoli, intranuclear inclusions, and pigment suggest melanoma

cytologic features can help in pinpointing towards a specific diagnosis (Figs 6-38–6-43). Identification of carcinomas as metastatic is often straightforward if clinical information and/or prior surgical or cytologic specimens are available. In cases in which this correlation is

FIGURE 6-38 Metastatic urothelial carcinoma. The aspirate material is cellular, consisting of discohesive cells with a moderate amount of cytoplasm and centrally placed, hyperchromatic nuclei. Note in the inset, the cercariform cells, with elongated unipolar cytoplasmic processes and nuclei placed at the apical pole. Diff-Quik stain, low power (inset: Diff Quik stain, high power).

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FIGURE 6-39 Metastatic urothelial carcinoma. Flat sheet of cells with a moderate amount of cytoplasm and hyperchromatic, round, slightly irregular nuclei. This appearance can be confused with squamous cell carcinoma. Finding cercariform cells (inset) is a clue to the diagnosis of metastatic urothelial carcinoma. Papanicolaou stain, low power (inset: Papanicolaou stain, high power).

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FIGURE 6-40 Metastatic breast carcinoma. The FNA yields a cellular aspirate with discohesive, tridimensional clusters with depth of focus. The cells have the typical features of an adenocarcinoma, high N/C ratios, hyperchromatic nuclei, and scant to modest amounts of cytoplasm. On cytomorphology alone, the distinction between primary lung and metastatic breast carcinoma is very difficult. Comparison with previous material (if available) and immunohistochemical studies on the cell block material are necessary in the majority of cases. Diff-Quik stain, low power.

FIGURE 6-41 Metastatic renal cell carcinoma. The aspirate material is highly cellular, with clusters and discohesive vacuolated cells. Tumor fragments are associated with small blood vessels and fibrovascular cores. The cells have mildly increased N/C ratios, round regular nuclei with finely granular chromatin, and abundant finely vacuolated cytoplasm. Most of the cells retain their cytoplasm during smear preparation. Diff-Quik stain, medium power.

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FIGURE 6-42 Metastatic colonic adenocarcinoma. The FNA yields highly cellular smears which show large fragments rather than discohesive cells. Nuclei are fairly uniform and hyperchromatic, but tend to be elongated and basally oriented, almost in a picket-fence array. The inset shows cell block with a small fragment of tumor with glandular formation and necrosis, both luminal and in the background. Diff-Quik stain, high power (inset: H&E stain).

FIGURE 6-43 Metastatic malignant melanoma. The aspirated material consists of discohesive, somewhat plasmacytoid, single cells. The cells have enlarged nuclei, with irregular contours, unevenly distributed chromatin, and prominent nucleoli. Note the intranuclear cytoplasmic inclusion, a non-specific but common finding in malignant melanoma. The inset shows a binucleated cell with ‘mirror image’ nuclei. Papanicolaou stain, high power (inset: Papanicolaou stain, high power).

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B

FIGURE 6-44 Metastatic osteosarcoma. Cellular aspirate with discohesive, bizarre-shaped, multinucleated malignant cells. Note the eosinophilic osteoid matrix material, a useful clue towards the correct diagnosis. Clinical history is critical in such cases. A, Diff-Quik stain, medium power. B, Papanicolaou stain, medium power.

not possible, immunohistochemical stains need to be performed on the cell block material or alcohol-fixed slides. Primary pulmonary sarcomas are rare tumors; the most common is leiomyosarcoma, which may arise from the pulmonary vasculature. Because of the rarity of primary mesenchymal tumors, metastatic sarcomas are usually accurately identified (Fig. 6-44). Synovial sarcoma, chondrosarcoma, alveolar soft part sarcoma, and osteosarcoma are just some of the types of sarcomas that can metastasize to the lungs. Both primary and secondary sarcomas that are composed of spindle cells will show single, discohesive cells and/or clusters of cells. The individual cells often have fragile cytoplasm and granular to coarse chromatin, and there are occasional bizarre multinucleated cells. The sarcomas can be differentiated from sarcomatoid carcinomas and melanoma by immunostaining.

Fritscher-Ravens A, Sriram PV, Topalidis T, et al. Diagnosing sarcoidosis using endosonography-guided fine-needle aspiration. Chest 2000;118: 928–935. Wildi SM, Judson MA, Fraig M, et al. Is endosonography guided fine needle aspiration (EUS-FNA) for sarcoidosis as good as we think? Thorax 2004;59:794–799. Wu JJ, Rashcovsky Schiff K. Sarcoidosis. Am Fam Physician 2004;70: 312–322. Tuberculosis Maygarden SJ, Flanders E. Mycobacteria can be seen as ‘negative images’ in cytology smears from patients with acquired immunodeficiency syndrome. Mod Pathol 1989;2:239–243. Niederman MS, Sarosi GA, Glassroth J. Respiratory Infections, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2001. Palmer PES. The Imaging of Tuberculosis with Epidemiological, Pathological, and Clinical Correlation. Berlin: Springer-Verlag, 2002. Powers CN. Diagnosis of infectious diseases: a cytopathologist’s perspective. Clin Microb Rev 1998;11:341–365. Silverman JF, Holter JF, Berns LA, et al. Negative images due to clofazimine crystals simulating MAI infection in a bronchoalveolar lavage specimen. Diagn Cytopathol 1993;9:534–540. Fungal Infections

SUGGESTED READINGS Introduction Bonfiglio TA. Cytopathologic interpretation of transthoracic fine-needle biopsies. Masson Monographs in Diagnostic Cytopathology. New York: Masson Publishing USA, 1983. Mullan CP, Kelly BE, Ellis PK, et al. CT-guided fine-needle aspiration of lung nodules: effect on outcome of using coaxial technique and immediate cytological evaluation. Ulster Med J 2004;73:32–36. Stewart CJ, Stewart IS. Immediate assessment of fine needle aspiration cytology of lung. J Clin Pathol 1996;49:839–843.

Chen KTK. Cytodiagnostic pitfalls in pulmonary coccidioidomycosis. Diagn Cytopathol 1995;12:177–180. Niederman MS, Sarosi GA, Glassroth J. Respiratory Infections, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2001. Raab SS, Silverman JF, Zimmerman KG. Fine-needle aspiration biopsy of pulmonary coccidioidomycosis. Spectrum of cytologic findings in 73 patients. Am J Clin Pathol 1993;99:582–587. Powers CN. Diagnosis of infectious diseases: a cytopathologist's perspective. Clin Microbiol Rev 1998;11:341–365. Sarosi GA, Davies SF. Fungal Diseases of the Lung, 3rd ed. Philadelphia: Lippincott Williams &Wilkins, 2000. Wheat LJ, Goldman M, Sarosi G. State-of-the-art review of pulmonary fungal infections. Semin Respir Infect 2002;17:158–181.

Sarcoidosis Annema JT, Veselic M, Rabe KF. Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of sarcoidosis. Eur Respir J 2005;25: 405–409.

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Hamartoma Hughes JH, Young NA, Wilbur DC, Renshaw AA, Mody DR. Fine-needle aspiration of pulmonary hamartoma: a common source of false-positive

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diagnoses in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Arch Pathol Lab Med 2005;129:19–22. Clear Cell (Sugar) Tumor Nguyen GK. Aspiration biopsy cytology of benign clear cell (‘sugar’) tumor of the lung. Acta Cytol 1989;33:511–515. Primary Malignant Tumors Detterbeck FC, Rivera MP, Socinski MA, Rosenman JG. Diagnosis and Treatment of Lung Cancer. An Evidence-Based Guide for the Practicing Clinician. Philadelphia: WB Saunders, 2001. Linder J. Lung cancer cytology. Something old, something new. Am J Clin Pathol 2000;114:169–171. Liu J, Farhood A. Immunostaining for thyroid transcription factor-1 on fine-needle aspiration specimens of lung tumors: a comparison of direct smears and cell block preparations. Cancer (Cancer Cytopathol) 2004;102:109–114. Silverman JF, Weaver MD, Shaw R, Newman WJ. Fine needle aspiration cytology of pulmonary infarct. Acta Cytol 1985;29:162–166. Travis WD, Colby TV, Corrin B, et al. World Health Organization International Classification of Tumours. Histological Typing of Lung and Pleural Tumours, 3rd ed. Berlin: Springer Verlag, 1999. Travis WD. Pathology of lung cancer. Clin Chest Med 2002;23:65–81.

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Anderson C, Ludwig ME, O’Donnell M, Garcia N. Fine needle aspiration cytology of pulmonary carcinoid tumors. Acta Cytol 1990;34:505–510. Cai YC, Banner B, Glickman J, Odze RD. Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors. Hum Pathol 2001; 32:1087–1093. Fekete PS, Cohen C, DeRose PB. Pulmonary spindle cell carcinoid. Needle aspiration biopsy, histologic and immunohistochemical findings. Acta Cytol 1990;34:50–56. Gal AA, Nassar VH, Miller JI. Cytopathologic diagnosis of pulmonary sclerosing hemangioma. Diagn Cytopathol 2002;26:163–166. Nicholson SA, Ryan MR. A review of cytologic findings in neuroendocrine carcinomas including carcinoid tumors with histologic correlation. Cancer (Cancer Cytopathol) 2000;90:148–161. Metastases Flint A, Lloyd RV. Colonic carcinoma metastatic to the lung: cytologic manifestations and distinction from primary pulmonary adenocarcinoma. Acta Cytol 1992;36:230–235. Hummel P, Cangiarella JF, Cohen JM, et al. Transthoracic fine-needle aspiration biopsy of pulmonary spindle cell and mesenchymal lesions. A study of 61 cases. Cancer (Cancer Cytopathol) 2001;93:187–198.

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7

Mediastinum Maureen F Zakowski

INTRODUCTION Fine needle aspiration (FNA) cytology is commonly used to investigate space-occupying lesions of the mediastinum. As with many other body sites sampled by FNA, experience on the part of the cytopathologist is essential in the correct identification of lesions in this area. Knowledge of the anatomy of the mediastinum and familiarity with the normal structures that it contains is necessary for the correct interpretation of pathologic conditions. Although a variety of lesions, reactive and neoplastic, benign and malignant, occur, some of which are cystic (foregut cysts, bronchogenic cysts, neuroenteric cysts, and pericardial cysts), this discussion will not focus on the predominantly benign cystic lesions of the mediastinum. Additionally, tumors originating from the thyroid and parathyroid which may be encountered in the mediastinum are not discussed here, but are the subject of Chapter 2.

MEDIASTINUM The mediastinum is the middle compartment between the right and left thoracic cavities; it extends from the thoracic inlet cranially to the diaphragm caudally. It extends from the sternum anteriorly to the spine posteriorly, and between the pleural cavities laterally and from the diaphragm up to the thoracic inlet (Table 7-1). The majority of lesions of the mediastinum, both benign and malignant, present as asymptomatic masses found on chest radiography. When symptomatic, these lesions are a result of impingement of vital structures. Pain, dyspnea, cough, or superior vena cava syndrome may result from involvement of these structures. Metastases are more common than primary tumors in the adult population. Age plays an important role in the correct diagnosis of tumors of this area because very different lesions are expected in childhood as compared to adulthood (Table 7-2). The majority of mediastinal lesions in childhood are primary malignant tumors. Frequent here are the neurogenic tumors, specifically neuroblastoma and

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• Anil V Parwani

ganglioneuroblastoma, lymphoma, germ cell tumors, and mesenchymal tumors. In adults, metastatic lesions are the most common tumors aspirated, most often small cell carcinoma of the lung, followed by neurogenic tumors, nerve sheath tumors, paragangliomas, cysts, thymomas, germ cell tumors, and endocrine tumors such as thyroid, parathyroid, and carcinoid. Mesechymal tumors occur infrequently in the adult mediastinum and one-half of these are endothelial in origin. The FNA method for sampling the mediastinum is the same as that for the lung, with the same contraindications to the procedure and a lower complication rate. The highest rate of complications is found in the middle mediastinum, probably due to the presence of the great vessels. Complications include pneumothorax, hemothorax, local hemorrhage, and pain. Mortality is rare. Sensitivity and specificity are good, but vary with the series reported. The overall sensitivity and specificity of FNA versus core biopsy are nearly identical, but some investigators prefer core biopsy in cases of suspected mesenchymal lesions because of increased accuracy of tumor typing and availability of more tissue for ancillary studies. FNA can distinguish benign from malignant lesions and most often accurately subtype the malignancy. Particular diagnostic challenges are seen with spindle cell lesions, perhaps due to their rarity and lack of experience on the part of pathologists. Other areas of challenge include the subclassification of small cell malignancies, including the misdiagnosis of small cell carcinoma for lymphoma and the separation of the germ cell tumors from adenocarcinoma. False positive diagnoses are rare and false negative rates here, as in other sites, are due to sampling errors and fibrotic or necrotic conditions. The unsatisfactory rate as presented in the literature is approximately 10%. Studies have found that a single needle pass is sufficient in approximately half the patients, but that as many as three biopsies may be needed in the remaining half. Age is not a factor in performing the FNA of the mediastinum; so pediatric lesions can be easily aspirated as well. Most aspirations are done under radiologic guidance, with computerized tomography (CT) preferred over fluoroscopy. Ultrasound-guidance is often employed in the anterior mediastinum. Adults, for example, have a much lower incidence of neuroblastoma, ganglioneuroblastoma, and mesenchymal lesions than do children. Metastases, while they do occur, are 201

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TABLE 7-1

TABLE 7-3

The Mediastinum

Location of Mediastinal Lesions by Compartment in Adults

• The middle space between the right and left thoracic cavities • Boundaries: • From thoracic inlet above to diaphragm below • From sternum in front to spine in back • Majority of space-occupying lesions are asymptomatic • FNA is an excellent method for sampling the mediastinum

TABLE 7-2 Differential Diagnosis of Mediastinal Masses Pediatric

Adults

Neurogenic: Neuroblastoma Ganglioneuroblastoma Lymphoma Cysts Germ cell Mesenchymal Thymoma (unlikely) Carcinoid (unlikely)

Metastases Neurogenic: Nerve sheath Paraganglioma Cysts Thymoma Germ cell Mesenchymal Endocrine: Thyroid Parathyroid Carcinoid

infrequent in the pediatric population, and almost always follow a known primary. Dividing the mediastinum into compartments is helpful in determining which lesions may be encountered (Table 7-3). The mediastinum can be considered to contain several compartments: the superior mediastinum, the inferior mediastinum, and the middle mediastinum. The inferior mediastinum is further divided into the anterior and posterior compartments. The superior mediastinum contains the thymus, lymph nodes, thyroid, and parathyroid; therefore, thymoma, carcinoid tumor, lymphoma, goiter, thyroid and parathyroid adenomas, and various cysts can be found. The anterior mediastinum is the site for tumors and cysts of the thymus as well as germ cell tumors. Lymphoid tissue is present in all compartments and lymphoma may be encountered in any part of the mediastinum. The middle mediastinum is composed mainly of the heart and great vessels, and atrial myxomas and associated cardiac lesions may be found here. Neurogenic tumors, both benign and malignant, are most commonly located in the posterior mediastinum. Singh et al (1997) examined and reported on 189 cases of mediastinal FNAs. In their series, less than half of the patients had surgical follow-up. Approximately

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Superior Metastases (in all compartments) Thymoma Thymic cysts Thyroid lesions Parathyroid neoplasms Lymphoma Anterior

Middle

Posterior

Thymoma Thymic cysts Thyroid lesion Parathyroid neoplasm Lymphoma Paraganglioma Angioma Lipoma

Pericardial cysts Bronchogenic cysts Lymphoma Metastases

Neurogenic tumor Schwannoma Neurofibroma Ganglioneuroma Ganglioneuroblastoma Malignant peripheral nerve sheath tumor Neuroblastoma Paraganglioma Gastroenteric cysts Lymphoma Metastases

15% of the cases were unsatisfactory and a 6% discordance rate between cytology and histology was found. This was mostly due to the misclassification of carcinomas. They also encountered difficulty in separating Hodgkin from non-Hodgkin lymphoma. Geisinger (1995) divided mediastinal tumors into categories by morphologic pattern. As expected, small cell patterns were usually seen in lymphomas, carcinoid, and small cell carcinoma. Polygonal or epithelioid patterns were seen in thymomas, germinomas, embryonal carcinoma, and metastatic carcinoma. Powers et al (1996) found that 71% of their 189 cases were neoplastic. Interestingly, most of the primary tumors were thymoma and lymphoma, and the majority of the metastases were small cell carcinoma from the lung. The remainder of the cases equally divided between unsatisfactory and non-neoplastic. The sensitivity in this series was 87%; specificity, 88% for neoplasms and 82% for distinguishing benign from malignant. The positive predictive value for tumors was 97%. There were three false positive diagnoses in this group. As the majority of mediastinal FNAs are done under radiologic guidance, the benefit of immediate assessment and feedback to the operator by an experienced cytopathologist or cytotechnologist is obvious. It is also especially important when considering mediastinal pathology, because of the frequency of lymphomas here. On-site assessment can assure material is sent for flow cytometry or additional molecular studies such as

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needed for germ cell tumor analysis. Careful teamwork involving cytology and interventional radiology can make the difference between a satisfactory specimen and the need to re-biopsy the patient. Treatment can be undertaken when the results of the FNA are unequivocal, and can eliminate the need for surgery in cases of inoperable disease. As always, ancillary studies on cytology material can be done to support diagnoses, and material such as cell blocks and liquid-based preparations lend themselves well to immunoperoxidase, molecular, and genetic analyses. The cytomorphologic appearances of cysts and inflammation of the mediastinal compartments are similar to these conditions at any other site and will not be further discussed. Chronic sclerosing mediastinitis can be confused with tumors having a significant sclerotic or collagenous component, such as nodular sclerosing Hodgkin disease. This condition, however, would probably not yield much material from an aspirate, and would likely need surgical biopsy for confirmation.

THYMOMA – DISEASE FACT SHEET Definition ៉ A primary neoplasm of thymic epithelial cells which is associated with lymphocytes, predominantly immature T cells Incidence ៉ Most common primary tumor of the anterior mediastinum ៉ Incidence: 0.15 cases per 100,000 ៉ 25% of all primary mediastinal tumors

Gender and Age Distribution ៉ Males = females ៉ Most occur in adults, with a mean age of 50 years. ៉ Rare in children

Clinical Features ៉ Most are asymptomatic ៉ Some patients present with chest pain, cough, dyspnea, or

superior vena cava syndrome ៉ Myasthenia gravis is associated with thymoma and is more

common in women ៉ Often large (5–10 cm) at presentation

THYMOMA AND THYMIC LESIONS THYMOMA CLINICAL FEATURES Thymoma – a primary neoplasm of thymic epithelial cells, with secondary reactive mature T lymphocytes – is the most common neoplasm of the anterior mediastinum in adults, with a median age of 50 years. Thymomas can also be found in the superior middle mediastinum, but rarely in the posterior. The various classification systems depend on the proportion of epithelial cells and lymphocytes, but it is difficult to apply a classification system to these tumors using only FNA material. Most often these masses are asymptomatic, and are discovered on incidental chest films. Some patients may experience symptoms from mass lesions such as cough, dyspnea, and chest pain. A subset of patients may come to medical attention because of associated paraneoplastic syndromes such as myasthenia gravis.

CYTOPATHOLOGIC FEATURES

Prognosis and Treatment Mixed: associated with aggressive behavior Spindle: associated with better prognosis Cytologic appearance does not predict behavior Prognosis dependent upon capsular invasion Generally responsive to chemotherapy

៉ ៉ ៉ ៉ ៉

THYMOMA – PATHOLOGIC FEATURES Cytopathologic Findings Usually well encapsulated with fibrous septations Cystic change common Some have components that are necrotic and hemorrhagic Dual population of epithelial and lymphoid components in variable proportions ៉ Epithelial cells: bland nuclei, smooth contour; nucleoli prominent but not macro; intranuclear invaginations can occur; few mitoses; +/− rosettes and Hassall’s corpuscles; spindle and clear cell variants ៉ Lymphocytes: small and mature-appearing; polymorphic pattern possible with immature lymphocytes, clefting, chromocenters, and nucleoli ៉ ៉ ៉ ៉

Ancillary Studies

Since thymoma is a neoplasm with thymic epithelial cells and secondary reactive mature T lymphocytes, a correct diagnosis of thymomas is dependent on the recognition of the two cell types, epithelial and lymphocytic. Either component can dominate. Multiple classification systems have been used to classify thymomas. A common classification used is that of Bernatz et al., which divides thymoma into four categories: 1) epithelial predominant, 2) lymphocytic predominant,

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៉ Pancytokeratin, cytokeratin 5/6 ៉ CD5 is usually positive in thymic carcinomas

Differential Diagnosis and Pitfalls ៉ If the lymphocytic component predominates, the lesion may be

mistaken for a lymphoproliferative disorder ៉ If the epithelial component predominates, the lesion may be

mistaken for a metastatic carcinoma

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FIGURE 7-1 Thymoma. The classic bimodal population of neoplastic epithelial and non-neoplastic lymphoid elements. The cluster of epithelial cells is cohesive in the background of scattered lymphocytes, with occasional single cells. The neoplastic cells are variable in size and shape, with usually scant to moderate amounts of cytoplasm. Nuclei are bland with often-conspicuous nucleoli. DiffQuik stain, low magnification.

3) mixed lymphoepithelial, and 4) spindle cell types. Suster and Moran (1999) have proposed a classification system with three categories (thymoma, atypical thymoma, and thymic carcinoma). A well-characterized prognostic factor for predicting the behavior of a thymoma is if it invades into or through the capsule. More recently, the World Health Organization has proposed that the classification of thymomas and thymic carcinomas should be as type A thymoma (spindle cell, medullary), type B thymoma (B1 thymoma [lymphocyte-rich, lymphocytic, predominantly cortical, organoid], B2 thymoma [cortical], B3 thymoma [epithelial, atypical, squamoid, well-differentiated thymic carcinoma]), type AB thymoma (mixed), and type C thymoma (thymic carcinoma). The smears obtained from a thymoma are often cellular with a characteristic dual (bimodal) population of cells: the classic neoplastic epithelial cells and the nonneoplastic lymphoid cells (thymocytes) (Fig. 7-1). The epithelial cells of thymoma are variable in size and shape, with usually scant to moderate amounts of cytoplasm. Nuclei are bland with conspicuous nucleoli. Mitoses are often not observed (Fig. 7-2). Spindle cell morphology is common in the epithelial component of thymomas, and, when plentiful, usually signifies a good prognosis. The epithelial cells, even in cases of lymphocytepredominant thymoma, will demonstrate significant cohesion. Clusters of epithelial cells can be seen with interspersed loosely arranged lymphocytes surrounded by vascular structures (Fig. 7-1). This arrangement of vessels is similar to that seen in hepatocellular carcinoma. The epithelial cells are often arranged in such a way to suggest cystic structures (Fig. 7-2).

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FIGURE 7-2 Thymoma. Split screen showing cohesive fragments of epithelial cells on the left with cystic spaces similar to what is seen in histology. Few lymphocytes are visible among epithelial cells on the right. Papanicolaou stain, low and high magnification.

A predominance of lymphocytes or epithelial cells may sometimes be obvious. Because malignancy here is dependent on the demonstration of vascular or capsular invasion, cytology is not useful in making the diagnosis of malignant thymoma (Fig. 7-3). Only when the cytologic atypia is sufficient to categorize a tumor here as thymic carcinoma, should the word malignant be used in the diagnosis. ‘Suspicious for malignancy’, ‘malignancy cannot be ruled out’, and ‘satisfactory for evaluation consistent with thymoma’ are some of the phrases that are useful when diagnosing a thymoma using cytologic material.

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FIGURE 7-3 Malignant thymoma. Cellular smear from a patient with a malignant thymoma. There is a predominance of epithelial cells. Because malignancy here is dependent on the demonstration of vascular or capsular invasion, cytology alone is not useful in making the diagnosis of malignant thymoma. Thymoma with a predominant epithelial component may be mistaken for a metastatic carcinoma. Diff-Quik stain, low magnification.

ANCILLARY STUDIES The thymoma lymphocytes are mostly small mature T cells in a polymorphous pattern with some immature cells and mitotic figures. Immunocytochemical stains for keratin can demonstrate the epithelial cells when they are not obvious and thymoma is suspected. Many of the thymic carcinomas are positive for CD5, while germ cell tumors and metastatic carcinomas are negative.

DIFFERENTIAL DIAGNOSIS AND PITFALLS For an accurate diagnosis of thymoma, the characteristic dual population of epithelial and lymphoid elements must be recognized. If the lymphocytic component is predominant but, due to sampling the epithelial component, is not recognized, the thymic lesion may be mistaken for a lymphoproliferative disorder. Similarly, if the epithelial component is predominant, thymoma may be mistaken for a metastatic non-small cell carcinoma (Fig. 7-3). Metastatic thymomas are cytologically similar to the primary tumor. Hassall’s corpuscles (squamous pearls) can be present, but are rarely seen and are not necessary for the diagnosis. Care must be taken not to mistake Hassall’s corpuscles for metastatic squamous cell carcinoma. Unlike in Hodgkin disease, eosinophils are not a feature of this tumor. When the number of lymphocytes is large, lymphoma must be included in the differential diagnosis and excluded by ancillary studies.

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FIGURE 7-4 Thymic carcinoma. Note the presence of large obviously malignant cells with pleomorphic and hyperchromatic nuclei. Differential diagnosis here must include metastatic disease. Papanicolaou stain, low magnification.

THYMIC CARCINOMAS When necrosis, marked atypia, or epithelial mitosis is significant, thymic carcinomas must be considered. Thymic carcinomas are aggressive epithelial malignancies. They are exceedingly rare, and are most frequent in middle-aged men. Patients often present with cough, dyspnea, and chest pain and weight loss. In contrast to thymomas, thymic carcinomas are cytologically atypical with features of malignancy (Figs 7-4 & 7-5). The most common type of thymic carcinoma

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A

B

FIGURE 7-5 Well-differentiated thymic carcinoma. Cohesive fragments of neoplastic cells with few lymphocytes in the background. Occasional cells have a spindled morphology. The nuclei are moderately sized, with predominantly coarse, granular chromatin. A, Diff-Quik stain, low magnification. B, H&E stain, high magnification.

is squamous cell carcinoma, but almost any subtype of carcinoma, including small cell, clear cell, carcinosarcoma, and lymphoepithelioma-like, can be seen. Epithelial markers are useful to confirm the epithelial origin of the tumors when the differential diagnosis includes melanoma and lymphoma. The differential diagnosis of thymic carcinomas includes embryonal carcinoma and metastatic carcinomas. Ruling out metastasis must prove primary origin in the thymus from a distant site. Germ cell tumors can have a mixture of epithelial cells and lymphocytes, but the epithelial component here is outright malignant. Treatment is dependent on tumor stage and grade. Complete surgical resection is the primary treatment.

MEDIASTINAL GERM CELL TUMORS – DISEASE FACT SHEET Definition ៉ The mediastinum is a common site of extragonadal germ cell

tumors, which are thought to arise from primitive germ cells that failed to migrate completely during embryonic development Incidence ៉ The mediastinum is a common site of extragonadal germ cell

tumors ៉ 25% of all primary mediastinal tumors in children are germ cell

tumors ៉ 15% of all primary mediastinal tumors in adults are germ cell

tumors ៉ Mature cystic teratoma is the most common mediastinal germ cell

THYMIC FOLLICULAR HYPERPLASIA

tumor Gender and Age Distribution

Thymic follicular hyperplasia with an increased number of follicles is associated with myasthenia gravis and other autoimmune diseases. True thymic hyperplasia is a marked increase in the size of the thymus, both epithelial and lymphocytic components. This condition usually occurs in children and can be difficult to separate from normal thymic tissue on cytology.

GERM CELL TUMORS

៉ Men more than women, except for mature cystic teratoma, which

has equal incidence in men and women Clinical Features ៉ Rapid growth and invasion of the tumor result in symptoms ៉ Patients may present with chest pain, dyspnea, superior

vena cava syndrome, cough, weight loss, night sweats, and dysphagia. ៉ Elevated β-HCG (choriocarcinoma, embryonal carcinoma, some seminomas) and AFP (yolk sac tumors and embryonal carcinoma) in serum Prognosis ៉ Non-seminomatous mediastinal germ cell tumors are more

CLINICAL FEATURES

aggressive and metastasize earlier than mediastinal seminomas

Only a small percentage of primary germ cell tumors arise in the mediastinum, but this site accounts for the majority of all extragonadal germ cell tumors

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(50% to 70%). They are more common in children than in adults. The anterior mediastinum is the preferred site for these tumors and a metastasis to the mediastinum from the gonads is far more common than a primary tumor here. Mediastinal germ cell tumors account for 1–15% of adult anterior mediastinal tumors. A gonadal primary must always be excluded when making the diagnosis of primary mediastinal germ cell tumor. Males are far more likely to have mediastinal germ cell tumors than are females. The germ cell tumors that occur in the mediastinum include seminoma, endodermal sinus tumor (yolk sac tumors), embryonal carcinoma, and teratomas. Mature teratomas represent the majority of mediastinal germ cell tumors (60% to 70%). The remaining mediastinal germ cell tumors are divided between seminomas (40%) and non-seminomatous germ cell tumors (60%). Most of the malignant germ cell tumors are symptomatic, but only about half of the teratomas produce symptoms.

CYTOPATHOLOGIC FEATURES M ATURE CYSTIC TERATOMA

Mature cystic teratoma is the most common mediastinal germ cell tumor and is found equally in men and women, unlike the other germ cell tumors. This tumor is large, calcified, cystic, and filled with grumous granular material identical to its ovarian counterpart. FNA can show these components and skin adnexal structures, gastrointestinal, respiratory, and cartilaginous material (Fig. 7-6). Foreign body granulomas are common in response to the keratin found in teratomas. Hair is not often seen in a cytology specimen, but short strands can sometimes be observed. Immature teratomas are more common in men and show the presence of immature epithelial, mesenchymal, and neural material. It is an uncommon tumor in the mediastinum.

MEDIASTINAL GERM CELL TUMORS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Teratoma: ៉ Tumor is large, calcified, cystic, and filled with grumous granular material ៉ An FNA smear may show these components and skin structures, gastrointestinal, respiratory, and cartilaginous material ៉ Foreign body granulomas are common in response to the keratin found in teratomas ៉ Hair is not often seen in a cytology specimen, but short strands can sometimes be noted ៉ Seminoma: ៉ Tumor cells are infiltrated by reactive lymphocytes ៉ Plasma cells are common ៉ Poorly cohesive, and appears malignant at first glance ៉ Hyperchromatic enlarged nuclei are seen with very consistent, prominent nucleoli; cytoplasm is clear ៉ An often-reported feature is the striped or ‘tigroid’ pattern in the background seen in air-dried smears ៉ Granulomas and multinucleated giant cells are common ៉ Yolk sac tumor: ៉ Irregular, large, cohesive, 3-D balls and papillae, few single cells ៉ Large cells with abundant vacuolated cytoplasm ៉ Schiller-Duval bodies: glomeruloid structures formed by the invagination of malignant cells into an empty space ៉ Hyaline globules: large, round, PAS-positive intracytoplasmic inclusions containing AFP (also free in background) ៉ Embryonal carcinoma: ៉ Smears show large clusters and papillae of poorly differentiated cells with vacuolated cytoplasm ៉ Nuclei are large with coarsely granular chromatin and prominent nucleoli ៉ Close resemblance to poorly differentiated adenocarcinoma Ancillary Studies ៉ Seminoma: positive for immunostaining with c-kit and PLAP ៉ Embryonal carcinoma: positive for CD30 ៉ Yolk sac tumor: positive for AFP ៉ Choriocarcinoma: positive for HCG ៉ The most common karyotype abnormality is i(12p), present in about 40% of patients Differential Diagnosis and Pitfalls ៉ Metastatic disease must be excluded

SEMINOMA

Germinomas or seminomas occur exclusively in men. This is the most frequent mediastinal germ cell tumor in males. The tumor cells here are infiltrated by reactive lymphocytes, and because of this dual population, thymoma enters the differential; however, unlike in thymoma, plasma cells are common. Seminoma is poorly cohesive and appears malignant at first glance. Hyperchromatic enlarged nuclei are seen with very consistent, prominent nucleoli. Cytoplasm is clear. An oftenreported feature is the striped or ‘tigroid’ pattern in the background seen in air-dried smears. We find this feature more often mentioned in the literature than actually seen on slides. Granulomas and multinucleated giant cells are common. These giant cells are of the syncytotrophoblast type, and not the cytotrophoblast type seen in choriocarcinoma.

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YOLK SAC (ENDODERMAL SINUS) TUMOR

Yolk sac tumor is similar to embryonal carcinoma in its vacuolated cytoplasm and malignant-appearing cells. The cytoplasm of these tumor cells contains large redstaining hyaline globules, which are also found free in the background. These globules contain alphafetoprotein (AFP), which can be also elevated in the serum of these patients. The background is bloody with tumor cell fragments and a ‘dirty’ appearance. An inflammatory component may be present (Figs 7-7 & 7-8). The presence of glomeruloid or Schiller-Duval bodies, which are the invagination of cells into a sinus or small space, signify the yolk sac nature of this tumor (Fig. 7-9).

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FIGURE 7-6 Benign cystic teratoma. This cell block shows benign epithelial glandular elements. The corresponding smear consisted of anucleated squames and benign squamous cells, proteinaceous debris, and mixed infl ammatory infiltrate. H&E stain, high magnification.

FIGURE 7-7 Yolk sac tumor. Papillary-like structure with large cells and prominent nucleoli. Infl ammation and mucoid material are present. Diff-Quik stain, high magnification.

EMBRYONAL CARCINOMA

Embryonal carcinoma is seen as large clusters and papillae of poorly differentiated cells with vacuolated cytoplasm. The nuclei are large with coarsely granular chromatin and prominent nucleoli (Fig. 7-10). The resemblance to poorly differentiated adenocarcinoma is significant, and tumor and/or serum markers may be necessary to identify these tumors as germ cell in origin.

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FIGURE 7-8 Yolk sac tumor. The tumor shows large cells with prominent nucleoli and intracytoplasmic hyaline globules. Multiple bizarre cell shapes are present. Papanicolaou stain, high magnification.

ANCILLARY STUDIES Immunohistochemistry may be helpful in confirming the diagnosis of germ cell tumors. Seminoma is highlighted by immunostain for c-kit and placental-like alkaline phosphatase (PLAP), while CD30 stains the embryonal component. AFP stains for yolk sac tumor. Molecular analysis of i(12p), which is characteristic of

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or respiratory tract carcinoma with a defining t(15;19). This tumor occurs in young people and can involve the area of the thymus. It is a poorly differentiated carcinoma showing varying degrees of squamous differentiation.

THYMIC NEUROENDOCRINE (CARCINOID) TUMORS CLINICAL FEATURES

FIGURE 7-9 Yolk sac tumor. A cell block of yolk sac tumor showing a Schiller-Duval body invaginating into a vascular space. Papanicolaou stain, high magnification.

Thymic neuroendocrine (carcinoid) tumors are a rare neoplasm of the anterior mediastinum. These tumors frequently exhibit a wide spectrum of histology and appear to follow a more aggressive behavior than their non-thymic counterparts. Primary neuroendocrine tumors may occur in the mediastinum and are characterized as atypical or malignant carcinoid tumors. Rarely, primary small cell carcinomas of the thymus may also occur. Carcinoid tumors that occur in the mediastinum, like pulmonary carcinoid, are thought to be of foregut origin. This disease of adults can have paraneoplastic symptoms and a minority of these tumors are associated with multiple endocrine neoplasia (MEN) type 1. Thymic carcinoids are more aggressive and have a poorer clinical outcome than do their

THYMIC NEUROENDOCRINE (CARCINOID) TUMORS – DISEASE FACT SHEET

FIGURE 7-10 Embryonal carcinoma. The smear shows large, undifferentiated epithelial cells with enlarged nuclei and conspicuous nucleoli. Papanicolaou stain, high magnification.

germ cell tumors, can be done on fresh tissue taken at the time of the FNA, either as a needle core or as an additional pass for cytologic material.

Definition ៉ A malignant tumor, cytologically similar to carcinoid tumors found at other sites Incidence ៉ Highest incidence is in the 4th to 5th decades of life

Gender and Age Distribution ៉ Three out of four patients are men Clinical Features ៉ Associated with Cushing syndrome and multiple endocrine

neoplasia (MEN) syndromes

DIFFERENTIAL DIAGNOSIS AND PITFALLS

៉ Presents as a large and lobulated mass in the anterior

mediastinum ៉ Patients may experience cough, dyspnea, superior vena cava

A feature common to germ cell tumors in cytology is the resemblance to poorly differentiated carcinoma, such as seen in the lung. Care must be taken to accurately diagnose germ cell tumors, which generally have a good prognosis with appropriate treatment, from poorly differentiated/undifferentiated midline carcinoma, where the prognosis is not favorable. Germ cell tumor and other midline tumors must be differentiated from the recently described lethal midline

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syndrome, fatigue, fever, and night sweats Prognosis and Treatment ៉ Metastasis is common (one-third with bone metastases) ៉ Thymic carcinoid associated with MEN syndrome is more

malignant in behavior ៉ Treatment is complete surgical resection ៉ Radiation and chemotherapy may have limited roles

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pulmonary counterparts, even when morphology is similar.

CYTOPATHOLOGIC FEATURES This tumor is composed of a single population of poorly cohesive, small, round to oval, bland-appearing cells with a distinctive ‘salt and pepper’ chromatin pattern (Fig. 7-11). Inconspicuous nucleoli and scant cytoplasm characterize carcinoid of the mediastinum and of any site (Figs 7-11 & 7-12). Rosettes and spindle cells may be present. The mitotic count is the primary tool for distinguishing typical from atypical carcinoid, but mitotic figures are often difficult to identify in cytologic material, even when they are multiple and obvious in the corresponding tissue. Additionally, it is not practical to count mitotic figures per high-power fields in cytology; therefore, we recommend the diagnosis of carcinoid on FNA material without an attempt to classify it into typical or atypical. The differential diagnosis of thymic or mediastinal carcinoids includes small cell carcinoma metastatic from, usually, lung.

ANCILLARY STUDIES Immunohistochemical markers such as chromogranin and synaptophysin must confirm the neuroendocrine nature of the cells. These tumors react with antibodies to cytokeratin and chromogranin A, as well as other neuroendocrine markers, including synaptophysin.

FIGURE 7-11 Thymic carcinoid tumor. Bland and loosely cohesive fragment of spindled cells, with fine chromatin. Nucleoli are not conspicuous. The chromatin pattern is distinctively ‘salt and pepper’. A vessel is seen in the mid to upper field. Diff-Quik stain, low magnification.

Parathyroid tumors may occur in this location and can be distinguished by their staining with antibody to parathormone. Lymphomas will be immunopositive for leukocyte common antigen, and germ cell tumors will react with immunostain for PLAP.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Carcinoid tumors may be distinguished from thymomas by the lack of background lymphocytes, rosette formation, granularity of cytoplasm, and ‘salt and pepper’ chromatin (Fig. 7-12).

THYMIC NEUROENDOCRINE (CARCINOID) TUMORS – PATHOLOGIC FEATURES Cytopathologic Findings

MEDIASTINAL LYMPHOMAS

៉ Composed of single population of poorly cohesive, small, round

to oval, bland-appearing cells with a distinctive ‘salt and pepper’ chromatin pattern ៉ Inconspicuous nucleoli and scant cytoplasm characterize carcinoid of the mediastinum and of any site ៉ Rosettes and spindle cells may be present Ancillary Studies ៉ Tumors react with antibodies to cytokeratin and chromogranin

A, as well as other neuroendocrine markers, including synaptophysin

CLINICAL FEATURES Malignant lymphoma is the most common primary middle mediastinal tumor, but occurs more frequently in the anterior and superior mediastinum overall. Most mediastinal lymphomas are Hodgkin lymphomas, usually the nodular sclerosing subtype.

Differential Diagnosis and Pitfalls ៉ The differential diagnosis of thymic or mediastinal carcinoids

includes small cell carcinoma metastatic from, usually, lung, and lymphomas ៉ Lymphomas will be immunopositive for leukocyte common antigen, and germ cell tumors will react with immunostains for PLAP

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CYTOPATHOLOGIC FEATURES In Hodgkin lymphoma, the FNA may be scant due to sampling of the collagen and it may be difficult to identify the necessary Reed-Sternberg (R-S) cells. Nodular lymphocyte-predominant Hodgkin disease (NLPHD)

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FIGURE 7-12 Thymic carcinoid tumor. A cellular smear with cohesive fragments of monotonous neoplastic cells with round to ovoid nuclei, and fine chromatin. Nucleoli are not conspicuous. Papanicolaou stain, low magnification.

THYMIC LYMPHOMAS (HODGKIN AND NON-HODGKIN TYPES) – DISEASE FACT SHEET Definition ៉ The three most common types of mediastinal lymphomas include

nodular sclerosing Hodgkin disease, large B-cell lymphoma, and lymphoblastic lymphoma ៉ Hodgkin disease (HD) is a lymphoma with large abnormal cells termed Reed-Sternberg (R-S) cells and Hodgkin cells present in a mixed background of lymphocytes and mixed inflammatory cells ៉ Lymphoblastic lymphoma is the most common lymphoma of children and most arise in the thymus Incidence ៉ Malignant lymphoma is the most common primary neoplasm of

the middle mediastinum, but in absolute numbers it is more common in the anterior and superior mediastinum ៉ HD is the most common mediastinal lymphoma (70%) and nodular sclerosing is the most common subtype ៉ HD has an incidence of 2–4 per 100,000 Gender and Age Distribution ៉ HD: slightly more common in males; peak age, 15 to 35 years ៉ Non-Hodgkin lymphoma: highest incidence is in white men with a

mean age of 55 years ៉ Lymphoblastic lymphoma: mean age, 28 years

Clinical Features ៉ Subclassification of HD is less important now than earlier (age

and stage most important) ៉ Systemic symptoms (fever, night sweats, weight loss) carry worse

prognosis Prognosis ៉ HD is curable in >90% with stage I–II disease ៉ Lymphoblastic lymphoma is highly aggressive

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has somewhat pleomorphic, lobated, ‘popcorn-like’ R-S cell variants (CD30- and CD15-negative), while classical Hodgkin lymphoma contains the highly pleomorphic classic R-S cells (CD30- and CD15-positive). Smears may show large abnormal lymphoid cells, crush artifact, and several R-S cells (Fig. 7-13). The background present in the smears is similar to that in Hodgkin lymphoma from any other site, with a heterogeneous population of lymphocytes with plasma cells and eosinophils (Fig. 7-14). The presence of lymphoglandular bodies is often reported in the background of air-dried smears in lymphoma. These pinched-off bits of cytoplasm can be found with all stains and indicate a heavy lymphoid infiltrate. They make no comment on benign or malignant conditions. We do not find them of particular help in classifying lymphomas or even in recognizing lymphoid populations, as cytoplasm fragments from any other cell can mimic lymphoglandular bodies. Large cell, B-cell lymphomas also occur, and may be extranodal or primary in the thymus. All cell types present are lymphoid, in contrast to the picture of lymphoid and epithelial cells in thymoma. Large cell lymphoma has large, vesicular nuclei and often-irregular nuclear membranes (Figs 7-15–7-17). These large lymphoid cells may be mixed with smaller reactive cells. Lymphomas on cytology are rarely of a single population of cells and the presence of reactive cells and tingible-body macrophages should not distract the observer from the presence of the diagnostic large malignant lymphocytes (Figs 7-15 & 7-16). Lymphoblastic lymphoma is the most common lymphoma of children and most arise in the thymus. These tumors are of pre-T-cell lineage, present with respiratory distress, and are often fatal. The diagnostic feature of these lymphomas is lymphoid blasts, which are

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FIGURE 7-13 Hodgkin lymphoma. Note the large abnormal lymphoid cells, crush artifact, and several Reed-Sternberg cells. Diff-Quik stain, low magnification.

FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 7-14 Hodgkin lymphoma. This smear shows a classic Reed-Sternberg cell (left of center) and polymorphous background. Diff-Quik stain, low magnification.

THYMIC LYMPHOMA (HODGKIN AND NON-HODGKIN TYPES) – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Hodgkin disease (HD): ៉ Arises in thymus or lymph nodes, almost never extranodal ៉ Reed-Sternberg (R-S) cells contain bilobed nuclei with prominent eosinophilic nuclei ៉ R-S cells may be rare; they are necessary but insufficient for diagnosis ៉ Background important: lymphocytes, plasma cells, eosinophils, histiocytic ៉ +/− cellular (sparse aspirate from a large node is suspicious in itself) ៉ Inverse relationship between number of R-S cells and lymphocytes ៉ Metachromatic material present in smears ៉ Non-Hodgkin lymphoma: ៉ Large vesicular nuclei ៉ Nucleoli prominent but not macro ៉ Irregular (cleaved) or smooth (non-cleaved) membranes ៉ Large cells may be mixed with smaller cells ៉ Cellularity may be quite limited when sclerotic Ancillary Studies ៉ Classical HD: R-S cells are positive for CD15 and CD30, and negative for CD20 ៉ Flow cytometry is helpful for the classification of non-Hodgkin lymphoma

FIGURE 7-15 Non-Hodgkin lymphoma. Monotonous population of malignant lymphocytes displaying occasional conspicuous nucleoli. Papanicolaou stain, low magnification.

characterized by a delicate chromatin pattern and irregular nuclear outlines. Nucleoli are not prominent. Necrosis, mitosis, eosinophils, granulomas, and macrophages may accompany the blasts. Since these lymphomas infiltrate thymic tissue, normal thymic components may be present in the aspirates.

Differential Diagnosis and Pitfalls ៉ Differential diagnosis includes thymoma, and germinoma ៉ Cleaved lymphocytes may mimic cells in thymoma but all cell

ANCILLARY STUDIES

types here are lymphoid ៉ Sclerotic large cell lymphomas are common in the mediastinum

and may mimic HD ៉ Chronic sclerosing mediastinitis can be confused with tumors having a significant sclerotic or collagenous component such as nodular sclerosing HD

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Flow cytometric studies can be done on cytologic material; therefore the importance of on-site cytopathologic evaluation is critical. Cell blocks may be prepared and appropriate immunostain may be used to further classify and subtype the lymphomas. These details are discussed in greater length in Chapter 3.

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NEUROGENIC TUMORS – DISEASE FACT SHEET Definition and Incidence ៉ Neurogenic tumors account for the majority of tumors arising in the posterior mediastinum ៉ Neurogenic tumors include nerve root tumors such as schwannoma and neurofibroma, and sympathetic ganglion tumors such as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma ៉ Paragangliomas may rarely present as posterior mediastinal masses ៉ Schwannoma is the most common neurogenic tumor of the mediastinum; it is generally solitary and large, with cystic change or calcification common Gender and Age Distribution

FIGURE 7-16 Non-Hodgkin lymphoma. High-power view of monotonous population of large malignant lymphocytes with prominent nucleoli. Papanicolaou stain, high magnification.

៉ 20% of all adult mediastinal neoplasms ៉ 40% of all pediatric mediastinal neoplasms

Clinical Features ៉ 95% of these tumors in adults are benign and are usually

asymptomatic ៉ In children, most neurogenic tumors are malignant

Prognosis ៉ 80% of these tumors are benign

Ganglioneuroblastoma occurs in children and is a neuroblastoma with the presence of ganglion cell differentiation; ganglioneuroma is a tumor of adults and is composed of mature ganglion cells. Ganglia have large prominent nucleoli and can be bi- or multinucleated. On a cursory inspection, they can be mistaken for malignant cells.

FIGURE 7-17 Non-Hodgkin lymphoma. High-power view of malignant lymphoma cells. Note mitoses and cleaved nuclei. Diff-Quik stain, high magnification.

NEUROGENIC TUMORS CLINICAL FEATURES Neurogenic tumors are most frequently located in the posterior mediastinum and most are malignant sympathetic tumors of childhood. Nerve sheath tumors and gangliomas are more commonly found in the adult population. When benign, these neurogenic tumors are often paucicellular, making FNA diagnosis difficult. Neuroblastoma appears as atypical small round blue cell tumor and has the same differential diagnosis and work-up as elsewhere in the body, remembering that small cell carcinoma is not expected in children.

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CYTOPATHOLOGIC FEATURES Neurofibroma and schwannoma both have bland spindle cells loosely arranged and may be calcified. Schwannomas are more common, and when there is degeneration or atypia present, they can be mistaken for sarcoma or melanoma. The smears may show an extensively degenerative background, fragile cytoplasm, and occasional large atypical cells (Fig. 7-18). Antoni A and B growth patterns can often be seen in cellular cytology preparations of schwannomas (Fig. 7-19). However, malignant schwannoma and malignant peripheral nerve sheath tumors do occur in the posterior mediastinum and they can be recognized by necrosis, mitoses, and nuclear atypia (Figs 7-20–7-22). Paragangliomas can arise in the superior or anterior mediastinum and are very vascular tumors of the sympathetic nerve chain. The tumors are composed of cells grouped into ball-like arrangements, the ‘Zellballen’. The tumor has large cells with generous, pale, somewhat granular eosinophilic cytoplasm. The nuclei of these benign cells may show marked atypia and

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FIGURE 7-18 Schwannoma. Smear showing degenerative background, spindled cells with fragile cytoplasm, and occasional large pleomorphic cells. DiffQuik stain, high magnification.

A

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FIGURE 7-20 Malignant peripheral nerve sheath tumor. Note the bizarre pleomorphic cells. This tumor was located in the posterior mediastinum of an adult. The differential diagnosis includes sarcoma NOS and sarcomatoid carcinoma. Diff-Quik stain, high magnification.

B

FIGURE 7-19 Schwannoma. A, Large tissue fragment from an FNA of a schwannoma, showing Antoni A and B areas. B, Higher power of the spindled cells with uniform oval nuclei. Papanicolaou, low and high magnification.

FIGURE 7-21 Malignant peripheral nerve sheath tumor. Note the spindle and large atypical cells. The appearance is that of a malignant spindle cell neoplasm, and clinical history and ancillary studies are vital for an accurate diagnosis. Papanicolaou stain, low magnification.

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FIGURE 7-22 Malignant peripheral nerve sheath tumor. Note the bizarre multinucleate giant cell on the left and sarcomatoid appearance on the right. Papanicolaou stain, low magnification (left); H&E stain (right).

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NEUROGENIC TUMORS – PATHOLOGIC FEATURES

METASTATIC TUMORS – DISEASE FACT SHEET

Cytopathologic Findings

Definition

៉ Schwannomas: ៉ Tumor has cellular (Antoni A) and degenerated/myxoid

៉ Metastatic lesions are the common cause of a mediastinal mass in

៉ ៉ ៉ ៉ ៉ ៉ ៉ ៉

(Antoni B) areas Variable cellularity with large thick fragments, smaller clusters, and single cells Cells are elongated and spindle-shaped and may palisade Uniform, round to plump to oval nuclei with fine chromatin and inconspicuous nucleoli Regressive or degenerative changes and increased cellularity possible Intranuclear cytoplasmic invaginations can be seen Cytoplasm is fragile and sometimes strips away Ground substance is fibrillar No mitoses or necrosis

Ancillary Studies ៉ Immunohistochemistry for S-100 may be helpful when confirming the neurogenic origin of these tumors Differential Diagnosis and Pitfalls ៉ Cytologic atypia, mitosis, necrosis – think malignancy

adults ៉ FNA can establish the diagnosis and subtype metastatic lesions to

the mediastinum ៉ This may be a secondary lesion in a patient with a previous

history of cancer or a new presentation Incidence ៉ Dependent on the tumor type ៉ Small cell carcinoma is the most common type

Gender and Age Distribution ៉ Dependent on the tumor type

Clinical Features ៉ Most common source of mediastinal metastasis is small cell

carcinoma of lung ៉ Associated with multiple endocrine neoplasia type 1

Prognosis and Treatment ៉ Metastatic small cell carcinoma is aggressive with extensive

metastases ៉ Treatment for small cell carcinoma: radiation therapy and

chemotherapy

enlargement. Small amounts of focal necrosis can be present even in benign tumors, and the tumor cells can resemble the cells of carcinoid, but carcinoids lack the usual atypia of paragangliomas. Paragangliomas have been misdiagnosed on cytology material as anaplastic carcinoma with giant cells and that was thought to be due to the presence of vascular-rich papillary structures, acinar-glandular structures, cellular pleomorphism, the prominent nucleoli, and the ‘squamoid’ appearance of the cytoplasm. Mesenchymal tumors are rare in the mediastinum and resemble their counterparts in other body sites.

METASTATIC TUMORS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Variable, but usually overtly malignant features are needed to document malignancy Ancillary Studies ៉ Immunohistochemical stains for defining the origin of the lesion,

such as TTF (lung), CK7/CK20 profile, melanoma markers, S-100, germ cell markers (PLAP, CD30), lymphoma markers Differential Diagnosis and Pitfalls

METASTATIC LESIONS

៉ FNA can establish the diagnosis and subtype metastatic lesions to

the mediastinum ៉ Other common metastatic lesions include breast, thyroid, head and

FNA is highly reliable for establishing a diagnosis of metastatic lesions in the mediastinum. The aspirate and the material collected concurrently, may be helpful in establishing a new diagnosis or used to confirm that a secondary lesion is metastatic from a previously known primary. The material may also be useful for molecular diagnostic testing, such as the evaluation of the recently discovered epidermal growth factor receptor (EGFR) mutation, to ascertain therapeutic efficacy of tyrosine kinase inhibitors Studies have highlighted that most metastatic lesions to mediastinal lymph nodes are derived from the lung and that small cell carcinoma represents one of the most common metastatic lesions to the mediastinum. Typical

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neck, kidney, prostate, and testicular tumors, and melanoma

features of small cell carcinoma seen in the primary lesion are present here, including crush artifact and nuclear molding (Figs 7-23 & 7-24). Squamous cell carcinoma from the head and neck or a lung primary may present as a metastatic lesion in the mediastinum (Fig. 7-25). Other common metastatic lesions include breast, thyroid, kidney, prostate, and testicular tumors, and melanoma.

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FIGURE 7-23 Metastatic small cell carcinoma. Smear depicts cells with prominent nuclear molding, scant cytoplasm, mitoses, and nuclear crush artifact. This is indistinguishable from a primary mediastinal small cell carcinoma. Diff-Quik stain, low magnification.

FIGURE 7-24 Metastatic small cell carcinoma. Characteristic features of small cell carcinoma, with fine nuclear membranes, powdery chromatin, and inconspicuous nucleoli. Papanicolaou stain, high magnification.

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FIGURE 7-25 Metastatic squamous cell carcinoma. Smear showing bizarre, pleomorphic cells with dark nuclear chromatin, thick opaque cytoplasm, and conspicuous nucleoli. Papanicolaou stain, high magnification.

SUGGESTED READINGS Introduction/Mediastinal Masses Belfiore G, Camera L, Moggio G, Vetrani A, Fraioli G, Salvatore M. Middle mediastinum lesions: preliminary experience with CT-guided fine-needle aspiration biopsy with a suprasternal approach. Radiology 1997;202: 870–873. Blegvad S, Lippert H, Simper LB, Dybdahl H. Mediastinal tumours. A report of 129 cases. Scand J Thorac Cardiovasc Surg 1990;24:39–42. Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest 2005;128:2893–2909. Geisinger KR. Differential diagnostic considerations and potential pitfalls in fine-needle aspiration biopsies of the mediastinum. Diagn Cytopathol 1995;13:436–442. Panelli F, Erickson RA, Prasad VM. Evaluation of mediastinal masses by endoscopic ultrasound and endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol 2001;96:401–408. Powers CN, Silverman JF, Geisinger KR, Frable WJ. Fine-needle aspiration biopsy of the mediastinum. A multi-institutional analysis. Am J Clin Pathol 1996;105:168–173. Shabb NS, Fahl M, Shabb B, Haswani P, Zaatari G. Fine-needle aspiration of the mediastinum: a clinical, radiologic, cytologic, and histologic study of 42 cases. Diagn Cytopathol 1998;19:428–436. Singh HK, Silverman JF, Powers CN, Geisinger KR, Frable WJ. Diagnostic pitfalls in fine-needle aspiration biopsy of the mediastinum. Diagn Cytopathol 1997;17:121–126. Sterrett G, Whitaker D, Shilkin KB, Walters MN. The fine needle aspiration cytology of mediastinal lesions. Cancer 1983;51:127–135. Wakely PE Jr. Cytopathology-histopathology of the mediastinum: epithelial, lymphoproliferative, and germ cell neoplasms. Ann Diagn Pathol 2002;6:30–43. Wakely PE Jr. Cytopathology-histopathology of the mediastinum II. Mesenchymal, neural, and neuroendocrine neoplasms. Ann Diagn Pathol 2005;9:24–32. Thymic Lesions Ali SZ, Erozan YS. Thymoma. Cytopathologic features and differential diagnosis on fine needle aspiration. Acta Cytol 1998;42:845–854.

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Bangerter M, Behnisch W, Griesshammer M. Mediastinal masses diagnosed as thymus hyperplasia by fine needle aspiration cytology. Acta Cytol 2000;44:743–747. Chhieng DC, Rose D, Ludwig ME, Zakowski MF. Cytology of thymomas: emphasis on morphology and correlation with histologic subtypes. Cancer 2000;90:24–32. Dadmanesh F, Sekihara T, Rosai J. Histologic typing of thymoma according to the new World Health Organization classification. Chest Surg Clin N Am 2001;11:407–420. Dahlgren S, Sandstedt B, Sundstrom C. Fine needle aspiration cytology of thymic tumors. Acta Cytol 1983;27:1–6. Morgenthaler TI, Brown LR, Colby TV, Harper CM Jr, Coles DT. Thymoma. Mayo Clin Proc 1993;68:1110–1123. Okumura M, Ohta M, Miyoshi S, et al. Oncological significance of WHO histological thymoma classification. A clinical study based on 286 patients. Jpn J Thorac Cardiovasc Surg 2002;50:189–194. Ritter JH, Wick MR. Primary carcinomas of the thymus gland. Semin Diagn Pathol 1999;16:18–31. Sherman ME, Black-Schaffer S. Diagnosis of thymoma by needle biopsy. Acta Cytol 1990;34:63–68. Shin HJ, Katz RL. Thymic neoplasia as represented by fine needle aspiration biopsy of anterior mediastinal masses. A practical approach to the differential diagnosis. Acta Cytol 1998;42:855–864. Suster S, Moran CA. Primary thymic epithelial neoplasms showing combined features of thymoma and thymic carcinoma. A clinicopathologic study of 22 cases. Am J Surg Pathol 1996;20:1469–1480. Tao LC, Pearson FG, Cooper JD, Sanders DE, Weisbrod G, Donat EE. Cytopathology of thymoma. Acta Cytol 1984;28:165–170. Germ Cell Tumors Chhieng DC, Lin O, Moran CA, et al. Fine-needle aspiration biopsy of nonteratomatous germ cell tumors of the mediastinum. Am J Clin Pathol 2002;118:418–424. Kiffer JD, Sandeman TF. (Primary malignant mediastinal germ cell tumours: a literature review and a study of 18 cases. Australas Radiol 1999; 43:58–68. Kwon MS. Aspiration cytology of mediastinal seminoma: report of a case with emphasis on the diagnostic role of aspiration cytology, cell block and immunocytochemistry. Acta Cytol 2005;49:669–672.

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218 Moran CA, Suster S, Koss MN. Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum – a clinicopathologic and immunohistochemical study of 64 cases. Cancer 1997;80:699–707. Moran CA, Suster S, Przygodzki RM, Koss MN. Primary germ cell tumors of the mediastinum: II. Mediastinal seminomas – a clinicopathologic and immunohistochemical study of 120 cases. Cancer 1997;80:691– 698. Motoyama T, Yamamoto O, Iwamoto H, Watanabe H. Fine needle aspiration cytology of primary mediastinal germ cell tumors. Acta Cytol 1995;39: 725–732. Weidner N. Germ-cell tumors of the mediastinum. Semin Diagn Pathol 1999;16:42–50. Thymic Neuroendocrine (Carcinoid) Tumors Caceres W, Baldizon C, Sanchez J. Carcinoid tumor of the thymus: a unique neoplasm of the mediastinum. Am J Clin Oncol 1998;21:82–83. Moran CA, Suster S. Spindle-cell neuroendocrine carcinomas of the thymus (spindle-cell thymic carcinoid): a clinicopathologic and immunohistochemical study of seven cases. Mod Pathol 1999;12:587–591. Nichols GL Jr, Hopkins MB 3rd, Geisinger KR. Thymic carcinoid. Report of a case with diagnosis by fine needle aspiration biopsy. Acta Cytol 1997;41:1839–1844. Slagel DD, Powers CN, Melaragno MJ, Geisinger KR, Frable WJ, Silverman JF. Spindle-cell lesions of the mediastinum: diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 1997;17:167–176. Wick MR, Scheithauer BW. Thymic carcinoid. A histologic, immunohistochemical, and ultrastructural study of 12 cases. Cancer 1984;53: 475–484. Mediastinal Lymphomas Friedman HD, Hutchison RE, Kohman LJ, Powers CN. Thymoma mimicking lymphoblastic lymphoma: a pitfall in fine-needle aspiration biopsy interpretation. Diagn Cytopathol 1996;14:165–169; discussion 169– 171. Sheibani K, Nathwani BN, Winberg CD, et al. Antigenically defined subgroups of lymphoblastic lymphoma. Relationship to clinical presentation and biologic behavior. Cancer 1987;60:183–190. Silverman JF, Raab SS, Park HK. Fine-needle aspiration cytology of primary large-cell lymphoma of the mediastinum: cytomorphologic findings with potential pitfalls in diagnosis. Diagn Cytopathol 1993;9:209–214; discussion 214–215. Strickler JG, Kurtin PJ. Mediastinal lymphoma. Semin Diagn Pathol 1991;8:2–13. Yu GH, Salhany KE, Gokaslan ST, Cajulis RS, De Frias DV. Thymic epithelial cells as a diagnostic pitfall in the fine-needle aspiration diagnosis of primary mediastinal lymphoma. Diagn Cytopathol 1997;16:460– 465.

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FINE NEEDLE ASPIRATION CYTOLOGY Neurogenic Tumors de Montpreville VT, Mussot S, Gharbi N, Dartevelle P, Dulmet E. Paraganglioma with ganglioneuromatous component located in the posterior mediastinum. Ann Diagn Pathol 2005;9:110–114. Geisinger KR. Differential diagnostic considerations and potential pitfalls in fine-needle aspiration biopsies of the mediastinum. Diagn Cytopathol 1995;13:436–442. Khanlou H, Khanlou N, Eiger G. Schwannoma of posterior mediastinum: a case report and concise review. Heart Lung 1998;27:344–347. Marchevsky AM. Mediastinal tumors of peripheral nervous system origin. Semin Diagn Pathol 1999;16:65–78. Slagel DD, Powers CN, Melaragno MJ, Geisinger KR, Frable WJ, Silverman JF. Spindle-cell lesions of the mediastinum: diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 1997;17:167–176. Strollo DC, Rosado-de-Christenson ML, Jett JR. Primary mediastinal tumors: part II. Tumors of the middle and posterior mediastinum. Chest 1997;112:1344–1357. Topcu S, Alper A, Gulhan E, Kocyigit O, Tastepe I, Cetin G. Neurogenic tumours of the mediastinum: a report of 60 cases. Can Respir J 2000;7:261–265. Wakely PE Jr. Cytopathology-histopathology of the mediastinum II. Mesenchymal, neural, and neuroendocrine neoplasms. Ann Diagn Pathol 2005;9:24–32. Metastatic Lesions Al-Haddad M, Wallace MB. Molecular diagnostics of non-small cell lung cancer using mediastinal lymph nodes sampled by endoscopic ultrasound-guided needle aspiration. Cytopathology 2006;17:3–9. Bavi P, Shet T, Gujral S. Malignant melanoma of mediastinum misdiagnosed as a spindle cell thymoma in a fine needle aspirate: a case report. Acta Cytol 2005;49:424–426. Blanco N, Kirgan DM, Little AG. Metastatic squamous cell carcinoma of the mediastinum with unknown primary tumor. Chest 1998;114:938– 940. Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest 2005;128:2893–2909. Lau CL, Bentley RC, Gockerman JP, Que LG, D’Amico TA. Malignant melanoma presenting as a mediastinal mass. Ann Thorac Surg 1999;67: 851–852. Saad RS, Landreneau RJ, Liu Y, Silverman JF. Utility of immunohistochemistry in separating thymic neoplasms from germ cell tumors and metastatic lung cancer involving the anterior mediastinum. Appl Immunohistochem Mol Morphol 2003;11:107–112. Singh HK, Silverman JF, Powers CN, Geisinger KR, Frable WJ. Diagnostic pitfalls in fine-needle aspiration biopsy of the mediastinum. Diagn Cytopathol 1997;17:121–126. Sinner WN. Directed fine needle biopsy of anterior and middle mediastinal masses. Oncology 1985;42:92–96. Sterrett G, Whitaker D, Shilkin KB, Walters MN. The fine needle aspiration cytology of mediastinal lesions. Cancer 1983;51:127–135.

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8

Liver Syed Z Ali

• Natasha Rekhtman

Along with the pancreas, the liver is one of the most common visceral organs targeted by fine needle aspiration (FNA). The usual clinical scenario is that of an asymptomatic patient presenting with a solitary or multiple liver lesions. In a significant number of cases, there is no prior history of malignancy and the liver lesion is a totally incidental finding, therefore adding to the diagnostic challenge when such lesion is aspirated. Liver is approached through a percutaneous transabdominal route with radiologic guidance. At Johns Hopkins, almost all liver lesions are aspirated via ultrasound guidance, which is a much faster and safer procedure than computed tomography (CT) guidance and offers real-time visualization of the needle positioning and aspiration. All FNAs are evaluated on-site by a cytopathologist for adequacy. Material is triaged for ancillary studies (flow cytometry, microbial culture, etc.) and, if needed and technically feasible, the radiologist is asked for tissue core biopsy as well. As in other body sites, it is extremely important to be familiar with the appearances of normal cells comprising a liver FNA (Table 8-1; Figs 8-1 & 8-2). It is imperative to be aware of the exact location of the lesion in the liver since unusual cell types (representing needle contaminants; Table 8-2) can be seen in addition to hepatic tissue; for example, gastric-type epithelium may be observed in lesions of the left hepatic lobe if the needle traverses the stomach wall, or respiratory-type epithelium may be seen in lesions located deep in the hepatic dome (Fig. 8-3). Another uncommon cell type which may add to diagnostic confusion to an inexperienced interpreter is mesothelium, often seen as a flat, monolayered sheet with characteristic spacing in between individual cells. Liver FNA is an extremely safe procedure in experienced hands, with rare morbidity (Table 8-3). Mortality is also extremely rare, having been reported in the literature as isolated case reports. In our experience, we have seen only two cases of hepatic FNA that led to significant intraperitoneal bleeding requiring some amount of intensive care. Both cases had occurred in patients with large hepatocellular carcinomas. A recent review of the literature on this subject revealed a mortality rate less than 0.1%. There are relatively rare contraindications for liver FNA in view of an overall excellent safety profile of this procedure (Table 8-4).

In our experience, benign hepatic entities are often more taxing to diagnose on FNA, perhaps because they are rarer than malignancies in the liver and also because of a relative lack of characteristic findings on cytopathologic evaluation (Table 8-5).

NON-NEOPLASTIC DISEASES OF THE LIVER MACROREGENERATIVE NODULE CLINICAL FEATURES Macroregenerative nodules (MRNs), also referred to as adenomatous hyperplasia, are, in essence, large regenerative nodules arising in cirrhotic livers. Some authors have applied the size cut-off of 0.8 cm to distinguish these lesions from typical nodules of macronodular cirrhosis. MRNs are found in up to 50% of cirrhotic livers. MRNs are usually asymptomatic and are discovered incidentally during the radiographic surveillance of patients with cirrhosis. Serum alpha-fetoprotein (AFP) is not increased. MRNs are present in the population with cirrhosis: incidence increases with advancing age, and men are

MACROREGENERATIVE NODULE – DISEASE FACT SHEET Incidence ៉ Present in up to 50% of cirrhotic livers

Gender and Age Distribution ៉ Reflects the demographic of cirrhosis ៉ After age 60 in the USA; younger age in Asia and Africa ៉ Men > women (worldwide)

Prognosis ៉ Premalignant potential is controversial ៉ Up to 25% of lesions regress

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FIGURE 8-1 Normal liver. Small fragment of hepatocytes with polygonal cell shapes, granular cytoplasm, and small nucleoli. Focal bile staining is evident. Papanicolaou stain, high power.

FIGURE 8-3 Needle contamination. Diaphragmatic skeletal muscle in an FNA of a hepatic dome lesion. Diff Quik stain, intermediate power.

TABLE 8-2 Normal Non-liver Cell Component (Needle Contaminants) • • • •

Mesothelium Respiratory epithelium Gastrointestinal tract epithelium Skeletal muscle and skin

TABLE 8-3 FIGURE 8-2 Normal liver. Biliary epithelium with a more cohesive appearance of the cells, high N/C ratio, and glandular formations (middle of the field). Numerous hepatocytes are present in the background. Diff Quik stain, high power.

TABLE 8-1 Liver – Normal Cytologic Constituents • • • • •

Hepatocytes Biliary epithelium Endothelium Kupffer’s cells Pigments: • Bile • Hemosiderin • Lipofuscin

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Complications of Hepatic FNA (n = number of cases reported in the English-language literature) • Tumor seeding of the needle tract (n = 12): • Hepatocellular carcinoma [HCC] (n = 9) • Metastatic colonic adenocarcinoma (n = 3) • Bleeding (n = 8): • HCC (n = 5) • Hemangioma (n = 2) • Angiosarcoma (n = 1) • Bile peritonitis (n = 1) • Carcinoid crisis (n = 1) • Lymphorrhea (n = 1) • Biliary venous fistula (n = 1) • Sudden hypoglycemia – clear cell HCC (n = 1)

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TABLE 8-4 Contraindications of Hepatic FNA • Bleeding diathesis • Difficult anatomic location of the lesion (such as close proximity to vessels) • Hydatid disease

TABLE 8-5 Benign Hepatic Diseases on FNA • Non-neoplastic: • Granulomatous disease • Infection: • Hydatid disease • Other (amebic, schistosomiasis) • Congenital cysts • Focal nodular hyperplasia (FNH) • Cirrhosis • Benign neoplasm: • Hepatic adenoma • Hemangioma

affected more frequently than women. The premalignant potential of MRNs is a controversial subject. It is generally believed that MRNs are not associated with an increased risk of hepatocellular carcinoma (HCC), and up to 25% of lesions regress on radiographic followup. MRNs may pose a challenge differentiating them clinically and pathologically from HCC. Patients with MRNs are followed with more frequent radiographic studies.

PATHOLOGIC FEATURES Grossly, MRNs are similar in appearance to the surrounding liver, although more pronounced bile staining may be present. Lesions are commonly multiple, and can measure over 5 cm. MRNs are circumscribed by a rim of fibrous tissue, analogous to the usual smaller nodules in macronodular cirrhosis. Histologically, MRNs are indistinguishable from the surrounding liver: cell plates are of normal thickness (less than two cells), reticulin network is intact, and cytologic atypia is absent or minimal. Portal tracts are present, although they may be decreased in number and usually show architectural distortion. Cytopathologic findings are non-specific and may require intact tissue architecture for a definitive diagnosis. Therefore, in this setting, a core biopsy accompanying the FNA is extremely helpful (Figs 8-4 & 8-5).

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FIGURE 8-4 Nodular regenerative hyperplasia. Disorganized fragment of liver tissue. Cells display prominent nucleoli. However, there is lack of vascular proliferation and single cells. Papanicolaou stain, low power.

MACROREGENERATIVE NODULE – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Reactive hepatocytes (high N/C ratio, often prominent nucleoli) ៉ Higher than normal amount of biliary epithelium ៉ Varying amount of fibroconnective tissue fragments ៉ Marked focal atypia of hepatocytic or biliary epithelium ៉ Varying amount of lympho-mononuclear cells ៉ Cholestasis ៉ Focal necrosis (rare) Histopathologic Findings ៉ Gross: ៉ Usually multiple lesions ៉ Can measure over 5 cm ៉ Background cirrhotic liver ៉ Microscopic: ៉ Indistinguishable from surrounding liver ៉ Normal cell plates (<2 cells thick) ៉ Reticulin network intact ៉ Cytologic atypia absent or minimal ៉ Portal tracts present but decreased and distorted

Ancillary Studies ៉ CD34: no endothelial cell wrapping (unlike hepatocellular carcinoma [HCC]) ៉ Reticulin stain: reticulin framework intact (unlike HCC) Differential Diagnosis and Pitfalls ៉ Well-differentiated HCC: like MRN, arises in cirrhotic liver;

increased cell plate thickness (>2 cells thick); disrupted reticulin framework; cytologic atypia present, but may be minimal ៉ Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HA): distinction impossible based on cytology alone; arise in non-cirrhotic liver; FNH – central scar, fibrous septae with bile ducts and infl ammation; HA – history of oral contraceptive use, absent bile ducts

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ducts are absent in HA, whereas they are present in MRN.

FOCAL NODULAR HYPERPLASIA CLINICAL FEATURES

FIGURE 8-5 Nodular regenerative hyperplasia. Trabecular arrangement of hepatocytes displaying atypia. Although the N/C ratio is low, the cells have macronucleoli. Papanicolaou stain, high power.

ANCILLARY STUDIES Immunoperoxidase staining has a limited role. CD34 may be used to help differentiate MRN from HCC: CD34 highlights endothelial cell wrapping in HCC, whereas this feature is absent in MRNs. Some studies (including our own) have demonstrated that expression of proliferation markers (Ki67 and PCNA) and p53 is higher in HCC as compared to MRN. Special stain for reticulin is helpful in distinguishing MRN from HCC: reticulin stain highlights a disrupted reticulin network in HCC, whereas reticulin network in MRN is preserved.

An uncommon benign lesion, focal nodular hyperplasia (FNH) is characterized by hyperplastic hepatocytes and associated stellate scar. The lesion occurs predominantly in adult women (3rd to 5th decades of life; M : F = 8 : 1); however, cases have been reported in children. It has been recently suggested that FNH results from a vascular malformation which causes a hyperplastic hepatocellular reaction. A histopathogenetic relationship with oral contraceptives (OCPs) has been suggested. In contrast to hepatocellular adenoma, OCPs are not directly related to the initial development of FNH. However, it appears that OCPs cause subsequent increase in vascularity and enlargement of FNH, which leads to an increased risk of rupture. Approximately 80% of FNH are solitary, and 80% are clinically asymptomatic. In symptomatic cases, the clinical presentation includes palpable mass, pain or discomfort, and, rarely, manifestations of portal hypertension. Unlike hepatocellular adenoma, FNH rarely if ever results in hemoperitoneum. Liver function tests (including serum AFP) are within normal limits. FNH is treated by local or segmental liver resection. Small lesions or lesions that are deep seated often do not require surgical intervention. Prognosis is excellent and risk of complications (rupture or hemorrhage) for unresected lesions is extremely low. Radiologic studies may show the central scar in 65% of the cases. Enhanced magnetic resonance imaging (MRI) is considered the imaging modality of choice for FNH, with a high sensitivity and specificity, often making a tissue diagnosis unnecessary in these cases.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The most important differential diagnosis for MRN is a well-differentiated hepatocellular carcinoma (WDHCC). Both MRN and WD-HCC arise in a cirrhotic liver and may look identical radiographically. The distinction is based primarily on an increased cellplate thickness and accompanying loss of reticulin framework in HCC. Cytologic atypia, if present, favors HCC, but atypical features may be subtle in welldifferentiated cases. MRN is difficult or impossible to definitively distinguish from hepatocellular adenoma (HA) and focal nodular hyperplasia (FNH) based on cytologic examination alone. Clinical features may be helpful: in contrast to MRN, both FNH and HA arise in non-cirrhotic liver. In addition, FNH frequently displays a central scar, which may be apparent radiographically. Finally, bile

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FOCAL NODULAR HYPERPLASIA – DISEASE FACT SHEET Incidence ៉ Uncommon

Gender and Age Distribution ៉ Male to female ratio is 8 : 1 ៉ Adults (usually 30–50 years old)

Clinical Features ៉ Normal AFP

Prognosis ៉ Benign; no known association with hepatocellular carcinoma ៉ Hemoperitoneum rare (unlike hepatocellular adenoma)

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PATHOLOGIC FEATURES Grossly, FNH has a very characteristic appearance: circumscribed, bulging, lobulated, with a firm to rubbery consistency and multinodular cut surface due to multiple stellate scars. Most lesions present as a solitary mass and measure less than 5 cm. Histologic examination shows thick fibrous bands dividing hyperplastic but normal-appearing hepatocytes into nodules. Fibrous septae contain prominent bile ductule proliferations and inflammatory infiltrate. Hepatocyte plates are not thickened (one to two cells thick). No portal tracts or central veins are present within the hepatocellular nodules. Cytopathologic evaluation does not show any specific characteristics. When FNH is suspected on radiologic and clinical examination, the cytopathologic analysis can only be supportive of such lesion. In our experience,

FIGURE 8-6 Focal nodular hyperplasia. Abundant fibrosis representing sampling of the central stellate scar and fragments of reactive hepatocytes. Papanicolaou stain, low power.

FOCAL NODULAR HYPERPLASIA – PATHOLOGIC FEATURES Cytopathologic Findings Normal-appearing hepatocytes (most often large fragments) Biliary epithelium (slightly increased in amount) Fragments of fibrous tissue Absence of endothelial/vascular proliferation Lack of atypia (as opposed to cirrhotic liver) Cell block/tissue core may be extremely helpful

៉ ៉ ៉ ៉ ៉ ៉

Histopathologic Findings ៉ Gross: ៉ Focal lesion in the background of non-cirrhotic liver ៉ Central stellate scar is often present ៉ Microscopic: ៉ Bands of fibrosis that separate bland hepatocytes into

nodules ៉ Abnormally thick-walled vessels often in the center of the

lesion ៉ Infl ammation and bile ductule proliferation within the fibrous

septae ៉ Cell plates are not thickened (1–2 cells) ៉ No portal tracts or central veins

Ancillary Studies ៉ CD34: no endothelial cell wrapping (unlike hepatocellular carcinoma [HCC]) ៉ Reticulin stain: reticulin framework intact (unlike HCC) Differential Diagnosis and Pitfalls

FIGURE 8-7 Focal nodular hyperplasia. Smear shows abundance of biliary epithelium and unremarkable hepatocytes. The findings are non-specific. Diff Quik stain, intermediate power.

rarely if ever is a definitive diagnosis of FNH is made on cytology alone. Cytomorphologic changes, therefore, are non-specific (Figs 8-6 & 8-7).

៉ Well-differentiated HCC: arises in cirrhotic liver; increased cell

plate thickness (>2 cells); disrupted reticulin framework; cytologic atypical present, but may be minimal ៉ Macroregenerative nodule: arises in cirrhotic liver; cannot be distinguished from focal nodular hyperplasia based on cytology alone ៉ Hepatocellular adenoma: like FNH, arises in non-cirrhotic liver; strong association with oral contraceptive use; cannot be distinguished from FNH based on cytology alone

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ANCILLARY STUDIES As for MRN, CD34 may help differentiate FNH from well-differentiated hepatocellular carcinoma (WDHCC). As is the case for MRN, reticulin may be helpful in differentiating FNH (reticulin framework intact) from WD-HCC (reticulin framework disrupted).

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DIFFERENTIAL DIAGNOSIS AND PITFALLS Similarly to MRN, the most important differential diagnosis for FNH is WD-HCC. The distinction is based predominantly on cytologic atypia in HCC. In addition, unlike WD-HCC, FNH has an intact reticulin framework and a normal cell-plate thickness. Based on cytologic parameters alone, FNH cannot be distinguished from hepatocellular adenoma (HA) and MRN in cirrhosis. Clinical features, such as background cirrhosis (favors MRN), history of OCP use (favors HA), or presence of stellate scar (favors FNH), may be helpful in this differential diagnosis.

TABLE 8-6 Cystic Lesions of the Liver • • • • • •

Congenital/simple cyst Ciliated foregut cyst Hydatid cyst Abscess Granulomatous disease Cystic neoplasms

TABLE 8-7

CYSTIC LESIONS OF THE LIVER These are distinctly rare compared to more common solid mass-forming diseases and may include nonneoplastic diseases, i.e. pseudotumors (e.g. parasitic cysts) and, rarely, cystic neoplasms (Tables 8-6 & 8-7).

HYDATID DISEASE CLINICAL FEATURES Hydatid disease is caused by the flat tapeworm Echinococcus granulosus. It is the most common cause of hepatic cysts worldwide, particularly in the Middle East. In the United States, the disease primarily affects immigrants. Approximately 75% of infected patients develop hepatic cysts, which may be multiple and predominantly located in the right hepatic lobe. Hydatid

HYDATID DISEASE – DISEASE FACT SHEET Incidence Most common hepatic cysts worldwide A common disease in the Middle East Primarily affects immigrant population in the United States Disease is caused by Echinococcus granulosus

៉ ៉ ៉ ៉

Gender and Age Distribution ៉ No gender predilection ៉ Any age can be affected

Treatment ៉ Surgical removal or percutanous drainage of cyst ៉ Treatment of the cyst with scolicidal agents ៉ Systemic therapy with antihelminthic medication

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Parasitic Cysts of the Liver • Hydatid cyst (Echinococcus granulosus) • Schistosoma mansoni • Entamoeba histolytica

disease can involve all ages and there is no gender predilection. Cysts are asymptomatic until they enlarge to the size of at least 10 cm. Clinical manifestations of hepatic cysts include hepatomegaly, obstructive jaundice, and cholangitis. If untreated, infection can be fatal. Treatment is surgical removal of cysts or percutanous drainage and treatment of the cyst with scolicidal agents such as hypertonic saline or alcohol. The treatment is usually in parallel with the use of antihelminthic medication to prevent recurrence of disease. Ultrasonography of the liver lesions demonstrates cystic membranes, septa, and hydatid sand. CT and MRI scan show cyst wall calcification and cyst wall defects, as well as the passage of contents through a defect.

PATHOLOGIC FEATURES Grossly, the cysts are usually unilocular and solitary. Circular ‘egg-shell’ calcification of the outer layer of the cyst is present in 25% of cases. Histologically, the cyst contains a laminated membrane and is filled with colorless fluid with acellular debris and occasional protoscolices (future heads of the adult tapeworm) and loose hooklets. Dense fibroinflammatory tissue with prominent eosinophils surrounds the cyst. Cytopathologic findings on FNA include fragments of scolices or hooklets (Figs 8-8 & 8-9). The hooklets stain positive for modified acid-fast bacilli (AFB) stain. Cyst wall may be highlighted by periodic acid–Schiff (PAS) and Gomori methenamine silver (GMS).

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FIGURE 8-8 Hydatid disease. ‘Shark tooth’ appearance of a loose hooklet in a dirty smear background. Diff Quik stain, high power.

FIGURE 8-9 Hydatid disease. Dense granular debris with an embedded protoscolex. Papanicolaou stain, high power.

CILIATED HEPATIC FOREGUT CYST HYDATID DISEASE – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Scolices or hooklets ៉ Hooklets stain positive with modified AFB stain Histopathologic Findings ៉ Gross: ៉ Usually solitary, unilocular ៉ ’Egg-shell’ calcifications of the cyst wall (25%) ៉ Microscopic: ៉ Laminated cyst membrane ៉ Cyst fl uid with acellular debris and occasional protoscolices

and loose hooklets Ancillary Studies ៉ PAS and GMS: highlight cyst wall ៉ AFB: highlights hooklets Differential Diagnosis and Pitfalls ៉ Other parasitic diseases: Schistosoma, Clonorchis, Entamoeba ៉ Non-parasitic solitary cysts: simple unilocular cyst, ciliated

foregut cyst, pseudocyst, neoplastic cysts (bile duct cystadenoma and bile duct cystadenocarcinoma)

CLINICAL FEATURES Ciliated foregut cysts are extremely rare. Only several dozen case reports were reviewed by the Armed Forces Institute of Pathology (AFIP). The average age is 48 years, with an equal incidence in males and females. Malignant transformation is exceptionally rare. Only one case of a squamous cell carcinoma arising in a ciliated foregut cyst has been reported.

PATHOLOGIC FEATURES Ciliated foregut cyst represents a developmental anomaly. It is thought to arise from displaced embryonic foregut differentiating toward bronchial epithelium. Ciliated foregut cyst is usually subcapsular, solitary, and unilocular. It is lined by respiratory-type epithelium consisting of ciliated columnar and mucous cells. Cyst fluid is clear or, less commonly, mucinous.

CILIATED HEPATIC FOREGUT CYST – DISEASE FACT SHEET Incidence

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis includes other parasitic diseases that present as hepatic mass lesions, including Schistosoma, Clonorchis, and Entamoeba. Non-parasitic solitary cysts are also considered in the differential diagnosis. These include simple unilocular cyst, ciliated foregut cyst, pseudocysts, and neoplastic cysts (bile duct cystadenoma and bile duct cystadenocarcinoma).

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៉ Extremely rare

Gender and Age Distribution ៉ Equal gender distribution ៉ Average age 48 years

Prognosis ៉ Malignant transformation is exceedingly rare

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FIGURE 8-10 Ciliated foregut cyst. Fragments of glandular epithelium with focal ciliated cell differentiation (arrow). Possibility of bronchial epithelial contamination should be considered in such cases before rendering a definitive diagnosis. Papanicolaou stain, high power.

FIGURE 8-11 Ciliated foregut cyst. Cell block section shows the partially intact cyst wall with fibrous capsule overlying hepatic tissue. Cells are pseudostratified with ciliated lining. H&E stain, low power.

tamination by bronchial tissue (in subdiaphragmatic lesions) should also be kept in mind. CILIATED HEPATIC FOREGUT CYST – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Clear to viscid material ៉ Clusters and fragments of tall columnar cells, often with welldefined ciliated borders ៉ Numerous foamy macrophages ៉ Mucinous background Histopathologic Findings ៉ Gross: ៉ Subcapsular, solitary, and unilocular ៉ Microscopic: ៉ Lined by respiratory-type epithelium (ciliated columnar and

mucous cells) ៉ Clear, less commonly mucinous, cyst fl uid

Differential Diagnosis and Pitfalls ៉ Other solitary hepatic cysts: simple unilocular cyst, pseudocyst, bile duct cystadenoma and bile duct cystadenocarcinoma, parasitic cysts (e.g. echinococcal)

On FNA, the aspirate reveals clear to viscid material. Clusters of tall columnar cells, often with well-defined ciliated borders, are noted, as well as numerous foamy macrophages, often in a mucinous background (Figs 8-10 & 8-11).

BENIGN TUMORS OF THE LIVER HEMANGIOMA (CAVERNOUS HEMANGIOMA) CLINICAL FEATURES Hemangioma is the most common benign hepatic tumor and the liver is the most common visceral site of hemangioma. The lesion is usually small and asymptomatic, discovered incidentally during radiographic evaluation for other diseases. Hemangiomas are found in 1–7% of autopsies. Hemangioma may present at any age, with the mean age at diagnosis being 46 years. They are more commonly found in women than in

HEMANGIOMA (CAVERNOUS HEMANGIOMA) – DISEASE FACT SHEET Incidence ៉ Most common benign hepatic tumor

Gender and Age Distribution

DIFFERENTIAL DIAGNOSIS AND PITFALLS

៉ More common in women ៉ Any age (mean age at diagnosis, 46 years)

Prognosis and Treatment

The differential diagnosis for ciliated foregut cyst includes other solitary hepatic cysts: simple unilocular cyst, pseudocyst, bile duct cystadenoma, and bile duct cystadenocarcinoma. The possibility of needle con-

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៉ Usually asymptomatic, discovered incidentally ៉ Spontaneous rupture is very uncommon ៉ No resection required for asymptomatic hemangioma

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men. Spontaneous rupture is a very uncommon complication of hemangiomas, occurring predominantly with giant hemangiomas (>4 cm in size). Asymptomatic hemangiomas do not require surgical resection.

PATHOLOGIC FEATURES Hemangiomas are typically solitary, less often multiple. Most commonly they are located in a subcapsular region. Lesions are grossly dark red with a spongy consistency. Histologically, hemangiomas are characterized by anastomosing dilated thin-walled vessels, which may have intramural thrombi. Vessels are lined by flat blandappearing endothelial cells. Areas of central scarring and hyalinization are typical. Large ‘feeder vessels’ are occasionally present at the periphery. Cytopathologic features include: extremely bloody smears (fresh blood), scant cellularity (‘unyielding FNAs’), fragments of acellular fibrous tissue, occasional small, loosely arranged fragments of vascular endothe-

FIGURE 8-12 Hemangioma. Cohesive fragment of stromal tissue with uniform fusiform nuclei and background fresh blood. Vascular endothelium is not usually evident. Papanicolaou stain, intermediate power.

HEMANGIOMA (CAVERNOUS HEMANGIOMA) – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Extremely bloody smears (fresh blood) ៉ Scant cellularity (‘unyielding FNAs’) ៉ Fragments of fibrous stromal tissue ៉ Occasional small fragments of vascular endothelium with slender to plump, fusiform, often grooved nuclei, loosely arranged ៉ Well-formed vascular channels rarely observed ៉ Cell blocks usually diagnostic Histopathologic Findings ៉ Gross: ៉ Usually solitary, but may be multiple ៉ Usually subcapsular ៉ Appear dark red with a spongy consistency ៉ Microscopic: ៉ Anastomosing dilated thin-walled vessels ៉ Bland fl at endothelial cells ៉ Intramural thrombi Ancillary Studies ៉ Endothelial markers: CD34, CD31, Factor VIII, and Ulex europaeus ៉ Electron microscopy: Weibel-Palade bodies

FIGURE 8-13 Hemangioma. Single, bland-appearing, spindled nuclei with long tapering cytoplasmic processes representing stromal cells of the tumor. Diff Quik stain, high power.

lium with slender to plump, fusiform, often grooved nuclei. Well-formed vascular channels are rarely observed. Cell blocks are usually diagnostic and depict tissue fragments with interconnecting vascular channels (Figs 8-12–8-14).

Differential Diagnosis and Pitfalls ៉ Other vascular lesions: angiosarcoma, epithelioid

hemangioendothelioma ៉ Non-vascular spindle cell lesions: leiomyosarcoma, granulomatous hepatitis, spindle cell-predominant angiomyolipoma

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ANCILLARY STUDIES The vascular nature of the lesion may be confirmed by immunohistochemical stains including CD34, CD31, and Factor VIII.

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FIGURE 8-14 Hemangioma. Core biopsy accompanying one of the aspiration samples clearly displays interconnecting vascular lumina with attenuated endothelial lining supported by a sclerotic stroma. H&E stain, low power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis includes other spindle cell lesions of the liver, most common of which are metastatic leiomyosarcoma, granulomatous hepatitis, and spindle cell-predominant angiomyolipoma. Other vascular lesions, such as angiosarcoma and epithelioid hemangioendothelioma, are also in the differential diagnosis.

HEPATOCELLULAR ADENOMA CLINICAL FEATURES Overall, hepatocellular adenomas (HAs) are rare. The estimated yearly incidence is 3 to 4 cases per 100,000 women with a history of long-term oral contraceptive (OCP) use. Over 90% of HAs develop in women of

HEPATOCELLULAR ADENOMA – DISEASE FACT SHEET Incidence ៉ Rare: per year, 3–4 cases per 100,000 women with a history of long-term oral contraceptive (OCP) use Gender and Age Distribution ៉ 90% of cases are women with a history of OCP use ៉ Most patients are under 30 years of age Prognosis and Treatment ៉ May cause intratumoral and intraperitoneal hemorrhage ៉ 10% association with hepatocellular carcinoma ៉ Resection generally recommended

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reproductive age who have a history of OCP use. The majority of these women are under 30 years of age. In some cases, OCP use may be remote. Save for OCP use, hepatic adenomas are seen in only a few other clinical settings, including patients with androgen use and patients with glycogen storage diseases (types I and III). Unlike focal nodular hyperplasia, HAs are more often symptomatic. Complication of HA includes intratumoral hemorrhage, which may present with acute abdominal pain. In addition, HA may rupture through the liver capsule, causing intraperitoneal hemorrhage and shock. Malignant transformation to HCC has traditionally been considered highly unusual. However, more recent studies estimate that about 10% of unresected HAs evolve into HCC. Resection is generally recommended.

PATHOLOGIC FEATURES HAs arise in non-cirrhotic livers and typically present as solitary lesions, but occasionally patients may present with multiple adenomas. Histopathologically, HAs

HEPATOCELLULAR ADENOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Could be entirely non-specific ៉ Abundant normal-appearing hepatocytes ៉ Lack of biliary epithelium, fibrous tissue fragments ៉ Lack of endothelial/vascular proliferation Histopathologic Findings ៉ Gross: ៉ Solitary, rarely multiple ៉ Background non-cirrhotic liver ៉ Microscopic: ៉ Well-circumscribed, majority encapsulated ៉ Hepatocytes lack normal acinar structure: no portal tracts ៉ Atypia is absent or minimal ៉ Normal cell-plate thickness (<2 cells) ៉ Reticulin framework intact

Ancillary Studies ៉ CD34: no endothelial cell wrapping (unlike hepatocellular carcinoma [HCC]) ៉ Reticulin stain: reticulin framework intact (unlike HCC) Differential Diagnosis and Pitfalls ៉ Well-differentiated HCC: arises in cirrhotic liver; increased cell

plate thickness (>2 cells); disrupted reticulin framework; cytologic atypia present, but may be minimal ៉ Focal nodular hyperplasia: cannot be distinguished from adenoma based on cytology alone; stellate scar; bile ducts present in fibrous septae ៉ Macroregenerative nodule: arises in cirrhotic liver; cannot be distinguished from adenoma based on cytology alone

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macroregenerative nodule is generally impossible based on cytologic parameters alone.

BILE DUCT ADENOMA CLINICAL FEATURES Bile duct adenoma is found incidentally in approximately 30% of autopsies. These lesions are also frequently discovered during intra-abdominal surgery for other disease (70% in one study). Bile duct adenoma can occur at any age (mean age, 55 years), with a similar rate in men and women. Bile duct adenoma is always discovered incidentally. The behavior of this lesion is benign. FIGURE 8-15 Hepatic adenoma. Bland-appearing hepatocytes with a slightly disorganized architecture and lacking the second cell component, i.e. biliary epithelium. Diff Quik stain, low power.

consist entirely of hepatocytes and lack the normal acinar architecture (bile ducts and central veins are absent). HAs are well-circumscribed lesions, 75% are encapsulated. Background liver is always non-cirrhotic. HAs are composed of bland hepatocytes, indistinguishable from normal hepatocytes. Hepatocyte plates are not thickened (one to two cells thick). Increased steatosis is a common feature. Cytomorphologic features are often entirely nonspecific. Abundant normal-appearing hepatocytes are seen. There is a total lack of biliary epithelium, fibrous tissue fragments, and endothelial/vascular proliferation (Fig. 8-15).

PATHOLOGIC FEATURES Bile duct adenomas are solitary in the vast majority of cases. Most of the lesions are subcapsular and measure less than 0.5 cm, not exceeding 2 cm. Histologically, bile duct adenomas are well circumscribed, but are not encapsulated. They are composed of numerous angulated tubules with little or no lumen. They are lined by a single layer of bland biliary epithelium. No atypia or mitotic figures are present. Stroma is generally fibrotic and hyalinized, often containing numerous inflammatory cells. Cytomorphology reveals abundant, normal-appearing biliary epithelium, often admixed with benign hepatocytes (needle pick-up). Cell blocks may be helpful.

ANCILLARY STUDIES ANCILLARY STUDIES As described above, CD34 may be useful to distinguish HA from well-differentiated hepatocellular carcinoma (WD-HCC): CD34 highlights endothelial cell wrapping in WD-HCC, whereas this feature is absent in HA. Preserved reticulin framework is helpful for distinguishing HA from WD-HCC.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

These have a limited role in the diagnosis.

BILE DUCT ADENOMA – DISEASE FACT SHEET Incidence ៉ Very common ៉ Always discovered incidentally ៉ Found incidentally in ~30% of autopsies Gender and Age Distribution

The main differential diagnosis for HA is WD-HCC. The majority of WD-HCCs in the United States arise in the background of cirrhosis, whereas HAs arise in non-cirrhotic livers. In addition, cytologic atypia is a feature of HCC but not HA. As discussed above, distinction of HA from focal nodular hyperplasia and

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៉ No gender predilection ៉ Occurs at any age (mean age, 55 years)

Prognosis ៉ Behavior is benign

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BILE DUCT ADENOMA – PATHOLOGIC FEATURES

HEPATOBILIARY CYSTADENOMA – DISEASE FACT SHEET

Cytopathologic Findings

Incidence

៉ Abundant, normal-appearing biliary epithelium ៉ Often admixed with benign hepatocytes (‘needle pick-up’) ៉ Cell blocks may be helpful

៉ Accounts for 5% of solitary hepatic cysts

Histopathologic Findings ៉ Gross: ៉ Majority are solitary ៉ Usually subcapsular ៉ Usually <0.5 cm; always <2 cm ៉ Microscopic: ៉ Well circumscribed, but unencapsulated ៉ Angulated tubules with little or no lumen ៉ Lined by a single layer of bland biliary epithelium ៉ No atypia or mitotic figures ៉ Stroma fibrotic and hyalinized ៉ Prominent stromal infl ammation ៉ No intraluminal bile

Differential Diagnosis and Pitfalls ៉ Cholangiocarcinoma and metastatic adenocarcinoma: cytologic atypia present; may be larger than 2 cm ៉ Von Meyenburg complexes: not a solitary lesion (present diffusely); lumina dilated; contain intraluminal bile

DIFFERENTIAL DIAGNOSIS AND PITFALLS The main differential diagnoses for bile duct adenoma are intrahepatic cholangiocarcinoma and metastatic adenocarcinoma. The distinction is based on the presence of cytologic atypia in the carcinomas, but not bile duct adenoma. Von Meyenburg complexes may look histologically and cytologically similar to bile duct adenoma. However, unlike the solitary bile duct adenoma, von Meyenburg complexes are present diffusely throughout the liver. In addition, ductal lumina of von Meyenburg complexes are generally dilated and contain bile plugs, whereas these features are not present in bile duct adenoma.

HEPATOBILIARY CYSTADENOMA CLINICAL FEATURES Hepatobiliary cystadenoma accounts for 5% of solitary hepatic cysts, with almost 95% developing in women. Virtually all cases are from adults, with a mean age at diagnosis of 45 years. Patients usually present with abdominal pain and, occasionally, jaundice. Development of malignancy is a recognized complication of cystadenoma. Complete surgical resection is the treatment of choice, which is generally curative. Delayed recurrence has been reported.

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Gender and Age Distribution ៉ 95% develop in women ៉ Adults (mean age, 45 years)

Prognosis and Treatment ៉ May develop into a malignancy ៉ May show delayed recurrence ៉ Complete surgical resection is recommended

PATHOLOGIC FEATURES Hepatobiliary cystadenomas are generally solitary, ranging in size from 2.5 to 28 cm. The cysts are grossly multilocular and generally contain mucinous secretions. Benign hepatobiliary cystadenomas are lined by a single layer of cuboidal or tall columnar mucinous epithelium, similar to bile duct or gastric foveolar epithelium. In women, the surrounding stroma shows distinctive dense spindle cells, resembling ovarian stroma. These stromal cells are immunoreactive for estrogen receptors (ER) and progesterone receptors (PR). These lesions are histologically identical to mucinous cystadenomas of other organs.

HEPATOBILIARY CYSTADENOMA – PATHOLOGIC FEATURES Cytopathologic Findings Single population of benign-appearing ductal epithelium Monotonous with uniform round nuclei devoid of nucleoli Mucinous differentiation with goblet cells Background of extracellular mucin

៉ ៉ ៉ ៉

Histopathologic Findings ៉ Gross: ៉ Solitary ៉ Size range 2.5 to 28 cm ៉ Multilocular ៉ Contain mucinous secretions ៉ Microscopic: ៉ Mucinous epithelial lining (bile duct or gastric foveolar-type) ៉ Ovarian-type spindle cell stroma ៉ Epithelial cells are bland (no dysplasia) Ancillary Studies ៉ Ovarian-type stroma: ER- and PR-reactive Differential Diagnosis and Pitfalls ៉ Hepatobiliary cystadenocarcinoma: epithelial dysplasia; stromal invasion; must be differentiated from metastases (pancreas, ovary, appendix)

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DIFFERENTIAL DIAGNOSIS AND PITFALLS Benign hepatobiliary cystadenoma should be distinguished from hepatobiliary cystadenocarcinoma. This distinction is based on the presence of high-grade dysplasia and areas of overt stromal invasion in the carcinoma. Metastases from other sites, such as pancreas, ovary, or appendix, should be excluded.

INFLAMMATORY MYOFIBROBLASTIC TUMOR (INFLAMMATORY PSEUDOTUMOR) CLINICAL FEATURES FIGURE 8-16 Hepatobiliary cystadenoma. A tight, three-dimensional fragment of ductal-type epithelium. Cells have high N/C ratios, some appearing as naked nuclei. Nuclei are round, uniform, and lack nucleoli. No background hepatocytes are seen. Papanicolaou stain, high power.

Inflammatory myofibroblastic tumor (IMT) is a lesion of unclear etiology, currently thought to represent a neoplastic process in most instances. IMT affects various organs, most commonly lung. Liver is an unusual site of involvement by IMT. IMT presents in adults (mean age, 37 years; range, 10 months to 83 years), with a male to female ratio of 3 : 1. Patients may present with symptoms of vague abdominal pain, weight loss, and low-grade fever. Surgical resection is curative. There are case reports of subsequent recurrence as malignant sarcoma.

PATHOLOGIC FEATURES

FIGURE 8-17 Hepatobiliary cystadenoma. Cell block section displays well-formed glandular epithelium with mucinous differentiation. Numerous goblet cells are seen. H&E stain, intermediate power.

On FNA, the smears show a single population of benign-appearing ductal-type glandular epithelium. Cells are monotonous with uniform round nuclei devoid of nucleoli (Figs 8-16 & 8-17). Mucinous differentiation is evident in the form of well-developed goblet cells. Occasionally, the smears show extracellular background mucin as well. Cellular necrosis is not observed.

IMTs are generally solitary and well circumscribed, varying in size from 1 to 25 cm. The tumor is composed of plump spindle-shaped myofibroblasts, interspersed with a prominent inflammatory infi ltrate consisting of plasma cells, histiocytes, lymphocytes, and granulocytes. Mitotic rate may be brisk, but no atypical mitotic figures should be present. On FNA, IMT shows hypercellular smears with an admixture of various cell types (Figs 8-18 & 8-19), including inflammatory cells with predominance of plasma cells, fibroblastic proliferation, granulation tissue

INFLAMMATORY MYOFIBROBLASTIC TUMOR (INFLAMMATORY PSEUDOTUMOR) – DISEASE FACT SHEET Incidence ៉ Extremely rare (less than 90 cases reported) Gender and Age Distribution ៉ Male to female ratio is 3 : 1 ៉ Adults (mean age, 37 years; range, 10 months to 83 years)

Prognosis and Treatment

ANCILLARY STUDIES

៉ Surgical resection is curative ៉ Case reports of recurrence as malignant sarcoma

ER and PR are reactive in the ovarian-type stroma.

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INFLAMMATORY MYOFIBROBLASTIC TUMOR (INFLAMMATORY PSEUDOTUMOR) – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Hypercellular smears with an admixture of various cell types ៉ Infl ammatory cells with predominance of plasma cells ៉ Fibroblastic proliferation, granulation tissue formation ៉ Atypical-appearing histiocytes with enlarged nuclei, occasional nuclear grooves, and intranuclear inclusions Histopathologic Findings ៉ Gross: ៉ Solitary ៉ Well circumscribed ៉ Size 1 to 25 cm ៉ Microscopic: ៉ Plump spindle cells ៉ Interspersed infl ammatory infiltrate (plasma cells, histiocytes,

FIGURE 8-18 Infl ammatory pseudotumor. Hypercellular smear with predominantly single cells, comprised of a mixture of infl ammatory cells, macrophages, endothelial cells, and fibroblasts. Diff Quik stain, intermediate power.

lymphocytes, granulocytes) ៉ Mitotic figures allowed ៉ Should have no atypical mitoses

Ancillary Studies ៉ ALK-negative (unlike IMT of some other organs, e.g. bladder) ៉ Aberrant cytokeratin reactivity Differential Diagnosis and Pitfalls ៉ Spindle cell sarcomas (e.g. leiomyosarcoma): frank

pleomorphism; atypical mitotic figures

DIFFERENTIAL DIAGNOSIS AND PITFALLS Many hepatic masses of various types may be associated with a brisk inflammatory response and these lesions should be differentiated from IMT. Particularly, IMT should be distinguished from spindle-cell sarcomas (e.g. leiomyosarcoma). Presence of frank pleomorphism and atypical mitotic features favors the latter. FIGURE 8-19 Infl ammatory pseudotumor. Endothelial cells, macrophages with grooved nuclei, and infl ammatory cells with predominance of plasma cells. Papanicolaou stain, high power.

formation, and atypical-appearing histiocytes with enlarged nuclei, occasional nuclear grooves, and intranuclear inclusions. Fibroblastic proliferation with mitoses may mimic mesenchymal neoplasms. Cytomorphology is nonspecific and IMT is usually a diagnosis of exclusion.

MALIGNANT TUMORS OF THE LIVER Primary malignant and metastatic/secondary malignant tumors of the liver are listed in Table 8-8 and Table 8-9, respectively.

PRIMARY MALIGNANT EPITHELIAL TUMORS ANCILLARY STUDIES HEPATOCELLULAR CARCINOMA Anaplastic lymphoma kinase (ALK) expression has been found in some IMTs, such as IMT involving the bladder. However, expression of ALK has not been found in the hepatic IMT. Aberrant cytokeratin expression has been reported in IMT of various sites and should not be misinterpreted as evidence of carcinoma.

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CLINICAL FEATURES The most important risk factors for HCC are infection with hepatitis B virus (HBV) and hepatitis C virus

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TABLE 8-8 Malignant Tumors – Primary • Epithelial: • Hepatocellular carcinoma • Cholangiocarcinoma • Neuroendocrine neoplasms (extremely rare) • Non-epithelial: • Angiosarcoma/other sarcomas • Non-Hodgkin lymphoma/Hodgkin lymphoma

TABLE 8-9 Malignant Tumors – Metastatic/Secondary • Epithelial: • Adenocarcinoma • Squamous cell carcinoma • Small cell carcinoma • Other (adenoid cystic carcinoma, renal cell carcinoma, etc.) • Non-epithelial: • Malignant melanoma • Granulosa cell tumor • Sarcomas • Non-Hodgkin lymphoma/Hodgkin lymphoma • Other

HEPATOCELLULAR CARCINOMA – DISEASE FACT SHEET Incidence ៉ >80% of primary hepatic malignancies ៉ United States: 4 cases per 100,000 ៉ Asia, Africa: higher rates (80% of cases arise in Asia) Gender and Age Distribution ៉ Male to female ratio is between 2 : 1 and 5 : 1 ៉ Asia and Africa: 20–40 years (HBV; cirrhosis in <50%) ៉ USA: 61 years (HCV; cirrhosis in 75–90%)

Clinical Features ៉ Elevated AFP (>4000 ng/mL highly suggestive of HCC)

Prognosis ៉ Extremely poor (mean survival, 11 months)

(HCV). The most common cause of HCC worldwide is HBV, particularly in the areas where HBV infection is endemic, including Asia and Africa. Nearly 80% of all HCCs develop in Asian countries. In the United States, the most important risk factors for HCC are HCV and chronic alcoholism; HBV is less

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common. The estimated annual incidence of HCC in the United States is 4 cases per 100,000. HCC accounts for more than 80% of primary liver carcinomas. In addition to hepatitis viruses and alcohol, a number of chemical carcinogens have been linked to HCC, including aflatoxin B1 (a toxic metabolite of Aspergillus flavus). A high risk of HCC is seen in patients with hereditary hemochromatosis and hereditary tyrosinemia. Elevated AFP is present in 50–75% of patients, with values usually over 1000 ng/mL. Levels greater than 4000 ng/mL are highly suggestive of HCC. Elevated AFP is, however, not present in all cases of HCC, and AFP elevation may also be seen with yolk-sac tumors and several non-neoplastic conditions, including massive liver necrosis and fetal neural tube defects. Epidemiology of HCC shows stark geographic variability. In Asia and Africa, where HBV predominates, HCC develops at a young age (20–40 years); cirrhosis is present in less than 50% of cases. In contrast, in the United States, where HCV predominates, HCC rarely develops before the age of 60 and cirrhosis is present in 75–90% of cases. In the United States, the average age at the time of HCC diagnosis is 61 years. Worldwide, HCC is more common in men than in women (M : F ratio is 2 : 1 to 5 : 1). The prognosis is extremely poor, with mean survival of 11 months. The factors that influence survival are age (older patients do worse), gender (men do worse than women), tumor stage and grade, and presence of cirrhosis (worse prognosis if cirrhosis is present).

PATHOLOGIC FEATURES Grossly, HCC may be solitary, multinodular, or diffuse. In cirrhotic liver, HCC tends to present as a solitary mass with multiple satellite nodules. The tumor ranges in size from those at the threshold of radiographic detection to those replacing the entire liver. Histologically, HCC is characterized by the loss of normal liver architecture: hepatocyte plates are thickened (greater than two cells thick) and the normal acinar structure, including portal tracts and central veins, is absent. The neoplastic cells show crowding and cytologic atypia, which increases in severity in highergrade lesions. Vascular invasion is present in two of three cases. Presence of cytoplasmic bile pigment and lipid vacuoles (steatosis) is helpful for differentiating primary HCC from metastatic tumors. Multiple architectural patterns may be present, including trabecular, glandular, and solid. Cytologic variants include pleomorphic (giant cell), clear cell, oncocyte-like, and sarcomatoid HCC (Table 8-10). Cytologic grading of HCC is helpful for a number of reasons (Table 8-11). A three-tier system of FNA grading is employed at Johns Hopkins: well-differentiated (Figs 8-20–8-22), moderately differentiated (Figs 8-23 & 824), and poorly differentiated (Figs 8-25–8-28).

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HEPATOCELLULAR CARCINOMA – PATHOLOGIC FEATURES

TABLE 8-10

Cytopathologic Findings ៉ Well-differentiated HCC: ៉ Hypercellularity ៉ Bland-appearing hepatocytes, minimally pleomorphic, mildly increased N/C ratio, small nucleoli ៉ Predominantly cohesive fragments, trabecular growth pattern, often smooth round fragment outline ៉ Prominent bile staining ៉ Vascular proliferation associated with loosely hanging nests of hepatocytes ៉ Moderately differentiated HCC: ៉ Hypercellular smears, cohesive nests or trabeculae ៉ Fragments with irregular edges, numerous single cells ៉ High N/C ratio, irregular nuclear membrane ៉ Numerous atypical naked nuclei ៉ Prominent nucleoli, intranuclear inclusions ៉ Vascular/endothelial proliferation present (less obvious than in well-differentiated HCC) ៉ Poorly differentiated HCC: ៉ Extremely hypercellular ៉ Loose nests, occasional 3-D fragments (gland-like) ៉ Marked pleomophism, high N/C ratio, macronucleoli ៉ Endothelial wrap-arounds ‘packeting’ ៉ Large naked nuclear population ៉ Tumor giant cells ៉ Vascular/endothelial proliferation rarely seen ៉ Numerous mitoses, necrosis

Hepatocellular Carcinoma – Uncommon Variants

Histopathologic Findings ៉ Gross: ៉ Solitary, multinodular, or diffuse ៉ Size ranges from small to massive ៉ Microscopic: ៉ Thickened hepatocyte plates (>2 cells thick) ៉ Absence of normal acinar structure (no portal tracts) ៉ Cellular crowding and cytologic atypia ៉ Cytoplasmic bile and lipid vacuoles (steatosis) may be present

• • • • • • • •

Clear cell Mixed hepatocellular–cholangiocarcinoma Acinar or adenoid cell Fibrolamellar Giant cell Sarcomatoid Osteoclastic Sclerotic

FIGURE 8-20 Hepatocellular carcinoma. Well-differentiated tumor with irregular nests of malignant hepatocytes loosely arranged around arborizing capillaries. Few single cells are seen as well. Papanicolaou stain, low power.

Ancillary Studies ៉ HepPar-1, AFP, canalicular polyclonal CEA and CD10 ៉ Reticulin highlights the loss of reticulin framework and the expansion of cell plates ៉ Mucicarmine-negative Differential Diagnosis and Pitfalls ៉ Well-differentiated HCC: ៉ Normal liver ៉ Hepatocellular adenoma (HA), focal nodular hyperplasia

(FNH), macroregenerative nodule (MRN): hepatocyte plates not thickened (<2 cells thick); reticulin framework intact; for HA and FNH, background liver non-cirrhotic ៉ Metastatic tumors: renal cell carcinoma, adrenal cortical carcinoma ៉ Moderately differentiated HCC: ៉ Metastatic tumors: renal cell carcinoma, melanoma, adenocarcinoma ៉ Poorly-differentiated HCC: ៉ Cholangiocarcinoma: no bile, no lipid (steatosis); prominent desmoplasia; mucin; HepPar-1-negative, usually CK7 and CK20 double-positive ៉ Metastatic carcinoma, melanoma, sarcoma, lymphoma: no bile, no lipid (steatosis); mucin in some adenocarcinomas; melanin pigment in some melanomas

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FIGURE 8-21 Hepatocellular carcinoma. Well-differentiated tumor cells show a delicate attachment to fine branching capillaries. The diagnosis is often made at low magnification, as individual cells may not appear too different from benign hepatocytes. Diff Quik, low power.

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TABLE 8-11 Cytologic Grading of Hepatocellular Carcinoma: Why Do We Grade? • Difference in clinical prognosis and survival • Treatment options • Differential diagnosis

FIGURE 8-24 Hepatocellular carcinoma. Moderately differentiated tumor shows a diffuse population of naked nuclei with macronucleoli in a very granular smear background. Papanicolaou stain, intermediate power.

FIGURE 8-22 Hepatocellular carcinoma. Well-differentiated neoplasm with large polygonal hepatocytes anchored to vascular endothelium. Cells have a low N/C ratio and lack macronucleoli. Papanicolaou stain, high power.

FIGURE 8-25 Hepatocellular carcinoma. Poorly differentiated tumor with a large syncytial-like fragment of malignant cells. N/C ratio is extremely high, with all the cells displaying macronucleoli. Morphologic kinship to hepatocytes is lost and distinction of this lesion from other primary and metastatic carcinomas may require immunostaining. Papanicolaou stain, intermediate power.

FIGURE 8-23 Hepatocellular carcinoma. Moderately differentiated tumor displays greater pleomorphism, macronucleoli, and a sprinkling of naked nuclei in the background. Diff Quik stain, high power.

ANCILLARY STUDIES (Figs 8-29–8-32) CD34 highlights endothelial cell wrapping in HCC, and may be helpful for distinguishing HCC from benign hepatocellular lesions, including focal nodular hyperplasia, hepatocellular adenoma, and macroregenerative

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nodule. In addition, increased p53 expression has recently been shown to favor HCC. A number of immunohistochemical stains may be applied to help distinguish primary HCC from cholangiocarcinoma or metastatic carcinomas (Table 8-12). The markers that favor HCC include HepPar-1 (highly specific), AFP (non-specific), and a canalicular pattern of polyclonal carcinoembryonic antigen (pCEA) and CD10. Also, HCC is unique in its cytokeratin profile: HCC reacts with low molecular weight cytokeratin antibodies (such as CAM 5.2), but is generally non-reactive with pancytokeratin antibodies (such as AE1/AE3) or high molecular weight cytokeratin antibodies (such as K903). HCC is most commonly CK7 and CK20 double-negative.

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FIGURE 8-26 Hepatocellular carcinoma. Poorly differentiated tumor shows large fragment with tightly packed malignant cells reflecting a markedly expanded hepatic plate. Cells display macronucleoli and are wrapped around by endothelium ‘cell packets’. Papanicolaou stain, intermediate power.

FIGURE 8-27 Hepatocellular carcinoma. Poorly differentiated tumor shows a threedimensional gland-like fragment (middle of the field) with numerous single naked nuclei in the background admixed with non-neoplastic liver. It is not possible to differentiate this from an adenocarcinoma without immunostaining. Diff Quik stain, high power.

FIGURE 8-28 Hepatocellular carcinoma. Poorly differentiated tumor with thick tissue fragments and abundant necrosis. Necrosis is not a usual feature and is often noted focally in high-grade HCC. Diff Quik stain, low power.

FIGURE 8-29 Hepatocellular carcinoma. Polyclonal CEA (pCEA) immunostain displays the characteristic one-sided ‘canalicular’ staining pattern of the cell surface. Intermediate power.

FIGURE 8-30 Cholangiocarcinoma. In contrast to hepatocellular carcinoma, the malignant cells display diffuse immunostaining of the cytoplasm with pCEA. Intermediate power.

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FIGURE 8-31 Hepatocellular carcinoma. Immunostaining with CD31 shows the characteristic endothelial reactivity creating ‘packets’ of malignant hepatocytes. High power.

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Reticulin stain highlights the loss of reticulin framework and the expansion of cell plates in HCC. Mucin reactivity is vanishingly rare in HCC; mucin staining (with mucicarmine or PAS) strongly favors cholangiocarcinoma or metastatic adenocarcinoma over HCC. In a recent (as yet unpublished) study, we found that in a few cases of well-differentiated HCC where the exclusion of macroregenerative nodule, focal nodular hyperplasia, or hepatocellular adenoma could be difficult, p53 immunostaining can play an important role. However, p53, although quite specific, suffers from relatively low sensitivity (55% for HCC in our experience). Results are summarized in Table 8-13.

FIGURE 8-32 Hepatocellular carcinoma. p53 immunostaining shows focal nuclear positivity in the core biopsy of a difficult case of well-differentiated tumor where hepatocellular adenoma was difficult to exclude based on morphology alone. Intermediate power.

TABLE 8-12 Hepatocellular Carcinoma – Immunoperoxidase Staining • Conventional markers: • CAM 5.2 • Polyclonal CEA • CD34/CD31 • HepPar-1 • Vimentin • Alpha-fetoprotein (AFP) • Alpha-1-antitrypsin (AAT) • More recent markers: • TTF-1 • Glut-1 • MOC-31 • CA 15-3

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis for well-differentiated HCC includes other hepatocellular lesions: hepatocellular adenoma, focal nodular hyperplasia, and macroregenerative nodule. The differential diagnosis for poorly differentiated HCC includes cholangiocarcinoma as well as metastatic neoplasms, including carcinoma, melanoma, sarcoma, and lymphoma.

FIBROLAMELLAR HEPATOCELLULAR CARCINOMA CLINICAL FEATURES Fibrolamellar carcinoma (FLC) represents approximately 5% of all hepatocellular carcinomas. FLC arises in younger patients, with a mean age of 25 years, and has a slight female predominance. Traditionally, it has been suggested that the prognosis of FLC is better than for typical HCC. However, it appears that after correcting for age, stage, and other factors, the difference in prognosis may not be significant. FLC has a stronger propensity for lymph node metastasis than has typical HCC.

TABLE 8-13 p53 Immunoreactivity in Hepatic FNA

p53 Beta-catenin Ki-67(moderate-high)

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Hepatocellular Carcinoma

Focal Nodular Hyperplasia

Regenerative Nodule

Hepatic Adenoma

6/11 (55%) 7/11 (64%) 4/11 (36%)

0/5 (0%) 4/6 (67%) 0/6 (0%)

0/5 (0%) 4/6 (67%) 0/6 (0%)

0/5 (0%) 5/5 (100%) 0/5 (0%)

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FIBROLAMELLAR HEPATOCELLULAR CARCINOMA – DISEASE FACT SHEET Incidence ៉ Represents 5% of all HCC

Gender and Age Distribution ៉ Slight female predominance ៉ Younger patients (mean age, 25 years)

Prognosis ៉ Thought to have a better prognosis than typical HCC

PATHOLOGIC FEATURES Histopathologically, in contrast to the usual-type HCC, FLC arises in the background of non-cirrhotic liver. The tumor is characterized by dense bands of fibrosis that tend to run in parallel arrays (lamellar architecture). On FNA, the smears show predominantly single discohesive cells; trabeculae are distinctly uncommon. The neoplastic cells are large and polygonal with prominent nucleoli, densely granular eosinophilic ‘oncocytic-appearing’ cytoplasm, and prominent intranuclear inclusions. Cytoplasmic hyaline inclusion bodies as well as occasional cytoplasmic ‘pale bodies’ are characteristically seen. Lymphocytes and fragments of loose fibroconnective tissue may also be seen (Figs 8-33–8-35).

FIGURE 8-33 Hepatocellular carcinoma, fibrolamellar variant. Large pleomorphic hepatocytes loosely arranged around branching capillaries. Distinction from a conventional well-differentiated hepatocellular carcinoma can be difficult, and clinical information is crucial for accurate subtyping. Papanicolaou stain, low power.

FIBROLAMELLAR HEPATOCELLULAR CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Discohesive cells, trabeculae distinctly uncommon ៉ Large polygonal cells, prominent nucleoli, granular eosinophilic cytoplasm ៉ Prominent intranuclear inclusions ៉ Cytoplasmic hyaline inclusion bodies, cytoplasmic ‘pale bodies’

FIGURE 8-34 Hepatocellular carcinoma, fibrolamellar variant. Pleomorphic hepatocytes, often with bizarre shapes, densely granular ‘oncocytic’ cytoplasm and macronucleoli. Papanicolaou stain, high power.

ANCILLARY STUDIES Histopathologic Findings ៉ Background of non-cirrhotic liver ៉ Similar features as HCC, but with dense bands of lamellar fibrosis Ancillary Studies

The immunohistochemical profi le of FLC is similar to that of HCC, except that FLC is usually CK7-positive, whereas HCC is generally CK7-negative. In addition, AFP is generally non-reactive.

៉ Immunostaining pattern similar to HCC, except CK7 usually

positive and AFP usually non-reactive Differential Diagnosis and Pitfalls ៉ Typical HCC: background cirrhotic liver; older patients; absence of lamellar fibrosis ៉ Cholangiocarcinoma and metastatic malignancies (see HCC)

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DIFFERENTIAL DIAGNOSIS AND PITFALLS FLC is distinguished from typical HCC based on the above morphologic features (lamellar fibrosis) and demographics (non-cirrhotic liver in young patients).

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setting of primary biliary cirrhosis. Patients usually present with abdominal pain and weight loss. Unlike its extrahepatic counterpart, intrahepatic cholangiocarcinoma rarely presents with obstructive jaundice. Patients with cholangiocarcinoma generally have a dismal prognosis, with most patients succumbing to disease within 1 year of diagnosis. Patients die as a result of extensive tumor burden, liver failure, gastrointestinal bleeding, or infection. At autopsy, 75% of patients have metastases. Treatment options include resection, but 80% of tumors are deemed unresectable at diagnosis. Transplantation is no longer performed, since recurrence of carcinoma is nearly universal.

PATHOLOGIC FEATURES FIGURE 8-35 Hepatocellular carcinoma, fibrolamellar variant. Fragment of sclerotic tissue, possibly arising from lamellar fibrosis in the tumor, accompanying bizarre malignant hepatocytes. Papanicoalou stain, high power.

INTRAHEPATIC CHOLANGIOCARCINOMA

Cholangiocarcinoma may present either as a solitary mass or as multiple masses. Tumors are typically firm and gritty, owing to the exuberant desmoplastic reaction. Histologically, the tumor may be well circumscribed but is never encapsulated. Tumors are usually well to

CLINICAL FEATURES INTRAHEPATIC CHOLANGIOCARCINOMA – PATHOLOGIC FEATURES

Cholangiocarcinoma is the second most common primary hepatic tumor after HCC; however, it is much less frequent. Cirrhosis is not a risk factor. Risk factors for cholangiocarcinoma include the diseases that cause chronic inflammation of the biliary tree: primary sclerosing cholangitis, Caroli’s disease, hepatolithiasis, and parasitic infestation (Clonorchis sinesis or Opisthorchis viverrini). Other risk factors are exposure to Thorotrast and anabolic steroids. However, no identifiable risk factor is present in the majority of cases (80–90%). Patients typically present with obstructive jaundice. Serum elevation of CA 19-9 and CEA is typical, and AFP is not increased. Most cases of cholangiocarcinoma occur after age 60. Men and women are affected similarly; however, there is a strong male predominance in cases arising in the

INTRAHEPATIC CHOLANGIOCARCINOMA – DISEASE FACT SHEET Incidence ៉ Second most common primary hepatic tumor ៉ Much less frequent than HCC Gender and Age Distribution ៉ No gender predilection ៉ Majority after age 60

Prognosis and Treatment ៉ Dismal prognosis (survival <1 year) ៉ 80% unresectable at diagnosis

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Cytopathologic Findings ៉ Usually appears well differentiated ៉ Hypercellular, predominantly crowded fragments ៉ Monolayered or 3-D fragments with acinar formations ៉ High N/C ratio, prominent nucleoli ៉ Occasionally, pleomorphic cells, giant cells ៉ Rarely, mitoses and necrosis Histopathologic Findings ៉ Gross: solitary mass or multinodular ៉ Microscopic: ៉ Malignant glandular proliferation ៉ Usually well to moderately differentiated ៉ Prominent desmoplastic reaction ៉ No cytoplasmic bile ៉ Cytoplasmic mucin nearly always present Ancillary Studies ៉ Usually CK7 and CK20 double-positive (unlike HCC, which is CK7 and CK20 double-negative) ៉ High molecular weight cytokeratin and pancytokeratin positive (unlike HCC) ៉ HepPar-1 and canalicular CEA and CD10 negative (unlike HCC) Differential Diagnosis and Pitfalls ៉ Hepatocellular carcinoma with a glandular pattern: bile and

steatosis are hints when present; immunostains are helpful (see above) ៉ Metastatic adenocarcinomas: distinction generally requires immunostains ៉ Benign and reactive bile duct proliferations (e.g. bile duct adenoma): no cytologic atypia; no perineural or vascular invasion

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240 moderately differentiated and a prominent desmoplastic response is typical. In contrast to HCC, bile is not produced. Intracytoplasmic mucin is nearly always present. FNA shows a usually well-differentiated glandforming tumor (Figs 8-36–8-39). Smears are hypercellular and there is a predominance of crowded cellular fragments with a three-dimensional architecture with acinar formations. A significant number of cases display flat monolayered sheets with minimal nuclear enlargement and mild anisonucleosis; therefore, exclusion of reactive biliary epithelium with atypia could become a tricky issue. Few, if any, benign hepatocytes are present in the background, possibly representing needle sampling outside the main lesion. Poorly differentiated

FIGURE 8-36 Cholangiocarcinoma. Well-differentiated tumor shows a single crowded fragment of biliary epithelium. Nuclei are small, hyperchromatic, and tightly packed with a vague three-dimensional architecture. Few background benign hepatocytes are seen. Diff Quik stain, high power.

FIGURE 8-37 Cholangiocarcinoma. Well-differentiated tumor with a somewhat fl at monolayered sheet of ductal-type epithelium. Cells show enlarged nuclei with inconspicuous nucleoli. Differentiation from reactive biliary epithelium can become a challenge in limited samples. Papanicolaou stain, high power.

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cholangiocarcinomas show high nuclear to cytoplasmic (N/C) ratio cells, often in smaller fragments or single cells with prominent nucleoli. Pleomorphic cells, giant cells, and, rarely, mitoses and necrosis are seen as well.

ANCILLARY STUDIES There are no markers that are entirely specific for cholangiocarcinoma. The pattern of cytokeratin expression may be used to differentiate cholangiocarcinoma from poorly differentiated HCC: cholangiocarcinoma is

FIGURE 8-38 Cholangiocarcinoma. Poorly differentiated tumor with large pleomorphic nuclei, some naked, with macronucleoli. Focal gland-like architecture is evident. This case needed immunostaining to prove its glandular origin and distinction from hepatocellular carcinoma. Diff Quik stain, high power.

FIGURE 8-39 Cholangiocarcinoma. Poorly differentiated tumor with high N/C ratio cells, macronucleoli, and three-dimensional architecture. Papanicolaou stain, high power.

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typically CK7 and CK20 double-positive, whereas HCC is usually CK7 and CK20 double-negative. Unlike HCC, cholangiocarcinoma reacts with pancytokeratins (e.g. AE1/AE3) and high molecular weight cytokeratins (e.g. K903). Unlike HCC, cholangiocarcinoma does not react with HepPar-1 and does not display canalicular staining with polyclonal CEA and CD10. Cholangiocarcinoma may be distinguished from metastatic adenocarcinoma by virtue of negative staining for various organ-specific markers, such as ER and PR (breast and ovary), TTF-1 (lung and thyroid), and those used for colon (CDX-2, CK7-negative, CK20-positive). Distinction from pancreatic adenocarcinoma may be aided by the loss of DPC4 expression in 40% of cases.

HEPATOBLASTOMA – DISEASE FACT SHEET Incidence ៉ Most common primary hepatic tumor in young children ៉ Rare overall (0.5% of all pediatric neoplasms) Gender and Age Distribution ៉ Male to female ratio is 2 : 1 ៉ Children <5 years of age

Clinical Features ៉ Elevated serum AFP ៉ No association with cirrhosis Prognosis and Treatment

DIFFERENTIAL DIAGNOSIS AND PITFALLS Cholangiocarcinoma should be differentiated from HCC with a glandular pattern. Clinically, history of cirrhosis and elevated AFP strongly favor HCC over cholangiocarcinoma. Bile and steatosis, when present, are helpful hints for the diagnosis of HCC over cholangiocarcinoma, but frequently immunohistochemical markers are required to make a definitive diagnosis. With the exception of colon cancer, cholangiocarcinoma is difficult or impossible to distinguish from metastatic adenocarcinoma from other sites based on morphologic grounds alone. As described above, immunomarkers may be helpful in distinguishing cholangiocarcinoma from metastases from other organs. In addition, well-differentiated cholangiocarcinoma should be differentiated from benign and reactive bile duct proliferations, including bile duct adenoma and bile duct hamartoma.

HEPATOBLASTOMA CLINICAL FEATURES Hepatoblastoma, although rare as such, represents the most common primary hepatic tumor in infants and young children (Table 8-14). Hepatoblastoma accounts for about 50% of all primary hepatic malignancies in children and about 0.5% of all pediatric neoplasms.

៉ Surgical resection and chemotherapy ៉ Long-term survival is 60–70% after resection

The majority of hepatoblastomas occur in children under 5 years of age. Few cases have been diagnosed at birth and it rarely occurs after age 15. There is a male predominance (M : F = 2 : 1). Patients usually present with an abdominal mass. Patients with familial adenomatous polyposis have a significantly increased risk of hepatoblastoma. Serum AFP is elevated with high titers. There is no association with cirrhosis. Hepatoblastoma is managed by resection and chemotherapy. With current therapy, nearly 90% of tumors are considered resectable, with 60–70% having longterm survival.

PATHOLOGIC FEATURES Hepatoblastoma presents as a solitary mass, more commonly involving the right lobe of the liver. It measures from 3 to 20 cm. Prominent calcifications are often evident on gross examination. Histologically, hepatoblastomas are classified as either epithelial or mixed epithelial–mesenchymal. Epithelial cells resemble hepatocytes (fetal pattern) or may consist of more poorly differentiated cells (embryonal pattern). Osteoid production may be present prominently in the mixed epithelial–mesenchymal type of hepatoblastoma, particularly following chemotherapy. Foci of admixed extramedullary hematopoiesis may be found, which may help differentiate hepatoblastoma from HCC. Cytopathologic characteristics (Fig. 8-40) depend on the subtype of hepatoblastoma.

TABLE 8-14 Pediatric Liver Tumors

ANCILLARY STUDIES • Hepatoblastoma • Embryonal sarcoma • Fibrolamellar hepatocellular carcinoma

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Similar to HCC, hepatoblastoma reacts with HepPar-1 and AFP and shows canalicular staining with polyclonal CEA and CD10.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS In children, hepatoblastoma should be primarily differentiated from metastases from other pediatric malignancies, including neuroblastoma, lymphoblastic lymphoma, Wilms tumor, and rhabdomyosarcoma. Primary hepatic neoplasms that enter the differential diagnosis for hepatoblastoma include undifferentiated (embryonal) sarcoma and HCC. If an epithelial component is present, embryonal sarcoma can be excluded. HCC is uncommon in children under 5 years of age. Presence of foci of extramedullary hematopoiesis may help differentiate hepatoblastoma from HCC.

FIGURE 8-40 Hepatoblastoma. Primitive-appearing small round blue cells with a high N/C ratio, speckled chromatin, and densely pink cytoplasm. No hepatocytic differentiation is evident. Diagnosis is usually straightforward due to the young age of the patient and a markedly elevated serum AFP. H&E stain, high power.

PRIMARY MALIGNANT MESENCHYMAL TUMORS OF THE LIVER EPITHELIOID HEMANGIOENDOTHELIOMA CLINICAL FEATURES

HEPATOBLASTOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Depend on the subtype ៉ Epithelial (fetal, embryonal): resemble HCC – hypercellular smears with cords, nests, or trabeculae of small crowded monotonous hepatocytes; cells often oval to spindle-shaped, high N/C ratio, frequent mitosis ៉ Mixed epithelial–mesenchymal: more pleomorphic; also contains a neoplastic mesenchymal component (cartilage, bone, or skeletal muscle) ៉ Anaplastic/small cell undifferentiated: hypercellular smears with uniform primitive-appearing small blue cells, high mitotic index, karyorrhexis, necrosis Histopathologic Findings ៉ Gross: ៉ Usually solitary ៉ Prominent calcifications frequent ៉ Microscopic: ៉ Epithelial or epithelial-mesenchymal types ៉ Prominent osteoid production, particularly after

chemotherapy ៉ Foci of extramedullary hematopoiesis Ancillary Studies ៉ Similar to HCC: positive for HepPar-1, AFP, canalicular polyclonal CEA and CD10 Differential Diagnosis and Pitfalls ៉ Metastases from other pediatric malignancies: neuroblastoma,

lymphoblastic lymphoma, Wilms tumor, rhabdomyosarcoma ៉ Other primary liver neoplasms: ៉ HCC: rare in children less than age 5 years; no foci of

Epithelioid hemangioendothelioma (EHE) is an uncommon tumor arising in the liver and various other organs. The risk factors for EHE are not well characterized. Oral contraceptive use and vinyl chloride exposure have been implicated in isolated cases. EHE most commonly develops in middle-aged women. Patients generally present with abdominal pain, weight loss, and, occasionally, hepatic rupture. In approximately 40% of cases, EHE is found incidentally. Clinical course is unpredictable, although overall survival rates are better than for angiosarcoma. Survival ranges from several months to 27 years. Treatment of EHE is a controversial subject. Resection is generally the treatment of choice. Extrahepatic involvement of other organs, such as lung, has been found in nearly 50% of cases.

EPITHELIOID HEMANGIOENDOTHELIOMA – DISEASE FACT SHEET Incidence ៉ Rare Gender and Age Distribution ៉ Most common in middle-aged women

Prognosis and Treatment ៉ Unpredictable clinical course ៉ Resection generally the treatment of choice

extramedullary hematopoiesis ៉ Undifferentiated (embryonal) sarcoma: no epithelial

component; cytokeratin-negative

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PATHOLOGIC FEATURES EHE presents are multiple liver nodules, involving both lobes of the liver in 80% of cases. Nodule sizes vary from 1 to 12 cm. The tumor cells form single-fi le cords, which course through the myxohyaline matrix. A diagnostic clue to the vascular nature of this neoplasm is the presence of ‘blister cells’, characterized by cytoplasmic vacuoles representing incipient vascular lumina. These lumina may contain erythrocytes. FNA shows a paucicellular aspirate with discohesive, large polygonal-round epithelioid cells, rarely with gland-like formations (Fig. 8-41). Cells have large nuclei, often with vesicular chromatin and prominent nucleoli, and granular-pale, abundant eosinophilic cytoplasm. Also observed are intracytoplasmic lumina/vacuoles as well as intracytoplasmic hemosiderin pigment.

ANCILLARY STUDIES Electron microscopy may be used to identify WeibelPalade bodies, which are the components of endothelial cells. EHE reacts with endothelial markers (CD34, CD31, Factor VIII, Ulex europaeus). Up to 15% of EHE react with cytokeratin stains, which should not be misinterpreted as evidence of carcinoma.

EPITHELIOID HEMANGIOENDOTHELIOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Paucicellular aspirate ៉ Discohesive, large polygonal–round epithelioid cells, rarely gland-like formations ៉ Large nuclei, often vesicular chromatin, prominent nucleoli ៉ Granular–pale, abundant eosinophilic cytoplasm, intracytoplasmic lumina/vacuoles, hemosiderin Histopathologic Findings ៉ Gross: ៉ Multiple liver nodules (1 to 12 cm) ៉ Microscopic: ៉ Single-file cords of cells ៉ Myxohyaline matrix ៉ ’Blister cells’: cytoplasmic vacuoles with erythrocytes (incipient vascular lumina) Ancillary Studies ៉ Endothelial markers: CD34, CD31, Factor VIII, Ulex europaeus ៉ Cytokeratin reactivity in up to 15% of cases ៉ Electron microscopy: Weibel-Palade bodies

FIGURE 8-41 Epithelioid hemangioendothelioma. Epithelioid cells with round to oval uniform nuclei resembling a non-small cell carcinoma. An intranuclear inclusion is also seen. Diagnosis is dependent on immunostaining. Diff Quik stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Vacuoles in blister cells may be mistaken for signet-ring cells. Unlike signet-ring cells, the blister cells do not react with mucicarmine. EHE should also be differentiated from angiosarcoma.

ANGIOSARCOMA CLINICAL FEATURES Although rare as such, angiosarcoma is considered the most common primary hepatic sarcoma. It represents

ANGIOSARCOMA – DISEASE FACT SHEET Incidence ៉ Most common primary hepatic sarcoma ៉ Overall rare (<1% of primary hepatic neoplasms) Gender and Age Distribution ៉ Male to female ratio is 3 : 1 ៉ Age 60 to 70 years

Clinical Features ៉ Associated with cirrhosis in 30% of cases

Prognosis and Treatment Differential Diagnosis and Pitfalls ៉ Angiosarcoma ៉ Signet-ring cell carcinoma

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៉ Prognosis extremely poor, most patients dying of disease within 6

months of diagnosis ៉ Recommended treatment is surgical resection and radiation

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less than 1% of primary hepatic neoplasms. Most patients are in their sixth or seventh decade of life, with a male to female ratio of 3 : 1. Similar to HCC, angiosarcoma is associated with cirrhosis (30%). Other etiologic factors include exposure to vinyl chloride, Thorotrast, and arsenic. Most patients present with hepatomegaly, abdominal pain, ascites, and, uncommonly, acute abdomen due to spontaneous rupture of the tumor. Most cases are treated with surgery and radiation. Prognosis is extremely poor, with most patients dying of disease within 6 months. CT scans show solitary or multiple low-density masses with lobular or irregular outlines, clear or illdefined margins, and curvilinear calcification. Postcontrast CT scans display progressive and isodense enhancement.

PATHOLOGIC FEATURES As in other organs, angiosarcoma is characterized by formation of anastomosing vascular channels lined by pleomorphic epithelioid or spindled endothelial cells. ‘Hobnail’ morphology is common. The tumor grows along the sinusoids. Cytopathologic characteristics include hypercellular smears with variably sized fragments and numerous single cells with prominent pleomorphism (Fig. 8-42). The malignant cells are predominantly spindly/fusiform and less often epithelioid in shape. Necrosis is often observed.

FIGURE 8-42 Angiosarcoma. Spindled cells with long tapering nuclei densely arranged in a tissue fragment. Diagnosis usually hinges upon immunostaining with vascular markers. Diff Quik stain, high power.

ANCILLARY STUDIES Electron microscopy may be used to identify WeibelPalade bodies. Endothelial markers (CD34, CD31, Factor VIII, and Ulex europaeus) may be used to confirm the vascular origin of this neoplasm. Lack of expression of smooth muscle markers (actin, desmin, calponin) may be used to rule out a metastatic leiomyosarcoma.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

ANGIOSARCOMA – PATHOLOGIC FEATURES Cytopathologic Findings

The differential diagnosis includes epithelioid hemangioendothelioma and metastatic sarcomas, particularly leiomyosarcoma.

៉ Hypercellular smears, variably sized fragments, numerous single

cells ៉ Pleomorphism, with predominantly spindly cells, less often

epithelioid cells ៉ Necrosis Histopathologic Findings ៉ Anastomosing vascular channels ៉ Channels lined by pleomorphic ‘hobnail’ epithelioid or spindled endothelial cells ៉ Growth along the sinusoids Ancillary Studies ៉ Positive for endothelial markers (CD34, CD31, Factor VIII, and

Ulex europaeus) ៉ Electron microscopy: Weibel-Palade bodies

Differential Diagnosis and Pitfalls ៉ Epithelioid hemangioendothelioma ៉ Metastatic sarcoma (particularly leiomyosarcoma)

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PRIMARY HEPATIC LYMPHOMA CLINICAL FEATURES Primary hepatic lymphoma is defined as lymphoma predominantly involving the liver in the absence of nodal or disseminated disease. Primary hepatic lymphoma is exceedingly rare, representing less than 0.5% of extranodal lymphomas. Only approximately 100 cases have been reported in the literature. More commonly, the liver is involved by lymphomatous infiltrate as part of disseminated lymphoma or hepatosplenic T-cell lymphoma. Liver involvement is present at diagnosis in up to 10% of patients with Hodgkin lymphoma and up to 40% of patients with non-Hodgkin lymphoma. There is a wide age spectrum, ranging from 7 to 87 years, with a median age of 55

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PRIMARY HEPATIC LYMPHOMA – CLINICAL FEATURES Incidence ៉ Exceedingly rare ៉ Approximately 100 cases reported in the literature Gender and Age Distribution ៉ Male to female ratio is 3 : 1 ៉ Wide age spectrum (7 to 87 years; median age, 55 years)

Treatment ៉ Non-surgical

245 lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, MALT lymphoma, and angiocentric lymphoma. Histologic and cytologic features of primary tumors correspond to the patterns characteristic of the nodal disease. FNA shows hypercellular smears with a distinct population of monotonous-appearing lymphocytes (Figs 8-43–8-45). Mitoses and karyorrhexis are often observed, reflecting the high-grade phenotype of the lymphoma process. In cases of Hodgkin lymphoma, the smears are often not as cellular, and depending on the subtype of the disease, Reed-Sternberg cells are observed in varying numbers. The differential diagnosis involves small round blue cell tumors (metastatic islet cell tumor in particular) and, in rare instances, nodular form of extramedullary hematopoiesis (Figs 8-46 & 8-47).

years. The male to female ratio is 3 : 1. Therapy is nonsurgical. The chemotherapeutic regimen depends on lymphoma type.

PATHOLOGIC FEATURES Primary hepatic lymphoma may present as either a solitary or multiple liver masses. All described cases are of a non-Hodgkin lymphoma variety. The vast majority of primary hepatic lymphomas are of B-cell origin, with over 75% representing the diffuse large B-cell lymphoma. Other patterns of primary B-cell lymphoma include follicular lymphoma, small lymphocytic

PRIMARY HEPATIC LYMPHOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Depends on the type of lymphoma; similar to nodal disease

FIGURE 8-43 Primary hepatic lymphoma. Monotonous population of small lymphocytes. Immunostaining and flow analysis was consistent with a MALTtype lymphoma. Papanicolaou stain, high power.

Histopathologic Findings ៉ Gross: ៉ Solitary or multiple masses ៉ Microscopic: ៉ All cases non-Hodgkin lymphoma ៉ Vast majority B-cell lymphoma ៉ 75% diffuse large B-cell lymphoma

Ancillary Studies ៉ Pan-hematopoietic marker, LCA (CD45), distinguishes lymphoma from carcinoma, melanoma, or sarcoma ៉ Lymphomas further subtyped with CD3 (T-cell marker), CD20 (B-cell marker) and various other hematopoietic markers ៉ Fresh specimen should be submitted for flow cytometry Differential Diagnosis and Pitfalls ៉ Poorly differentiated carcinoma, melanoma, and sarcoma ៉ Hepatic involvement by disseminated lymphoma: most common type of hepatic lymphoma; liver involved in 40% of patients with non-Hodgkin lymphoma ៉ Hepatic involvement by hepatosplenic T-cell lymphoma

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FIGURE 8-44 Primary hepatic lymphoma. High-grade tumor shows medium-sized lymphocytes with abundant mitoses and fine cytoplasmic vacuoles consistent with an aggressive Burkitt-type lymphoma. Diff Quik stain, high power.

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FIGURE 8-45 Plasmacytoma. Malignant plasma cells with the characteristic speckled chromatin and intranuclear inclusions. Papanicolaou stain, high power.

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FIGURE 8-47 Extramedullary hematopoiesis. Megakaryocyte in a background of mononuclear cells of different lineages. Papanicolaou stain, high power.

this differential diagnosis. Primary hepatic lymphoma should also be differentiated from hepatic involvement by disseminated lymphoma and hepatosplenic T-cell lymphoma.

METASTATIC TUMORS TO THE LIVER CLINICAL FEATURES (Table 8-15)

FIGURE 8-46 Extramedullary hematopoiesis. Polymorphous cells with lymphoid and erythroid elements. Diff Quik stain, high power.

Liver, along with the lung, is the organ that is most frequently involved by metastatic tumors. In the United States, metastases represent 98% of all hepatic malignancies. However, in patients with cirrhosis, primary liver malignancies (mainly HCC) are three times more common than metastases. In adults, malignancies that most frequently metastasize to the liver include those from the colorectum, pancreas, breast, lung, stomach, kidney, and skin

ANCILLARY STUDIES Leukocyte common antigen, LCA (CD45), is a panhematopoietic marker used to distinguish lymphoma from carcinoma, melanoma, or sarcoma. Lymphomas can be further subtyped with CD3 (T-cell marker), CD20 (B-cell marker), and various other hematopoietic antigens. If lymphoma is suspected, a fresh specimen should be submitted for a flow cytometric analysis.

METASTATIC TUMORS – DISEASE FACT SHEET Incidence ៉ Most common type of hepatic malignancy ៉ Metastases represent 98% of hepatic malignancies (in the United

States) ៉ In cirrhotic livers, primary neoplasms are three times more

common than metastases Gender and Age Distribution

DIFFERENTIAL DIAGNOSIS AND PITFALLS Lymphoma should be differentiated from poorly differentiated carcinoma, melanoma, and sarcoma. Immunohistochemical stains and flow cytometry aid in

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៉ Depends on tumor type

Prognosis and Treatment ៉ Depends on tumor type

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TABLE 8-15 Metastatic Tumors in the Liver – Common Facts • Most common cancer in the liver • Most common indication for hepatic FNA • Most common – colon, pancreas, breast, lung, kidney, melanoma • Source of the primary tumor could be occult • Cytomorphology alone may not be able to diagnose an unknown primary (immunoperoxidase stains could be helpful)

(melanoma). Leiomyosarcoma is the most common soft tissue tumor to metastasize to the liver. In contrast, it is unusual for prostate tumors to metastasize to the liver. In children, neoplasms that commonly metastasize to the liver include neuroblastoma, Wilms tumor, and rhabdomyosarcoma.

FIGURE 8-48 Hepatectomy specimen shows a subcapsular nodule of metastatic colonic adenocarcinoma. This presents the most common scenario for a liver FNA procedure, which provides an accurate answer within a short time.

PATHOLOGIC FEATURES Metastatic tumors frequently present as multiple masses. Histopathology and cytopathology depend on the tumor of origin (Figs 8-48–8-58). Metastatic melanoma is a frequently observed secondary tumor in the liver and may depict significant morphologic overlap with poorly differentiated HCC. This necessitates a careful evaluation of subtle morphologic differences between the two tumor types (Table 8-16). METASTATIC TUMORS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Depends on the type of primary tumor

FIGURE 8-49 Hepatic metastasis: colonic adenocarcinoma. Columnar-shaped cells in a background of ‘dirty necrosis’. Papanicolaou stain, high power.

Histopathologic Findings ៉ Gross: usually present as multiple nodules ៉ Microscopic: depends of the tumor of origin Ancillary Studies ៉ HepPar-1 to distinguish from primary HCC or hepatoblastoma ៉ CK7 and CK20 ៉ Organ- and tissue-specific markers: ER/PR (breast, ovary), TTF-1 (lung, thyroid), PSA (prostate), S-100/Melan A/HMB-45 (melanoma), actin/desmin (leiomyosarcoma) Differential Diagnosis and Pitfalls ៉ Common metastatic malignancies in adults: colorectum,

pancreas, breast, lung, stomach, kidney, melanoma, leiomyosarcoma ៉ Common metastatic malignancies in children: neuroblastoma, Wilms tumor, rhabdomyosarcoma ៉ Primary hepatic neoplasms: hepatocellular carcinoma, cholangiocarcinoma, and mesenchymal neoplasms are in the differential diagnosis for metastatic malignancies

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FIGURE 8-50 Hepatic metastasis: adenosquamous carcinoma from a pancreatic primary. Note admixture of adenocarcinoma with brightly pink keratinized squamous cells. Papanicolaou stain, high power.

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FIGURE 8-51 Hepatic metastasis: renal cell carcinoma. Clear cell tumor with large nuclei and macronucleoli. Renal cell carcinoma shares several morphologic features with hepatocellular carcinoma and usually requires immunostaining for definitive diagnosis. Papanicolaou stain, high power.

FIGURE 8-53 Hepatic metastasis of malignant melanoma. Large pleomorphic and naked nuclei resembling poorly differentiated hepatocellular carcinoma. Macronucleoli are visible. Note lack of pigmented cells. Diff Quik stain, high power.

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FIGURE 8-52 Hepatic metastasis: malignant melanoma from a cutaneous primary. Discohesive, heavily pigmented malignant cells with an epithelioid appearance. Note prominent nucleoli and focal resemblance to hepatocytes. Papanicolaou stain, high power.

FIGURE 8-54 Hepatic metastasis: squamous cell carcinoma from an esophageal primary. Extensive cystic necrosis (left side) with densely keratinized malignant cells (right side). Papanicolaou stain, low to high power.

TABLE 8-16 Hepatocellular Carcinoma (HCC) versus Metastatic Malignant Melanoma (MM) • Closest mimic of HCC • Liver is a very common site for visceral spread of MM • Cytomorphologic features (MM over HCC): • More often single cells or sheet-like arrangement • Plasmacytoid cells (eccentric nuclei) • More frequent binucleation • Cytoplasmic tails/prolongations • Melanin-like pigment • Necrosis

FIGURE 8-55 Hepatic metastasis: small cell carcinoma from a lung primary. Small, hyperchromatic nuclei with prominent molding, nuclear ‘streak’ artifact, and lack of nucleoli. Diff Quik stain, high power.

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FIGURE 8-56 Hepatic metastasis: islet cell tumor (pancreatic endocrine neoplasm). Monotonous population of neoplastic cells with eccentric nuclei (‘plasmacytoid’ appearance) and speckled chromatin. Uniformity of cells with a relatively smaller size, lack of prominent nucleoli, and glandular formations differentiate this from an adenocarcinoma. Papanicolaou stain, intermediate power.

FIGURE 8-58 Hepatic metastasis: gastrointestinal stromal tumor from a gastric primary. Loose fragment of plump fusiform nuclei arranged in a haphazard fashion. Papanicolaou stain, intermediate power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Metastatic neoplasms must be differentiated from primary HCC, cholangiocarcinoma, and mesenchymal neoplasms.

SUGGESTED READINGS Nodular Regenerative Hyperplasia Cohen MB, Haber MM, Holly EA, Ahn DK, Bottles K, Stoloff AC. Cytologic criteria to distinguish hepatocellular carcinoma from nonneoplastic liver. Am J Clin Pathol 1991;95:125–130. Yang GC, Yang GY, Tao LC. Distinguishing well-differentiated hepatocellular carcinoma from benign liver by the physical features of fine-needle aspirates. Mod Pathol 2004;17:798–802. FIGURE 8-57 Hepatic metastasis: hemangiopericytoma from a brain primary. Monotonous, round to oval cells with mostly naked nuclei and scant to no cytoplasm. Diff Quik stain, intermediate power.

ANCILLARY STUDIES

Focal Nodular Hyperplasia Kong CS, Appenzeller M, Ferrell LD. Utility of CD34 reactivity in evaluating focal nodular hepatocellular lesions sampled by fine needle aspiration biopsy. Acta Cytol 2000;44:218–222. Ruschenburg I, Droese M. Fine needle aspiration cytology of focal nodular hyperplasia of the liver. Acta Cytol 1989;33:857–860. Hydatid Disease

Various markers may be applied to determine the site of origin of a metastatic carcinoma. For example: ER and PR support breast or gynecologic tract primary; TTF-1, lung or thyroid primary; CDX-2, colorectal primary; and PSA or PSAP, prostate primary. Metastatic melanoma reacts with S-100, Melan A, and HMB45. Metastatic leiomyosarcoma expresses actin, desmin, and calponin. In contrast, primary HCC may be distinguished from metastatic carcinomas based on expression of HepPar-1, AFP, and canalicular polyclonal CEA and CD10.

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Agarwal PK, Husain N, Singh BN. Cytologic findings in aspirated hydatid fluid. Acta Cytol 1989;33:652–654. Parwani AV, Burroughs FH, Ali SZ. Echinococcal cyst of the liver. Diagn Cytopathol 2004;31:111–112. Extramedullary Hematopoiesis Lemos LB, Baliga M, Benghuzzi HA, Cason Z. Nodular hematopoiesis of the liver diagnosed by fine-needle aspiration cytology. Diagn Cytopathol 1997;16:51–54. Parwani AV, Ali SZ. Pathologic quiz case: a 52-year-old woman with a liver mass. Arch Pathol Lab Med 2003;127:631–632.

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Hemangioma

Fibrolamellar Hepatocellular Carcinoma

Guy CD, Yuan S, Ballo MS. Spindle-cell lesions of the liver: diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 2001;25:94–100. Layfield LJ, Mooney EE, Dodd LG. Not by blood alone: diagnosis of hemangiomas by fine-needle aspiration. Diagn Cytopathol 1998;19: 250–254.

Davenport RD. Cytologic diagnosis of fibrolamellar carcinoma of the liver by fine-needle aspiration. Diagn Cytopathol 1990;6:275–279. Kunz G Jr, Chung J, Ali SZ. Hepatocellular carcinoma-fibrolamellar variant: cytopathology of an unusual case. Diagn Cytopathol 2002;26:257– 261.

Hepatocellular Adenoma

Intrahepatic Cholangiocarcinoma

Pedio G, Landolt U, Zobeli L, Gut D. Fine needle aspiration of the liver. Significance of hepatocytic naked nuclei in the diagnosis of hepatocellular carcinoma. Acta Cytol 1988;32:437–442. Suen KC. Diagnosis of primary hepatic neoplasms by fine-needle aspiration cytology. Diagn Cytopathol 1986;2:99–109.

Dalton-Clarke HJ, Pearse E, Krause T, McPherson GA, Benjamin IS, Blumgart LH. Fine needle aspiration cytology and exfoliative biliary cytology in the diagnosis of hilar cholangiocarcinoma. Eur J Surg Oncol 1986;12: 143–145. Pitman MB. Fine needle aspiration biopsy of the liver. Principal diagnostic challenges. Clin Lab Med 1998;18:483–506, vi.

Ciliated Hepatic Foregut Cyst Hornstein A, Batts KP, Linz LJ, Chang CD, Galvanek EG, Bardawil RG. Fine needle aspiration diagnosis of ciliated hepatic foregut cysts: a report of three cases. Acta Cytol 1996;40:576–580. Zaman SS, Langer JE, Gupta PK. Ciliated hepatic foregut cyst. Report of a case with findings on fine needle aspiration. Acta Cytol 1995;39: 781–784.

Hepatoblastoma Wakely PE Jr, Silverman JF, Geisinger KR, Frable WJ. Fine needle aspiration biopsy cytology of hepatoblastoma. Mod Pathol 1990;3:688–693. Weir EG, Ali SZ. Hepatoblastoma: cytomorphologic characteristics in serious cavity fluids. Cancer 2002;96:267–274. Primary Malignant Mesenchymal Tumors

Bile Duct Adenoma Bhathal PS, Hughes NR, Goodman ZD. The so-called bile duct adenoma is a peribiliary gland hamartoma. Am J Surg Pathol 1996;20:858–864. Shibahara H, Tamada S, Goto M, et al. Pathologic features of mucinproducing bile duct tumors: two histopathologic categories as counterparts of pancreatic intraductal papillary-mucinous neoplasms. Am J Surg Pathol 2004;28:327–338.

Smith MB, Silverman JF, Raab SS, Towell BD, Geisinger KR. Fine-needle aspiration cytology of hepatic leiomyosarcoma. Diagn Cytopathol 1994; 11:321–327. Wee A, Nilsson B. Fine needle aspiration biopsy of hepatic leiomyosarcoma. An unusual epithelioid variant posing a potential diagnostic pitfall in a hepatocellular carcinoma-prevalent population. Acta Cytol 1997;41:737–743. Epithelioid Hemangioendothelioma

Hepatobiliary Cystadenoma Devaney K, Goodman ZD, Ishak KG. Hepatobiliary cystadenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients. Am J Surg Pathol 1994;18:1078–1091. Logrono R, Rampy BA, Adegboyega PA. Fine needle aspiration cytology of hepatobiliary cystadenoma with mesenchymal stroma. Cancer 2002; 96:37–42

Pettinato G. Fine-needle aspiration cytology of epithelioid hemangioendothelioma. Diagn Cytopathol 1990;6:438–439. Soslow RA, Yin P, Steinberg CR, Yang GC. Cytopathologic features of hepatic epithelioid hemangioendothelioma. Diagn Cytopathol 1997;17: 50–53. Angiosarcoma

Infl ammatory Pseudotumor Hosler GA, Steinberg DM, Sheth S, Hamper UM, Erozan YS, Ali SZ. Inflammatory pseudotumor: a diagnostic dilemma in cytopathology. Diagn Cytopathol 2004;31:267–270. Malhotra V, Gondal R, Tatke M, Sarin SK. Fine needle aspiration cytologic appearance of inflammatory pseudotumor of the liver. A case report. Acta Cytol 1997;41:1325–1328.

Hepatocellular Carcinoma Kulesza P, Torbenson M, Sheth S, Erozan YS, Ali SZ. Cytopathologic grading of hepatocellular carcinoma on fine-needle aspiration. Cancer 2004;102: 247–258. Soyuer I, Ekinci C, Kaya M, Genc Y, Bahar K. Diagnosis of hepatocellular carcinoma by fine needle aspiration cytology. Cellular features. Acta Cytol 2003;47:581–589. Takenaka A, Kaji I, Kasugai H, et al. Usefulness of diagnostic criteria for aspiration cytology of hepatocellular carcinoma. Acta Cytol 1999;43: 610–616. Wee A, Nilsson B, Tan LK, Yap I. Fine needle aspiration biopsy of hepatocellular carcinoma. Diagnostic dilemma at the ends of the spectrum. Acta Cytol 1994;38:347–354.

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Boucher LD, Swanson PE, Stanley MW, Silverman JF, Raab SS, Geisinger KR. Cytology of angiosarcoma. Findings in fourteen fine-needle aspiration biopsy specimens and one pleural fluid specimen. Am J Clin Pathol 2000;114:210–219. Nguyen GK, Husain M. Fine-needle aspiration biopsy cytology of angiosarcoma. Diagn Cytopathol 2000;23:143–145. Primary Hepatic Lymphomas Collins KA, Geisinger KR, Raab SS, Silverman JF. Fine needle aspiration biopsy of hepatic lymphomas: cytomorphology and ancillary studies. Acta Cytol 1996;40:257–262. Rappaport KM, DiGiuseppe JA, Busseniers AE. Primary hepatic lymphoma: report of two cases diagnosed by fine-needle aspiration. Diagn Cytopathol 1995;13:142–145. Metastatic Tumors Bizjak-Schwarzbartl M. Fine-needle aspiration biopsy in the diagnosis of metastases in the liver. Diagn Cytopathol 1987;3:278–283. Parwani AV, Chan TY, Mathew S, Ali SZ. Metastatic malignant melanoma in liver aspirate: cytomorphologic distinction from hepatocellular carcinoma. Diagn Cytopathol 2004;30:247–250.

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9

Pancreas Martha Bishop Pitman

INTRODUCTION Cytologic specimens are obtained from the pancreas most commonly by fine needle aspiration biopsy (FNAB). The aspirated tissue from any lesion can be prepared in a number of different ways: direct smears, cytospins (Thermo Shandon Instruments), liquidbased preparations (ThinPrep® [Cytyc Corporation, Marlborough, MA] or SurePathTM [TriPath, Inc, Burlington, NC]) and cell blocks. Direct smears are the most common, particularly for solid masses, but specimens aspirated as a fluid from a cyst are often processed as cytospins or liquid-based specimens. Liquid-based preparations eliminate obscuring blood and inflammation and provide excellent cellular preservation; however, cellular and extracellular material such as mucin is attenuated and not as apparent as on direct smears. Preserving some fluid in the liquid form from cyst aspirates allows for additional slides dedicated to special stains for mucin, which may assist in detecting subtle background or intracellular mucin. Aspirates rinsed in saline can be used for flow cytometry analysis in cases suspicious of lymphoma. Cell block preparations are advantageous given the readily available tissue for immunocytochemistry. Percutaneous FNAB with computed tomography (CT) guidance is most commonly used; however, endoscopic ultrasound (EUS)-guided FNAB is becoming increasingly utilized. It is important to recognize that EUS-guided biopsies traverse the stomach or duodenal wall, thereby introducing the potential for epithelial and mucin contamination. The interpretation of pancreatic cytology should not occur in a vacuum, and all clinical, radiologic, and ancillary tests need to be incorporated in order to provide an accurate diagnosis. The differential diagnosis of pancreatic masses is initially established from the radiographic appearance of the mass, and generally falls into two categories: solid versus cystic mass lesions. Solid masses are much more common than cystic masses, and adenocarcinoma is by far the most common neoplasm in the pancreas. Solid mass lesions in the differential diagnosis include chronic pancreatitis, pancreatic endocrine neoplasm, acinar cell carcinoma, pancreatoblastoma, and metastatic neoplasms. The most common cyst in the pancreas is a pseudocyst. This non-neoplastic cyst needs to be distinguished from a neoplastic mucinous cyst,

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serous cyst, and solid neoplasms with cystic degeneration. Cysts with thick septa and significant internal debris are suspicious for malignancy, and the presence of a solid mass in the wall of a cyst in suspicious for an invasive cystic neoplasm.

NORMAL PANCREAS A significant pitfall in the interpretation of pancreatic cytology is the over-interpretation of normal pancreatic epithelium as neoplastic. The pancreas is composed of exocrine (acinar cells and ducts) and endocrine (islets of Langerhans) cells. Eighty-five percent of the pancreas is exocrine tissue, predominantly acinar epithelium. In benign processes, except in late chronic pancreatitis, acinar cells dominate aspiration smears. Acinar epithelium presents as cohesive, small, grapelike clusters of cells and scattered polygonal single cells with occasional stripped nuclei (Fig. 9-1). The round, regular nuclei are central to eccentric, with uniform chromatin and often quite prominent nucleoli. The typically abundant granular cytoplasm stains blue– green with the Papanicolaou stain and purple with a Romanowsky stain (Fig. 9-2). The Romanowsky stain highlights scattered small vacuoles in the cytoplasm. The cytoplasmic granules may not be very visible. The architectural arrangement of the cells is key to differentiating benign acinar cells from a neoplastic acinar cell proliferation, the latter generally forming large sheets and clusters as apposed to the small, uniform, grape-like clusters of a benign process (see acinar cell carcinoma). Normal pancreatic ducts present as large, flat, cohesive sheets of epithelium with round, uniform, evenly spaced nuclei, yielding the classic glandular ‘honeycombed’ appearance (Fig. 9-3). The cytoplasm of normal ductal cells is not visibly mucinous and can best be seen when the epithelium is present in strips yielding a ‘picket fence’ arrangement, or in sheets with a luminal edge (Fig. 9-4). Ductal cells have round to oval nuclei, even chromatin, and generally small, inconspicuous nucleoli. Features consistent with a non-neoplastic process on cytology include cohesion and nuclei with uniform size, shape, chromatin distribution, and spacing. Distinguishing benign pancreatic ductal epithelium 251

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FIGURE 9-1 Normal pancreatic acinar epithelium. The smear pattern of normal acinar epithelium is one in which the majority of acinar epithelial cells maintain a cohesive small grape-like clustering. Occasional stripped nuclei can be identified in the background. Papanicolaou stain, low power.

A

B

FIGURE 9-2 Benign pancreatic acinar epithelium. Acinar cells are uniform with round, regular, central to slightly eccentric nuclei and often quite prominent nucleoli. The cytoplasm is granular, staining blue–green with the Papanicolaou stain (A) and purple with the Romanowsky stain, which also highlights scattered small cytoplasmic vacuoles (B). A, Papanicolaou stain, high power. B, Romanowsky stain, high power.

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FIGURE 9-3 Benign pancreatic ductal epithelium. Benign pancreatic ducts often present as fl at cohesive sheets with round, uniform, evenly spaced nuclei, yielding the classic glandular honeycombed appearance. Papanicolaou stain, high power.

Cytologically, individual islet cells appear uniform and polygonal with round nuclei, coarse clumped chromatin, small inconspicuous nucleoli, and pale amphophilic cytoplasm.

NON-NEOPLASTIC MASS LESIONS CHRONIC PANCREATITIS Chronic pancreatitis is a progressive inflammatory disease of the pancreas that destroys the exocrine component – and, in some severe cases, the endocrine component – of the gland, leading to irreversible morphologic changes and function. FIGURE 9-4 Benign pancreatic ductal epithelium. Occasionally, ductal epithelial cells can be seen in strips on edge demonstrating basal nuclei and apical columnar cytoplasm. Note that the cytoplasm is non-mucinous. Papanicolaou stain, high power.

from gastrointestinal epithelium, especially gastric epithelium, may be impossible. The misinterpretation of gastrointestinal epithelium as benign ductal epithelium aspirated from a solid mass can lead to a false negative biopsy that, in reality, has not sampled the mass at all. Benign islet cells are not often appreciated on aspirate smears of a non-neuroendocrine neoplasm.

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CLINICAL FEATURES In the United States, chronic alcohol abuse accounts for roughly 70% of all cases of chronic pancreatitis. Other causes of chronic pancreatitis include obstruction (stones, abnormal anatomy, scarring, extrinsic compression), autoimmune disease (lymphoplasmacytic sclerosing pancreatitis), chronic malnutrition, and heredity. The condition is more common in men than in women, and occurs over a wide age range, generally 40–60 years of age.

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CHRONIC PANCREATITIS – DISEASE FACT SHEET

CHRONIC PANCREATITIS – PATHOLOGIC FEATURES

Incidence

Cytopathologic Findings

៉ 70% associated with long-term alcohol abuse

៉ Mixed ductal and acinar epithelium ៉ Infl ammation in the background and embedded in stromal

Gender and Age Distribution ៉ M > F ៉ 40–60 years

Radiologic Features ៉ Irregular ductal dilation associated with strictures and

calcifications ៉ Focal areas of expansive fibrosis produce a mass-like lesion

simulating carcinoma Prognosis and Treatment ៉ A benign disease, but the variable loss of exocrine and endocrine function is irreversible and the risk of developing carcinoma is increased ៉ Therapy includes enzyme or hormone supplementation

The morphologic changes of the gland, e.g. loss of exocrine or endocrine tissue and fibrosis, are irreversible. The risk of developing carcinoma is increased, particularly with hereditary chronic pancreatitis. The therapy for exocrine or endocrine dysfunction is enzyme or hormone supplementation.

R ADIOLOGIC FEATURES Most cases of chronic pancreatitis are associated with non-focal lesions, irregular ductal dilation that is often associated with stricture formation, obstruction, and calcifications. Pseudocyst formation may also be present. Focal involvement of the gland may occur, as well as dense expanses of fibrosis in more diffuse disease, both conditions creating mass-like lesions that mimic pancreatic carcinoma.

fragments ៉ Cellular stromal fragments with infl ammatory cells >30/60× HPF

is associated with autoimmune etiology ៉ Fat necrosis and calcific debris may be present ៉ Ductal epithelium contains relatively evenly spaced, uniform,

polarized nuclei with even to slightly coarse chromatin and smooth nuclear membranes; nucleoli may be prominent ៉ Cytoplasm is usually non-mucinous (may see mucinous metaplasia in pancreatic intraepithelial neoplasia) Differential Diagnosis and Pitfalls ៉ Ductal adenocarinoma ៉ Gastrointestinal contamination (pitfall)

necrosis supports chronic pancreatitis over adenocarcinoma (Fig. 9-7). Ductal cells are almost always present, although they may be quite scant, and can show some nuclear crowding and coarse chromatin. The benign ‘honeycombed’ pattern of nuclear spacing is generally maintained and chromatin is evenly distributed in the nucleus, although it may be somewhat coarse and display conspicuous nucleoli (Fig. 9-8). Patients with classic clinical and radiologic evidence of chronic pancreatitis, however, rarely undergo FNAB for confirmation of the diagnosis. It is the expansive sclerosis in chronic pancreatitis, especially in autoimmune pancreatitis, and focal gland involvement by chronic pancreatitis that results in a mass lesion often associated with irregular pancreatic duct contours and bile duct stricture, radiologic features highly suspicious for adenocarcinoma. The dominance of ductal cells without acinar cells or calcific debris is the cytologic finding that raises the differential diagnosis of adenocarcinoma.

ANCILLARY STUDIES CYTOPATHOLOGIC FEATURES The classic cytologic findings in patients with clinical and endoscopic evidence of the more common alcoholrelated disease include the presence of fibrotic acinar tissue, fragments of relatively acellular fibrosis, scant reactive ductal epithelium, and, occasionally, saponified fat necrosis and/or chalky to granular calcific debris (Fig. 9-5). Mixed inflammation and histiocytes may also be present in the background. Cellular stromal fragments populated with inflammatory cells (>30 per 60×) (Fig. 9-6) is strongly suggestive of autoimmune pancreatitis – a condition important to recognize, as patients can be treated with steroids rather than surgery. Fat necrosis in contrast to coagulative cellular

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Currently there is no reliable ancillary study that distinguishes between benign and malignant pancreatic glandular epithelium. In early studies, immunocytochemical staining using B72.3 was shown not to stain benign pancreatic ductal epithelium, while demonstrating fine perinuclear punctate staining in gastric and duodenal epithelium, and strong cytoplasmic staining in malignant pancreatic ductal epithelium; however, not all carcinomas label with B72.3, so a negative stain does not exclude carcinoma. Evaluation of the patient or pancreatic tissue for mutation of the K-ras gene, a proto-oncogene on chromosome 12p12, remains controversial. Although most carcinomas tend to harbor a K-ras gene mutation, some cases of chronic pancreatitis

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FIGURE 9-5 Chronic pancreatitis. A mixture of fibrotic acinar tissue, acellular fragments of fibrous tissue, scant ductal epithelium, reactive acinar epithelium, infl ammation, saponified fat necrosis, and chalky granular calcific debris are characteristic features of chronic pancreatitis. Papanicolaou stain, low power.

FIGURE 9-6 Autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis). The presence of cellular stromal fragments populated with infl ammatory cells of at least 30 per 60× high-power field correlates with an autoimmune etiology. Papanicolaou stain, medium power.

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A

B

FIGURE 9-7 Fat necrosis compared to coagulative cellular necrosis. Fat necrosis is identified by the presence of foamy histiocytes, infl ammatory cells, and background cellular debris, and is characteristic of chronic pancreatitis (A). Cellular necrosis of carcinoma is distinguished by the presence of ghost cells, infl ammation, and typically residual atypical epithelial cells in the background (B). A and B, Papanicolaou stain, low power.

FIGURE 9-8 Reactive ductal epithelium of chronic pancreatitis. The honeycombed pattern of nuclei with relatively even spacing is maintained in reactive ductal groups of chronic pancreatitis. The nuclei may demonstrate slight chromatin clumping and nucleoli. Papanicolaou stain, high power.

and pancreatic intraepithelial neoplasia do as well, and not all carcinomas will demonstrate the mutation, so the diagnostic utility of the test is limited. Patients suspected of having autoimmune pancreatitis should undergo serologic testing for IgG4. Although not elevated in all patients with the condition, an elevated level is strongly associated with autoimmune pancreatitis and supports a cytologic diagnosis.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS The primary differential diagnosis of chronic pancreatitis is ductal adenocarcinoma. The distinction between benign and reactive ductal epithelium in chronic pancreatitis and the malignant ductal epithelium of ductal adenocarcinoma can be challenging. The

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A

B

FIGURE 9-9 Reactive ductal epithelium compared to adenocarcinoma. The reactive ductal epithelium of pancreatitis maintains relative even nuclear spacing, uniform nuclear size and nuclear membranes, mild nuclear enlargement, and variation within a single group (A). In contrast and although sometimes quite subtle, adenocarcinomas demonstrate more variability in nuclear size within a single group, uneven nuclear spacing, a loss of polarity, irregular nuclear membranes with notches, divots, and grooves, as well as nuclear membrane thickening (B). A and B, Papanicolaou stain, high power.

overall cellularity of smears in chronic pancreatitis is relatively low compared to adenocarcinoma, and is often composed of ductal epithelium with acinar epithelium and inflammation, in contrast to a pure ductal cell population in adenocarcinoma. If biopsies are being performed by EUS, care must be taken not to include the contaminating epithelium from the gastrointestinal tract, which may present in the assessment of overall cellularity, or to misinterpret the gastrointestinal epithelium as benign ductal epithelium of pancreatitis. The architecture of cell groups in pancreatitis is generally organized, with flat, monolayered sheets of ductal cells that display relatively polarized nuclei with minimal crowding and overlap compared to the subtle loss of nuclear polarity and nuclear crowding in adenocarcinoma. Nuclear size is also more uniform and nuclear membrane abnormalities minimal in chronic pancreatitis, whereas nuclear enlargement and variation of nuclear size within a single group of cells, and nuclear membranes with notches, divots, grooves, and thickening favors adenocarcinoma (Fig. 9-9). The nuclear chromatin pattern of benign and reactive cells in chronic pancreatitis demonstrates evenly distributed granular chromatin, whereas in adenocarcinoma there is hyperchromasia or, in well-differentiated adenocarcinoma, parachromatin clearing. The cytoplasm of ductal cells in chronic pancreatitis does not usually contain mucin visible on routine light microscopy, but may be present and even abundant in well-differentiated adenocarcinoma, leading to an exaggerated uneven arrangement of nuclei, a pattern also referred to as ‘drunken honeycomb’ (see adenocarcinoma section). Pitfalls in the cytologic diagnosis include misinterpreting gastrointestinal epithelial contamination from endoscopic biopsies as originating from the pancreas, leading to a false adequacy assessment. In addition, aspirates of chronic pancreatitis with significant amounts

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of residual acinar epithelium can present a diagnostic pitfall. Cellular smears of reactive and injured acinar cells with a loss of the normal cohesive grape-like clustering, interpreted in the setting of a solid mass lesion, can be misinterpreted as a neoplasm such as acinar cell carcinoma, solid-pseudopapillary neoplasm, or pancreatic endocrine neoplasm (Fig. 9-10). Ductal cells with mucinous metaplasia (PanIN), especially with dysplasia (PanIN-2 or -3), may be aspirated in chronic pancreatitis and can cause a false positive interpretation.

PSEUDOCYST A pancreatic pseudocyst is a localized collection of pancreatic secretions, necrotic debris, and blood that, by definition, has no epithelial lining.

CLINICAL FEATURES Pseudocysts occur as a consequence of damage to the pancreatic parenchyma that results in hemorrhage, necrosis, and autodigestion of pancreatic tissue from the release and activation of pancreatic enzymes. The incidence of this pancreatic injury is highest in patients with a well-established history of acute pancreatitis, the most common etiology of which is alcohol abuse. Approximately 10% of patients with acute pancreatitis will develop a pseudocyst. The age and gender of patients with pseudocysts parallels that of pancreatitis. Alcohol-related pseudocysts are more common in middle-aged men, while

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FIGURE 9-10 Disrupted acinar epithelial cells in autoimmune pancreatitis. A relatively cellular smear composed of disrupted acinar epithelial cells with a loss of the grape-like organized clustering and reactive atypia can mimic a neoplasm such as pancreatic endocrine neoplasm, solid-pseudopapillary neoplasm, and acinar cell carcinoma. Papanicolaou stain, low power.

PSEUDOCYST – DISEASE FACT SHEET Incidence ៉ Occurs in ∼10% of patients with acute pancreatitis; also associated with chronic pancreatitis and trauma Gender and Age Distribution ៉ Age and gender are dependent on etiology ៉ Alcohol-related cysts are more common in middle-aged men ៉ Traumatic, biliary, and hereditary causes of pancreatitis lead to

pseudocysts relatively equally in men and women Radiologic Features ៉ Typically, single, unilocular, thin-walled cysts without septations,

occurring anywhere in the pancreas Prognosis and Treatment ៉ Pseudocysts may resolve spontaneously, but can grow in size ៉ Undrained pseudocysts can rupture, erode into vessels, cause

obstruction, and get infected ៉ Treatment is usually drainage or resection

pseudocysts secondary to trauma, biliary disease, and heredity pancreatitis are relatively equal in men and women. Pseudocysts can be complicated by rupture, hemorrhage due to erosion into a vessel, obstruction of surrounding structures, and infection. Pseudocysts may be medically managed, but most are drained or resected.

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R ADIOLOGIC FEATURES Pseudocysts are usually solitary, small to very large (up to 20 cm), well-demarcated, thin-walled, unilocular peripancreatic cysts that can occur anywhere in the pancreas, but are most common in the pancreatic tail.

CYTOPATHOLOGIC FEATURES The cyst fluid aspirated from an uncomplicated pseudocyst is generally thin, brown to green, and nonmucinous. A complicated pseudocyst, however, may produce thick mucoid-appearing fluid due to the presence of inflammation. Cytologically, the characteristic features include degenerative cyst debris with acute and chronic inflammatory cells, histiocytes, hemosiderin, and often bile (Fig. 9-11). By definition, there are no cyst-lining epithelial cells.

ANCILLARY STUDIES To exclude a mucinous cyst, testing the fluid for thin mucin not appreciated on routine cytology can be done on cytospin preparations. The typical special stains for mucin include mucicarmine and Alcian blue pH 2.5. Chemical analysis of the fluid for amylase and

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FIGURE 9-11 Pseudocyst. The characteristic contents of a pseudocyst include infl ammatory debris, histiocytes, and, occasionally, bile pigment. Papanicolaou stain, high power.

PSEUDOCYST – PATHOLOGIC FEATURES Cytopathologic Features Scant cellularity Amorphous cyst debris Infl ammation and bile variable Histiocytes No epithelial cells

៉ ៉ ៉ ៉ ៉

Ancillary Studies ៉ Histochemical stains: mucicarmine and/or Alcian blue pH 2.5 are

negative ៉ Cyst fluid analysis: amylase high; CEA low

Differential Diagnosis and Pitfalls Lymphoepithelial cyst Unilocular or oligolocular variant of serous cystadenoma Mucinous cystic neoplasm Intraductal papillary mucinous neoplasm Solid-pseudopapillary neoplasm Cystic pancreatic endocrine neoplasm Gastrointestinal contamination (pitfall)

៉ ៉ ៉ ៉ ៉ ៉ ៉

carcinoembryonic antigen (CEA) is also very helpful. Amylase is consistently elevated (thousands of U/L) in pseudocysts, due to the connectivity of the cyst with the pancreatic ductal system. A cyst fluid with a very low amylase level is highly unlikely to be a pseudocyst. Pseudocysts typically have an undetectable or very low CEA level, whereas mucinous cysts generally have levels of CEA >200 ng/mL.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of pseudocyst includes true cysts of the pancreas and peri-pancreas. True cysts of the pancreas that can be confused with pseudocyst include lymphoepithelial cyst, oligocystic and unilocular variants of serous cystadenoma, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm. Peripancreatic cysts in the differential diagnosis include duodenal duplication cysts, cystic gastrointestinal stromal tumors, and mesenteric cysts. Solid neoplasms with cystic degeneration should also be considered, such as solid-pseudopapillary neoplasm and pancreatic endocrine neoplasms. Contamination of the specimen with epithelial or mesothelial cells from the surrounding pancreatic parenchyma, peritoneum, and especially the gastrointestinal tract from EUS-guided biopsies may produce a potential diagnostic pitfall. Duodenal epithelium is relatively characteristic in appearance, presenting as large, folded sheets of glandular epithelium with uniformly spaced, round, regular nuclei and studded with goblet cells (see Fig. 9-49). Gastric epithelium is more difficult to recognize and distinguish from the cyst-lining epithelium of a mucin-producing cystic neoplasm, as it often presents in smaller sheets and clusters as well as single cells, and can display cytoplasmic mucin (see Fig. 9-50). Histiocytes can also be mistaken for mucinous epithelial cells, leading to the incorrect diagnosis of mucin-producing neoplastic cyst. On the other hand, the absence of cystlining epithelium and detectable mucin in mucinous cystic neoplasms may lead to the incorrect diagnosis of

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pseudocyst. As such, correlation of the cytologic features and ancillary studies with the clinical and radiologic findings is imperative.

LYMPHOEPITHELIAL CYST – PATHOLOGIC FEATURES

LYMPHOEPITHELIAL CYST

Cytopathologic Findings ៉ Keratinous debris with anucleated and nucleated squamous cells ៉ Background lymphocytes, histiocytes, and cholesterol crystals ៉ May see intact cyst wall with squamous lining cells and subepithelial lymphoid tissue

Lymphoepithelial cysts are benign cysts lined by squamous epithelium with subepithelial non-neoplastic lymphoid tissue.

៉ Pseudocyst ៉ Dermoid cyst ៉ Epidermoid cyst with accessory splenic tissue

CLINICAL FEATURES These cysts are rare, representing approximately 0.05% of all pancreatic cysts. They are much more common in men than in women, with a male to female ratio of 4 : 1. It is a cyst of older adults, with a mean age of 56 years. Lymphoepithelial cysts are benign, with no reported cases of malignant transformation. Conservative resection is curative.

Differential Diagnosis and Pitfalls

CYTOPATHOLOGIC FEATURES The cytologic appearance is similar to that of an epidermal inclusion cyst, with nucleated and anucleated squamous cells, keratinous and cholesterol debris. Histiocytes and lymphocytes may be noted in the background. Intact cyst wall with subepithelial lymphoid tissue may also be seen (Fig. 9-12).

DIFFERENTIAL DIAGNOSIS AND PITFALLS R ADIOLOGIC FEATURES Lymphoepithelial cysts may be unilocular or multilocular and generally have thick-appearing walls with internal debris that corresponds to keratinous debris. The cysts average almost 5 cm in diameter, with a wide range of little over 1 cm to 17 cm. They can occur anywhere in the pancreas, and may even appear extra-pancreatic.

The differential diagnosis is with other squamous-lined cysts such as a dermoid cyst of the pancreas and splenic epidermoid cyst, both benign cysts more rare than lymphoepithelial cyst. A pseudocyst is also in the differential diagnosis due to the necrotic appearance of the keratinous debris. The keratinous nature of the cyst contents is usually apparent on close inspection, however.

SOLID NEOPLASMS LYMPHOEPITHELIAL CYST – DISEASE FACT SHEET Incidence ៉ ∼0.05% of all pancreatic cysts Gender and Age Distribution ៉ Male to female ratio is 4 : 1 ៉ Mean age 56 years

Radiologic Features ៉ Unilocular or multilocular cysts averaging ∼5 cm anywhere in the

DUCTAL ADENOCARCINOMA AND ITS VARIANTS Ductal adenocarcinoma is an invasive malignant neoplasm arising from the glandular epithelium of the pancreatic ducts which may produce mucin and which can have variant morphology including signet-ring cells, squamous cells, pleomorphic giant cells, and osteoclasttype giant cells.

pancreas or extra-pancreatic area, with thick-appearing walls and internal debris Prognosis and Treatment ៉ The cysts are benign and prognosis is excellent ៉ Conservative resection is curative

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CLINICAL FEATURES Ductal adenocarcinoma is the fourth leading cause of death from cancer in men, women, and overall in the

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FIGURE 9-12 Lymphoepithelial cyst. A background of anucleated squamous cells and keratinous debris are typical of the contents of a lymphoepithelial cyst. The presence of an intact cyst wall with squamous cell lining and subepithelial lymphoid tissue may occasionally be seen, as shown here. Papanicolaou stain, high power.

DUCTAL ADENOCARCINOMA – DISEASE FACT SHEET

sis is directly related to resectability, surgical resection being the treatment of choice. Patients with unresectable tumors typically survive less than 6 months.

Incidence ៉ 11 per 100,000 ៉ 4th leading cause of cancer death in men and women

R ADIOLOGIC FEATURES Gender and Age Distribution ៉ M > F by 30% ៉ Peak incidence, 7th to 8th decade Radiologic Features ៉ Hypodense mass with a poorly defined periphery and often a

‘double duct’ sign from dilation of both the pancreatic and bile ducts Prognosis and Treatment ៉ 5-year survival rate is 3–4% ៉ Surgical resection is the treatment of choice

United States. It is the eighth leading cause of cancer death worldwide. This malignancy, including variants, represents approximately 90% of all pancreatic malignancies. Heredity accounts for approximately 10% of cases. Most cases of pancreatic cancer occur between 60 and 80 years of age, and it is more common in men than in women by about 30%. The prognosis of pancreatic cancer is universally poor, with a 5-year survival rate of less than 5%, a rate that has not significantly improved in decades. Progno-

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Ductal carcinomas are most commonly staged by highresolution helical CT and/or EUS. On CT, tumors appear as poorly defined, hypodense masses with central attenuation that deform the normal lobulations of the pancreas and frequently demonstrate an abrupt stricture in the main pancreatic duct. When tumors occur in the pancreatic head, the characteristic ‘double duct’ sign corresponding to the dually dilated main pancreatic and bile ducts may be present. On EUS, the tumors typically appear hypoechoic. A loss of a tissue interface between the tumor and the large peripancreatic vessels (superior mesenteric or celiac axis) indicates invasion and stages the tumor as unresectable.

CYTOPATHOLOGIC FEATURES CONVENTIONAL TUBULAR-TYPE DUCTAL ADENOCARCINOMA

The morphologic features of ductal adenocarcinoma vary by tumor grade. High-grade (moderately and poorly differentiated) tumors typically do not pose a diagnostic challenge, given the overt malignant features of the

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DUCTAL ADENOCARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellularity varies with degree of sclerosis ៉ Relatively pure population of ductal cells ៉ Loss of honeycomb architecture with nuclear crowding, overlapping, loss of polarity, and uneven spacing (‘drunken honeycomb’) ៉ Irregular nuclear membranes; may be subtle in welldifferentiated carcinoma ៉ Hyperchromasia generally, but often pale nuclei with parachromatin clearing in well-differentiated carcinoma ៉ Cytoplasm may be scant to abundant and may show vacuolization ៉ Variant cytology: adenosquamous; colloid (mucinous noncystic); undifferentiated (anaplastic); undifferentiated with osteoclast-type giant cells; signet-ring cell Ancillary Studies ៉ Immunocytochemical stains (+): cytokeratins AE1/AE3, CAM 5.2,

CK7, CK8, CK13, CK18, and CK19; CA 19-9, B72.3, CA 125, and DUPAN-2; MUC1, MUC3, MUC4, and MUC5C Differential Diagnosis and Pitfalls ៉ Chronic pancreatitis, including autoimmune or

lymphoplasmacytic sclerosing pancreatitis ៉ Intraductal papillary mucinous neoplasm with invasive ៉ ៉ ៉ ៉

carcinoma Mucinous cystic neoplasm with invasive carcinoma Metastatic adenocarcinoma Acinar cell carcinoma Pancreatic endocrine neoplasm

neoplasm, whereas well-differentiated tumors present more of a challenge. In general, aspiration biopsy of carcinoma produces cellular smears; however, cellularity can vary greatly and aspirates may be quite paucicellular in tumors with dense sclerosis. Overall cellularity is also related to the experience of the interventional radiologist and the method of biopsy. The technical difficulty of EUS-guided biopsy relative to percutaneous biopsy can result in a lower cellular yield. Gastrointestinal contamination can contribute to what appears to be a highly cellular specimen on EUS-guided biopsy and care must be taken to carefully distinguish epithelium from the stomach and duodenum from pancreatic ductal epithelium. The smear background can contain helpful clues to the diagnosis. Abundant background mucin and coagulative necrosis are features suspicious for, but not independently diagnostic of, carcinoma. Coagulative necrosis is cellular necrosis with ghost tumor cells still visible, which contrasts with fat necrosis, where saponification and liquefactive necrosis contain foamy histiocytes with the inflammation (see Fig. 9-7). If the biopsy is by EUS, background mucin may be a contaminant, but contaminating mucin is typically not abundant, as can be present in mucin-producing invasive adenocarcinoma. The composition of the cellular elements on the slide is important in assessing benign versus malignant.

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Smears of carcinoma typically contain only ductal groups. Smears composed of acinar and ductal groups should increase the threshold for a malignant diagnosis. The presence of granulation tissue and fibrous tissue fragments with inflammation are also features that are more associated with pancreatitis than with carcinoma. The architectural arrangement of epithelial cells in carcinoma ranges from large crowded sheets to small three-dimensional clusters and balls to single cells. Single intact cells are common in high-grade carcinoma and may be scattered in the smear background or seen at the edge of more cohesive groups (Fig. 9-13). The presence of single atypical intact epithelial cells in welldifferentiated carcinoma is significant and supports a malignant interpretation. In high-grade carcinoma, the cellular features of malignancy are overt. The cells have a high nuclear to cytoplasmic (N/C) ratio and thus increased nuclear density in cell clusters and sheets relative to benign ductal groups (Fig. 9-14). Dense nucleation results in cellular crowding, nuclear overlapping, and loss of nuclear polarity. The nuclei are enlarged, usually at least two to three times the size of a normal ductal cell nucleus, with anisonucleosis of at least three times within a single sheet, hyperchromasia, irregular nuclear membranes, and, often, prominent nucleoli (Fig. 9-15). In well-differentiated carcinomas, the nuclei are not as enlarged as in high-grade carcinomas (2.5 times the size of a red blood cell on air-dried smears) (Fig. 9-16), and can be subtly crowded or show wide and uneven spacing. When crowded, the nuclei have a tendency to overlap at least focally and demonstrate a loss of polarity and loss of smoothness of the nuclear membranes. With more abundant, often mucinous cytoplasm, the variation in cell size and cytoplasmic volume leads to an irregular and uneven spacing of the nuclei in the sheet or group, which has been termed ‘drunken honeycomb’, a feature that contrasts to the generally regular and even nuclear spacing seen in benign ductal groups (Fig. 9-17). An extremely benign-appearing, well-differentiated variant of adenocarcinoma with voluminous mucinous cytoplasm, termed ‘foamy gland adenocarcinoma’ (Fig. 9-18), has been described. The nuclear chromatin in well-differentiated carcinomas can be hyperchromatic, but commonly demonstrates more clearing than clumping (parachromatin clearing) (Fig. 9-19). These subtle nuclear changes coupled with slight nuclear crowding and overlapping are the key to a diagnosis of welldifferentiated carcinoma. CYTOMORPHOLOGY OF ADENOCARCINOMA VARIANTS

Adenosquamous carcinoma is an extremely aggressive variant of ductal adenocarcinoma in which dual lines of glandular and squamous differentiation are present. The cytologic diagnosis is dependent on recognizing these two malignant cellular components on aspirate smears. The diagnosis is straightforward when both the glandular and squamous components are prominent (Fig. 9-20); however, when either component is scant,

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FIGURE 9-13 Ductal adenocarcinoma. Hyperchromatic crowded groups and intact single malignant cells are architectural features typical of adenocarcinoma. Papanicolaou stain, high power.

FIGURE 9-14 Ductal adenocarcinoma, high grade. High-grade adenocarcinomas are relatively easy to recognize due to the overt features of malignancy, including dense nucleation, high N/C ratio, loss of nuclear polarity, and irregular nuclear membranes. Papanicolaou stain, high power.

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FIGURE 9-15 Adenocarcinoma compared to benign ductal epithelium. The group of adenocarcinoma on the right is distinguished from the benign ductal group on the left by the nuclear enlargement, uneven nuclear spacing, and anisonucleosis of at least three times within a single sheet. Papanicolaou stain, low power.

FIGURE 9-16 Adenocarcinoma, well differentiated. The anisonucleosis in welldifferentiated adenocarcinoma is not as dramatic as with high-grade carcinomas, demonstrating mild variability and nuclear enlargement of approximately 2 1/2 times the size of a red blood cell (which is noted to the right of the cell cluster). Hema III stain, high power.

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FIGURE 9-17 Adenocarcinoma, well differentiated. The uneven nuclear spacing combined with abundant voluminous cytoplasm yields a disarray often referred to as ‘drunken honeycomb’. Papanicolaou stain, high power.

FIGURE 9-18 Foamy gland adenocarcinoma. This variant of well-differentiated adenocarcinoma is characterized by voluminous mucinous cytoplasm and a very bland, almost benign cytologic appearance. Papanicolaou stain, high power.

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FIGURE 9-19 Adenocarcinoma, well differentiated. In contrast to hyperchromasia typical of most adenocarcinomas of the pancreas, the presence of nuclear clearing with peripheral clumping (also known as parachromatin clearing) is a feature characteristic of well-differentiated neoplasms. Papanicolaou stain, medium power.

FIGURE 9-20 Adenosquamous carcinoma. This variant of ductal adenocarcinoma is recognized by the presence of both malignant glandular and squamous components. Papanicolaou stain, medium power.

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FIGURE 9-21 Signet-ring cell adenocarcinoma. This variant of ductal adenocarcinoma is recognized by the prominence of the signet-ring cell, a small malignant cell with a cytoplasmic vacuole that indents the nucleus. Papanicolaou stain, high power.

the diagnosis can be challenging. A careful search for glandular differentiation is warranted in squamouspredominant cases, in particular, given the virtual nonexistence of primary squamous cell carcinoma of the pancreas and thus the potential for a misdiagnosis of a metastasis. Colloid (mucinous non-cystic) carcinoma on histology is similar to colloid carcinomas of the colon and breast, where the vast majority of the infiltrating tumor cells (>80% in the pancreas) are present floating in pools of mucin. These neoplasms are rare and most are found in association with an intraductal papillary mucinous neoplasm. Aspiration produces thick viscous mucin that may or may not contain an identifiable epithelial component. Recognition of malignant cells in the thick mucin, however, is necessary for the diagnosis of a malignant mucin-producing neoplasm. The distinction from an in-situ neoplasm that may also produce only thick viscous mucin is by the fact that the aspiration is of a solid mass that may or may not be arising in the wall of a cyst or dilated duct. The issue of gastrointestinal contamination should not be of concern, given the abundance of thick mucin. Signet-ring cell carcinoma is a variant of ductal adenocarcinoma in which the predominant infiltrating tumor cell is a signet-ring cell. Aspirate smears are characterized by small collections of cells or individual cells with a vacuole of intracellular mucin that typically indents the nucleus, a feature that is helpful in distinguishing the tumor cells from histiocytes (Fig. 9-21).

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Undifferentiated (anaplastic) carcinoma is a variant of ductal adenocarcinoma in which there is a loss of glandular differentiation and tumor cells display large, polygonal to spindled, often bizarre (anaplastic) and multinucleated features. The aspirate smears may not be hypercellular, but the malignant cells present are unquestionably malignant, with wildly pleomorphic mononuclear and multinuclear tumor giant cells (Fig. 9-22). These large tumor cells are present in small clusters, and singly may appear spindled and sarcomatoid. Frequent mitotic activity, cellular cannibalism, and background necrosis are commonly noted. Undifferentiated carcinoma with osteoclast-type giant cells is a rare variant of ductal adenocarcinoma in which the malignant, usually mononuclear, epithelial cells are admixed with benign osteoclast-type giant cells. Approximately 40% of these tumors arise in association with a glandular neoplasm such as conventional adenocarcinoma and mucinous cystic neoplasms. Aspirate smears are typically hypercellular with two cell populations, an obviously malignant mononuclear epithelial proliferation and benign-appearing osteoclast-like giant cells. The giant cells vary in number and often contain 10 or more bland-appearing, centrally clustered and slightly overlapping nuclei with even chromatin and occasionally prominent nucleoli (Fig. 9-23). The mononuclear cells appear singly or in small clusters and can range from medium-sized polygonal epithelioid cells with clear cytoplasm to large bizarre sarcomatoid cells with dense and/or spindled cytoplasm.

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FIGURE 9-22 Undifferentiated carcinoma. This variant of ductal adenocarcinoma is characterized by large, bizarre, anaplastic or pleomorphic, mononuclear to multinucleated giant tumor cells. Papanicolaou stain, high power.

FIGURE 9-23 Undifferentiated carcinoma with osteoclast-type giant cells. This rare variant of ductal adenocarcinoma is composed of a malignant mononuclear epithelial cell population admixed with benign osteoclast-type giant cells. Papanicolaou stain, low power.

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ANCILLARY STUDIES Special stains for mucin (mucicarmine, Alcian blue pH 2.5) may demonstrate intracytoplasmic mucin that helps to classify the neoplasm as an adenocarcinoma. Immunocytochemical stains can help specify the adenocarcinoma as pancreatic in origin. Most pancreatic adenocarcinomas are positive for cytokeratins AE1/ AE3, CAM 5.2, CK7, CK8, CK18, and CK19, with about half expressing CK17 and less than 20% expressing CK20. CEA, B72.3, CA 125, and DUPAN-2 also stain tumor cells of pancreatic adenocarcinoma. Mucin glycoproteins (MUC) are variably expressed, with most tumors expressing MUC1, MUC3, MUC4, and MUC5AC, and a minority expressing MUC6 (∼25%) and MUC2 (<10%). Antibodies against the protein product dpc4 correlates with the DPC4/MADH4 gene status, so the loss of dpc4, noted in a little more than 50% of pancreatic adenocarcinomas, helps to distinguish malignant from benign, since all benign glandular epithelium of the pancreas demonstrate dpc4 positivity.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of pancreatic carcinoma is dependent on grade. High-grade adenocarcinoma can be confused with acinar cell carcinoma, pancreatic endocrine neoplasms, and metastatic malignancies. The smear pattern of adenocarcinoma tends to be more

269 clustered with scattered single cells, whereas acinar cell carcinoma and pancreatic endocrine neoplasms produce a more single cell smear pattern with occasional cell clusters. The cells of high-grade carcinoma demonstrate much more nuclear atypia than the cells of the typical acinar cell carcinoma and neuroendocrine neoplasm, showing significant nuclear membrane abnormalities and marked hyperchromasia. This is in contrast to the rounder, more central and less convoluted nuclei of both acinar cell carcinoma and pancreatic endocrine neoplasms. Nucleoli may be prominent in all three of these neoplasms, but are usually more prominent and irregular in adenocarcinoma. The chromatin is also more coarse and clumped (‘salt and pepper’) in endocrine neoplasms than in adenocarcinoma. The cytoplasmic differences are also important, as high-grade adenocarcinomas display either scant, wispy cytoplasm or abundant, often mucinous cytoplasm, whereas acinar cells tend to have granular cytoplasm and endocrine neoplasms display eccentric, dense to finely granular, non-mucinous cytoplasm. Although extremely rare compared to primary adenocarcinoma, metastatic malignancies should always be considered in the differential diagnosis of a high-grade adenocarcinoma. A common carcinoma metastatic to the pancreas is renal cell carcinoma. Renal cell carcinoma is recognized by the large polygonal cells which may be single, in small clusters, or loosely attached to traversing vessels. The nuclei are usually round and central with large macronucleoli frequently surrounded by a clear halo (‘owl’s eye appearance’) (Fig. 9-24). The cytoplasm is distinguished from that of ductal adenocarcinoma by the presence of multiple fine vacuoles (best

FIGURE 9-24 Metastatic renal cell carcinoma. Metastases should always be considered in the evaluation of carcinomas in the pancreas. One of the more common carcinomas metastatic to the pancreas, renal cell carcinoma is characterized by a polygonal cell shape, clear to dense cytoplasm, and a prominent central nucleolus that may be surrounded by a clear halo, yielding an ‘owl’s eye’ appearance. Papanicolaou stain, high power.

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appreciated on air-dried smears), in contrast to the often large single vacuoles of adenocarcinoma. Well-differentiated adenocarcinoma can be confused with benign ductal epithelium in chronic pancreatitis (discussed more fully in the section on chronic pancreatitis), high-grade dysplastic ductal epithelium (pancreatic intraepithelial neoplasia, PanIN-2 or -3), and with reactive glandular epithelium from the stomach or duodenum contaminating the specimen in EUS-guided biopsies.

such as the absence of vascular or perineural invasion, and less than two mitoses per high-powered field. As such, it is prudent to confine the cytologic diagnosis to ‘pancreatic endocrine neoplasm’ in most cases.

R ADIOLOGIC FEATURES By CT scan, most PENs appear as enhancing, solid, well-circumscribed masses. Cystic degeneration can occur and calcification is occasionally seen.

PANCREATIC ENDOCRINE NEOPLASM Pancreatic endocrine neoplasms (PENs) are mostly low-grade well-differentiated malignant neoplasms of the endocrine cells of the pancreas, which are classified by grade, size, and functional status.

CLINICAL FEATURES The vast majority of PENs are well-differentiated tumors, representing about 5% of all pancreatic tumors. The peak age of incidence is 50–60 years of age, but PENs can occur in all age groups. Men and women are equally affected. The biologic behavior of PENs is difficult, if not impossible, to predict from cytologic evaluation. The architectural pattern and cellular pleomorphism, features of the neoplasms that can be evaluated on cytology, do not correlate with prognosis. Prognosis is highly dependent on tumor size at detection, a feature that is often related to the association of the neoplasm with a syndrome, in addition to ‘favorable’ histologic features

PANCREATIC ENDOCRINE NEOPLASM – DISEASE FACT SHEET Incidence ៉ ∼2–5% of pancreatic neoplasms ៉ ∼50% are functional and 50% non-functional

Gender and Age Distribution ៉ M = F ៉ Any age, but most between 40 and 60 years

Radiologic Features ៉ Solid, well-circumscribed masses, usually small (<2 cm), but may

be large (>6 cm); can be cystic Prognosis and Treatment ៉ Prognosis is related to tumor size, mitotic rate, necrosis, extra-

pancreatic invasion, vascular invasion, and nodal or distant metastases ៉ Small neoplasms without adverse prognostic features are curable by surgical resection

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CYTOPATHOLOGIC FEATURES Aspirate smears are generally hypercellular, often with a bloody background, and are composed of a monotonous population of small to medium-sized polygonal cells. The tumor cells are mostly single (Fig. 9-25), but small to medium-sized groups can also be seen. The nuclei are round, usually bland and uniform, with coarse, stippled ‘salt and pepper’ chromatin (Fig. 9-26). Nucleoli may be inconspicuous, but can be quite prominent (Fig. 9-26). Nuclear atypia is variable. Significant pleomorphism may be present (Fig. 9-27), but this feature should not lead to a malignant diagnosis. The relatively scant cytoplasm is usually dense and eccentric, yielding a plasmacytoid appearance. Rare variants of PEN, such as oncocytic (Fig. 9-28) and clear cell

PANCREATIC ENDOCRINE NEOPLASM – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Dyshesive, single cell smear pattern; few small clusters ៉ Uniform, monotonous population of cells with plasmacytoid features ៉ Coarse, speckled, ‘salt and pepper’ chromatin pattern ៉ Nucleoli may be prominent ៉ Dense, finely granular cytoplasm; rarely clear or oncocytic cytoplasm Ancillary Studies ៉ Histochemical stains: positive for Grimelius stain and PAS ៉ Immunocytochemical stains: cytokeratins CAM 5.2 and AE1/AE3

are usually positive; chromogranin, synaptophysin, Leu-7, and NSE are typically positive; insulin, glucagon, somatostatin, and pancreatic polypeptide are variably positive; gastrin, vasoactive intestinal polypeptide, cholecystokinin, and adrenocorticotropic hormone may occasionally be positive ៉ Electron microscopy: neurosecretory granules Differential Diagnosis and Pitfalls Acinar cell carcinoma Solid-pseudopapillary neoplasm Pancreatoblastoma Plasmacytoma Normal acinar cell epithelium (pitfall)

៉ ៉ ៉ ៉ ៉

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FIGURE 9-25 Pancreatic endocrine neoplasm. The typical aspirate smears are hypercellular, composed of a predominantly single cell population of small to medium-sized, monotonous polygonal cells that may be associated with a prominent vascular component. Papanicolaou stain, medium power.

FIGURE 9-26 Pancreatic endocrine neoplasm (PEN) with cystic degeneration. Cystic PENs are cytologically similar to solid PENs. The typical coarse stippled ‘salt and pepper’ chromatin pattern is similar in both neoplasms. Although nucleoli are not very prominent in most PENs, they can be quite prominent, as illustrated here. Papanicolaou stain, high power.

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FIGURE 9-27 Pancreatic endocrine neoplasm. The presence of nuclear pleomorphism and mitotic activity cannot be used as criteria for the diagnosis of malignancy. Papanicolaou stain, high power.

FIGURE 9-28 Pancreatic endocrine neoplasm, oncocytic variant. The presence of abundant dense, oncocytic cytoplasm characterizes this variant. Papanicolaou stain, medium power.

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FIGURE 9-29 Pancreatic endocrine neoplasm (PEN), clear cell variant. In contrast to the typical dense granular cytoplasm of most PENs, the cytoplasm of the clear cell variant demonstrates cytoplasmic vacuolization ranging from large vacuoles to small multiple vacuoles. These neoplasms can identically mimic renal cell carcinomas. Hema III stain, high power.

(Fig. 9-29), exist. Mitotic figures and necrosis are uncommon features but may be seen on cytology and are features that should be noted in the cytology report. The cytologic features of a cystic PEN are similar to those of solid neoplasms. High-grade large cell neuroendocrine carcinoma and small cell neuroendocrine carcinoma are neoplasms that appear cytologically malignant, resembling similar neoplasms in the lung.

ANCILLARY STUDIES Documenting endocrine differentiation is most commonly performed with immunocytochemical staining for chromogranin and/or synaptophysin, markers positive in over 95% of tumors. Synaptophysin produces a consistently strong and diffuse staining pattern, whereas chromogranin staining can be quite focal. CD57 (Leu-7) and CD56 (neural cell adhesion molecule) also stain most tumors. Labeling the tumors for specific peptides demonstrates a wide range of positivity, the nature of which does not necessarily correlate with a syndrome. Most PENs also stain with cytokeratins CAM 5.2 and AE1/AE3. Flow cytometry of aspirated tissue may be useful in distinguishing PEN from non-Hodgkin lymphoma and plasmacytoma. Electron microscopy will identify numerous and randomly distributed neurosecretory granules in PEN.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis is dependent on the degree of cellular atypia. The differential diagnosis of well-differentiated PEN most commonly includes solidpseudopapillary tumor, acinar cell carcinoma, nonHodgkin lymphoma, and plasmacytoma. Clear cell and oncocytic PEN variants can be confused with primary and metastatic neoplasms with similar cytoplasmic features. High-grade PEN demonstrating significant cellular atypia and pleomorphism can be misdiagnosed as high-grade pancreatic adenocarcinoma and other highgrade malignancies. Normal acinar cells when aspirated in abundance and with a disrupted architecture are a pitfall for a false positive diagnosis of PEN (see Fig. 9-10). One of the more common neoplasms to be confused with PEN in women especially is the solid-pseudopapillary tumor. This tumor is distinguished by papillary groups with vascular cores and myxoid stroma, but this smear pattern may not be well demonstrated in all cases. When absent, the bland, oval more than round nuclei, nuclear grooves, small perinuclear vacuoles, and scant non-plasmacytoid cytoplasm help to diagnose a solidpseudopapillary tumor. Recognizing the stippled chromatin of PEN is also helpful. Acinar cell carcinoma can also closely resemble PEN on smears. Aspirates of PEN produce mostly single cells and some cell clusters, in contrast to acinar cell carcinoma, where cell clusters predominate. Although nucle-

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FIGURE 9-30 Plasmacytoma. Although rare in the pancreas, plasmacytoma with the typical single cell smear pattern, eccentric nucleus, and coarse stippled chromatin mimics a pancreatic endocrine neoplasm (PEN). Notice, however, the chromatin clumps in a clock-face distribution, in contrast to the even distribution throughout the nucleus in PEN. Also notice the pale perinuclear huff (Golgi zone) in the cell at 11 o’clock. Papanicolaou stain, high power.

oli are typically more prominent in acinar cell carcinoma, PEN can demonstrate very prominent nucleoli, so this feature is not discriminatory, but the characteristic stippled ‘salt and pepper’ chromatin pattern of PEN, a pattern absent in acinar cell carcinoma, is useful. Granular cytoplasm, when present and visible on smears, helps to define an acinar cell carcinoma, in contrast to the dense to finely granular eccentric cytoplasm of PEN. Non-Hodgkin lymphoma enters the differential diagnosis owing to the single cell smear pattern common to both neoplasms and the tendency of the delicate cytoplasm of some PENs to get stripped from the cells, yielding small round cells mimicking lymphoma. The differences in the chromatin pattern, cytoplasm of intact PEN cells, and the absence of lymphoglandular bodies, stripped globules of cytoplasm from the delicate lymphoma cells, help to differentiate PEN from lymphoma. Extracellular plasmacytoma shares features of eccentric cytoplasm and stippled chromatin, but the distribution of the chromatin is more ‘clock-face’ in plasmacytoma and the eccentric cytoplasm of PEN does not contain a perinuclear huff (Golgi zone) as may be seen in plasmacytoma (Fig. 9-30).

ACINAR CELL CARCINOMA Acinar cell carcinoma is a malignant proliferation of the enzyme-producing exocrine (acinar) cells of the pancreas.

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ACINAR CELL CARCINOMA – DISEASE FACT SHEET Incidence ៉ ∼1–2% of adult pancreatic neoplasms Gender and Age Distribution ៉ Male to female ratio is 4 : 1 ៉ Children << adults; peak incidence, 7th decade

Radiologic Features ៉ Solid masses with well-demarcated borders; rarely cystic Prognosis and Treatment ៉ Prognosis is directly related to tumor stage and is better than for

ductal adenocarcinoma ៉ Resection is the treatment of choice

CLINICAL FEATURES Acinar cell carcinoma is a malignant neoplasm of adults and children, comprising 1–2% of pancreatic neoplasms in adults and 15% of pancreatic neoplasms in children. The tumors are most common in adults. Most tumors occur in the seventh decade and the male to female ratio is almost 4 : 1. In the pediatric group, the tumors generally occur between 10 and 20 years of age. Acinar cell carcinomas generally have a poor prognosis, with a median survival of about 11/2 years. The reported 5-year survival is between 6% and 25%. Chil-

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FIGURE 9-31 Acinar cell carcinoma. The presence of stripped naked nuclei with a granular background from the dispersed cytoplasm is a rather characteristic feature of this neoplasm. Hema III stain, high power.

dren are believed to have a slightly better prognosis, with reports of long-term survival and cure in this population.

R ADIOLOGIC FEATURES Acinar cell carcinomas are typically solid, occasionally cystic, well-circumscribed, usually large masses (average size, 10 cm) that may arise in any portion of the pancreas.

ACINAR CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Small glandular clusters, single cells ៉ Stripped naked nuclei; +/− loose cytoplasmic granules ៉ May be disarmingly bland, with a polygonal cell shape and low N/C ratio ៉ Coarse chromatin usually with prominent nucleoli, but not always ៉ Granular cytoplasm, variably prominent Ancillary Studies ៉ Histochemical stains: positive for PAS/dPAS ៉ Immunocytochemical stains: trypsin, chymotrypsin, lipase, and

elastase usually positive; amylase is usually negative; positive for CAM 5.2 and AE1/AE3, but negative for cytokeratins 7, 19, and 20; EMA is positive in about 50%

CYTOPATHOLOGIC FEATURES Aspirate smears of acinar cell carcinoma are usually moderately cellular and often display a relatively clean background devoid of necrosis and cyst debris, but the background may contain cytoplasmic granules from the stripped cytoplasm of tumor cells. Stripped cells leave naked tumor nuclei, a rather characteristic feature of acinar cell carcinoma (Fig. 9-31). These nuclei can resemble lymphocytes, especially when nucleoli are not prominent, but when compared to the intact tumor cells, the similarity is apparent. The clusters of tumor cells form irregular-shaped groups, sheets, and small glandular clusters (Fig. 9-32), a pattern that contrasts to the organoid, grape-like clustering typical of benign acinar epithelium. Individual tumor cells are frequently very bland with a polygonal cell shape, low N/C ratio, and uniform nuclei (Fig. 9-33), resembling to a remark-

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Differential Diagnosis and Pitfalls Pancreatic endocrine neoplasms Solid-pseudopapillary tumor Pancreatoblastoma Normal acinar epithelium (pitfall)

៉ ៉ ៉ ៉

able degree the normal acinar cell. The cells can be pleomorphic, and may occasionally appear plasmacytoid; however, the marked and rather diffuse plasmacytoid appearance common in endocrine neoplasms is not present in acinar cell carcinoma. The nuclear chromatin in the tumor cells is generally coarsely clumped, and one, sometimes two, prominent

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FIGURE 9-32 Acinar cell carcinoma. In contrast to the organoid grape-like clustering of benign acinar epithelial cells, the cell clusters of acinar cell carcinoma are of varying sizes and are irregular in shape. Papanicolaou stain, low power.

FIGURE 9-33 Acinar cell carcinoma. The individual tumor cells are frequently quite bland with a polygonal cell shape, low N/C ratio, and uniform nucleus. Prominent nucleoli may not be present, and the cells can resemble normal acinar epithelial cells. Papanicolaou stain, high power.

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FIGURE 9-34 Acinar cell carcinoma. The dense granularity of the cytoplasm is best appreciated on H&E-stained smears. H&E stain, high power.

nucleoli may be seen. This feature and the coarsely granular cytoplasm are helpful diagnostic findings when present. The cytoplasmic granularity is not always readily apparent and is more easily identified on hematoxylin and eosin (H&E)-stained smears than on Papanicolaou- or Romanowsky-stained smears (Fig. 9-34). The absence of striking cytoplasmic granularity and large, prominent nucleoli are not uncommon in acinar cell carcinoma, adding to the diagnostic difficulty. Identification of mitotic activity supports a neoplastic process.

ANCILLARY STUDIES Documenting the presence of zymogen granules or exocrine enzyme production by the tumor cells establishes the diagnosis of acinar cell carcinoma. When sufficient in quantity, a periodic acid–Schiff (PAS) stain with and without diastase digestion will highlight the redstaining intracytoplasmic granules. Electron microscopy can also be used to detect the granules. Although not widely used, the butyrate esterase stain detects lipase activity in about 75% of cases, and 75–95% of cases will label with antibodies to exocrine enzymes including trypsin, chymotrypsin, lipase, and elastase. Low and high molecular weight cytokeratins (CAM 5.2 and AE1, respectively) as well as cytokeratins 8 and 18 stain the carcinoma cells, but cytokeratins 7, 19, and 20 are typically negative. Because acinar cell carcinomas can contain a small number of endocrine cells (1– 2%), positive immunocytochemical staining with the

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endocrine markers chromogranin and synaptophysin should not be misinterpreted.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The cytologic differential diagnosis includes PEN, pancreatoblastoma, solid-pseudopapillary tumor, and non-neoplastic acinar parenchyma. The most common neoplasm mistaken cytologically for acinar cell carcinoma is the PEN. These neoplasms have in common a uniformity of nuclei, the presence of numerous individual cells, and a moderate amount of dense nonvacuolated cytoplasm. Endocrine neoplasms tend to have a more uniform, dyshesive, single cell smear pattern with plasmacytoid cells, and less well-developed microglandular (acinar) groups than has acinar cell carcinoma. Acinar cell carcinoma also lacks the typical endocrine ‘salt and pepper’ chromatin pattern. However, given that endocrine tumors can demonstrate prominent nucleoli and acinar cell carcinomas may not demonstrate obviously granular cytoplasm, many cases require immunohistochemical staining for accurate diagnosis. Features helpful in distinguishing solid-pseudopapillary tumor from acinar cell carcinoma include the formation of pseudopapillary structures with the characteristic myxoid stroma, the fragility of the cytoplasm (with numerous stripped nuclei), and the presence of longitudinal nuclear grooves and small perinuclear vacuoles in solid-pseudopapillary tumors. Pancreatoblastoma is nearly impossible to distinguish from acinar cell carcinoma on the basis of cytology,

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since the characteristic squamoid corpuscles of pancreatoblastoma are rarely detectable in cytologic smears. Since both of these neoplasms exhibit acinar differentiation by immunohistochemistry, it may be impossible to exclude a pancreatoblastoma in a neoplasm otherwise having cytologic features of acinar cell carcinoma. The misinterpretation of benign acinar cells as neoplastic (acinar cell carcinoma), and vice versa, are diagnostic pitfalls. Rarely, aspiration of normal pancreatic parenchyma may produce a smear with many acini without the typical organoid grape-like clustering and uniform acinar formation, raising the possibility of acinar cell carcinoma. Similarly, a scantily cellular aspirate of a neoplasm may be mistaken for normal acini.

presence of metastases at the time of diagnosis. Patients typically present with unresectable tumors and over a third have metastases upon diagnosis.

R ADIOLOGIC FEATURES CT scans reveal a well-defined, often large (up to 20 cm), heterogenous and mostly enhancing pancreatic mass, the minority of which will demonstrate scattered calcifications.

CYTOPATHOLOGIC FEATURES PANCREATOBLASTOMA Pancreatoblastoma is a malignant neoplasm with multiple lines of epithelial differentiation, most commonly acinar differentiation, which also contains squamous nests and usually a mesenchymal component.

CLINICAL FEATURES Pancreatoblastoma is an extremely rare neoplasm of adults and children, with approximately two-thirds occurring in children and one-third occurring in adults. It is the most common malignant pancreatic tumor in children, representing approximately 25% of all pancreatic neoplasms in the pediatric population. There is a bimodal age distribution when pediatric and adult populations are evaluated separately. In children, the peak age is almost 21/2 years, whereas in the adult, the peak age is 40 years. As a whole, the average age is about 10 years. Across all ages, the male to female ratio is equal. Prognosis appears to be worse in adults than in children, and is dependent on tumor resectability and the

Aspirate smears of pancreatoblastoma are cellular, composed of cell clusters and single cells. The appearance of the epithelial cells will vary depending on the direction of differentiation. Cells with acinar differentiation have an oval to cuboidal cell shape, round, central to eccentric nuclei, one or more small nucleoli, and a moderate amount of granular, amphophilic to eosinophilic cytoplasm that is impossible to distinguish from acinar cell carcinoma (Fig. 9-35). Cells with endocrine differentiation can resemble acinar cells but demonstrate a more cuboidal shape, a higher N/C ratio, denser, less granular cytoplasm, and less conspicuous nucleoli. Squamoid cells, singly or in clusters, are rec-

PANCREATOBLASTOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular smears with varying sized cell clusters and single cells ៉ Epithelial cells will vary in appearance depending on their direction of differentiation: cells with acinar differentiation dominate and have a polygonal shape, round, central to eccentric nucleus, one or more small nucleoli, and a moderate amount of granular cytoplasm ៉ Squamoid nests are recognized in cell block preparations ៉ Stromal fragments with traversing capillaries may be present Ancillary Studies

PANCREATOBLASTOMA – DISEASE FACT SHEET Incidence ៉ Rare in adults; 25% of pancreatic tumors in children Gender and Age Distribution ៉ M = F ៉ Mean age in children is 21/2 years, and in adults, 40 years

Radiologic Features ៉ A well-defined heterogeneous pancreatic or peripancreatic mass

៉ Histochemical stains: ៉ Acinar cells: positive for PAS/dPAS ៉ Immunocytochemical stains: ៉ Acinar cells: positive for pancytokeratin, trypsin,

chymotrypsin, and lipase ៉ Endocrine cells: positive for chromogranin, synaptophysin,

and NSE, but usually negative for insulin, glucagon, or somatostatin ៉ Ductal cells: positive for cytokeratin, CEA, B72.3, and DUPAN-2 ៉ Stroma: positive for vimentin ៉ Squamoid corpuscles are generally not immunoreactive

that may contain calcifications Prognosis and Treatment ៉ Prognosis is generally poor and is worse in adults than in children ៉ Surgical resection is the treatment of choice

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Differential Diagnosis and Pitfalls ៉ Acinar cell carcinoma ៉ Pancreatic endocrine neoplasm ៉ Solid-pseudopapillary neoplasm ៉ Normal acinar epithelium (pitfall)

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FIGURE 9-35 Pancreatoblastoma. Acinar differentiation is the most common cell line of differentiation in this neoplasm, which can undergo multiple lines of epithelial differentiation. As such, pancreatoblastoma can identically mimic an acinar cell carcinoma. Hema III stain, high power.

ognized in cell block preparations rather than on direct smears (Fig. 9-36). Stromal fragments may be scant or prominent, and traversing capillaries may be seen.

SEROUS CYSTADENOMA – DISEASE FACT SHEET Incidence

ANCILLARY STUDIES

៉ 2% of all pancreatic neoplasms but ∼10% of resected cysts

Gender and Age Distribution

The neoplastic cells will be highlighted by histochemical and immunohistochemical markers depending on the line of differentiation of the cells. Most neoplasms develop an acinar cell phenotype and therefore the tumor cells will demonstrate zymogen granules that stain with PAS/dPAS and exocrine antibodies such as trypsin, chymotrypsin and lipase.

៉ F >> M ៉ Mean age 65 years

Radiologic Features ៉ Large, mostly microcystic, masses with characteristic ‘soap bubble’

pattern on ultrasound ៉ Central stellate scar frequently with ‘starburst’ pattern of

microcalcifications noted on CT ៉ Oligocystic, macrocystic, and unilocular variants can occur

DIFFERENTIAL DIAGNOSIS AND PITFALLS The primary neoplasm in the differential diagnosis is acinar cell carcinoma, which is discussed in detail on page 277–278.

Prognosis and Treatment ៉ The cysts are benign and prognosis is excellent ៉ Therapy includes resection, or observation for small (<4 cm) cysts

in poor surgical candidates

CLINICAL FEATURES CYSTIC NEOPLASMS SEROUS CYSTADENOMA Serous cystadenoma is a benign, typically microcystic, proliferation of small cuboidal epithelial cells rich in cytoplasmic glycogen which produces serous fluid.

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The incidence of these often asymptomatic neoplasms is increasing with the common use of CT scanning for the work-up of patients for other conditions. Of all the neoplasms arising from the exocrine pancreas, serous cystadenomas account for roughly 2%, but of resected cysts of the pancreas, the percentage increases to 10%. There is an association with von Hippel–Lindau syndrome.

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FIGURE 9-36 Pancreatoblastoma. This cell block preparation demonstrates a cluster of squamoid cells surrounded by neoplasm with acinar cell differentiation. The cell block is the best preparation to identify squamoid cells. This finding helps distinguish pancreatoblastoma from acinar cell carcinoma. H&E stain, high power.

Serous cystadenomas are much more common in women than in men and have greater than a 70-year age range (18–91 years) with a mean of approximately 65 years. These neoplasms are benign, with very rare reports of malignant transformation. Complications of large neoplasms such as rupture or erosion into a large vessel can cause death. Complete surgical resection is curative.

R ADIOLOGIC FEATURES Microcystic serous cystadenoma often demonstrates very characteristic radiographic findings precluding the need for tissue confirmation. Ultrasound demonstrates a ‘soap bubble’ pattern owing to the numerous microcysts that average less than 2 cm each. CT scan shows a well-defined mass with multiple, sometimes innumerable, small cysts separated by delicate septa. Many tumors will contain a central stellate scar, and about 30% of these will demonstrate a ‘starburst’ pattern of microcalcifications within the scar. Oligocystic and unilocular variants of serous cystadenomas do exist and produce radiologic features that usually cannot be distinguished from other cysts in the pancreas. A solid variant has also been reported.

CYTOPATHOLOGIC FEATURES The fluid aspirated from serous cystadenomas is clear and thin and may be bloody, but is not mucoid as in

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SEROUS CYSTADENOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Scantily cellular smears with clean or bloody background ៉ Uniform cuboidal cells with round nuclei, smooth nuclear membranes, and inconspicuous nucleoli ៉ Scant, pale to finely vacuolated but non-mucinous cytoplasm Ancillary Studies ៉ Histochemical stains: PAS-positive, dPAS-negative; confirms cytoplasmic glycogen ៉ Immunocytochemical stains (+): cytokeratins AE1/AE3, CAM 5.2, CK7, CK8, CK18, and CK19; CEA, MUC2, and MUC5 ៉ Cyst fluid analysis: low amylase and CEA Differential Diagnosis and Pitfalls ៉ Pseudocyst ៉ Mucinous cysts: mucinous cystic neoplasm and side-branch

intraductal papillary mucinous neoplasm ៉ Gastrointestinal contamination (pitfall) ៉ Histiocytes (pitfall)

most mucinous cysts. Smears are frequently very paucicellular and it is not uncommon for smears to be acellular. Many cases are considered inadequate for interpretation due to insufficient cellularity, but identification of even a couple of small clusters of cells with bland cuboidal morphology can be very helpful in the appropriate clinical setting, even if not technically considered ‘diagnostic’. Tumor cells are uniform cuboidal cells in small clusters and flat sheets with round, central

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FIGURE 9-37 Serous cystadenoma. The tumor cells are uniform cuboidal cells with bland central nuclei, smooth nuclear membranes, and even chromatin. The cytoplasm is finely vacuolated but non-mucinous. The cells may resemble histiocytes. Papanicolaou stain, high power.

to slightly eccentric nuclei and scant but visible cytoplasm that is homogeneous to finely vacuolated (Fig. 9-37). The nuclei have smooth nuclear membranes, an even chromatin pattern, and inconspicuous to no nucleoli, and the cytoplasm is scant and finely vacuolated or dense, but not mucinous (Fig. 9-38).

ANCILLARY STUDIES PAS stain with and without diastase will confirm the presence of cytoplasmic glycogen and exclude the presence of mucin. Tumor cells immunolabel with cytokeratins CAM 5.2, AE1/AE3, CK7, CK8, CK18, and CK19. MUC6 and α-inhibin are positive in most cases, and MUC1 is positive in about one-third. CEA, MUC2 and MUC5, and all endocrine markers are negative. Cyst fluid analysis typically shows low levels of amylase and CEA.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Bloody specimens that may contain inflammation and debris and lack epithelial cells can be misinterpreted as pseudocysts. Cyst fluid analysis helps by showing an elevated amylase level in pseudocysts. Smears with epithelial cells demonstrating vacuolated cytoplasm may indicate the presence of a neoplastic mucinous cyst (see below).

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FIGURE 9-38 Serous cystadenoma. This air-dried preparation highlights the nonmucinous finely vacuolated cytoplasm. Hema III stain, high power.

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282 Gastrointestinal epithelium and mucin contaminating the smears from EUS-guided biopsies adds to this diagnostic pitfall. Cyst fluid analysis is helpful if CEA is elevated above 200 ng/mL.

SOLID-PSEUDOPAPILLARY NEOPLASM Solid-pseudopapillary neoplasm is a low-grade malignant solid neoplasm with secondary cystic degeneration that produces a proliferation of small bland cells of uncertain lineage in solid nests and around delicate blood vessels, creating a pseudopapillary appearance on histology.

CLINICAL FEATURES This neoplasm is relatively rare, accounting for less than 3% of all pancreatic malignancies. It occurs almost exclusively in women, with an approximate female to male ratio of 9 : 1. Most women are in their third decade, but the reported ages range from 7 to 79 years. Surgical resection is the treatment of choice. The overall prognosis is excellent, with only about 15% of patients developing recurrence or metastatic disease, and this is typically the result of incomplete resection. Complete resection of node-negative patients is considered curative. Even with recurrence or metastatic disease, long-term survival is common.

R ADIOLOGIC FEATURES Like for serous cystadenomas, solid-pseudopapillary neoplasms are often diagnosed from the characteristic clinical and radiologic features. CT and ultrasound

SOLID-PSEUDOPAPILLARY NEOPLASM – DISEASE FACT SHEET Incidence ៉ ∼1–3% of all pancreatic malignancies, 6% of exocrine tumors,

and ∼24% of all surgically resected cystic lesions in the pancreas

Gender and Age Distribution ៉ ∼90% of patients are female ៉ Most are in their 20s; mean age is 28 years Radiologic Features ៉ Well-circumscribed mass with solid and cystic components,

commonly in the pancreatic tail Prognosis ៉ Excellent – only 15% develop recurrence or metastases

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demonstrate a typically large, well-demarcated, solid and cystic heterogeneous neoplasm commonly located in the tail of the pancreas of a young woman. Calcifications may also be noted.

CYTOPATHOLOGIC FEATURES Aspirate smears are hypercellular with a population of small, uniform cells in cohesive, often branching and papillary cell clusters, interspersed with many single cells (Fig. 9-39). The background may be clean or filled with hemorrhagic cyst debris laden with foamy histiocytes and multinucleated giant cells. Delicate fibrovascular cores with myxoid stroma and a zone of cytoplasm sometimes separating the nuclei of the cells from the vessel is a diagnostic finding (Fig. 9-40). Individual tumor cells are uniform with round to oval nuclei, smooth to slightly indented or grooved nuclear membranes, even and finely granular chromatin, and inconspicuous nucleoli (Fig. 9-41). The cytoplasm is scant to moderate, non-granular to finely granular, and may be stripped from the nucleus. When intact, a small perinuclear vacuole and, occasionally, intracytoplasmic hyaline globule may be noted (Fig. 9-42).

SOLID-PSEUDOPAPILLARY NEOPLASM – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Highly cellular smears with branching and papillary cell clusters interspersed with single cells ៉ Smear background may be clean or filled with hemorrhagic cyst debris, foamy histiocytes, and multinucleated giant cells ៉ Fibrovascular cores with myxoid stroma is characteristic ៉ Individual tumor cells are homogeneous with little anisonucleosis and no mitotic activity ៉ Nuclei are round to oval with smooth nuclear membranes except for frequent nuclear grooves or focal indentations, finely granular chromatin, and inconspicuous nucleoli ៉ Cytoplasm is scant to moderate and may contain a small perinuclear vacuole or intracytoplasmic hyaline globule Ancillary Studies ៉ Histochemical stains: myxoid stroma is positive for PAS/dPAS ៉ Immunocytochemical stains: positive for vimentin, α-1-

antitrypsin, CD10, NSE, CD56, and progesterone receptor; synaptophysin and cytokeratin (AE1/AE3, CAM 5.2) are variably positive; CK7 and CK19 are usually negative; β-catenin will demonstrate abnormal cytoplasmic and nuclear staining in >90% of tumors; intracytoplasmic hyaline globules stain with antibodies to α-1-antitrypsin ៉ Molecular analysis: almost all harbor somatic point mutations in exon 3 of the β-catenin gene Differential Diagnosis and Pitfalls ៉ Pancreatic endocrine neoplasm ៉ Pseudocysts ៉ Acinar cell carcinoma ៉ Normal acinar epithelium (pitfall)

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FIGURE 9-39 Solid-pseudopapillary neoplasm. The typical aspirate smears are hypercellular, composed of a population of small uniform cells in cohesive, often branching and papillary cell clusters interspersed with many single cells. Papanicolaou stain, high power.

FIGURE 9-40 Solid-pseudopapillary neoplasm. The myxoid stroma that separates the tumor cells from the vessels can be seen as globules within acinar structures, as demonstrated here. Papanicolaou stain, medium power.

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FIGURE 9-41 Solid-pseudopapillary neoplasm. The individual tumor cells are bland with oval to indented nuclei, even chromatin, nuclear grooves, and no nucleoli. Note the characteristic small perinuclear vacuole seen in some of the cells. Papanicolaou stain, high power.

FIGURE 9-42 Solid-pseudopapillary neoplasm. Intracytoplasmic hyaline globules may also be seen in some tumor cells, as demonstrated in this neoplasm, most prominent in the cell at 2 o’clock. Note also the occasional perinuclear vacuole. Hema III stain, high power.

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ANCILLARY STUDIES Solid-pseudopapillary neoplasms often do not express cytokeratin (CAM 5.2 or AE1/AE3) and usually do not express cytokeratins 7 and 19. Most tumors stain with antibodies to vimentin, CD10 (neprilysin), neuronspecific enolase (NSE), CD56, β-catenin, cyclin D1, progesterone receptors, and α-1-antitrypsin, a marker that also stains the intracytoplasmic hyaline globules. Cyst fluid analysis demonstrates low amylase and CEA levels.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The primary solid neoplasm in the differential diagnosis is PEN. The uniform, bland-appearing, often dispersed epithelial cells of solid-pseudopapillary neoplasm can greatly resemble those of PEN. Careful attention to the nuclear details, including the presence of nuclear grooves, indentations, and the occasional perinuclear vacuole or intracytoplasmic hyaline droplet seen in many solid-pseudopapillary neoplasms, will help distinguish the two when papillary architecture is absent. Pseudocyst enters the differential diagnosis when only the hemorrhagic and necrotic cyst debris is aspirated. Clinical correlation and cyst fluid analysis helps distinguish these entities. Pseudocysts are more common in men with a history of pancreatitis. Unlike pseudocysts, solid-pseudopapillary neoplasms have a low amylase level on cyst fluid analysis.

MUCINOUS CYSTIC NEOPLASM – DISEASE FACT SHEET Incidence ៉ ∼6% of all primary pancreatic neoplasms and pancreatic cysts Gender and Age Distribution ៉ Almost all female ៉ 40–50 years

Radiologic Features ៉ Typically, solitary, multiloculated, well-circumscribed masses,

often with peripheral calcifications and a thick capsule; 90% in the body or tail ៉ Communication with the large pancreatic ducts is absent in almost all cases ៉ A cyst wall mass suggests an invasive component Prognosis and Treatment ៉ Prognosis is directly related to the presence or absence of

invasive carcinoma ៉ Surgical resection is the treatment of choice and is curative for

non-invasive neoplasms

component, given that these neoplasms tend to be very heterogeneous in their lining and that an invasive component may not be apparent from gross inspection of the resected cyst. Complete resection of thoroughly evaluated, non-invasive neoplasms is considered curative.

CYTOPATHOLOGIC FEATURES MUCINOUS CYSTIC NEOPLASM Mucinous cystic neoplasm (MCN) is a neoplastic mucinproducing cyst that, in almost all cases, does not communicate with the pancreatic ductal system, is lined by mucinous epithelial cells with varying degrees of atypia, and contains subepithelial ovarian-type stroma.

CLINICAL FEATURES Mucinous cystic neoplasms comprise approximately 6% of all primary pancreatic tumors. With rare exception, patients are female, and the average age is between 40 and 50 years. Mucinous cystic neoplasms with invasive carcinoma often occur in patients in their 60s. Complete surgical resection is the treatment of choice. Regardless of the atypia of the lining epithelium, the prognosis is directly related to the presence or absence of an invasive carcinoma. As such, cytologic evaluation cannot predict outcome. Complete and thorough histologic sampling is essential to rule out an invasive

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Aspiration of MCNs produces highly variable amounts of extracellular mucin and cyst-lining epithelium. In addition, the degree of epithelial atypia may be variable and not representative of the highest degree of atypia of the cyst, owing to the heterogeneity of the cyst lining. As such, the cytologic diagnosis often underestimates the ultimate histologic grade of the tumor. In addition, a specific diagnosis of MCN is less common than a more general diagnosis of neoplastic mucinous cyst, a generic term that encompasses both intraductal papillary mucinous neoplasm (IPMN) and MCN. This is primarily due to a lack of architectural specificity of the glandular epithelium. The presence of a neoplastic mucinous cyst is often first suspected at the time of aspiration when thick, viscous mucus is grossly appreciated by the aspirator. This mucus is difficult to draw into and express from the needle. Such thick and viscous cyst fluid is reflected on the slide as a thick sheet of ‘colloid-like’ mucin that frequently covers most of the slide (Fig. 9-43). Mucin contamination from the gastrointestinal tract will not be ‘colloid-like’. Degenerated inflammatory cells and histiocytes within the mucin is a feature that also helps to distinguish contaminating mucin from neoplastic

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FIGURE 9-43 Mucinous cystic neoplasm (MCN). Colloid-like mucin is typical of a neoplastic mucinous cyst, including MCN and intraductal papillary mucinous neoplasm. This quality of mucin is not seen from gastrointestinal contamination. Papanicolaou stain, medium power.

MUCINOUS CYSTIC NEOPLASM – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Mucin quality and quantity can vary: thick, ‘colloid-like’ mucin

is consistent with origin from the cyst (rather than gastrointestinal contamination from EUS biopsy) ៉ Epithelial cells vary in quantity and may be absent in highgrade neoplasms with only mucin on smears ៉ Epithelial cells range from fl at sheets and single bland columnar mucinous cells (adenoma) to high-grade dysplastic cells with a high N/C ratio and irregular nuclei with or without cytoplasmic mucin Ancillary Studies ៉ Histochemical stains: mucicarmine and Alcian blue pH 2.5 +/− ៉ Immunocytochemistry (+): cytokeratins AE1/AE3, CAM 5.2, CK7,

CK8, CK18, CK19; CEA, DUPAN-2, CA 19-9, and MUC5AC ៉ Cyst fluid analysis: low amylase and variable CEA (usually

>200 ng/mL)

Differential Diagnosis and Pitfalls Pseudocyst Side-branch IPMN Serous cystadenoma Gastrointestinal contamination (pitfall)

៉ ៉ ៉ ៉

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mucin. However, not all MCNs will have such mucoid contents. Extracellular mucin can appear as focally thick clumps, thin wisps, and as focal or diffuse thin background mucin, not easily visualized on routine preparations, especially liquid-based preparations where the mucin can be quite attenuated during processing (Fig. 9-44). An aliquot of the cyst fluid, if sufficient in quantity, can be used to prepare cytospin slides for mucicarmine and/or Alcian blue pH 2.5 to assess for mucin. Negative special stains, however, do not exclude the presence of a MCN. Mucinous cystadenomas are typically scantily cellular, aspirates producing single cells, small clusters, and flat sheets of bland glandular epithelial cells that typically demonstrate cytoplasmic mucin visible on routine light microscopy (Fig. 9-45). The nuclei are basally located, round and regular, with even chromatin and inconspicuous to occasionally prominent nucleoli. Occasionally, muciphages (foamy histiocytes) may be the only cells in the cyst contents. The epithelial lining of MCNs with moderate dysplasia and higher-grade neoplasms demonstrates epithelial cells with nuclear crowding, loss of polarity, nuclear elongation or rounding, hyperchromasia, and increased N/C ratio (Fig. 9-46). Cells in small tight bud-like clusters or singly with these same nuclear features, and cytoplasm with or without mucin is also consistent with the presence of a MCN with moderate dysplasia or higher. Crowded groups of cells with open chromatin, irregular nuclear membranes and nucleoli, significant background inflammation, and necrosis support the interpretation of malignancy (Fig. 9-47).

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FIGURE 9-44 Mucinous cystic neoplasm. Mucin can appear fragmented and quite attenuated in liquid-based preparations, making recognition difficult. ThinPrep®, Papanicolaou stain, medium power.

FIGURE 9-45 Mucinous cystic neoplasm-adenoma. Bland adenomatous epithelium maintains a uniform honeycomb arrangement and single columnar cells demonstrate diffuse cytoplasmic mucin. ThinPrep®, Papanicolaou stain, high power.

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FIGURE 9-46 Mucinous cystic neoplasm with moderate dysplasia. Increased nuclear density, nuclear crowding, loss of polarity, and increased N/C ratio that may be associated with a loss of cytoplasmic mucin and cellular degeneration are features that correlate with a neoplasm of at least moderate dysplasia. Papanicolaou stain, high power.

FIGURE 9-47 Mucinous cystadenocarcinoma. Crowded three-dimensional groups containing cells with either hyperchromasia or open chromatin, irregular nuclear membranes, and nucleoli in a background with significant infl ammation and necrosis support the interpretation of malignancy. Invasion, however, can only be determined from aspiration of an associated mural nodule. Papanicolaou stain, low power.

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FIGURE 9-48 Mucinous cystic neoplasm. Thin background mucin may not be appreciated on routine stains. Special stains for mucin, including this Alcian blue at pH 2.5, can highlight extracellular and intracellular mucin. Alcian blue pH 2.5, medium power.

Invasion can be determined only by the aspiration of a mural nodule, as the cytologic features distinguishing in-situ from invasive carcinoma have not been definitely established.

ANCILLARY STUDIES Aspirates producing thin white fluid, not grossly mucoid, may benefit from special stains for mucin on cystospin preparations, as mentioned above (Fig. 9-48). The epithelial cells of MCN stain with antibodies to cytokeratins (pancytokeratin, CAM 5.2, CK7, CK8, CK18, and CK19), DUPAN-2, CA 19-9, and MUC5AC. Almost all MCNs are negative for CK20, MUC1, and MUC6. MUC2 will stain goblet cells. Chemical analysis of the cyst fluid can aid in the diagnosis and classification of pancreatic cysts. CEA levels above 200 ng/mL have been found to aid in the distinction of non-mucinous from mucinous cysts, with very high levels of CEA correlating with malignancy. Amylase levels are not high in MCN as in IPMN, due to the absence of connectivity with the pancreatic duct.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Distinction of mucinous cystadenomas from contaminating gastrointestinal epithelium is particularly challenging, especially gastric epithelium. In contrast to duodenal epithelium, which is recognized

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by the presence of large, uniform, flat sheets of glandular epithelium with a brush-bordered luminal edge studded with goblet cells containing clear cytoplasm (Fig. 9-49), gastric epithelium more often presents as small groups and occasionally as single columnar glandular epithelial cells that can be confused with the bland epithelium of an adenoma (Fig. 9-50). A cup-like apical pocket of mucinous cytoplasm seen in the foveolar cells of the gastric epithelium is a feature that can help differentiate it from the cyst lining of a MCN adenoma that demonstrates a full columnar column of mucinous epithelium (see Fig. 9-45). The differential diagnosis of MCN also includes IPMN, pseudocyst, oligocystic and unilocular variants of serous cystadenoma, and cystic PEN. Mucinous cystic neoplasms devoid of identifiable mucin or epithelial cells can be mistaken for a pseudocyst. Oligocystic, macrocystic, and unilocular variants of serous cystadenoma radiologically mimic MCN. The presence of thick, viscous mucin excludes the diagnosis of a serous cyst and pseudocyst. Serous cysts produce thin, clear, nonviscous fluid and scant epithelium. The epithelial cells are bland cuboidal cells with non-mucinous cytoplasm. In the absence of background mucin, the small, often individual cells of a MCN with moderate dysplasia or carcinoma are similar to the cells of cystic PEN. The most helpful distinguishing features are those of the nucleus. In cystic PEN, the nuclei are round with relatively smooth nuclear membranes and have chromatin that is coarse and stippled in the typical ‘salt and pepper’ neuroendocrine pattern. The presence of even focal intracytoplasmic vacuoles also supports a diagnosis of MCN over cystic PEN.

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FIGURE 9-49 Duodenal epithelium. During EUSguided biopsies of lesions in the pancreatic head, duodenal epithelium may contaminate the specimen. The epithelium is often recognized by the presence of large monolayered sheets with a uniform luminal edge of columnar cells with a brush border. Goblet cells frequently stud the sheets of epithelium but may not be overtly apparent in all groups, especially small groups. Papanicolaou stain, medium power.

FIGURE 9-50 Gastric epithelium. EUS-guided biopsies of neoplasms or lesions in the pancreatic body and tail traverse the gastric wall. Gastric epithelium may demonstrate mucinous cytoplasm which can be confused with mucin-producing neoplastic cysts. The mucinous cytoplasm is often present in an apical cup-like compartment. Papanicolaou stain, high power.

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INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing neoplastic cyst that arises from and is directly connected with the pancreatic ductal system, either the main duct and/or side-branch duct, and is lined by typically papillary and variably atypical mucinous epithelium. These neoplasms are classified by the WHO as IPMN-adenoma, IPMN with moderate dysplasia (also know as borderline tumor), IPMN with carcinoma in situ, and IPMN with invasive carcinoma (either tubular type or colloid type).

CLINICAL FEATURES It is difficult to establish an accurate incidence of IPMN owing to its relatively recent distinction as a specific entity separate from mucinous cystic neoplasms in the mid 1980s and from serous cysts in the 1970s. In addition, many small asymptomatic neoplasms are being incidentally recognized because of the increasing use of CT scans for other conditions. An estimated incidence from recent reports places IPMN at approximately 20% of all neoplastic pancreatic cysts and 5% of all pancreatic neoplasms. Most IPMNs occur in the elderly population, with a peak age of close to 65 years. The male to female ratio

INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM – DISEASE FACT SHEET Incidence ៉ ∼5% of all pancreatic neoplasms and ∼20% of all neoplastic pancreatic cysts Gender and Age Distribution ៉ M > F ៉ Mean age ∼65 years

Radiologic Features ៉ Main duct, side-branch, and combined types exist ៉ Copious ductal mucin produces filling defects ៉ Cysts are single or multiple and connect to the large pancreatic ducts ៉ 70% occur in the pancreatic head ៉ Cyst wall nodules and markedly dilated main pancreatic duct suggest malignancy

varies by study and institution, but most studies show a slight male predominance. Complete surgical resection is currently the treatment of choice. Prognosis is directly related to the presence or absence of an invasive carcinoma. Complete and thorough histologic sampling is essential to rule out an invasive component, given that these neoplasms tend to be very heterogenous in their lining and that an invasive component may not be apparent from gross inspection of the resected cyst. Non-invasive IPMNs have a greater than 90% 5-year survival rate. This rate drops to 40% in IPMN with invasive carcinoma, but this rate is still significantly better than for conventional ductal adenocarcinoma. The prognosis also depends on the type of IPMN and the type and size of the invasive component. Side-branch IPMN is reported to behave better than main duct and combined-type IPMN, and the invasive IPMN with colloid carcinoma is reported to have a better prognosis than one with invasive conventional tubular type carcinoma.

CYTOPATHOLOGIC FEATURES The gross features of the cyst fluid of IPMNs are identical to those of MCNs and the same discorrelation is present between the quality and quantity of mucin and cells on FNAB with the final grade of the tumor on histology.

INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Mucin quality and quantity can vary: thick, ‘colloid-like’ mucin is consistent with origin from the cyst (rather than gastrointestinal contamination from EUS biopsy) ៉ Epithelial cells vary in quantity and may be absent even in high-grade neoplasms ៉ Epithelial cells range from fl at sheets to papillary clusters and single cells with bland columnar mucinous cells (adenoma) to high-grade dysplastic cells singly or in tight epithelial clusters with a high N/C ratio and irregular nuclei with or without cytoplasmic mucin; abundant background infl ammation suggests at least moderate dysplasia, and necrosis at least carcinoma in situ Ancillary Studies ៉ Histochemical stains: mucicarmine and Alcian blue pH 2.5 +/− ៉ Immunocytochemical stains (+): cytokeratins AE1/AE3, CAM 5.2,

CK7, CK8, CK18, CK19; CEA, CA 19-9, and MUC5AC ៉ Cyst fluid analysis: high amylase and variable CEA (usually

>200 ng/mL)

Prognosis and Treatment ៉ Prognosis is directly related to the presence or absence of

invasive carcinoma ៉ Surgical resection is the treatment of choice and is curative for

non-invasive neoplasms ៉ Invasive side-branch IPMN has a better prognosis than main duct

IPMN

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Differential Diagnosis and Pitfalls Pseudocyst Mucinous cystic neoplasm Serous cystadenoma Gastrointestinal contamination (pitfall)

៉ ៉ ៉ ៉

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FIGURE 9-51 Intraductal papillary mucinous neoplasm-adenoma. The bland mucinous epithelium is appreciated by the low N/C ratio, round, regular nuclei, and abundant columnar cytoplasm that may or may not appear visibly mucinous. Papanicolaou stain, high power.

IPMN-adenoma is lined by bland columnar mucinous glandular cells arranged in small clusters and flat to folded sheets with a honeycombed pattern. Single cells may also be seen. Mucinous papillary epithelial fragments are not often appreciated in adenomas. Columnar cells with round basal nuclei and abundant columnar cytoplasm that may or may not appear visibly mucinous (Fig. 9-51). Dense, oncocytic cytoplasm is consistent with intraductal oncocytic papillary neoplasm (Fig. 952). Other epithelial types (intestinal, biliary, and gastric foveolar) are not readily distinguished on cytology. IPMN-moderate dysplasia and IPMN-carcinoma in situ are lined by atypical to malignant-appearing glandular epithelium. The cells display nuclear crowding, loss of polarity, nuclear elongation, and hyperchromasia. Hyperchromatic cells with irregular nuclear membranes and a high N/C ratio may be arranged in papillary clusters, where the length is usually twice the width of the group (Fig. 9-53), small tight epithelial cells clusters (Fig. 9-54), or singly (Fig. 9-55). Even if very scant in amount, the presence of these groups is significant. Open chromatin, irregular nuclear membranes and nucleoli, significant background inflammation, and necrosis support the interpretation of an in-situ or invasive carcinoma (Figs 9-56 & 9-57). Only necrosis appears to correlate with the presence of invasion, but this distinction cannot be made on aspirates of cyst contents alone. A mural nodule is indicative of an invasive carcinoma, and currently, aspiration of this nodule is necessary to cytologically document an invasive carcinoma.

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ANCILLARY STUDIES Aspirates producing thin white fluid, not grossly mucoid, may benefit from special stains for mucin on cystospin preparations, as mentioned above. Negative mucin stains, however, do not exclude the diagnosis of IPMN. The epithelial cells of IPMN label with antibodies to cytokeratins (AE1/AE3, CAM 5.2, CK7, CK8, CK18, and CK19; occasionally with CK20), CEA, and CA 19-9. Very few IPMNs stain for MUC1 and almost none stain for MUC7, but most stain for MUC2, MUC3, MUC4, and MUC5AC. Staining patterns for the MUC proteins have been correlated with the type of lining epithelium of the villi and the presence or absence of an invasive component on histology. Like in MCN, CEA levels above 200 ng/mL support a mucinous cyst, with very high levels of CEA correlating with malignancy. Amylase levels are high in IPMN but not MCN, due to the connectivity of IPMN with the pancreatic duct.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of IPMN is essentially the same as for MCN and is discussed in the above section.

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FIGURE 9-52 Intraductal papillary mucinous neoplasm, oncocytic variant. The presence of an intraductal lesion with abundant dense, granular, oncocytic cytoplasm characterizes this variant. Hema III stain, high power.

FIGURE 9-53 Intraductal papillary mucinous neoplasm (IPMN) with moderate dysplasia. Papillary clusters of epithelial cells with nuclear crowding, atypia, and overlap characterizes an IPMN with at least moderate dysplasia. Papanicolaou stain, medium power.

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FIGURE 9-54 Intraductal papillary mucinous neoplasm with moderate dysplasia. Small clusters of high N/C ratio cells with hyperchromatic nuclei and with or without mucinous cytoplasm suggests the presence of a neoplastic mucinous cyst with at least moderate dysplasia. This finding does not separate moderate dysplasia from carcinoma in situ or invasive carcinoma. Papanicolaou stain, high power.

FIGURE 9-55 Intraductal papillary mucinous neoplasm with carcinoma in situ. Some neoplasms may demonstrate only single dysplastic cells that resemble severe dysplasia of the cervix. Note the necrosis and infl ammatory debris surrounding this dysplastic cell. Papanicolaou stain, high power.

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FIGURE 9-56 Intraductal papillary mucinous neoplasm with carcinoma in situ. The hyperchromatic crowded group contains cells with nuclear overlapping and distinct parachromatin clearing, features that are consistent with carcinoma; however, they do not distinguish in-situ from invasive carcinoma. Papanicolaou stain, high power.

FIGURE 9-57 Intraductal papillary mucinous neoplasm with invasive carcinoma. The presence of coagulative cellular necrosis is the one feature that correlates with invasive carcinoma. Note the thick mucin in the right of the image. Papanicolaou stain, medium power.

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FINE NEEDLE ASPIRATION CYTOLOGY a 3-year experience and review of the literature. Cancer 2002;96: 362–369. Pseudocyst

Primary non-epithelial neoplasms account for approximately 1–2% of all pancreatic neoplasms, and metastases represent up to 4% of pancreatic tumors. The clinical behavior and cytologic features of neoplasms such as lymphangioma, schwannoma, lipoma, and (extra-) gastrointestinal stromal tumor are similar to those outside of the pancreas. Non-Hodgkin lymphoma may be primary or secondary. Carcinomas, particularly from the lung, are the most common malignant neoplasm metastatic to the pancreas. Other common metastatic carcinomas include those originating in the breast, kidney, stomach, and skin (melanoma).

Acknowledgement I would like to thank my co-authors on the 4th series AFIP fascicle on Tumors of the Pancreas, Drs Ralph Hruban and David Klimstra, for providing a rich reference on which I relied heavily to produce this chapter.

SUGGESTED READINGS General Centeno BA, Pitman MB. Fine Needle Aspiration Biopsy of the Pancreas. Boston: Butterworth-Heinemann, 1999. DeMay R. Pancreas. In: The Art and Science of Cytopathology. Chicago: ASCP Press, 1996:1053–1082. Geisinger KR, Stanley MW, Raab SS, Silverman JF, Abati A. Modern Cytopathology. Philadelphia: Churchill Livingstone, 2004. Hruban RH, Pitman MB, Klimstra DS. Atlas of Tumor Pathology: Tumors of the Pancreas, 4th ed. Silver Spring, MD: ARP Press, In press. Klimstra DS. Pancreas. In: Sternberg SS, ed. Histology for Pathologists. Philadelphia: Lippincott-Raven, 1997:613–647. Lack EE. Pathology of the Pancreas, Gallbladder, Extrahepatic Biliary Tract, and Ampullary Region. New York: Oxford University Press, 2003.

Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330–1336. Frossard JL, Amouyal P, Amouyal G, et al. Performance of endosonographyguided fine needle aspiration and biopsy in the diagnosis of pancreatic cystic lesions. Am J Gastroenterol 2003;98:1516–1524. Kloppel G. Pseudocysts and other non-neoplastic cysts of the pancreas. Semin Diagn Pathol 2000;17:7–15. Kloppel G, Maillet B. Pseudocysts in chronic pancreatitis: a morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas 1991;6:266–274. Kosmahl M, Pauser U, Peters K, et al. Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows Arch 2004;445:168–178. Lewandrowski K, Lee J, Southern J, Centeno B, Warshaw A. Cyst fluid analysis in the differential diagnosis of pancreatic cysts: a new approach to the preoperative assessment of pancreatic cystic lesions. AJR Am J Roentgenol 1995;164:815–819. Pinto M, Meriano F. Diagnosis of cystic pancreatic lesions by cytologic examination and carcinoembryonic antigen and amylase levels of cyst contents. Acta Cytol 1991;35:456–463. Lymphoepithelial Cyst Adsay NV, Hasteh F, Cheng JD, Klimstra DS. Squamous-lined cysts of the pancreas: lymphoepithelial cysts, dermoid cysts (teratomas), and accessory-splenic epidermoid cysts. Semin Diagn Pathol 2000;17:56–65. Adsay NV, Hasteh F, Cheng JD, et al. Lymphoepithelial cysts of the pancreas: a report of 12 cases and a review of the literature. Mod Pathol 2002;15:492–501. Bolis GB, Farabi R, Liberati F, Maccio T. Lymphoepithelial cyst of the pancreas. Report of a case diagnosed by fine needle aspiration biopsy. Acta Cytol 1998;42:384–386. Cappellari JO. Fine-needle aspiration cytology of a pancreatic lymphoepithelial cyst. Diagn Cytopathol 1993;9:77–81. Centeno BA, Stockwell JW, Lewandrowski KB. Cyst fluid cytology and chemical features in a case of lymphoepithelial cyst of the pancreas: a rare and difficult preoperative diagnosis. Diagn Cytopathol 1999;21: 328–330. Liu J, Shin HJ, Rubenchik I, Lang E, Lahoti S, Staerkel GA. Cytologic features of lymphoepithelial cyst of the pancreas: two preoperatively diagnosed cases based on fine-needle aspiration. Diagn Cytopathol 1999;21:346–350. Mitchell ML. Fine needle aspiration biopsy of peripancreatic lymphoepithelial cysts. Acta Cytol 1990;34:462–463.

Chronic Pancreatitis Bentz JS, Kochman ML, Faigel DO, Ginsberg GG, Smith DB, Gupta PK. Endoscopic ultrasound-guided real-time fine-needle aspiration: clinicopathologic features of 60 patients. Diagn Cytopathol 1998;18:98– 109. Deshpande V, Mino-Kenudson M, Pitman MB, Lauwers GY. Endoscopic ultrasound guided fine needle aspiration biopsy of autoimmune pancreatitis: diagnostic criteria and pitfalls. Am J Surg Pathol 2005;29: 1464–1471. Fritscher-Ravens A, Brand L, Knofel WT, et al. Comparison of endoscopic ultrasound-guided fine needle aspiration for focal pancreatic lesions in patients with normal parenchyma and chronic pancreatitis [see comment]. Am J Gastroenterol 2002;97:2768–2775. Hollerbach S, Klamann A, Topalidis T, Schmiegel WH. Endoscopic ultrasonography (EUS) and fine-needle aspiration (FNA) cytology for diagnosis of chronic pancreatitis. Endoscopy 2001;33:824–831. Stelow EB, Bardales RH, Lai R, et al. The cytological spectrum of chronic pancreatitis. Diagn Cytopathol 2005;32:65–69. Voss M, Hammel P, Molas G, et al. Value of endoscopic ultrasound guided fine needle aspiration biopsy in the diagnosis of solid pancreatic masses. Gut 2000;46:244–249. Ylagan LR, Edmundowicz S, Kasal K, Walsh D, Lu DW. Endoscopic ultrasound guided fine-needle aspiration cytology of pancreatic carcinoma:

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Ductal Adenocarcinoma Al-Kaisi N, Siegler EE. Fine needle aspiration cytology of the pancreas. Acta Cytol 1989;33:145–152. Cohen MB, Egerter DP, Holly EA, Ahn DK, Miller TR. Pancreatic adenocarcinoma: regression analysis to identify improved cytologic criteria. Diagn Cytopathol 1991;7:341–345. Fekete PS, Nunez C, Pitlik DA. Fine-needle aspiration biopsy of the pancreas: a study of 61 cases. Diagn Cytopathol 1986;2:301–306. Henke A, Jensen C, Cohen M. Cytologic diagnosis of adenocarcinoma in biliary and pancreatic duct brushings. Adv Anat Pathol 2002;9: 301–308. Lin F, Staerkel GA. Cytologic criteria for well differentiated adenocarcinoma of the pancreas in fine-needle aspiration biopsy specimens. Cancer 2003;99:44–50. Mitchell ML, Carney CN. Cytologic criteria for the diagnosis of pancreatic carcinoma. Am J Clin Pathol 1985;83:171–176. Nagle J, Wilbur DC, Pitman MD. Cytomorphology of gastric and duodenal epithelium and reactivity to B72.3: a baseline for comparison to pancreatic neoplasms aspirated by EUS-FNAB. Diagn Cytopathol 2005;33: 381–386. Robins DB, Katz RL, Evans DB, Atkinson EN, Green L. Fine needle aspiration of the pancreas. In quest of accuracy. Acta Cytol 1995;39:1–10.

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Van Heek T, Rader A, Offerhaus G. K-ras, p53, and DPC4 (MAD4) alterations in fine-needle aspirates of the pancreas: a molecular panel correlates with and supplements cytologic diagnosis. Am J Surg Oncol 2002;117: 755–765. Ductal Adenocarcinoma Variants Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol 2001;25:26–42. Chow LT, Chow WH. Signet-ring mucinous adenocarcinoma of the pancreas. Chin Med Sci J 1994;9:176–178. Gupta RK, Wakefield SJ. Needle aspiration cytology, immunocytochemistry, and electron microscopic study of unusual pancreatic carcinoma with pleomorphic giant cells. Diagn Cytopathol 1992;8:522–527. Manci EA, Gardner LL, Pollock WJ, Dowling EA. Osteoclastic giant cell tumor of the pancreas. Aspiration cytology, light microscopy, and ultrastructure with review of the literature. Diagn Cytopathol 1985;1: 105–110. Mullick SS, Mody DR. ‘Osteoclastic’ giant cell carcinoma of the pancreas. Report of a case with aspiration cytology. Acta Cytol 1996;40:975– 979. Paal E, Thompson LD, Frommelt RA, Przygodzki RM, Heffess CS. A clinicopathologic and immunohistochemical study of 35 anaplastic carcinomas of the pancreas with a review of the literature. Ann Diagn Pathol 2001;5:129–140. Rahemtullah A, Misdraji J, Pitman MB. Adenosquamous carcinoma of the pancreas: cytologic features in 14 cases. Cancer 2003;99:372–378. Silverman JF, Dabbs DJ, Finley JL, Geisinger KR. Fine-needle aspiration biopsy of pleomorphic (giant cell) carcinoma of the pancreas. Cytologic, immunocytochemical, and ultrastructural findings. Am J Clin Pathol 1988;89:714–720. Silverman JF, Finley JL, Berns L, Unverferth M. Significance of giant cells in fine-needle aspiration biopsies of benign and malignant lesions of the pancreas. Diagn Cytopathol 1989;5:388–391. Tracey KJ, O’Brien MJ, Williams LF, et al. Signet ring carcinoma of the pancreas, a rare variant with very high CEA values. Immunohistologic comparison with adenocarcinoma. Dig Dis Sci 1984;29:573–576. Walts AE. Osteoclast-type giant-cell tumor of the pancreas. Acta Cytol 1983;27:500–504. Pancreatic Endocrine Neoplasm Al-Kaisi N, Weaver MG, Abdul KFW, Siegler E. Fine needle aspiration cytology of neuroendocrine tumors of the pancreas. A cytologic immunocytochemical and electron microscopic study. Acta Cytol 1992;36: 655–660. Bell DA. Cytologic features of islet-cell tumors. Acta Cytol 1987;31: 485–492. Collins BT, Cramer HM. Fine-needle aspiration cytology of islet cell tumors. Diagn Cytopathol 1996;15:37–45. Dodd LG, Evans DB, Symmans F, Katz RL. Fine-needle aspiration of pancreatic extramedullary plasmacytoma: possible confusion with islet cell tumor. Diagn Cytopathol 1994;10:371–375. Labate AM, Klimstra DL, Zakowski MF. Comparative cytologic features of pancreatic acinar cell carcinoma and islet cell tumor. Diagn Cytopathol 1997;16:112–116. Ligneau B, Lombard-Bohas C, Partensky C. Cystic endocrine tumors of the pancreas: clinical, radiologic and histopathologic features in 13 cases. Am J Surg Pathol 2001;25:752–760. Shaw JA, Vance RP, Geisinger KR, Marshall RB. Islet cell neoplasms. A fine-needle aspiration cytology study with immunocytochemical correlations. Am J Clin Pathol 1990;94:142–149. Sneige N, Ordonez NG, Veanattukalathil S, Samaan NA. Fine-needle aspiration cytology in pancreatic endocrine tumors. Diagn Cytopathol 1987;3:35–40. Erratum in: Diagn Cytopathol 1987;3:176. Sun W, Sneige N, Staerkel G. Comparison of endoscopic ultrasound-guided and computed tomography-guided fine needle aspiration biopsy in the diagnosis of islet cell tumor of pancreas. Mod Pathol 2004;17(suppl. 1):82A. Acinar Cell Carcinoma Caruso RA, Inferrera A, Tuccari G, Barresi G. Acinar cell carcinoma of the pancreas. A histologic, immunocytochemical and ultrastructural study. Histol Histopathol 1994;9:53–58.

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Klimstra DS. Pancreas. In: Sternberg SS, ed. Histology for Pathologists. Philadelphia: Lippincott-Raven, 1997:613–647. Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar cell carcinoma of the pancreas. A clinicopathologic study of 28 cases. Am J Surg Pathol 1992;16:815–837. Labate AM, Klimstra DL, Zakowski MF. Comparative cytologic features of pancreatic acinar cell carcinoma and islet cell tumor. Diagn Cytopathol 1997;16:112–116. Samuel LH, Frierson HJ. Fine needle aspiration cytology of acinar cell carcinoma of the pancreas: a report of two cases. Acta Cytol 1996; 40:585–591. Villanueva RR, Nguyen-Ho P, Nguyen GK. Needle aspiration cytology of acinar-cell carcinoma of the pancreas: report of a case with diagnostic pitfalls and unusual ultrastructural findings. Diagn Cytopathol 1994;10: 362–364. Pancreatoblastoma Dhebri A, Connor S, Campbell F, Ghaneh P, Sutton R, Neoptolemos J. Diagnosis, treatment and outcome of pancreatoblastoma. Pancreatology 2004;4:441–453. Henke AC, Kelley CM, Jensen CS, Timmerman TG. Fine-needle aspiration cytology of pancreatoblastoma. Diagn Cytopathol 2001;25:118– 121. Klimstra D, Longnecker D. Pancreatoblastoma. In: Hamilton S, Aaltonen L, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press, 2000:244–245. Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg Pathol 1995;19:371–389. Pitman MB, Faquin WC. The fine-needle aspiration biopsy cytology of pancreatoblastoma. Diagn Cytopathol 2004;31:402–406. Silverman JF, Holbrook CT, Pories WJ, Kodroff MB, Joshi VV. Fine needle aspiration cytology of pancreatoblastoma with immunocytochemical and ultrastructural studies. Acta Cytol 1990;34:632–640. Serous Cystadenoma Hittmair A, Pernthaler H, Totsch M, Schmid KW. Preoperative fine needle aspiration cytology of a microcystic adenoma of the pancreas. Acta Cytol 1991;35:546–548. Lal A, Bourtsos EP, DeFrias DV, Nemcek AA, Nayar R. Microcystic adenoma of the pancreas: clinical, radiologic, and cytologic features. Cancer 2004;102:288–294. Lewandrowski K, Lee J, Southern J, Centeno B, Warshaw A. Cyst fluid analysis in the differential diagnosis of pancreatic cysts: a new approach to the preoperative assessment of pancreatic cystic lesions. AJR Am J Roentgenol 1995;164:815–819. Logrono R, Vyas SH, Molina CP, Waxman I. Microcytic adenoma of the pancreas: cytologic appearance on percutaneous and endoscopic ultrasoundguided fine-needle aspiration. Report of a case. Diagn Cytopathol 1999;20:298–301. Nguyen GK, Vogelsang PJ. Microcystic adenoma of the pancreas. A report of two cases with fine needle aspiration cytology and differential diagnosis. Acta Cytol 1993;37:908–912. Solid-Pseudopapillary Neoplasm Abraham SC, Klimstra DS, Wilentz RE, et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol 2002;160:1361–1369. Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL. Cystic neoplasms of the pancreas. N Engl J Med 2004;351:1218– 1226. Greenberg ML, Rennie Y, Grierson JM, Quin JW, Boadle RA. Solid and papillary epithelial tumour of the pancreas: cytological case study with ultrastructural and flow cytometric evaluation. Diagn Cytopathol 1993;9:541–546. Pelosi G, Iannucci A, Zamboni G, Bresaola E, Iacono C, Serio G. Solid and cystic papillary neoplasm of the pancreas: a clinico-cytopathologic and immunocytochemical study of five new cases diagnosed by fine-needle aspiration cytology and a review of the literature. Diagn Cytopathol 1995;13:233–246.

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298 Pettinato G, Di Vizio D, Manivel JC, Pambuccian SE, Somma P, Insabato L. Solid-pseudopapillary tumor of the pancreas: a neoplasm with distinct and highly characteristic cytological features. Diagn Cytopathol 2002;27:325–334. Pettinato G, Manivel JC, Ravetto C, et al. Papillary cystic tumor of the pancreas. A clinicopathologic study of 20 cases with cytologic, immunohistochemical, ultrastructural, and flow cytometric observations, and a review of the literature. Am J Clin Pathol 1992;98:478– 488.

Mucinous Cystic Neoplasms Brugge WR. Role of endoscopic ultrasound in the diagnosis of cystic lesions of the pancreas. Pancreatology 2001;1:637–640. Jhala NC, Jhala D, Eltoum I, et al. Endoscopic ultrasound-guided fine needle aspiration biopsy: a powerful tool to obtain samples from small lesions. Cancer (Cancer Cytopathol) 2004;102:239–246. Klapman JB, Logrono R, Dye CE, Waxman I. Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol 2003;98:1289–1294. Lau SK, Lewandrowski KB, Brugge WR, Warshaw AL, Centeno BA. Diagnostic significance of mucin in fine needle aspiration samples of pancreatic cysts. Mod Pathol 2000;13:48A. Lewandrowski KB, Southern JF, Pins MR, Compton CC, Warshaw AL. Cyst fluid analysis in the differential diagnosis of pancreatic cysts: a comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma. Ann Surg 1993;217:41– 47. Mallery JS, Centeno BA, Hahn PF, Chang Y, Warshaw AL, Brugge WR. Pancreatic tissue sampling guided by EUS, CT/US, and surgery: a comparison of sensitivity and specificity. Gastrointest Endosc 2002;56: 218–224. Nagle J, Wilbur DC, Pitman MD. The cytomorphology of gastric and duodenal epithelium and reactivity to B72.3: a baseline for comparison to pancreatic neoplasms aspirated by EUS-FNAB. Diagn Cytopathol 2005;33: 381–386. Pinto M, Meriano F. Diagnosis of cystic pancreatic lesions by cytologic examination and carcinoembryonic antigen and amylase levels of cyst contents. Acta Cytol 1991;35:456–463. Recine M, Kaw M, Evans DB, Krishnamurthy S. Fine-needle aspiration cytology of mucinous tumors of the pancreas. Cancer 2004;102: 92–99. Shin HJ, Lahoti S, Sneige N. Endoscopic ultrasound-guided fine-needle aspiration in 179 cases: the M. D. Anderson Cancer Center experience. Cancer 2002;96:174–180.

Intraductal Papillary Mucinous Neoplasm Faigel DO, Ginsberg GG, Bentz JS, Gupta PK, Smith DB, Kochman ML. Endoscopic ultrasound-guided real-time fine-needle aspiration biopsy of the pancreas in cancer patients with pancreatic lesions. J Clin Oncol 1997;15:1439–1443.

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FINE NEEDLE ASPIRATION CYTOLOGY Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004;28:977–987. Jhala NC, Jhala D, Eltoum I, et al. Endoscopic ultrasound-guided fine needle aspiration biopsy: a powerful tool to obtain samples from small lesions. Cancer (Cancer Cytopathol) 2004;102:239–246. Klapman JB, Logrono R, Dye CE, Waxman I. Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol 2003;98:1289–1294. Layfield LJ, Cramer H. Fine-needle aspiration cytology of intraductal papillary-mucinous tumors: a retrospective analysis. Diagn Cytopathol 2005;32:16–20. Maire F, Couvelard A, Hammel P, et al. Intraductal papillary mucinous tumors of the pancreas: the preoperative value of cytologic and histopathologic diagnosis. Gastrointest Endosc 2003;58:701–706. Michaels PJ, Brachtel EF, Bounds BC, Brugge WR, Pitman MB. Intraductal papillary mucinous neoplasm of the pancreas: cytologic features predict histologic grade. Cancer (Cancer Cytopathology) 2006;108:163–173. Recine M, Kaw M, Evans DB, Krishnamurthy S. Fine-needle aspiration cytology of mucinous tumors of the pancreas. Cancer 2004;102: 92–99. Shin HJ, Lahoti S, Sneige N. Endoscopic ultrasound-guided fine-needle aspiration in 179 cases: the M. D. Anderson Cancer Center experience. Cancer 2002;96:174–180. Stelow EB, Stanley MW, Bardales RH, et al. Intraductal papillary-mucinous neoplasm of the pancreas. The findings and limitations of cytologic samples obtained by endoscopic ultrasound-guided fine needle aspiration. Am J Clin Pathol 2003;120:398–404. Non-Epithelial and Secondary Neoplasms Adsay NV, Andea A, Basturk O, Kilinc N, Nassar H, Cheng JD. Secondary tumors of the pancreas: an analysis of a surgical and autopsy database and review of the literature. Virchows Arch 2004;444:527–535. Caffert L, Katz R, Ordonez N, Carrasco C, Cabanillas F. Fine needle aspiration diagnosis of intra-abdominal and retroperitoneal lymphomas by a morphologic and immunocytochemical approach. Cancer 1990;65:72– 77. Dong HY, Harris NL, Preffer FI, Pitman MB. Fine-needle aspiration biopsy in the diagnosis and classification of primary and recurrent lymphoma: a retrospective analysis of the utility of cytomorphology and flow cytometry. Mod Pathol 2001;14:472–481. Ferrozzi F, Zuccoli G, Bova D, Calculli L. Mesenchymal tumors of the pancreas: CT findings. J Comput Assist Tomogr 2000;24:622–627. Paal E, Thompson LD, Heffess CS. A clinicopathologic and immunohistochemical study of ten pancreatic lymphangiomas and a review of the literature. Cancer 1998;82:2150–2158. Wieczorek TJ, Faquin WC, Rubin BP, Cibas ES. Cytologic diagnosis of gastrointestinal stromal tumor with emphasis on the differential diagnosis with leiomyosarcoma. Cancer (Cancer Cytopathol) 2001;93:276–287. Young NA, Al-Saleem TI, Ehya H, Smith MR. Utilization of fine-needle aspiration cytology and flow cytometry in the diagnosis and subclassification of primary and recurrent lymphoma. Cancer 1998;84:252– 261.

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10

Kidney and Adrenal Gland Yener S Erozan

KIDNEY Fine needle aspiration (FNA), performed under ultrasound (US) or computed tomography (CT) guidance, is a safe and accurate technique for the diagnosis of mass lesions of the kidney (Table 10-1). It has been used in the diagnosis of single and multiple masses, as well as selected cystic lesions of kidney. The majority of single masses in the kidney are primary renal neoplasms, with renal cell carcinomas being the most common. Other single masses include urothelial carcinoma arising from kidney pelvis, benign neoplasms such as angiomyolipoma and oncocytoma, and tumor-like lesions such as xanthogranulomatous pyelonephritis and abscess. Childhood tumors of kidney are rarely sampled by FNA. Exceptions are nephroblastoma (Wilms tumor) and rhabdoid tumor, which can be diagnosed by FNA and will be presented in this chapter. Cystic lesions in kidney are common, and most are benign, simple cysts (Table 10-2). Only those for which imaging studies suggest a neoplasm, such as complex multilocular cysts, are aspirated. As in other FNAs, on-site evaluation of the specimens for adequacy improves the diagnosis. Based on the results, core biopsies can be performed or additional samples can be obtained for ancillary studies.

RENAL CELL CARCINOMA (RCC) CLINICAL FEATURES Renal cell carcinomas comprise about 3% of adult malignancies and occur in older age groups (median age, 55 years). They are more common in men than in women (approximately 1.5 : 1), and in the United States the incidence is higher in blacks than in whites. Heavy smoking and obesity increase the risk for RCC. Most RCCs are confined to the kidney for a long period of time, stay asymptomatic, and are detected incidentally during imaging studies. When they become symptomatic (i.e. hematuria, flank pain, or flank mass), they are usually in an advanced stage. Radiologic techniques (CT and US) are very effective for detecting

RENAL CELL CARCINOMA (RCC) – DISEASE FACT SHEET Incidence ៉ About 3% of adult malignancies ៉ In USA, higher in black population Gender and Age Distribution ៉ M : F = 1.5 : 1 ៉ Median age, 55 years

Clinical Features ៉ Most confined to kidney for a long time and stay asymptomatic ៉ Many detected incidentally (on CT or US) ៉ Hematuria, flank pain, or flank mass occurs in advanced stages

Genetic Abnormalities ៉ Multiple chromosomal abnormalities (specifically chromosome #3) ៉ Up to 55% of patients with von Hippel–Lindau syndrome develop RCC ៉ Increased risk in patients with tuberculous sclerosis and acquired cystic kidney disease Prognosis ៉ Determined by stage, nuclear grading, and tumor type

renal neoplasms, as well as for obtaining FNA samples and core biopsies from the lesions. Most RCCs have multiple chromosomal abnormalities, specifically involving chromosome 3. Up to 55% of patients with von Hippel–Lindau (VHL) syndrome develop RCC. There is an increased risk of RCC in patients with tuberous sclerosis and acquired cystic kidney disease, and an association between genetic alterations and specific types of RCC has been documented. Prognosis for RCC is determined by stage, nuclear grading, and type of the tumor.

CLASSIFICATION The current classification of RCC is shown in Table 10-3. The most common type of RCC is clear cell (about 70%), followed by papillary (10–15%) and chromophobe cell (approximately 5%). Collecting duct and medullary types of RCCs are very rare. 299

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FIGURE 10-1 Low-grade renal cell carcinoma (grade 1). Uniform, small, round nuclei with dense chromatin. No visible nucleoli. Papanicolaou stain, low power.

TABLE 10-1

TABLE 10-3

Mass Lesions of Kidney

Classification of Renal Cell Carcinoma

• Neoplasms: • Renal cell carcinoma • Oncocytoma • Nephroblastoma (Wilms tumor) • Rhabdoid tumor • Urothelial carcinoma • Angiomyolipoma • Lymphoma • Metastatic neoplasms • Non-neoplastic masses: • Xanthogranulomatous pyelonephritis • Abscess

From Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder, and Related Urinary Structures. Atlas of Tumor Pathology, 4th Series, Fascicle 1. Washington, D.C: Armed Forces Institute of Pathology, 2004.

TABLE 10-2 Cystic Lesions of Kidney • Benign cysts • Malignant cystic lesions: • Multilocular cystic clear cell carcinoma • Other renal cell carcinomas with cystic degeneration

NUCLEAR GRADING Nuclear grading (Fuhrman’s nuclear grading system) of RCC has been shown to be a significant prognostic tool, and similar criteria are applicable to both histologic and

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cytologic specimens. Grade 1 RCCs have small, round nuclei with dense chromatin and inconspicuous nucleoli (Fig. 10-1). Grade 2 RCCs have somewhat larger, round nuclei with finely granular chromatin and small nucleoli which are not visible under low power (10×) (Fig. 10-2). Grade 3 RCCs have larger, round or oval nuclei with a coarse granular chromatin pattern and prominent nucleoli (Fig. 10-3). Grade 4 RCCs have large pleomorphic nuclei with irregular nuclear borders and prominent nucleoli (Fig. 10-4). Correlation between cytopathologic and histopathologic grading is moderate. Accuracy increases when a two-grade system, ‘low grade’ (combined grades 1 and 2) and ‘high grade’ (combined grades 3 and 4), is used. When adequate cellular samples are obtained, discrepancies between cytopa-

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FIGURE 10-2 Low-grade renal cell carcinoma (grade 2). Uniform, somewhat larger nuclei. No visible nucleoli. Diff-Quik stain, low power.

FIGURE 10-3 High-grade renal cell carcinoma (grade 3). Large, round to oval nuclei, some with irregular borders. Prominent nucleoli. Papanicolaou stain, medium power.

thologic (FNA specimens) and histopathologic (resected tumor) specimens are usually caused by sampling error due to tumor heterogeneity. In our experience, interobserver concordance in FNA samples is higher than that of cytopathologic and histopathologic correlation, supporting sampling error as the major reason for disconcordance.

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CYTOPATHOLOGIC FEATURES The cytopathologic features of RCC presented in most textbooks are based on those of clear cell carcinoma, which is the most common type. There is also adequate information about papillary RCC in the literature;

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FIGURE 10-4 High-grade renal cell carcinoma (grade 4). Large pleomorphic nuclei with macronucleoli. Papanicolaou stain, medium power.

RENAL CELL CARCINOMA (RCC) – PATHOLOGIC FEATURES

specimens for cell blocks and/or needle core biopsies, when needed, increases the specificity of the diagnosis.

Classification ៉ Histologic subtypes of RCC: ៉ Clear cell (conventional) (~70%) ៉ Papillary (10–15%) ៉ Chromophobe cell (~5%) ៉ Collecting duct (very rare) ៉ Medullary (very rare)

Nuclear Grading (Fuhrman’s Grading System) ៉ Significant prognostic tool ៉ Similar criteria applicable to histologic and cytologic specimens ៉ Moderate correlation between histopathologic and cytopathologic grading ៉ Accuracy increases when a two-grade system is used: ៉ ‘Low grade’ (grades 1 and 2) ៉ ‘High grade’ (grades 3 and 4) Cytopathologic Findings ៉ Vary according to type and nuclear grading (discussed in detail under specific subtype) Differential Diagnosis and Pitfalls ៉ Well-differentiated RCC vs other clear cell neoplasms ៉ Poorly differentiated RCC vs metastatic neoplasm or urothelial carcinoma

CLEAR CELL (CONVENTIONAL-TYPE) RENAL CELL CARCINOMA CLINICAL FEATURES Clear cell is the most common subtype, comprising about 70% of RCCs. Granular cell RCCs, which were considered a separate category previously, are now included in this group. Both sporadic and familial forms (VHL) have genetic abnormalities involving chromosome 3. The VHL gene is located in 3p25, which is mutated or lost in clear cell papillary RCCs. Additional suppressor genes are found in chromosome 3, most commonly in the region of 3p14. Continuous deletion

CLEAR CELL (CONVENTIONAL-TYPE) RENAL CELL CARCINOMA – DISEASE FACT SHEET Incidence ៉ Most common type of RCC (70%)

however, FNA findings of chromophobe, collecting duct, and medullary RCCs are limited. Subtypes of RCC, as well as Fuhrman nuclear grading, can be determined fairly accurately in FNA specimens. Errors usually occur due to lack of adequate sampling or to the poor differentiation of the tumor. Obtaining adequate

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Genetic Abnormalities ៉ Both sporadic and familial forms (genetic abnormalities involving

chromosome #3) ៉ Continuous deletion from 3p24.2 to 3p25 in 96% of clear cell

RCCs

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FIGURE 10-5 Renal cell carcinoma, clear cell (conventional) type. Many large tissue fragments of tumor with scattered single cells or small groups. DiffQuik stain, low power.

FIGURE 10-6 Renal cell carcinoma, clear cell (conventional) type. A large fragment of tumor. Note the thin-walled blood vessels traversing the tumor. Diff-Quik stain, medium power.

from 3p24.2 to 3p25 is found in up to 96% of clear cell carcinomas.

CYTOPATHOLOGIC FEATURES Most FNAs yield abundant material comprised predominantly of tissue fragments of tumor (Fig. 10-5).

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Some, however, are predominantly blood and require multiple attempts to obtain adequate cellular material. Thin-walled blood vessels crossing the fragments is a characteristic feature (Fig. 10-6). Branching blood vessels surrounded by several layers of tumor cells form a papillary-like architecture (Fig. 10-7). Tumor cells have clear or finely vacuolated cytoplasm (Fig. 10-8) which contains lipids, cholesterol, and glycogen. Other cells may have acidophilic granular cytoplasm

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FIGURE 10-7 Renal cell carcinoma, clear cell (conventional) type. A large fragment of tumor with papillary-like formations. Diff-Quik stain, low power.

FIGURE 10-8 Renal cell carcinoma, clear cell (conventional) type. Tumor cells with intracytoplasmic, small, uniform vacuoles which are best seen in air-dried Romanowskystained specimens. These vacuoles contain lipids and glycogen, which could be shown by staining with Oil-Red O and PAS stains. Diff-Quik stain, high power.

(Fig. 10-9). Intracytoplasmic hyaline globules may be present; the nuclei of the tumor cells are usually round with finely granular chromatin. Nucleoli may be absent, small, or prominent, depending on the grade of the neoplasm.

ANCILLARY STUDIES Clear cell RCCs react to RCC and CD10 antibodies. They also react to antibodies to low molecular weight cytokeratins, epithelial membrane antigen (EMA), and vimentin.

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DIFFERENTIAL DIAGNOSIS AND PITFALLS Clear cell RCCs have distinct cytologic features, and the diagnosis is not difficult when the specimen is obtained by FNA of a mass in the kidney. The only challenging differential diagnosis might be for oncocytoma when the tumor contains a large number of tumor cells with granular eosinophilic cytoplasm rather than clear cells. Oncocytomas lack large nucleoli and mitoses. Unlike clear cell RCC, oncocytoma does not react to antibodies for vimentin and RCC.

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FIGURE 10-9 Renal cell carcinoma, clear cell (conventional) type. A fragment of high-grade RCC. Moderately pleomorphic nuclei with prominent nucleoli. Most of the cells have dense cytoplasm; a few have clear cell features. Papanicolaou stain, medium power.

CLEAR CELL (CONVENTIONAL-TYPE) RENAL CELL CARCINOMA – PATHOLOGIC FEATURES

PAPILLARY RENAL CELL CARCINOMA – DISEASE FACT SHEET Incidence

Cytopathologic Findings ៉ Abundant material, predominantly tissue fragments in FNAs ៉ Thin-walled blood vessels traversing tissue fragments ៉ Branching blood vessels surrounded by tumor cells form papillary-like architecture ៉ Finely vacuolated cytoplasm (lipids and glycogen) ៉ Other cells may have acidophilic granular cytoplasm ៉ Intracytoplasmic hyaline globules may be present ៉ Nuclei usually round with finely granular chromatin ៉ Nucleoli absent, small or prominent, depending on grade Ancillary Studies ៉ Reacts antibodies to RCC, CD10, low molecular weight

cytokeratins, EMA, and vimentin Differential Diagnosis and Pitfalls ៉ Could be confused with oncocytoma ៉ Oncocytomas lack large nucleoli and mitoses and do not react

to antibodies for vimentin and RCC

PAPILLARY RENAL CELL CARCINOMA

៉ 10–15% of RCCs ៉ Multiple tumors more common than in clear cell RCC

CYTOPATHOLOGIC FEATURES In type 1 papillary RCC, which comprises more than two-thirds of papillary RCCs, fine needle aspirates usually show abundant papillary structures with vascular cores (Fig. 10-10). Single or lobulated globular forms with sharp outlines may also be present (Fig. 10-11). Psammoma bodies (Fig. 10-12), lipid-laden histiocytes, and intracytoplasmic hemosiderin pigment in both histiocytes and tumor cells are characteristic features of this tumor, although they are not always present (Figs 10-13 & 10-14). Evidence of necrosis and hemorrhage, which commonly occur in the tumor, may also be seen in FNA specimens. In type 2 papillary RCC, the cells have large acidophilic cytoplasm and a higher nuclear grade (Grade 3) with prominent nuclei.

CLINICAL FEATURES ANCILLARY STUDIES Approximately 10–15% of RCCs are papillary type, and multiple tumors occur more commonly than in clear cell renal carcinoma.

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Most papillary RCCs react to RCC markers, pancytokeratins, low molecular weight cytokeratins, and CD9

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FIGURE 10-10 Renal cell carcinoma, papillary type. Papillary structure with vascular core. Diff-Quik stain, low power.

FIGURE 10-11 Renal cell carcinoma, papillary type. Lobulated, globular formations in a background of loosely attached tumor cells with ill-defined cytoplasm. One rosette-like structure with an early forming psammoma body in the center. Papanicolaou stain, medium power.

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FIGURE 10-12 Renal cell carcinoma, papillary type. Small tissue fragments and loose aggregates of tumor cells mixed with macrophages. Several psammoma bodies surrounded with tumor cells. Papanicolaou stain, medium power.

FIGURE 10-13 Renal cell carcinoma, papillary type. A tissue fragment of tumor. Tumor appears to be high grade. Hemosiderin-laden macrophages and several tumor cells next to a larger tissue fragment. Papanicolaou stain, medium power.

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FIGURE 10-14 Renal cell carcinoma, papillary type. Slightly enlarged, round or oval nuclei consistent with a low-grade (grade 2) tumor. Note the intracytoplasmic hemosiderin pigment in the tumor cells.

PAPILLARY RENAL CELL CARCINOMA – PATHOLOGIC FEATURES

and tumor cells, and psammoma bodies differentiates these tumors from other types of RCC.

Cytopathologic Findings ៉ Tumor tends to have hemorrhage, necrosis, and cystic

formations

CHROMOPHOBE RENAL CELL CARCINOMA

៉ Type 1 papillary RCC: abundant papillary structures with vascular

cores; single or lobulated globular forms; psammoma bodies, lipid-laden histiocytes, intracytoplasmic hemosiderin in histiocytes and tumor cells ៉ Type 2 papillary RCC: large acidophilic cytoplasm; higher nuclear grade, prominent nucleoli Ancillary Studies

CLINICAL FEATURES The chromophobe cell type comprises about 5% of RCCs. It occurs predominantly in middle-aged patients and in both sexes equally.

៉ React to RCC markers, pancytokeratins, low molecular weight

cytokeratins, CD9 and CD10 Differential Diagnosis and Pitfalls

CYTOPATHOLOGIC FEATURES

៉ Differentiating characteristics: papillary structures, lipid-laden

histiocytes, intracytoplasmic hemosiderin in histiocytes and tumor cells, and psammoma bodies

and CD10 (Fig. 10-15). Reaction to high molecular weight cytokeratins is rare and focal. Reactivity to vimentin is inconsistent.

In FNA specimens, chromophobe cell RCCs occur as single cells and in tight groups (Fig. 10-16). Tumor cells

CHROMOPHOBE RENAL CELL CARCINOMA – DISEASE FACT SHEET Incidence ៉ About 5% of RCCs

DIFFERENTIAL DIAGNOSIS AND PITFALLS The presence of papillary structures, lipid-laden histiocytes, intracytoplasmic hemosiderin in both histiocytes

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Gender and Age Distribution ៉ No gender predilection ៉ Predominantly middle-aged patients

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A

B

C

FIGURE 10-15 Renal cell carcinoma, papillary type. A, Strong positive reaction to RCC antibody. Cell block immunostain for RCC, medium power. B, Papillary RCC with psammoma bodies. Strong reactivity for AE1/AE3. Cell block, medium power. C, Membranous staining with CD10. Cell block, medium power.

FIGURE 10-16 Renal cell carcinoma, chromophobe cell type. Single cells and tight groups of tumor cells. Nuclei vary in size and are eccentrically located. Diff-Quik stain, low power.

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CHROMOPHOBE RENAL CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Single cells and tight groups ៉ Tumor cells vary in size with usually abundant cytoplasm ៉ Two types of cells: ៉ Classic: pale cytoplasm with distinct borders ៉ Eosinophilic: dense, granular cytoplasm ៉ Perinuclear halos rarely seen ៉ Hyperchromatic nuclei with mildly irregular borders ៉ Binucleation is common ៉ Small nucleoli may be present Ancillary Studies ៉ Reacts to antibodies to cytokeratins and EMA ៉ About half are positive for RCC marker ៉ Do not react for vimentin ៉ Diffuse cytoplasmic staining with Hale’s colloidal iron stain Differential Diagnosis and Pitfalls ៉ Most likely to be confused with oncocytoma ៉ Nuclear border irregularities and perinuclear halos are not

present in oncocytoma, binucleation is rare ៉ Hale’s colloidal iron stain is negative

vary in size with usually abundant cytoplasm, which could be pale with distinct borders or dense granular, corresponding to the ‘classic’ and ‘eosinophilic’ type cells in histologic preparations. Others have vacuolated or flocculent cytoplasm. Perinuclear halos may be seen; but, unlike in histologic preparations, they are rare and

not always clearly defined. Nuclei are hyperchromatic with mildly irregular borders and vary in size. Binucleation is common (Fig. 10-17). Occasional intranuclear pseudoinclusions may be seen (Fig. 10-18). Small nucleoli may be present.

ANCILLARY STUDIES Chromophobe cell RCCs react with antibodies to cytokeratins (i.e. 7, 14, and pancytokeratin) and EMA. Approximately half of the chromophobe cell RCCs are positive for the RCC marker. They do not react for vimentin. In cell blocks, chromophobe RCCs show diffuse cytoplasmic staining with Hale’s colloidal iron stain.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The main differential diagnosis of chromophobe cell RCC is from oncocytoma. The former shows frequent binucleation, pleomorphism (mostly variation in the size of nuclei), nuclear border irregularities, and perinuclear halos, in contrast to the round to oval uniform nuclei of oncocytomas. Binucleation is rare, and nuclear border irregularities and perinuclear halos are not present in oncocytomas. Hale’s colloidal iron stain, which is positive in chromophobe cell RCC and negative in oncocytomas, is also helpful in the differential diagnosis.

FIGURE 10-17 Renal cell carcinoma, chromophobe cell type. Tumor cells have abundant cytoplasm with well-defined borders. Note the cells with clear, pale and dense cytoplasm. Thin perinuclear clearing is noticeable in some cells. Binucleation is frequent. There is moderate anisocytosis and some nuclear border irregularity. Diff-Quik stain, medium power.

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FIGURE 10-18 Renal cell carcinoma, chromophobe cell type. Intranuclear pseudoinclusions. Occasional large nuclei with irregular borders. Tumor cells with pale and dense cytoplasm. Diff-Quik stain, high power.

COLLECTING DUCT RENAL CELL CARCINOMA CLINICAL FEATURES This type accounts for less than 1% of RCCs and occurs in a younger age group (34–43 years) with a male to female ratio of 2 : 1. It is an aggressive tumor with a poor prognosis and is located in the medulla. Cytogenetic abnormalities found in this tumor (loss of arms 6p, 8p, 13q, and 21q, and monosomies 1, 6, 14, 15, and 22) are different from those in conventional and

COLLECTING DUCT RENAL CELL CARCINOMA – DISEASE FACT SHEET Incidence ៉ Less than 1% of RCCs

papillary RCCs. Multicystic formations, due to dilated ducts, are frequent.

CYTOPATHOLOGIC FEATURES Fine needle aspirates reveal small tissue fragments and single cells with apparent malignant features (Figs 10-19 & 10-20). The former could be monolayer sheets COLLECTING DUCT RENAL CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Small tissue fragments and single cells with apparent malignant features ៉ Sheets and tubular, rarely papillary, forms ៉ Eccentrically located, enlarged pleomorphic nuclei, irregular nuclear borders, vesicular or coarse chromatin ៉ Single or multiple, prominent nucleoli ៉ Small to moderate amounts of cytoplasm ៉ Fine or larger vacuoles containing mucin may be present

Gender and Age Distribution ៉ Male to female ratio is 2 : 1 ៉ Occurs in younger age group (34–43 years of age)

Ancillary Studies ៉ Reacts to pankeratin, low and high molecular weight

cytokeratins, EMA, and peanut agglutinin Clinical Features ៉ Aggressive tumor with poor prognosis ៉ Located in the medulla ៉ Cytogenetic abnormalities are different from those in conventional and papillary RCCs ៉ Multicystic formations are frequent

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៉ RCC marker is negative

Differential Diagnosis and Pitfalls ៉ Differs from chromophobe RCC, which has low-grade nuclei ៉ Positive staining with high molecular weight cytokeratins and

intracytoplasmic mucin differentiate it from conventional RCC

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FIGURE 10-19 Renal cell carcinoma, collecting duct cell type. A tissue fragment of tumor. Many malignant features are present, including marked nuclear pleomorphism and marked variation in N/C ratio. Diff-Quik stain, medium power.

FIGURE 10-20 Renal cell carcinoma, collecting duct cell type. Markedly atypical single tumor cells. Diff-Quik stain, high power.

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FIGURE 10-21 Renal cell carcinoma, collecting duct cell type. Tumor cells with large nuclei, macronucleoli, and intracytoplasmic vacuoles. Papanicolaou stain, high power.

and tubular or, rarely, papillary forms. Desmoplastic stromal tissue fragments may be present. The tumor cells have eccentrically located, enlarged, pleomorphic nuclei with irregular borders, vesicular or coarse chromatin, single or multiple prominent nucleoli, and small or moderate amounts of cytoplasm, which may contain fine or larger vacuoles (Fig. 10-21). Mucin may be present.

ANCILLARY STUDIES The tumor cells react to pankeratin (AE1/AE3), low and high molecular weight cytokeratins, EMA, cytokeratins 7, 8, and 18, and peanut agglutinin. RCC marker is reported to be negative.

Differential diagnosis from medullary type RCC and metastatic neoplasms is difficult on cytomorphologic bases. Correlation with the clinical findings is necessary in most cases.

MEDULLARY-TYPE RENAL CELL CARCINOMA CLINICAL FEATURES This is a very aggressive, rare type of RCC which occurs in young African-American men with sickle cell disease or sickle cell trait. It is usually diagnosed in the advanced stage.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The collecting duct RCC has a distinctly different cytomorphology from those of conventional-type and chromophobe RCCs. The latter usually have low-grade nuclei, in contrast to the high-grade nuclei of collecting duct RCC. Positive staining with antibodies to high molecular weight cytokeratins, and the presence of intracytoplasmic mucin (mucicarmine and periodic acid–Shiff [PAS] with diastase digest), help to differentiate collecting duct RCC from conventional type.

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MEDULLARY-TYPE RENAL CELL CARCINOMA – DISEASE FACT SHEET Clinical Features ៉ Very aggressive, rare type of RCC ៉ Occurs in young African-American men with sickle cell disease or

sickle cell trait ៉ Usually diagnosed in advanced stage

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FIGURE 10-22 Medullary-type renal cell carcinoma. A tissue fragment. Poorly differentiated carcinoma with large nuclei, prominent nucleoli, and occasional intracytoplasmic vacuoles. H&E stain, low power. Courtesy of Srinivas R Mandavilli, MD.

CYTOPATHOLOGIC FEATURES There are limited data on the cytopathologic features of this tumor. Cytomorphology is similar to that of other high-grade carcinomas. Tumor cells appear predominantly in loosely cohesive groups. The nuclei are large and pleomorphic with prominent nucleoli. Cytoplasm may be dense or vacuolated (Fig. 10-22).

MEDULLARY-TYPE RENAL CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cytomorphology similar to other high-grade carcinomas ៉ Tumor cells appear predominantly in loosely cohesive groups ៉ Large pleomorphic nuclei with prominent nucleoli ៉ Cytoplasm may be dense or vacuolated Ancillary Studies ៉ Reacts to antibodies to cytokeratins ៉ Variable reaction for EMA and CEA ៉ Mucin is positive in the majority of the tumors Differential Diagnosis and Pitfalls ៉ Difficult to differentiate from collecting duct RCC, and other poorly differentiated primary or metastatic carcinomas; clinical correlation is necessary

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ANCILLARY STUDIES The tumor cells react to cytokeratins. Reaction to EMA and carcinoembryonic antigen (CEA) is variable. Mucin stains are positive in the majority of the tumors.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Cytopathologic features of this tumor overlap with those of collecting duct RCC and other poorly differentiated primary or metastatic carcinomas. Clinical correlation is usually necessary to establish a definitive diagnosis, since it occurs exclusively in patients with sickle cell disease or sickle cell trait.

SARCOMATOID RENAL CELL CARCINOMA CLINICAL FEATURES Sarcomatoid changes are present in 1% to 6.5% of RCCs, and many occur in large portions of the tumor. They may be found in all types of RCC and are not considered a separate type. Sarcomatoid changes indicate a poor prognosis. In spite of the sarcomatous morphology, tumor cells have the ultrastructural and histochemical features of epithelial differentiation.

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SARCOMATOID RENAL CELL CARCINOMA – DISEASE FACT SHEET Incidence ៉ Present in 1% to 6.5% of RCCs ៉ May occur in all types of RCC (not considered a separate type)

SARCOMATOID RENAL CELL CARCINOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Spindle cells with varying degrees of atypia, multinucleated giant cells, and significant pleomorphism may be present ៉ Associated with other types of RCC

Clinical Features ៉ Indicates a poor prognosis

Ancillary Studies ៉ Reaction to antibodies to cytokeratins and EMA varies ៉ RCC markers usually negative in sarcomatous cells

Differential Diagnosis and Pitfalls ៉ Rare metastatic sarcomas can be ruled out by reaction for

cytokeratins and the presence of other types of RCC

CYTOPATHOLOGIC FEATURES In fine needle aspirates, in addition to the cellular component presenting features of one of the specific types of RCC, there are spindle cells with varying degrees of atypia (Fig. 10-23). Multinucleated giant cells and significant nuclear pleomorphism may be present.

ANCILLARY STUDIES Immunohistochemical reaction with antibodies to cytokeratins and EMA varies. Both sarcomatous and epithelial components in some tumors have a positive

reaction for cytokeratins. RCC marker is usually negative in sarcomatous cells of the tumor.

DIFFERENTIAL DIAGNOSIS AND PITFALLS With adequate sampling, identification of other types of RCC and positive reaction to antibodies to cytokeratins helps to differentiate it from metastatic sarcomas.

FIGURE 10-23 Sarcomatoid renal cell carcinoma. Poorly differentiated atypical cells with sarcomatoid features. Papanicolaou stain, high power.

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ONCOCYTOMA ONCOCYTOMA – PATHOLOGIC FEATURES

CLINICAL FEATURES Oncocytomas are benign neoplasms comprising 3.5% of renal tumors in adults. The majority of these tumors occur in persons over the age of 50 years and are more common in men than in women (2.3 : 1). About twothirds of oncocytomas are incidentally detected by radiologic examinations performed for other reasons. The most common cytogenetic abnormalities are losses of chromosomes 1 and 7, deletion of chromosome 14, and rearrangements involving chromosome 11q13.

CYTOPATHOLOGIC FEATURES FNA usually provides a moderately cellular specimen with a combination of single, loose aggregates, and tissue fragments of oncocytic cells (Figs 10-24 & 1025). The cells have uniform, round nuclei with small,

Cytopathologic Findings ៉ Combination of single, loose aggregates and tissue fragments of oncocytic cells ៉ Uniform, round nuclei with small, bright red nucleoli ៉ Finely granular, acidophilic cytoplasm with well-defined borders Ancillary Studies ៉ Reacts to antibodies to EMA, low molecular weight cytokeratins, and most pancytokeratin cocktails ៉ CK7 strongly positive in scattered cells ៉ Reaction to CK20 varies ៉ Most oncocytomas are non-reactive to antibodies to vimentin ៉ RCC marker is negative Differential Diagnosis and Pitfalls Differential diagnoses include RCCs with oncocytic component With adequate sampling, other cell types can be ruled out Necrosis, mitoses, and macronucleoli rule out oncocytoma Eosinophilic-type chromophobe RCC vs oncocytoma can be difficult ៉ Chromophobe RCCs’ irregular nuclear borders with perinuclear halos contrast with the uniform nuclear borders of oncocytic cells ៉ Hale’s colloidal iron stain is negative in oncocytoma ៉ ៉ ៉ ៉

ONCOCYTOMA – DISEASE FACT SHEET Incidence, and Age and Gender Distribution ៉ Benign neoplasms comprising 3.5% of RCCs in adults over the age of 50 ៉ Male to female ratio is 2.3 : 1 ៉ About two-thirds are incidentally detected by imaging studies Genetic Abnormalities

bright red nucleoli and abundant, finely granular, acidophilic cytoplasm with well-defined borders. Mitoses and background necrosis are absent.

ANCILLARY STUDIES

៉ Cytogenetic abnormalities include loss of chromosomes 1 and 7,

deletion of 14, and rearrangement of 11q13

Oncocytomas react to EMA, low molecular weight cytokeratins, and most pancytokeratin cocktails. CK7

FIGURE 10-24 Oncocytoma. Round, uniform nuclei with prominent nucleoli and abundant cytoplasm. Diff-Quik stain, high power.

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FIGURE 10-25 Oncocytoma. These tumor cells show characteristic features of oncocytoma: single cells with large, centrally located nuclei and prominent nucleoli. Cytoplasm is granular. Papanicolaou stain, high power.

is strongly positive in scattered cells, and reaction to CK20 varies. Most oncocytomas are non-reactive to vimentin. The RCC marker is negative.

NEPHROBLASTOMA (WILMS TUMOR) – DISEASE FACT SHEET Incidence ៉ Most common genitourinary neoplasm in children ៉ Comprises ~90% of pediatric renal malignancies

DIFFERENTIAL DIAGNOSIS AND PITFALLS Gender and Age Distribution

Many RCCs have oncocytic cells; however, entirely oncocytic cell populations occur only in oncocytomas. Extensive samplings of the tumor, along with clinical and radiologic correlations, are necessary for a definitive diagnosis. The presence of necrosis, mitoses, and macronucleoli rules out a diagnosis of oncocytoma. The differential diagnosis between oncocytoma and the eosinophilic type of chromophobe RCC can be difficult. Chromophobe RCCs have irregular nuclear borders (‘raisinoid’ nuclei) with perinuclear halos, in contrast to the uniform, smooth nuclear borders of oncocytic cells of oncocytomas. Eosinophilic-type chromophobe RCC shows diffuse cytoplasmic staining with Hale’s colloidal iron, which is negative in oncocytoma. Lack of intracytoplasmic glycogen and mucin, and nonreactivity to RCC marker, can be helpful in distinguishing oncocytomas from RCCs.

៉ 98% of nephroblastomas occur in children under 10 years of age ៉ Mean age is 36 months for males and 42 months for females

Clinical Features ៉ Association with genetic syndromes involving WT1 and WT2 genes

has been shown ៉ The majority of tumors are single, but multiple synchronous

unilateral or bilateral tumors may occur

10 years of age, the mean age being 36 months for males and 42 months for females. Association with certain genetic syndromes involving WT1 and WT2 genes among others has been shown. The majority of nephroblastomas are single tumors; however, multiple synchronous unilateral or bilateral tumors may occur.

CYTOPATHOLOGIC FEATURES NEPHROBLASTOMA (WILMS TUMOR) CLINICAL FEATURES Nephroblastoma is a malignant embryonal neoplasm of childhood. It is the most common genitourinary malignant neoplasm in children, and comprises approximately 90% of pediatric renal malignancies. Ninety-eight percent of the nephroblastomas occur in children under

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Cytopathologic diagnosis of nephroblastoma requires adequate sampling of the tumor. Blastemal cells occur in sheets, groups, or single forms. Some molding is present. The cells are small with very scant, fragile cytoplasm (Fig. 10-26). Nuclei show fine, evenly distributed chromatin and inconspicuous nucleoli. Epithelial cells form glandular structures of primitive cells. Stromal cells are seen in cellular tissue fragments composed of tightly arranged spindle cells and capillaries.

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FIGURE 10-26 Wilms tumor. A fragment of undifferentiated carcinoma. Tumor cells have somewhat pleomorphic nuclei and high N/C ratio. On morphology alone, this tumor cannot be differentiated from other small cell tumors of childhood. Papanicolaou stain, high power.

NEPHROBLASTOMA (WILMS TUMOR) – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Blastemal cells occur in sheets, groups, or singly ៉ Small cells with scant, very fragile cytoplasm ៉ Fine, evenly dispersed chromatin, inconspicuous nucleoli ៉ Glandular structures of primitive epithelial cells ៉ Cellular tissue fragments of spindle cells and capillaries ៉ Admixture of blastemal epithelial and stromal cells ៉ Anaplasia characterized by hyperchromatic nuclei and multipolar mitotic figures Ancillary Studies ៉ Blastemal cells positive for vimentin, may be positive with NSE, and are positive with WT1 in early differential stages ៉ Also positive with desmin, but negative for primitive muscle markers Differential Diagnosis and Pitfalls ៉ Include other primary pediatric tumors of kidney ៉ These tumors are rare and, with a few exceptions, specific

diagnosis can only be made on tissue samples representative of the tumor

Areas of an admixture of two or all three components are present. Anaplasia can be diagnosed using the same criteria as those for histopathologic specimens. The presence of very large, hyperchromatic nuclei and multipolar mitotic figures confirms the diagnosis.

vimentin and may express neuron-specific enolase (NSE). Nuclear staining for WT1 is positive in blastemal cells and in epithelial cells in early differential stages. Blastemal cells are also positive for desmin, but they are usually negative for primitive muscle markers.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of nephroblastoma includes other primary pediatric tumors of kidney, such as rhabdoid tumor, clear cell carcinoma, congenital mesoblastic nephroma, and so-called small blue cell tumors. Blue cell tumors in childhood include neuroblastoma, primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, and lymphoma. These tumors are rare and together comprise about 15% of pediatric renal neoplasms. With a few exceptions, a specific diagnosis of these tumors can be made only by examining tissue samples representative of the tumor. In the appropriate clinical setting, the presence of three characteristic patterns of nephroblastoma with positive WT1 staining differentiates this tumor from others with similar morphology.

RHABDOID TUMOR CLINICAL FEATURES

ANCILLARY STUDIES Immunohistochemical reactions vary according to the differentiation. Blastemal cells are usually positive for

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Rhabdoid tumor is a highly malignant, rare renal neoplasm (2.5% of pediatric renal tumors), 95% of which occur in children under 3 years of age. Genetic

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RHABDOID TUMOR – DISEASE FACT SHEET

RHABDOID TUMOR – PATHOLOGIC FEATURES

Incidence and Age Distribution

Cytopathologic Findings

៉ Rare, highly malignant neoplasm ៉ Comprises ~2.5% of pediatric renal tumors ៉ 95% in children under 3 years of age

៉ Hypercellular aspirates ៉ Monotonous atypical tumor cells with abundant eosinophilic

Genetic Abnormalities ៉ Genetic abnormalities involving hSNF5/IN11 gene located at

chromosome 22q11

cytoplasm, eccentric large nuclei, centrally located prominent nucleoli ៉ Necrosis and frequent mitotic figures Ancillary Studies ៉ Immunohistochemistry: ៉ Intense reactivity for vimentin ៉ Scattered cells showing strong immunoreactivity for

abnormalities involving the hSNF5/INI1 gene located at chromosome 22q11 are present in both renal and extrarenal rhabdoid tumors of infancy.

cytokeratins and EMA in a background of non-reactive tumor cells ៉ Electron microscopy: intracytoplasmic whorls of thick intermediate filaments Differential Diagnosis and Pitfalls

CYTOPATHOLOGIC FEATURES FNA specimens are usually very cellular and composed of monotonous, atypical tumor cells with abundant eosinophilic cytoplasm and eccentric large nuclei with centrally located prominent nucleoli (Fig. 10-27). Necrosis and frequent mitotic figures are present.

៉ Neuroblastoma, nephroblastoma, congenital mesoblastic

nephroma, and clear cell sarcoma may have foci similar to rhabdoid tumor ៉ Differential diagnosis may be difficult, if not impossible, in limited samples

DIFFERENTIAL DIAGNOSIS AND PITFALLS ANCILLARY STUDIES Intense reactivity for vimentin and the presence of strong immunoreactivity for cytokeratins and EMA in a background of non-reactive tumor cells are characteristic of these tumors. Electron microscopy shows intracytoplasmic whorls of thick intermediate filaments, which are characteristic of this tumor (Fig. 10-28).

Neuroblastoma, nephroblastoma, congenital mesoblastic nephroma, and clear cell sarcoma of kidney may have foci similar to rhabdoid tumor, making the differential diagnosis difficult in limited samples. Examination of the entire tumor with ample sampling may be required to find areas characteristic of other types of tumors to differentiate them from rhabdoid.

FIGURE 10-27 Rhabdoid tumor. Large cells with eccentric nuclei and macronucleoli. High power. Courtesy of Paul E Wakely, Jr, MD.

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FIGURE 10-28 Rhabdoid tumor. Electron micrograph showing whorled intermediate filaments. They can also be found in other diseases. Courtesy of Paul E Wakely, Jr, MD.

ANGIOMYOLIPOMA CLINICAL FEATURES Angiomyolipoma is a benign mesenchymal neoplasm composed of a mixture of adipose tissue, smooth muscle cells, and thick-walled blood vessels. The tumor has a strong association with tuberous sclerosis, which is a genetic disorder caused by mutation of either the TSC1 or TSC2 gene. While about 80% of patients with tuberous sclerosis develop angiomyolipomas, less than half of patients with angiomyolipomas have tuberous sclerosis. Other hereditary disorders associated with angiomyolipoma include von Hippel–Lindau syndrome, von Recklinghausen disease, and autosomal dominant polycystic kidney disease. Angiomyolipomas comprise up to 2% of renal tumors, and the female to male ratio is 2 : 1. These tumors can be distinguished radiologically from other renal neoplasms.

CYTOPATHOLOGIC FEATURES FNA usually provides the diagnosis by allowing identification of adipose tissue and smooth muscle cells (Fig. 10-29). Thick-walled blood vessels are seen both in cell blocks and in core biopsies. Smooth muscle cells show varying degrees of nuclear atypia. In some cases, significant nuclear atypia may suggest a malignant neoplasm; but the presence of fat tissue and more differentiated elements of smooth muscle help to establish the correct diagnosis.

ANCILLARY STUDIES Muscle markers (desmin, smooth muscle actin, musclespecific actin) and vimentin are consistently positive. ANGIOMYOLIPOMA – PATHOLOGIC FEATURES

ANGIOMYOLIPOMA – DISEASE FACT SHEET Incidence ៉ Up to 2% of renal tumors

Cytopathologic Findings ៉ Varying proportion of adipose tissue and smooth muscle cells ៉ Thick-walled blood vessels seen in cell blocks and core biopsies ៉ Varying degrees of nuclear atypia in smooth muscle cells Ancillary Studies

Gender Distribution ៉ Female to male ratio is 2 : 1

៉ Muscle markers and vimentin consistently positive ៉ HMB-45 is usually expressed ៉ c-kit (CD117) is positive in all cases

Clinical Features ៉ Strong association with tuberous sclerosis ៉ About 80% of tuberous sclerosis patients develop angiomyolipoma ៉ Other hereditary disorders associated with angiomyolipoma are

von Hippel–Lindau syndrome, von Recklinghausen disease, and autosomal dominant polycystic kidney disease

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Differential Diagnosis and Pitfalls ៉ Rarely, atypical smooth muscle cells may be confused with

cancer ៉ Presence of adipose tissue and thick-walled blood vessels

confirms the diagnosis

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B A

C

D

FIGURE 10-29 Angiomyolipoma. Mixture of adipose tissue and large cells with atypical smooth muscle cells with large nuclei, one (D) with intranuclear pseudoinclusion. A, Diff-Quik stain, low power; B, Diff-Quik stain, high power; C,D, Papanicolaou stain, high power.

Melanocytic markers, specifically HMB-45, are usually expressed; and c-kit (CD117) is positive in all cases.

DIFFERENTIAL DIAGNOSIS AND PITFALLS In general, the cytopathologic findings are sufficient to establish a definitive diagnosis of this tumor. The presence of adipose tissue and characteristic blood vessels helps to differentiate it from benign and malignant smooth muscle tumors and sarcomatous RCC. Some angiomyolipomas with epithelioid features can be differentiated from melanoma with the help of immunohistochemistry, with positive staining for smooth muscle markers.

CYSTIC LESIONS OF KIDNEY – DISEASE FACT SHEET Clinical Features Common in kidney Most are benign, simple cysts FNA is indicated in multilocular complex cysts Multiloculated complex cysts are considered atypical

៉ ៉ ៉ ៉

(Figs 10-30 & 10-31). In addition to the renal neoplasms with cystic growth patterns, up to 15% of RCCs have degenerative cystic changes.

BENIGN CYSTS CYSTIC LESIONS OF KIDNEY CYTOPATHOLOGIC FEATURES Cystic lesions of kidney are common. Most are benign, simple cysts; however, multiloculated complex cysts are considered atypical, and FNA is indicated to rule out malignancy. In the aspirates of cystic fluid, exfoliated cells of benign epithelium may show significant atypia

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The predominant cell component of benign cysts is macrophages. In aspirates, they appear as single cells or loose aggregates. They have eccentric or centrally located nuclei with bland chromatin patterns and

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FIGURE 10-30 Cystic lesions. Rounded tissue fragment of atypical epithelial cells. This patient had a benign cyst with atypical epithelial lining. Papanicolaou stain, high power.

FIGURE 10-31 Cystic lesions. Two groups of atypical, but markedly degenerated cells, which may be of epithelial or histiocytic origin. Note that these are not true tissue fragments, but rather aggregates of cells with degenerative changes. Papanicolaou stain, high power.

BENIGN CYSTS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Macrophages are the predominant cell population in aspirates ៉ Appear singly or in loose aggregates ៉ Eccentric or centrally located nuclei, bland chromatin pattern ៉ Cytoplasm containing engulfed particles, usually hemosiderin ៉ Prominent nucleoli may be present ៉ Epithelial cells may represent renal tubular epithelium or cyst-lining epithelium Differential Diagnosis and Pitfalls ៉ Should be differentiated from malignant neoplasms ៉ Liesegang rings may be confused with cysts of ova of parasites

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moderate amounts of cytoplasm, which may contain engulfed particles, usually hemosiderin. Nucleoli, when present, are usually small, but prominent nucleoli may be seen. Ring-shaped structures with double walls (Liesegang rings) may be found in the cyst fluid (Fig. 10-32) Epithelial elements include fragments of renal tubular epithelium and cyst-lining epithelium.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Distinction from malignant cystic neoplasms can be difficult in FNA specimens, especially in aspirates with scant cellularity. The differential diagnosis

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B

A

FIGURE 10-32 Cystic lesions. Double-walled, round structures (Liesegang rings) in an infl ammatory background. A, Papanicolaou stain, low power; B, cell block, medium power.

will be discussed in detail under malignant cystic lesions.

MALIGNANT CYSTIC LESIONS The majority of malignant cystic lesions in kidney are cystic degeneration of various types of RCCs. Papillary RCCs usually present as a cystic lesion with a thick capsule. Multilocular cystic RCC is primarily a cystic malignant renal neoplasm considered to be a subtype of clear cell RCC.

MALIGNANT CYSTIC LESIONS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Tumor cells present singly, as small aggregates, or tissue fragments ៉ Necrotic debris and hemosiderin-laden macrophages may be present Differential Diagnosis and Pitfalls ៉ Differential diagnosis between benign cyst and RCC with cystic

degeneration can be difficult ៉ Tissue fragments with cytologic atypia, when present, are

indicative of malignancy ៉ Immunohistochemistry is of limited value in differential

diagnosis ៉ Macrophage and epithelial markers would help in differential

diagnosis of macrophages from RCC

CYTOPATHOLOGIC FEATURES Tumor cells are present singly or in small aggregates or tissue fragments. Cell morphology varies according to the tumor type and nuclear grade. In RCCs with degenerative changes, necrotic debris and hemosiderin-laden macrophages can be present.

MALIGNANT CYSTIC LESIONS – DISEASE FACT SHEET Clinical Features ៉ Majority of malignant cystic lesions are cystic degeneration of RCCs ៉ Papillary RCCs present as a cystic lesion with a thick capsule ៉ Multilocular cystic RCC is a subtype of clear cell RCC

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DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis between clear cell RCC and multilocular cystic RCC cannot be made in fine needle aspirates. The differential diagnosis between benign cysts and RCCs with cystic degeneration can also be difficult in cytologic samples. In benign cysts, macrophages and epithelial lining cells are present. Both may have vacuolated cytoplasm and prominent nucleoli. Intracytoplasmic hemosiderin pigment may occur in both macrophages and the papillary variant of RCC. Tissue fragments, when present, are a reliable feature for differentiating neoplastic cells from macrophages, which usually occur as single cells or loose aggregates. Although prominent nucleoli may be seen in macrophages and benign epithelial cells, the single

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macronucleoli, which are frequently present in RCCs, are not usually present in benign cyst-lining epithelium or in macrophages. In the absence of well-preserved tumor cells with macronucleoli or tissue fragments composed of atypical cells, the diagnosis of RCC should be made with great caution. Immunohistochemistry has limited use in the differential diagnosis. Macrophage markers (e.g. CD68 and HAM 56) and AE1/AE3 would help in the differential diagnosis of macrophages from RCC.

CYTOPATHOLOGIC FEATURES The majority of urothelial tumors of kidney pelvis are high grade. FNA specimens are usually cellular, comprised predominantly of loose aggregates, single cells, and some tissue fragments. Tumor cells have pleomorphic nuclei and a moderate to high nuclear to cytoplasmic (N/C) ratio. Tumor nuclei show uneven chromatin clumping, irregular nuclear borders, and prominent nucleoli (Fig. 10-33).

UROTHELIAL CARCINOMA OF RENAL PELVIS CLINICAL FEATURES UROTHELIAL CARCINOMA OF RENAL PELVIS – PATHOLOGIC FEATURES

Urothelial carcinomas of renal pelvis are rare. They occur in older populations (mean age, 67 years) and are more common in men. Approximately half of the patients also have lower urinary tract neoplasms.

UROTHELIAL CARCINOMA OF RENAL PELVIS – DISEASE FACT SHEET Incidence ៉ Rare Gender and Age Distribution ៉ Occurs in older population, mostly in men

Clinical Features ៉ Approximately half of patients also have lower urinary tract

neoplasms

Cytopathologic Findings ៉ Majority of these tumors are high grade ៉ Cellular specimen, predominantly loose aggregates, single cells, and some tissue fragments ៉ Moderate to high N/C ratio ៉ Uneven chromatin clumping, irregular nuclear borders, and prominent nucleoli Ancillary Studies ៉ Immunostains are positive for CK7 and CK20, thrombomodulin,

CK903, and CEA ៉ Uroplakin III is more specific, but not sensitive

Differential Diagnosis and Pitfalls ៉ Majority of RCCs have characteristic cytologic features

differentiating them from urothelial carcinoma ៉ Poorly differentiated RCCs, however, may not be differentiated

from high-grade carcinomas

FIGURE 10-33 Urothelial carcinoma of renal pelvis. Poorly differentiated carcinoma with pleomorphic nuclei. Although these cytopathologic features are unusual for RCC, the primary site cannot be determined on morphologic basis alone. Papanicolaou stain, high power.

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ANCILLARY STUDIES Tumor cells react to antibodies for CK7 and CK20, thrombomodulin, high molecular weight cytokeratin (CK903), and CEA; however, these antibodies are not specific. Uroplakin III is more specific, but not sensitive.

LYMPHOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Primary lymphomas are usually diffuse, large B-cell type ៉ FNA specimens contain uniform, round, single cells ៉ Morphology differs according to cell type ៉ In addition to cytopathologic examination, ancillary techniques are necessary to establish a diagnosis Ancillary Studies

DIFFERENTIAL DIAGNOSIS AND PITFALLS The majority of RCCs have characteristic cytologic features which differentiate them from urothelial carcinomas without difficulty. In limited samples, however, poorly differentiated, high-grade RCCs may not be differentiated from high-grade urothelial carcinomas.

LYMPHOMA Kidneys are commonly involved in the late stages of lymphomas. Primary lymphomas of kidney are rare and comprise less than 1% of primary extranodal lymphomas. Both kidneys are involved in more than 40% of the cases. FNA usually provides the diagnosis by cytopathologic examination and flow cytometry analysis.

CYTOPATHOLOGIC FEATURES Primary renal cell lymphomas are usually diffuse, large B-cell type, but other subtypes may occur. FNAs reveal a uniform, round, single cell population (Fig. 10-34). Lymphomas should be considered in any cytologic sample composed of uniform, single cells, with high N/C ratio. Cytomorphology differs according to the cell type, ranging from normal-appearing lymphocytes (e.g. MALT) to undifferentiated malignant tumor cells (e.g. anaplastic lymphomas). Ancillary techniques (i.e. flow cytometry or immunohistochemistry), in addition to cytopathologic examination, are necessary to determine the lymphoid nature and clonality of the tumor cells to establish a definitive diagnosis.

LYMPHOMA – DISEASE FACT SHEET Clinical Features ៉ Lymphomas in late stages commonly involve kidneys ៉ Primary lymphomas are rare (less than 1% of primary extranodal

lymphomas) ៉ Both kidneys are involved in more than 40% of cases

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៉ Flow cytometry from rinses of FNA samples, or

immunohistochemistry performed on cell blocks, core biopsies, or rinses is necessary for specific diagnosis Differential Diagnosis and Pitfalls ៉ In adult patients, small cell carcinoma of lung is the main tumor in differential diagnosis ៉ Presence of tissue fragments with nuclear molding differentiates small cell carcinoma from lymphoma, which has single cells ៉ Immunohistochemistry with neuroendocrine and lymphocytic markers usually establishes the diagnosis in equivocal cases ៉ In children, differential diagnoses include small blue cell tumors, which can also be differentiated using lymphocytic markers

ANCILLARY STUDIES A specific diagnosis of lymphoma requires phenotyping studies by flow cytometry from rinses of FNA samples or immunohistochemistry performed on cell blocks, core biopsies, or rinses. Detailed discussion of lymphomas is covered in Chapter 3.

DIFFERENTIAL DIAGNOSIS AND PITFALLS In adult patients, the main differential diagnosis is from metastatic small cell carcinoma of lung. The presence of tissue fragments with nuclear molding in small cell carcinoma versus single cells in lymphoma is a reliable differential diagnostic feature for both low- and high-grade lymphomas. It should be kept in mind that in air-dried, Diff-Quik-stained specimens, and in some alcohol-fi xed smears, tight cellular aggregates of lymphoma may give the impression of molding. Although the evenly dispersed, granular chromatin pattern (‘salt and pepper’) characteristic for neuroendocrine neoplasms is helpful in the differential diagnosis, it is not always present; and, depending on cell preservation, nuclei of small cell carcinomas can have irregular chromatin clumping or diffuse hyperchromasia. Immunohistochemistry with neuroendocrine and lymphocytic markers usually establishes the diagnosis in morphologically equivocal cases. Among primary small round

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FIGURE 10-34 Large B-cell lymphoma. Single round cells with prominent nucleoli.

cell tumors of kidney, immunohistochemical staining characteristics separate primitive neuroectodermal tumor (PNET) and nephroblastoma from lymphomas. PNET/Ewing sarcomas are characterized by MIC2/ CD99 expression. Immunostains show membranous staining.

CYTOPATHOLOGIC FEATURES Cytopathologic findings vary according to the tumor.

ANCILLARY STUDIES METASTATIC NEOPLASMS TO KIDNEY In late stages, malignant neoplasms from other sites may metastasize to the kidneys. Carcinomas of lung, breast, and gastrointestinal tract, malignant melanoma, as well as RCC of the contralateral kidney are among the most common metastatic neoplasms to kidney. Metastases into the RCC may also occur. In most cases, the primary tumor is clinically known.

Cytokeratins help to determine the epithelial nature of poorly differentiated malignant neoplasms. Organ- or tumor-specific antibodies, such as those for thyroglobulin, prostate-specific antigen (PSA), thyroid

METASTATIC NEOPLASMS TO KIDNEY – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Vary according to the tumor Ancillary Studies ៉ Cytokeratins help to identify the epithelial origin of poorly

differentiated neoplasms ៉ Organ- or tumor-specific antibodies, along with morphology,

METASTATIC NEOPLASMS TO KIDNEY – DISEASE FACT SHEET

determine the primary site

Clinical Features

Differential Diagnosis and Pitfalls

៉ Most common metastatic tumors are carcinomas of lung, breast,

៉ Majority of RCCs can be differentiated from metastatic tumors

and gastrointestinal tract, and malignant melanoma

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by their distinct morphology

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transcription factor-1 (TTF-1), and HepPar 1, are helpful in determining the primary site of neoplasms of unknown primary site or in the differential diagnosis of tumors with similar morphology.

left adrenal masses. The adequacy rate is 100% in most series, with a very high accuracy in diagnosis. Complications of FNA of the adrenal gland are rare. Pneumothorax, hemorrhage, abscess, and tumor implant in needle tract have been reported.

DIFFERENTIAL DIAGNOSIS AND PITFALLS ADRENAL CYSTS Differential diagnosis is usually not difficult. The majority of RCCs have distinct morphology which differentiates them from metastatic tumors. In addition to morphology, immunohistochemistry can be helpful for determining or confirming the specific type of the neoplasm. Poorly differentiated RCCs, including collecting duct type and medullary type, can be difficult to differentiate from metastatic poorly differentiated neoplasms on morphologic bases alone. In these cases, immunohistochemistry has limited value because of overlapping results. Core biopsies, as well as clinical and radiologic correlations, are helpful in establishing the diagnosis.

ADRENAL GLAND Fine needle aspirations of adrenal glands are performed on nodular lesions or diffusely enlarged glands to determine the nature of a lesion which is clinically and radiologically unclear. Nodular lesions may be symptomatic or asymptomatic and benign or malignant. The adrenal cortex secretes corticosteroids, aldosterone, cortisol, and sex steroids, and the medulla secretes catecholamines, epinephrine, and norepinephrine. Hypersecretory neoplasms or hyperplastic lesions have clinical symptoms caused by hypersecretion of one of these products. An increasing number of clinically occult neoplasms or hyperplastic nodules are incidentally detected by abdominal imaging studies (i.e. CT, MRI, or US) performed for other reasons. These lesions are called ‘incidentaloma’ in the literature. Clinically symptomatic, functional adrenal masses are usually removed without prior FNA. The majority of incidentalomas are benign, non-functioning adenomas; malignancy rates vary from 4% to 35% in published series. Larger masses (over 4 cm) have a higher incidence of malignancy, and they are usually operated on without prior FNA. Malignant neoplasms, however, have been reported in up to about 18% of nodules measuring less than 2 cm. Correlation of FNA and MRI is recommended as a cost-effective approach to the diagnosis of these tumors. In general, FNA has a high sensitivity (about 85%) and specificity (100%) in the diagnosis of mass lesions of the adrenal glands. Higher inadequacy rates (28– 33.3%) have been reported in some series of CT- or US-guided FNAs. In recent years, endoscopic ultrasound (EUS) has been used successfully for sampling

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CLINICAL FEATURES Cystic lesions of adrenal glands are rare. They are classified as pseudocysts, endothelial cysts (angiomatous and lymphangiomatous), epithelial cysts, and parasitic cysts. Pseudocysts are the most common type (56%) followed by endothelial cysts (24%). True epithelial cysts are very rare, comprising about 6% of the cystic lesions. Parasitic cysts, which are usually caused by Echinococcus, occur in areas endemic for this parasite. The majority of the cysts range between 5 and 10 cm (mean size, 9.6 cm), but very large cysts, over 20 cm, may occur (the largest reported was 50 cm). The female to male ratio is 2 : 1. The age distribution has two peaks: one at <1 month; the other in the fourth and fifth decades. Adrenal cysts may be either symptomatic or discovered incidentally (34%). Association with adrenal cortical neoplasms and pheochromocytomas has been reported. Metastatic carcinomas from various sites may form cystic lesions on rare occasions. Aspiration of the cysts is recommended for both diagnostic and therapeutic purposes. If the cyst fluid is bloody,

ADRENAL CYSTS – DISEASE FACT SHEET Incidence ៉ Cystic lesions of adrenal glands are rare ៉ Classified as pseudocysts, endothelial, epithelial, and parasitic

cysts ៉ Pseudocysts are the most common (56%), followed by endothelial

cysts (24%) ៉ True epithelial cysts are very rare (6%) ៉ Parasitic cysts, usually caused by Echinococcus, occur only in

areas where this parasite is endemic Gender and Age Distribution ៉ Male to female ratio is 2 : 1 ៉ Age distribution has two peaks: <1 month, and 4th and 5th

decades Clinical Features ៉ Majority of the cysts range between 5 and 10 cm, but cysts more

20 cm may occur ៉ About one-third are discovered incidentally ៉ FNA recommended for both diagnostic and therapeutic purposes ៉ Surgery is indicated if fluid is bloody, cystogram is irregular, or

pheochromocytoma or malignancy is suspected

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ADRENAL CYSTS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Specimen is usually hypocellular ៉ Bloody specimens may be seen in malignancy ៉ Hemosiderin- or lipid-laden macrophages may be present Differential Diagnosis and Pitfalls

MYELOLIPOMA – DISEASE FACT SHEET Incidence ៉ Rare benign neoplasm of adrenal gland Gender and Age Distribution ៉ Roughly equally distributed between males and females ៉ Average age is around 50 years

៉ Bloody fl uids should be examined carefully to rule out

malignancy ៉ Cortical adenomas can be difficult to differentiate from lipid-

laden macrophages in hypocellular specimens

Clinical Features ៉ Generally asymptomatic and incidentally found by imaging studies

or at autopsy ៉ Usually occurs unilaterally ៉ Tumor size varies greatly, ranging from <1 cm to >30 cm ៉ Because of their typical radiologic features (on CT and MRI), FNA

is rarely performed for diagnosis

cystogram is irregular, or pheochromocytoma or malignancy is suspected, surgery is indicated. radiologic features, specifically on CT and MRI, FNA is rarely performed for diagnosis.

CYTOPATHOLOGIC FEATURES Cyst fluid could be clear, turbid, or bloody. The latter may be seen in malignancy, but it also occurs in pseudocysts. The specimen is usually hypocellular. Erythrocytes, leukocytes, and hemosiderin- or lipid-laden macrophages may be present.

CYTOPATHOLOGIC FEATURES These are usually cellular specimens composed of a mixture of adipose tissue and hematopoietic cells in varying proportions (Fig. 10-35). Hematopoietic cells include myeloid, lymphoid, and erythroid elements in various stages of maturation, and megakaryocytes.

DIFFERENTIAL DIAGNOSIS AND PITFALLS In bloody cyst fluids, the specimen should be examined carefully to rule out malignancy. Benign neoplasms, such as cortical adenomas, can be difficult to differentiate from lipid-laden macrophages in hypocellular specimens.

MYELOLIPOMA CLINICAL FEATURES Myelolipoma is a rare, benign neoplasm of adrenal gland. It is generally asymptomatic and diagnosed incidentally by imaging studies or at autopsy. With the advancement of imaging techniques, an increasing number of myelolipomas are detected. The tumor is roughly equally distributed between males and females, the average age being around 50 years. Myelolipoma usually occurs unilaterally; bilateral occurrence is very rare. Tumor size varies greatly, ranging from less than 1 cm to more than 30 cm. Rare ‘giant myelolipomas’, over 4000 g (the largest, 6000 g), have been reported. These tumors may be associated with endocrine disorders. Because most of these tumors have typical

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DIFFERENTIAL DIAGNOSIS AND PITFALLS Combined with the radiologic findings, FNA diagnosis of myelolipoma is definitive. In cases with predominantly hematopoietic cells and minimal adipose tissue, extramedullary hematopiesis may be considered in the differential diagnosis. The latter usually involves multiple organs, in contrast to adrenal myelolipoma.

MYELOLIPOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cellular specimens composed of a mixture of adipose tissue and

hematopoietic cells in varying proportions ៉ Hematopoietic cells include myeloid, lymphoid, and erythroid

elements, and megakaryocytes Differential Diagnosis and Pitfalls ៉ Combined with radiological findings, FNA diagnosis of

myelolipoma is definitive ៉ Cases with predominantly hematopoietic cells may be mistaken

for extramedullary hematopoiesis; the latter usually involves multiple organs

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FIGURE 10-35 Myelolipoma. Low power: mixture of adipose tissue and myeloid and lymphoid elements. High power: megakaryocytes. Papanicolaou stain.

NODULAR CORTICAL HYPERPLASIA AND CORTICAL ADENOMA CLINICAL FEATURES Cortical nodules in adrenal glands are not uncommon. They are found incidentally in 2–9% of autopsies. With

abdominal CT scanning, 1.3–3.4% of patients may be found to have clinically occult adrenal masses more than 1 cm in size. Adrenal cortical hyperplasia and adenoma may be hyperfunctional and accompanied by clinical syndromes such as Cushing (excess cortisol secretion), Conn (hyperaldosteronism), and virilization or feminization (excess testosterone or estradiol).

CYTOPATHOLOGIC FEATURES NODULAR CORTICAL HYPERPLASIA AND CORTICAL ADENOMA – DISEASE FACT SHEET Incidence ៉ Cortical nodules in adrenal gland are not uncommon ៉ Found incidentally in 2–9% of autopsies ៉ With abdominal CT scanning, 1.3% to 3.4% of patients may be found to have occult adrenal masses larger than 1 cm Clinical Features ៉ Hyperfunctional nodules accompanied by clinical syndromes (e.g.,

Cushing’s, Conn’s, virilization of feminization)

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Cortical hyperplastic nodules and adenomas have similar cytomorphology and cannot be distinguished in FNA specimens. Functional hyperactivity also cannot be determined by morphology. FNA usually yields cellular material. The cells are arranged mostly singly, and have round, uniform nuclei and vacuolated cytoplasm which is best seen in Romanowsky-based stains (e.g. Diff-Quik). Anisonucleosis and intranuclear pseudoinclusions may be present. Because of the delicate cytoplasm, some cells are stripped of their cytoplasm, leaving bare nuclei in a ‘bubbly’ background (Fig. 10-36).

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FIGURE 10-36 Nodular cortical hyperplasia and cortical adenoma. Benign adrenal tissue. Cortical hyperplasia and cortical adenoma have the same morphology, mostly bare nuclei in a ‘bubbly’ background. Diff-Quik stain, medium power.

NODULAR CORTICAL HYPERPLASIA AND CORTICAL ADENOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Cortical hyperplastic nodules and adenomas have similar cytomorphology ៉ FNA usually yields cellular material ៉ Mostly single cells with round, uniform nuclei and vacuolated cytoplasm ៉ Anisonucleosis and intranuclear pseudoinclusions may be present ៉ Some cells, striped of their cytoplasm, appear as bare nuclei in a ‘bubbly’ background Ancillary Studies ៉ Neoplastic or non-neoplastic adrenal cortical cells react to anti-

A103 (Melan A) and anti-α-inhibin Differential Diagnosis and Pitfalls ៉ Differential diagnosis of adrenal cortical adenoma (ACA) includes adrenal cortical carcinoma (ACC), renal cell carcinoma (RCC), and, rarely, hepatocellular carcinoma ៉ Very rarely, small clusters of bare nuclei of cortical cells may mimic small cell carcinoma ៉ Differential diagnosis between ACA and well-differentiated ACC cannot be made on FNA ៉ Immunohistochemical stains in cell blocks are helpful to differentiate ACA from HCC and RCC

ANCILLARY STUDIES Diagnosis in FNA specimens is usually made on routine preparations stained by Papanicolaou and Diff-Quik stains. Immunohistochemistry can be helpful in the

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distinction from metastatic carcinomas with clear cell features. Adrenal cortical cells, neoplastic or non-neoplastic, react to anti-A103 (Melan A) and anti-α-inhibin.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The differential diagnosis of adrenal cortical adenoma (ACA) usually involves adrenal cortical carcinoma (ACC) and metastatic tumors with clear cell features, such as renal cell carcinoma (RCC) and, rarely, hepatocellular carcinoma (HCC). In rare instances, small clusters of bare nuclei of cortical cells may mimic metastatic small cell carcinoma of lung. Distinguishing between ACA and well-differentiated ACC can be very difficult without examining the entire tumor. Tumor size, invasion, and number of mitotic figures have been used as criteria for malignancy. Some cortical adenomas, however, can be very large; and invasion and mitotic count cannot be assessed in FNA specimens. Certain cytopathologic features, such as larger nuclei with scattered bizarre forms, may raise the suspicion of ACC. Immunohistochemical stains in cell blocks are helpful in the distinction from RCC and HCC. Immunostains for Melan A and inhibin are positive in ACA, but negative in RCC and HCC. Furthermore, CD10, which is positive in RCC, is negative in ACA. Characteristic canalicular-type staining with antibodies to polyclonal CEA and CD10 differentiates the HCC from ACA. Bare nuclei mimicking small cell carcinoma rarely causes a problem. The nuclei of ACA are round with small nucleoli, and they do not mold. Small cell carcinomas show molding and often irregular nuclear borders, and they lack nucleoli. The neuroendocrine

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CHAPTER 10

chromatin pattern in small cell carcinoma, if present, is helpful, but due to degenerative changes, diffuse hyperchromasia or irregular chromatin distribution may also be seen in small cell carcinoma.

ADRENOCORTICAL CARCINOMA (ACC) CLINICAL FEATURES Adrenocortical carcinoma is a rare tumor. In the literature, an incidence of 1–4 per million is cited. It occurs predominantly in the fourth and fi fth decades of life with another smaller peak in the first decade, and it is slightly more common (58.6%) in women. Approximately 60% of ACCs are functional hypercortisolism (e.g. Cushing syndrome) or Cushing syndrome with virilization. Hyperaldosteronism is very rare. The tumors are usually very large: an average weight ranging from 510 to 1200 g and an average size from 12.0 to 16.6 cm have been reported. Although the size of the tumor is considered one of the indications of malignancy, especially those larger than 6 cm, very large adenomas and small carcinomas may occur. The prognosis of ACC is poor. The mortality rate in adults is 50–90%, with the majority of deaths occurring within 2 years of diagnosis. Under 20 years of age, the worst survival rates occur in adolescents compared with children under 5 years old. Metastases usually develop within 10 years, the most common sites being liver, lungs, and intra-abdominal or intrathoracic lymph nodes.

ADRENOCORTICAL CARCINOMA (ACC) – DISEASE FACT SHEET Incidence ៉ ACC is a rare tumor (incidence of 1 to 4 per million) Gender and Age Distribution ៉ Slightly more common (58.6%) in women ៉ Occurs predominantly in the 4th and 5th decades of life, with

another smaller peak in the 1st decade Clinical Features ៉ Approximately 60% of ACCs are functional hypercortisolism or

Cushing syndrome with virilization ៉ Usually very large tumors: average weight, 510–1200 g; average

size, 12–16.6 cm ៉ Although the larger size is one of the indications of malignancy,

very large adenomas and small carcinomas may occur ៉ Prognosis is poor; mortality in adults is 50–90% ៉ Metastases usually develop within 10 years ៉ Most common sites of metastases are liver, lungs, and intra-

abdominal or intrathoracic lymph nodes

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CYTOPATHOLOGIC FEATURES Fine needle aspirates of ACC are very cellular with predominantly single cells and loose cellular groups; capillary vasculature traversing the groups has been described. Tumor cells have uniform to markedly pleomorphic nuclei with coarse chromatin, depending upon the differentiation of tumor (Figs 10-37 & 10-38). Nucleoli are usually prominent. Multinucleation and bizarre nuclear forms are common in poorly differentiated ACCs (Fig. 10-39). Cytoplasm is usually dense granular. Intranuclear pseudoinclusions may be present. Finely vacuolated (lipid-rich) cytoplasm may be present in some tumors, but is rarely observed in FNA specimens. Frequent mitotic figures, including atypical ones, and necrosis are commonly seen in poorly differentiated tumors; but they are less frequently observed in fine needle aspirates. Another feature, intracytoplasmic hyaline inclusions described in some of the ACCs, is not seen in fine needle aspirates.

ANCILLARY STUDIES ACCs react to antibodies for inhibin, Melan A, and calretinin. Immunostains for synaptophysin and CD56 are positive, but stain for chromogranin is negative.

ADRENOCORTICAL CARCINOMA (ACC) – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Very cellular specimens, predominantly single cells and loose cellular groups ៉ Uniform to markedly pleomorphic nuclei with coarse chromatin, usually prominent nucleoli; multinucleated bizarre nuclei are common in poorly differentiated ACC ៉ Intranuclear pseudoinclusions may be present ៉ Dense granular cytoplasm ៉ Frequent mitotic figures, including atypical ones Ancillary Studies ៉ ACC reacts to antibodies to inhibin, Melan A, and calretinin ៉ Immunostains for synaptophysin and CD56 are positive, but stain for chromogranin is negative Differential Diagnosis and Pitfalls ៉ Differential diagnosis between ACC and ACA cannot be made in FNA specimens alone ៉ Pheochromocytoma vs ACC morphologically can be similar ៉ Immunostains for inhibin, Melan A, calretinin, synaptophysin, chromogranin, and S-100 are helpful (see Table 10-4) ៉ Among metastatic neoplasms, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) should be considered in the differential diagnosis ៉ Immunohistochemistry again is helpful in morphologically similar cases (see Tables 10-5 and 10-6)

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FIGURE 10-37 Adrenocortical carcinoma. Large, relatively uniform nuclei. Better differentiated part of ACC. Papanicolaou stain, medium power.

FIGURE 10-38 Adrenocortical carcinoma. Pleomorphic tumor cells with multinucleated forms. Although there is significant atypia, this still could be a benign adenoma. Papanicolaou stain, medium power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS The distinction between ACC and ACA cannot be made with certainty in FNA specimens alone. Some ACAs may have significant cellular atypia, and some welldifferentiated ACCs could have the same cytomorphology as ACAs. The exact nature of some of the cortical neoplasms may not even be determined after examination of the resected tumor. The presence of metastasis and venous and/or capsular invasion is considered definitive evidence of malignancy. The number of mitoses, presence of atypical mitosis, and necrosis are stated as evidence of ACC in the literature. None of

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these features, perhaps with the exception of very poorly differentiated ACCs, can be accurately assessed in cytopathologic specimens. Among other primary adrenal neoplasms, pheochromocytoma should be considered. Nuclear pleomorphism and intranuclear inclusions may be seen in pheochromocytomas. Immunohistochemistry in cell blocks is helpful in the differential diagnosis (Table 10-4). Immunostains for inhibin, Melan A (A103), and calretinin are positive in ACC but negative in pheochromocytomas. Synaptophysin and CD56 are positive in both ACC and pheochromocytoma, but chromogranin is positive in pheochromocytoma and negative in ACC. p53 also is positive in pheochromocytoma but negative in ACC.

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FIGURE 10-39 Adrenocortical carcinoma. Bizarre nucleus in adrenocortical carcinoma. Diff-Quik stain, high power.

TABLE 10-4 Immunohistochemistry of ACN and Pheochromocytoma Inhibin A

Melan A (A103)

Calretinin

Ad4BP

Chromogranin

P53

S-100

+ −

+ −

+ −

+ −

− +

− +

− +*

ACN PHEO.

ACN, adrenocortical neoplasms; PHEO., pheochromocytoma. *Stains sustentacular cells.

TABLE 10-5 Immunohistochemistry of ACN and RCC

ACN RCC

CD10

Melan A (A103)

Inhibin A

Calretinin

Ad4BP

EMA

AE1/AE3

RCCa

− +

+ −

+ −

+ −

+ −

− +

− +

− +

ACN, adrenocortical neoplasms; RCC, renal cell carcinoma; RCCa, antibody for renal cell carcinoma.

S-100 stains sustentacular cells in pheochromocytomas, but it is negative in ACC. Among metastatic neoplasms, renal cell carcinoma, hepatocellular carcinoma, and, rarely, other carcinomas may be considered in the differential diagnosis of ACC. The cytomorphology of renal cell carcinomas (e.g. grade 3 RCCs) may resemble ACC. The latter, however, rarely have clear cell features and frequently have focal marked atypia. Immunohistochemistry is helpful in the differential diagnosis. RCC reacts to antibodies for CD10, RCC marker, AE1/AE3,

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and EMA, and does not react to Melan A (A103), inhibin, calretinin, and Ad4BP. Reactions to those antibodies are reverse in ACC (Table 10-5). Hepatocellular carcinoma may have similar cellular morphology to ACC with acidophilic, granular or finely vacuolated, lipid-rich cytoplasm and intranuclear inclusions. When present, well-defined tissue fragments of atypical hepatocytes surrounded with sinusoidal endothelial cells, are characteristic for HCC, differentiating it from ACC. Most HCCs, usually moderately

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TABLE 10-6 Immunohistochemistry of ACN and HCC

ACN HCC

Melan A (A103)

Ad4BP

Calretinin

Inhibin

CAM 5.2

HepPar-1

pCEA

CD10

+ −

+ −

+ −

+ −

− +

− +

± +*

− +*

ACN, adrenocortical neoplasms; HCC, hepatocellular carcinoma. *Staining in canalicular pattern.

differentiated ones, tend to show uniform atypicality with large round nuclei and single macronucleoli, without markedly atypical single cells or groups of cells as seen focally in ACC. Immunohistochemistry is also helpful (Table 10-6). Immunostains for Melan A, Ad4BP, calretinin, and inhibin are positive for ACC but negative for HCC. Immunostains for polyclonal CEA and CD10 stain HCCs in a canalicular pattern, and CD34 stains the sinusoidal endothelial cells surrounding tissue fragments (thick, abnormal trabeculae of the tumor).

METASTATIC NEOPLASMS CLINICAL FEATURES The majority of the malignant neoplasms of adrenal gland are metastatic tumors. The adrenal is the fourth most common site of metastases after lung, liver, and bone. About one-third of FNAs of adrenal gland are metastatic carcinomas. Lung and breast are reported to be the most common primary sites. Data published in recent years indicate that lung carcinoma is the leading type (up to 67.9%) of metastatic cancer diagnosed by FNAs, and non-small cell carcinomas, specifically adenocarcinoma, are the most common type. Other primary sites include kidney, gastrointestinal tract, pancreas, liver, and ovary. Bilateral involvement is common (30% to 49% in recently reported series). In most cases, patients have known cancers of the other sites; in rare instances, however, the metastatic tumor

is incidentally discovered by imaging studies performed on patients without any clinical evidence of cancer (incidentalomas).

CYTOPATHOLOGIC FEATURES Most of the metastatic carcinomas are adenocarcinomas with varying degree of differentiation (Fig. 10-40). Squamous cell carcinoma (Fig. 10-41), adenocarcinoma, and small cell carcinoma (Fig. 10-42) usually have the characteristic features seen in the primary site. Lymphomas secondarily involve adrenal glands (Fig. 1043). They are found in 18% to 25% of patients with disseminated lymphomas at autopsy. The specific diagnosis of most of the metastatic tumors can be made by correlating clinical and microscopic findings, in certain cases, with the help of ancillary techniques.

DIFFERENTIAL DIAGNOSIS AND PITFALLS One of the major diagnostic challenges is distinguishing metastatic clear cell carcinomas from primary adrenal cortical hyperplasia or neoplasms. Renal cell carcinomas are the most common type of clear cell

METASTATIC NEOPLASMS – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Most metastatic carcinomas are adenocarcinomas ៉ Metastatic tumors present varying cytomorphology depending

on the type of the tumor METASTATIC NEOPLASMS – DISEASE FACT SHEET Differential Diagnosis and Pitfalls Clinical Features ៉ Majority of malignant neoplasms of adrenal gland are metastatic tumors ៉ Lung and breast are the most common primary sites ៉ Bilateral involvement is common

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៉ Most of the metastatic tumors can be differentiated from

primary adrenal neoplasms without difficulty ៉ In morphologically similar cases of primary neoplasms of

adrenal glands, immunohistochemistry helps in the differential diagnosis (see Tables 10-4–10-6)

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FIGURE 10-40 Metastatic neoplasms: adenocarcinoma from lung. Fragment of tumor with large nuclei, macronucleoli, and cytoplasmic vacuoles characteristic of adenocarcinoma. Papanicolaou stain, medium power.

FIGURE 10-41 Metastatic neoplasms: squamous cell carcinoma from esophagus. Atypical keratinized squamous cells with hyperchromatic nuclei. One cell shows sharp angulation of the nucleus, which is characteristic of malignancy. Papanicolaou stain, medium power.

carcinoma. Well-differentiated RCCs (grades 1 and 2) are morphologically indistinguishable from adrenal cortical hyperplasia or cortical adenomas. Welldifferentiated ACCs have uniform cell populations with eccentric nuclei and scattered bizarre cells, with large pleomorphic, single or multiple nucleoli. Clear cell RCC has a uniform cell population with usually centrally located nuclei and finely vacuolated cytoplasm. Immunohistochemistry is helpful in differentiating adrenal cortical neoplasms from RCC (Table 10-5). Adrenal cortical neoplasms react to monoclonal antibody A103 (Melan A) and anti-α-inhibin, but do not react to CD10. Clear cell RCCs react to antibodies for CD10, EMA, and AE1/AE3, but do not react to Melan

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A, inhibin A, and Ad4BP. Metastatic hepatocellular carcinomas to adrenal gland have the typical canalicular pattern with pCEA and CD10. Metastatic adenocarcinomas are usually identifiable by their characteristic cytomorphology. Unlike adrenal cortical neoplasms, they react to antibodies for cytokeratin and EMA. In cases of unknown primary sites, CK7, CK20, and TTF-1 are helpful in suggesting the primary sites, specifically lung or gastrointestinal tract, the carcinomas of which are likely to metastasize to the adrenal gland. Melanomas may mimic adrenal cortical carcinomas and both react to Melan A. Other melanoma markers, HMB-45 and S-100, however, are negative in adrenal cortical carcinomas (Figs 10-44 & 10-45).

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FIGURE 10-42 Metastatic neoplasms: small cell carcinoma from lung. Undifferentiated malignant tumor cells with very high N/C ratio and nuclear molding. Some nuclei show a stippled chromatin pattern, which is typical of neuroendocrine differentiation. Papanicolaou stain, high power.

FIGURE 10-43 Metastatic neoplasms: large B cell lymphoma. Large, round, single cells. This was confirmed by phenotyping studies. Diff-Quik stain, medium power.

PHEOCHROMOCYTOMA CLINICAL FEATURES Pheochromocytoma is a rare tumor with an estimated incidence in the United States of 8 per 1 million personyears. Studies in other countries have shown an incidence of about 2 per million. It occurs roughly equally

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in both sexes. The peak age is at the fi fth decade, but it may occur at any age. More than 90% of the pheochromocytomas are sporadic. Between 5% and 10% of these tumors occur at extramedullary sites. About 5% of sporadic pheochromocytomas and 50% of familial pheochromocytomas are bilateral. In the pediatric age group, an increased number of cases occur bilaterally and at extramedullary sites. Approximately 5–10% of pheochromocytomas are familial. They are usually a part of one of the multiple endocrine neoplasia (MEN)

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FIGURE 10-44 Metastatic neoplasms: melanoma. This is the characteristic appearance of melanoma. Predominantly single cells, some with eccentrically located nuclei. Other cells have cytoplasmic extensions. Diff-Quik stain, medium power.

FIGURE 10-45 Metastatic neoplasms: melanoma. Positive immunostaining with HMB-45. High power.

syndromes, MEN IIA or MEN IIB. MEN IIA (Sipple syndrome) includes varying combinations of pheochromocytoma, medullary carcinoma of thyroid, and parathyroid hyperplasia. Pheochromocytomas occur in 50% of the cases with this syndrome. MEN IIB includes pheochromocytoma, medullary thyroid carcinoma, mucosal neuromas involving lips, tongue, and other mucosal surfaces, and ganglioneuromatosis of the gastrointestinal tract. More than one-third of pheochromocytomas are clinically unsuspected. In the great majority of cases, there is an increased level of vanillylmandelic acid (VMA) and catecholamines can be

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detected in urine and plasma. The majority of pheochromocytomas can be diagnosed based on combined clinical, radiologic, and biochemical studies. FNA is not performed in cases of clinically diagnosed or suspected pheochromocytomas, because of potentially serious complications. Clinically malignant pheochromocytomas are rare. The incidence of malignancy varies from 2.4% to 14% in published series. The 5-year survival rate in two series was reported as 44% and 53%. Hematogenous and lymphatic metastasis may occur. Liver, lymph nodes, and bone are the common sites for metastasis.

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PHEOCHROMOCYTOMA – DISEASE FACT SHEET Incidence ៉ Pheochromocytoma is a rare tumor ៉ Estimated incidence in the United States is 8 per 1 million

person-years Gender and Age Distribution ៉ Occurs roughly equally in both sexes ៉ Peak age is at the 5th decade, but may occur at any age

Clinical Features ៉ More than 90% are sporadic ៉ 5–10% occur at extramedullary sites ៉ About 5% of sporadic pheochromocytomas and 50% of familial ៉ ៉ ៉ ៉

pheochromocytomas are bilateral Approximately 5–10% are familial and usually a part of the multiple endocrine neoplasia syndromes (MEN IIA or MEN IIB) More than one-third of pheochromocytomas are clinically unsuspected Clinically malignant pheochromocytomas are rare; incidence of malignancy varies from 2.4% to 14% Common metastatic sites are liver, lymph nodes, and bone

PHEOCHROMOCYTOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ Hypercellular specimens with loose groups or single cells ៉ Tumor cells vary in size and shape, usually have large, illdefined cytoplasm ៉ Binucleated and multinucleated cells are present ៉ Smaller and more uniform tumor cells and rare intranuclear pseudoinclusions may be seen Ancillary Studies ៉ Immunohistochemistry: ៉ Synaptophysin, chromogranin, and NSE are positive ៉ S-100 stains the sustentacular cells ៉ Electron microscopy: numerous electron-dense neurosecretory-

type granules present Differential Diagnosis and Pitfalls ៉ Differential diagnosis includes adrenocortical carcinoma (ACC),

sarcomatoid renal cell carcinoma, and, rarely, retroperitoneal sarcomas ៉ Pheochromocytoma and ACC have some common cytomorphologic features ៉ Immunohistochemistry is helpful in the differential diagnosis (see Table 10-4)

CYTOPATHOLOGIC FEATURES FNA specimens are hypercellular with loose groups or single cells (Fig. 10-46). Tumor cells show a broad spectrum of changes ranging from large cells with multiple nucleoli to smaller, more monotonous cellular component. The cells vary in size and shape, and usually have large polygonal or ill-defined cytoplasm. Binucleated or multinucleated cells are present. Smaller and more uniform tumor cells and rare intranuclear pseudoinclusions may also be seen. Intracytoplasmic hyalin inclusions found in histologic specimens are not usually observed in FNA specimens. Spindle cell forms can be seen. Some tumor cells have a bland chromatin pattern with prominent nucleoli. Rare pigmented (lipofuscin or melanin) forms have been reported. The spectrum of the cytomorphology of pheochromocytoma can be seen in Figures 10-47 to 10-49.

cytoma and ACC have some common cytopathologic features, such as nuclear pleomorphism and intranuclear pseudoinclusions, and differential diagnosis can be difficult based on morphology alone. Immunohistochemistry is helpful in these cases (Table 10-6). Although both ACC and pheochromocytoma react to antibodies to synaptophysin, immunostain for chromogranin is positive only in pheochromocytomas. Furthermore, stains for inhibin and Melan A are positive in ACC and negative in pheochromocytes. Positive staining for neuroendocrine markers differentiates pheochromocytoma from sarcomatoid RCC and retroperitoneal sarcomas.

NEUROBLASTOMA AND GANGLIONEUROBLASTOMA

ANCILLARY STUDIES CLINICAL FEATURES Immunohistochemical stains for synaptophysin, chromogranin (Fig. 10-50), and NSE are positive. S-100 stains the sustentacular cells. With electron microscopy, numerous electron-dense, neurosecretory-type granules are seen.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Differential diagnosis includes ACC, sarcomatoid RCC, and, rarely, retroperitoneal sarcomas. Pheochromo-

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Neuroblastoma is the fourth most common malignant neoplasm of the pediatric age group, following leukemias, lymphomas, and brain tumors. The estimated incidence of neuroblastoma is 8.7 per 1 million; and for ganglioneuroblastoma, it is 6.8 per 1 million. Most neuroblastomas occur in children under the age of 5 years. Occurrence in adulthood is rare. Adrenal is the most common site for neuroblastoma, followed by abdomen and thoracic cavity. The tumor is almost always solitary. Age and stage are the most significant prognostic factors. However, some histologic grading systems

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FIGURE 10-46 Pheochromocytoma. Tumor cells occur singly or in loose groups. Scattered multinucleated cells are also present. Diff-Quik stain, low power.

FIGURE 10-47 Pheochromocytoma. Large cells with single or multiple nuclei. Cytomorphology characteristic of pheochromocytoma. Diff-Quik stain, medium power.

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FIGURE 10-48 Pheochromocytoma. Larger cells with single or double nuclei and prominent nucleoli represent ganglion cell differentiation. The fusiform nuclei in the background are probably sustentacular cells. Papanicolaou stain, high power.

FIGURE 10-49 Pheochromocytoma. Smaller cells with eccentric nuclei and scattered larger cells. There is a similarity between this cytomorphology and that of melanoma. Papanicolaou stain, medium power.

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FIGURE 10-50 Pheochromocytoma. Immunohistochemical stains of cell block – positive for chromogranin. Medium power.

NEUROBLASTOMA AND GANGLIONEUROBLASTOMA – DISEASE FACT SHEET Incidence ៉ Neuroblastoma is the fourth most common malignant neoplasm of

the pediatric age group ៉ Estimated incidence of neuroblastoma is 8.7 per 1 million, and

for ganglioneuroblastoma is 6.8 per 1 million Clinical Features ៉ Most tumors occur in children under the age of 5 years ៉ Adrenal is the most common site, followed by abdomen and

thoracic cavity ៉ Tumor is almost always solitary ៉ Age and stage are the most significant prognostic factors; some

distributed. Nucleoli are inconspicuous or absent. Occasional cells may show unipolar extension of cytoplasm (Fig. 10-51B). A fibrillar background resembling neutrophils, present in histologic preparations, can also be seen in both Diff-Quik- and Papanicolaoustained cytologic preparations. In some cases, neoplastic cells form Homer Wright rosettes surrounding round areas of fibrillary material. The fibrillary background is characteristic for neuroblastomas and helpful in the differential diagnosis. Ganglion cell differentiation is characterized by larger and denser cytoplasm and large nuclei with prominent nucleoli. Ganglioneuroblastomas are composed of predominantly neoplastic ganglion cells with large, dense cytoplasm and multiple nuclei with prominent nucleoli.

histologic grading systems linked to age have been used

ANCILLARY STUDIES linked to age have been shown to be effective in predicting the prognosis.

CYTOPATHOLOGIC FEATURES FNA specimens usually are hypercellular and composed of small cells with high N/C ratio. Tumor cells appear singly or in groups. Areas of nuclear molding may be seen. The nuclei vary slightly in size and are round, oval, or slightly irregular in shape (Fig. 10-51A). Nuclear chromatin is finely granular and evenly

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Immunostain for NSE is consistently positive (Fig. 10-52). Neuroblastomas and ganglioneuroblastomas also react to stains for neurofi lament proteins and microtubule-associated proteins (MAP1 and MAP2), and α and β tubulin.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Distinguishing neuroblastoma from other small round cell tumors of the pediatric age group – specifically,

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B

A

FIGURE 10-51 Neuroblastoma. Hypercellular specimen with predominantly single small cells and high N/C ratio. Occasional cells with unipolar cytoplasmic extensions are present. A, Diff-Quik stain, low power; B, Papanicolaou stain, high power.

NEUROBLASTOMA AND GANGLIONEUROBLASTOMA – PATHOLOGIC FEATURES Cytopathologic Findings ៉ FNA samples show small cells with high N/C ratio, appearing singly or in groups ៉ Areas of nuclear molding are present ៉ Nuclei are round, oval, or slightly irregular in shape and vary in size ៉ Nuclear chromatin is finely granular and evenly distributed ៉ Nucleoli are inconspicuous or absent ៉ Occasional cells may show unipolar cytoplasmic extensions ៉ A fibrillar background resembling neutrophils can be seen ៉ Homer Wright rosettes may be present ៉ Ganglion cell differentiation characterized by larger and denser cytoplasm and large nuclei with prominent nucleoli may be present in varying proportions ៉ Ganglioneuroblastomas are composed predominantly of neoplastic ganglion cells Ancillary Studies

FIGURE 10-52 Neuroblastoma. Immunostain of cell block – positive for NSE. High power.

៉ Immunostains for NSE consistently positive

Differential Diagnosis and Pitfalls ៉ Differential diagnoses include other small round cell tumors of

the pediatric age group ៉ Additional aspirations for flow cytometry and cell blocks, as

well as a core biopsy are usually needed ៉ In some cases, material for electron microscopy and cytogenetic

studies is also required for diagnosis ៉ NSE differentiates neuroblastoma from other tumors except for

PNET, which may react to stain for CD99, which is negative in neuroblastoma ៉ Lymphomas and rhabdomyosarcoma can be identified with lymphoma and muscle markers

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nephroblastoma, lymphomas, PNET/Ewing sarcoma, and rhabdomyosarcoma – often requires the use of ancillary techniques. Additional aspirations for flow cytometry and cell blocks, as well as a core biopsy, are usually needed. In some cases, material for electron microscopy and cytogenetic studies is also required. Positive staining for NSE differentiates neuroblastoma from others except for PNET. The latter may react to stain for CD99, which is negative in neuroblastoma. Lymphomas and rhabdomyosarcoma can be identified with lymphoma and muscle markers.

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FIGURE 10-53 Ganglioneuroma. Schwann cells. Papanicolaou stain, medium power.

GANGLIONEUROMA CLINICAL FEATURES Ganglioneuroma is a benign tumor, usually occurring in the posterior mediastinum, less frequently in adrenal glands. The age range is 6 to 20 years, and it occurs more commonly in females.

CYTOPATHOLOGIC FEATURES Mature ganglion cells and an abundant spindle cell (Schwann cells) background are seen (Figs 10-53 & 10-54). The proportion of ganglion cells varies. Some tumors have predominantly spindle cells.

DIFFERENTIAL DIAGNOSIS AND PITFALLS Because of the paucity of ganglion cells in some tumors, FNA samples contain only Schwann cells and can be misdiagnosed as neurofibroma.

GANGLIONEUROMA – DISEASE FACT SHEET GANGLIONEUROMA – PATHOLOGIC FEATURES Incidence ៉ A benign tumor, usually in the posterior mediastinum, less frequently in adrenal glands

Cytopathologic Findings ៉ Ganglion cells in an abundant Schwann cell background ៉ Proportion of ganglion cells and Schwann cells varies

Gender and Age Distribution ៉ More common in females ៉ Age range is 6 to 20 years

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Differential Diagnosis and Pitfalls ៉ Due to sampling error, may be misdiagnosed as neurofibroma

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FIGURE 10-54 Ganglioneuroma. Ganglion Diff-Quik stain, high power.

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Sarcomatous Renal Cell Carcinoma Auger M, Katz RL, Sella A, Ordonez RE, Thung SN, Szporn A. Fine needle aspiration cytology of sarcomatoid renal cell carcinoma: a morphologic and immunocytochemical study of 15 cases. Diagn Cytopathol 1993;9: 46–51. Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome. Am J Surg Pathol 2004;28:435– 441. Wadih GE, Raab SS, Silverman JF. Fine needle aspiration cytology of renal and retroperitoneal angiomyolipoma. Report of two cases with cytologic findings and clinico-pathologic pitfalls in diagnosis. Acta Cytol 1995;39:945–950. Wang J, Weiss LM, Hu B, et al. Usefulness of immunohistochemistry in delineating renal spindle cell tumours. A retrospective study of 31 cases. Histopathology 2004;44:462–471.

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Angiomyolipoma Glento JA, Partoft S. Ultrasound-guided percutaneous aspiration of renal angiomyolipoma: report of two cases diagnosed by cytology. Acta Cytol 1984;28:265–268. Kulkarni B, Desai SB, Dave B, Tongaonkar HB, Kulkarni JN, Chinoy RF. Renal angiomyolipomas: a study of 18 cases. Indian J Pathol Microbiol 2005;48:459–463. Mai KT, Yazdi HM, Perkins DG, Thijssen A. Fine needle aspiration biopsy of epithelioid angiomyolipoma. A case report. Acta Cytol 2001;45: 233–236.

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Wadih GE, Raab SS, Silverman JF. Fine needle aspiration cytology of renal and retroperitoneal angiomyolipoma. Report of two cases with cytologic findings and clinicopathologic pitfalls in diagnosis. Acta Cytol 1995;39:945–950. Cystic Lesions Horwitz CA, Manivel JC, Inampudi S, Kaye K. Diagnostic difficulties in the interpretation of needle aspiration material from large renal cysts. Diagn Cytopathol 1994;11:380–383. Katz LB, Ehya H. Liesegang rings in renal cyst fluid. Diagn Cytopathol 1990;6:197–200. Raso DS, Greene WB, Finley JL, Silverman JF. Morphology and pathogenesis of Liesegang rings in cyst aspirates: report of two cases with ancillary studies. Diagn Cytopathol 1998;19:116–119. Todd TD, Dhurandhar B, Mody D, Ramzy I, Truong LD. Fine needle aspirations of the cystic lesions of the kidney. Morphologic spectrum and diagnostic problems in 41 cases. Am J Clin Pathol 1999;111:317–328. Urothelial Carcinoma of Kidney Pelvis Olgac S, Mazumdar M, Dalbagni G, Reuter VE. Urothelial carcinoma of the renal pelvis: a clinicocytopathologic study of 130 cases. Am J Surg Pathol 2004;28:1545–1552. Lymphoma Truong LD, Caraway N, Ngo T, Laucirica R, Katz R, Ramzy I. Renal lymphoma. The diagnostic and therapeutic roles of fine-needle aspiration. Am J Clin Pathol 2001;115:18–31. Metastatic Neoplasms Gattuso P, Ramzy I, Truong LD, et al. Utilization of fine-needle aspiration in the diagnosis of metastatic tumors to kidney. Diagn Cytopathol 1999;21:35–38.

Adrenal Gland General deAugustin P, Lopez-Rios F, Alberti N, Perez-Barrios A. Fine-needle aspiration biopsy of the adrenal glands: a ten-year experience. Diagn Cytopathol 1999;21:92–97. Geisinger KR, Stanley MW, Raab SS, Silverman JF, Aboti A. Adrenal gland. In: Modern Cytopathology. New York: Churchill Livingstone, 2004: 619–624. Harisinghani MG, Maher MM, Gervais DA, et al. Incidence of malignancy in complex cystic renal masses (Bosniak category III): should imagingguided biopsy precede surgery? AJR Am J Roentgenol 2003;181: 1425–1426. Lack EE. The adrenal gland. In Silverberg SC, ed. Principles and Practice of Surgical Pathology and Cytopathology. New York: Churchill Livingston, 1997:2751–2799. Zaman MB. The adrenals. In Koss LG, ed. Koss’ Diagnostic Cytopathology and Its Histopathologic Bases, 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2005:1482–1494. Incidentalomas Kasperlik-Zeluska AA, Roslonowska E, Slowinska-Srzeclnicka J, et al. Incidentally discovered adrenal mass (incidentaloma): investigation and management of 208 patients. Clin Endocrinol (Oxf) 1997;46:29–37. Lumachi F, Borsato S, Tregnaghi A, et al. CT-scan, MRI and image-guided FNA cytology of incidental adrenal masses. EJSO 2003;29:689–692. Complications of FNA Mody MK, Kazerooni EA, Korobkin M. Percutaneous CT-guided biopsy of adrenal masses: immediate and delayed complications. J Comput Assist Tomogr 1995;19:434–439.

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346 EUS-Guided FNA Eloubeidi MA, Seewald S, Tamhane A, et al. EUS-guided FNA of the left adrenal gland in patients with thoracic or GI malignancies. Gastrointest Endosc 2004;59:627–633. Jhala NC, Jhala D, Eloubedi MA, et al. Endoscopic ultrasound-guided fineneedle aspiration biopsy of the adrenal glands: analysis of 24 patients. Cancer 2004;102:308–314. Stelow EB, Debol SM, Stanley MW, Mallery S, Lai R, Bardales RH. Sampling of the adrenal glands by endoscopic ultrasound-guided fine-needle aspiration. Diagn Cytopathol 2005;33:26–30. Varadarajulu S, Fraig M, Schmulewitz N, et al. Comparison of EUS-guided 19-gauge Trucut needle biopsy with EUS-guided fine-needle aspiration. Endoscopy 2004;36:397–401. Adrenal Cysts Akcay MN, Akcay G, Balik AA, Boyuk A. Hydatid cysts of adrenal gland: review of nine patients. World J Surg 2004;28:97–99. deBree E, Schoretsanitis G, Melissas J, Christodoulakis M, Tsiftsis D. Cysts of the adrenal gland: diagnosis and management. Int Urol Nephrol 1998;30:369–376. Ericksen LA, Lloyd RV, Harman R, Thompson G. Cystic adrenal neoplasms. Cancer 2004;101:1537–1544. Tung GA, Pfister RC, Papanicolaou N, Yoder JC. Adrenal cysts: imaging and percutaneous aspirations. Radiology 1989;173:107–110. Myelolipoma Meyer A, Behrend M. Presentation and therapy of myelolipoma. Int J Urol 2005;12:239–243. Settakorn J, Sirivanichai C, Rangdaeng S, Chaivun B. Fine-needle aspiration cytology of adrenal myelolipoma: case report and review of literature. Diagn Cytopathol 1999;21:4009–4012. Primary Neoplasms Handa U, Khullar U, Mohan H. Pigmented pheochromocytoma: report of a case with diagnosis by fine needle aspiration. Acta Cytol 2005;49: 421–423. Lumachi F, Borsato S, Brandes AA, et al. Fine-needle aspiration cytology of adrenal masses in noncancer patients: clinicoradiologic and histologic correlations in functioning and nonfunctioning tumors. Cancer 2001;93:323–329. Porcaro AB, Novella G, Ficarra V, D’Amico A, Antoniolli SZ, Curti P. Incidental adrenal pheochromocytoma. Report on 5 operated patients and update of literature. Arch Ital Urol Androl 2003;75:217–225.

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FINE NEEDLE ASPIRATION CYTOLOGY Saboorian MH, Katz RL, Charsangavec C. Fine needle aspiration cytology of primary and metastatic lesions of the adrenal gland. A series of 188 biopsies with radiologic correlation. Acta Cytol 1995;39:843–851. Sharma S, Singh R, Verma K. Cytomorphology of adrenocortical carcinoma and comparison with renal cell carcinoma. Acta Cytol 1997;41: 385–392. Suen KC, McNeely TB. Adrenal cortical cells mimicking small cell anaplastic carcinoma in a fine needle aspirate. Mod Pathol 1991;4:594–595. Wadih GE, Nance KV, Silverman JF. Fine-needle aspiration cytology of the adrenal gland. Fifty biopsies in 48 patients. Arch Pathol Lab Med 1992;116:841–846. Walther MM, Keiser HR, Linehan WM. Pheochromocytoma: evaluation, diagnosis, and treatment. World J Urol 1999;17:35–39.

Metastatic Neoplasms Candel AG, Gattuso P, Reyes CV, Prinz RA, Castelli MJ. Fine-needle aspiration biopsy of adrenal masses in patients with extraadrenal malignancies. Surgery 1993;114:1132–1136. Kocijancic K, Kocijancic I, Guna F. Role of sonographically guided fineneedle aspiration biopsy of adrenal masses in patients with lung cancer. J Clin Ultrasound 2004;32:12–16. Lack EE. Tumors metastatic to adrenal glands. In: Tumors of the Adrenal Gland and Extra-adrenal Paraganglia. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1997:199–212. Lam KY, Lo CY. Metastatic tumors of the adrenal glands: a 30-year experience in a teaching hospital. Clin Endocrinol (Oxf) 2002;56:95– 101.

Immunohistochemistry Fetsch PA, Powers CN, Zakowski MF, Abati A. Anti-alpha inhibin: marker of choice for the consistent distinction between adrenocortical carcinoma and renal cell carcinoma in fine-needle aspiration. Cancer (Cancer Cytopathol) 1999;87:168–172. Jorda M, De MB, Nadji M. Calretinin and inhibin are useful in separating adrenocortical neoplasms from pheochromocytoma. Appl Immunohistochem Mol Morphol 2002;10:67–70. Sasano H, Shizawa S, Suzuki T, et al. Transcription factor adrenal 4 binding protein as a marker of adrenocortical malignancy. Hum Pathol 1995;26:1154–1156. Shin SJ, Hoda RS, Ying L, DeLellis RA. Diagnostic utility of the monoclonal antibody A103 in fine-needle aspiration biopsies of the adrenal. Am J Clin Pathol 2000;113;295–302. Yang B, Ali SZ, Rosenthal DL. CD10 facilitates the diagnosis of metastatic renal cell carcinoma from primary adrenal cortical neoplasm in adrenal fine-needle aspiration. Diagn Cytopathol 2002;27:149–152.

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Index Abscess, breast, 127–8, 127f, 127t, 128f Acinar cell carcinoma, 274–8 ancillary studies, 277 clinical features, 274–5, 274t cytopathology, 275–7, 275f, 275t, 276f, 277f differential diagnosis and pitfalls, 277–8 radiologic features, 275 Acinic cell carcinoma, 25–7 clinical features, 25–6, 26t cytopathologic features, 26–7, 26f, 26t, 27f differential diagnosis and pitfalls, 27 Actinomycosis, 176–8 clinical features, 176–7, 176t cytopathologic features, 177f, 177t differential diagnosis and pitfalls, 177–8 radiographic features, 177 Adenocarcinoma basal cell, 4 ductal, 160–70 foamy gland, 262, 265f lung, 185–6 ancillary studies, 186 clinical features, 185t cytopathologic features, 185–6, 185t, 186f differential diagnosis, 186 radiological features, 185f polymorphous low-grade, 21–3, 21t, 22f signet-ring cell, 267f Adenocortical carcinoma, 331–4 ancillary studies, 331 clinical features, 331t cytopathologic features, 331t, 332f differential diagnosis and pitfalls, 332–4, 333f, 333t, 334t Adenoid cystic carcinoma, 19–21 clinical features, 19t cytopathologic features, 19–21, 19t, 20f, 21f Adenoma basal cell, 17–18 bile duct, 229–30, 229t, 230t cortical, 329–31 hepatocellular, 228–9, 228t, 229f Adipose tissue tumors, 93–7 lipoma, 93–4 liposarcoma, 94–7 Adrenal gland, 327–44 adenocortical carcinoma, 331–4 cysts, 327–8 ganglioneuroma, 343–4 metastatic neoplasms, 334–6 myelolipoma, 328–9 neuroblastoma, 338, 341–2 nodular cortical hyperplasia and cortical adenoma, 329–31 pheochromocytoma, 336–8 Alveolar pneumocytes, 159 Alveolar soft part sarcoma, 120–1, 120f, 120t, 121t Anaplastic carcinoma, 64–7 ancillary studies, 66 clinical features, 64–5, 65t cytopathologic features, 65–6, 65t, 66f, 67f differential diagnosis and pitfalls, 67f Angiomyolipoma, 320–1, 320t, 321f Angiosarcoma liver, 243–4 ancillary studies, 244 clinical features, 243–4, 243t differential diagnosis and pitfalls, 244 pathologic features, 244f, 244t soft tissue, 113–15, 243–4 ancillary studies, 115

clinical features, 113–14t differential diagnosis and pitfalls, 115 pathologic features, 114–15, 114f, 114t Apocrine carcinoma, 148–9, 148t, 149f Aspergillosis, 173–5 clinical features, 173–4, 173t cytopathologic features, 174–5, 174f, 175t differential diagnosis and pitfalls, 175 radiologic features, 174 Autoimmune pancreatitis, 255f, 258f Autoimmune sialadenitis, 4 Basal call adenocarcinoma, 18 Basal cell adenoma, 17–18 clinical features, 17t cytopathologic features, 17–18, 17f, 18f, 18t, 19f Benign cystic teratoma, 207, 208f Benign mixed tumor of salivary glands, 7–10 Bile duct adenoma, 229–30, 229t, 230t Blastomycosis, 167–8 clinical features, 167–8, 167t cytopathologic features, 168t, 169f differential diagnosis and pitfalls, 168 radiologic features, 168 Breast, 127–58 apocrine carcinoma, 148–9, 148t, 149f ductal carcinoma in situ, 140–2, 140t, 141f fi broadenoma, 132–4, 132t, 133f fi brocytic change, 136–40, 136t, 137f, 137t, 138f, 138t non-proliferative breast disease, 138, 138f, 139f proliferative breast disease with atypia, 139, 140f proliferative breast disease without atypia, 138–9, 139f granular cell tumor, 154f, 154t gynecomastia, 154–5, 155f, 155t infi ltrating lobular carcinoma, 149–51, 149t, 150f, 151f mastitis, abscess and fat necrosis, 127–8, 127f, 127t, 128f medullary carcinoma, 147–8, 147t, 148f, 148t metastases, 151–4, 151t, 152f, 152t, 153f mucinous carcinoma, 145–6, 145f, 145t papillary lesions, 134–6, 134t, 135f, 136f primary breast carcinoma, 142–3, 142t, 143f secretory, pregnancy and lactational changes, 130–2, 130t, 131f, 131t, 132f signet-ring cell carcinoma, 146–7, 146t, 147f treatment-induced changes, 128–30, 128t, 129f, 129t, 130f tubular carcinoma, 143–5, 144f, 144t Bronchial cells, 159, 160f Bronchioalveolar carcinoma, 186–9, 186t cytopathologic features, 187–8, 187f, 187t, 188f Burkitt lymphoma, 91f Carcinoid tumor lung, 191–3 ancillary studies, 193 clinical features, 191–2, 192t cytopathologic features, 192–3, 192f, 192t, 193f differential diagnosis and pitfalls, 193 radiologic features, 193 thymic neuroendocrine, 209–10, 211t Carcinosarcoma of salivary glands, 12f Cat-scratch disease, 76f Cavernous hemangioma see Hemangioma Cholesterol crystals, 45f Chromophobe renal cell carcinoma, 308–11 ancillary studies, 310 clinical features, 308t cytopathologic features, 209f, 308–10, 310t, 311f differential diagnosis and pitfalls, 310 Chronic lymphocytic thyroiditis see Hashimoto’s thyroiditis

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348 Chronic pancreatitis, 253–7 ancillary studies, 254, 256 clinical features, 253–4, 254t cytopathologic features, 254t, 255f, 256f differential diagnosis and pitfalls, 256–7, 257f, 258f radiologic features, 254 Ciliated hepatic foregut cyst, 225–6, 225t, 226f, 226t Clear cell renal carcinoma, 302–5 ancillary studies, 304 clinical features, 302–3, 302t cytopathologic features, 303–4, 303f, 304f, 405f differential diagnosis and pitfalls, 304 Clear cell (sugar) tumor, 180–1, 180t, 181f Coccidioidomycosis, 168–71 ancillary studies, 170 clinical features, 160t, 168–9 cytopathologic features, 170f, 170t, 171f differential diagnosis and pitfalls, 170–1 radiologic features, 169, 170f Collecting duct renal cell carcinoma, 311–13 ancillary studies, 313 clinical features, 311t cytopathologic features, 311–13, 311t, 312f, 313f differential diagnosis and pitfalls, 313 Cryptococcosis, 171–3 ancillary studies, 173 clinical features, 171–2, 171t cytopathologic features, 172–3, 172f, 173f, 173t differential diagnosis and pitfalls, 173 radiographic features, 172 Cystic lesions of kidney, 321–4, 322f, 322t, 323f, 323t Cystic papillary carcinoma, 46 Cysts adrenal gland, 327–8, 327t, 328t ciliated hepatic foregut, 225–6 lymphoepithelial, 260 retention, 4–5, 6f salivary glands, 4–5, 6f Dedifferentiated liposarcoma, 96f Dermatofi brosarcoma protuberans, 100–1 ancillary studies, 101 clinical features, 100t differential diagnosis, 101 pathologic features, 100f, 100t Ductal adenocarcinoma, 260–70 ancillary studies, 269 clinical features, 260–1, 261t cytopathologic features, 261–8, 262t, 263f, 264f, 265f, 266f, 267f, 268f differential diagnosis and pitfalls, 269–70, 269f radiologic features, 261 Ductal carcinoma in situ, 140–2, 140t, 141f Embryonal carcinoma, 208, 209f Entamoeba histolytica, 224t Epithelioid hemangioendothelioma, 242–3 ancillary studies, 243 clinical features, 242t differential diagnosis, 243 pathologic features, 243f, 243t Epithelioid sarcoma, 118–20 ancillary studies, 119 clinical features, 118–19, 118t differential diagnosis and pitfalls, 120 pathologic features, 119f, 119t Epstein-Barr virus, 77 Fat necrosis of breast, 127–8, 127f, 127t, 128f Fibroadenoma, 132–4, 132t, 133f Fibroblastic/fi brohistiocytic tumors, 97–103 dermatofi brosarcoma protuberans, 100–1 fi bromatosis, 98–100 fi brosarcoma, 101–2 malignant fi brous histiocytoma, 102–3 nodular fasciitis, 97–8

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INDEX Fibrolamellar hepatocellular carcinoma, 237–9 ancillary studies, 238 clinical features, 237, 238t differential diagnosis and pitfalls, 238 pathologic features, 238, 238f, 238t, 239f Fibromatosis, 98–100 ancillary studies, 99 clinical features, 98–9, 98t differential diagnosis pitfalls, 100 pathologic features, 99f, 99t Fibrosarcoma, 101–2 ancillary studies, 101 clinical studies, 101t differential diagnosis, 101–2 pathologic features, 101f, 101t Foamy gland adenocarcinoma, 262, 265f Focal nodular hyperplasia, 222–4 ancillary features, 223 clinical features, 222t differential diagnosis and pitfalls, 224 pathologic features, 223f, 223t Follicular lymphoma, 83, 84f Fungal infections lung, 165–76 aspergillosis, 173–5 blastomycosis, 167–8 coccidioidomycosis, 168–71 cryptococcosis, 171–3 histoplasmosis, 166–7 zygomycoses, 175–6 Ganglioneuroblastoma see Neuroblastoma Ganglioneuroma, 344f Gastrointestinal stromal tumor, 115–17 ancillary studies, 116–17 clinical features, 115t differential diagnosis and pitfalls, 117 pathologic features, 115–16, 115t, 116f Germ cell tumors mediastinum, 206–9 ancillary studies, 208–9 clinical features, 206–7, 206t cytopathologic features, 207–8, 207t, 208f, 209f differential diagnosis and pitfalls, 209 Glial fi brillary acidic protein, 13 Goitre see Nodular goitre Granular cell tumor, 106–7, 154f, 154t breast, 154f, 154t soft tissue ancillary studies, 107 clinical features, 106t differential diagnosis and pitfalls, 107 pathologic features, 106–7, 106t, 107f Granulomatous lymphadenopathy, 74–7 ancillary studies, 76f clinical features, 74–5, 75t cytopathologic features, 75–6, 75t, 76f differential diagnosis and pitfalls, 76–7 Granulomatous sialadenitis, 5f Gynecomastia, 154–5, 155f, 155t Hamartoma, 178–80 clinical features, 178t cytopathologic features, 178–80, 179f, 180t differential diagnosis and pitfalls, 180 radiologic features, 178f Hashimoto’s thyroiditis, 37–41 ancillary studies, 39 clinical features, 37–8, 38t cytopathologic features, 39f, 39t, 40f, 41f differential diagnosis and pitfalls, 39–40 Hassall’s corpuscles, 205 Hemangioma, 226–8 ancillary studies, 227 clinical features, 226–7, 226t

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349

INDEX differential diagnosis and pitfalls, 228 pathologic features, 227, 227f, 227t, 228f Hepatobiliary cystadenoma, 230–1, 230t, 231f Hepatoblastoma, 241–2, 241t, 242f, 242t Hepatocellular adenoma, 228–9, 228t, 229f Hepatocellular carcinoma, 232–7 clinical features, 232–3, 233t see also Fibrolamellar hepatocellular carcinoma Histiocytoid cells, 57 ancillary studies, 235, 236f, 237f, 237t differential diagnosis, 237 pathologic features, 233–5, 234f, 234t, 235f, 236f Histoplasmosis, 166–7 ancillary studies, 167 clinical features, 166t cytopathologic features, 166–7, 167f, 167t differential diagnosis and pitfalls, 167 radiologic features, 166 Hodgkin lymphoma, 78–81, 212f ancillary features, 79–80, 80t clinical features, 78–9t cytopathologic features, 79t, 80f, 81f differential diagnosis and pitfalls, 80–1 Hürthle cell neoplasms, 49–51 ancillary studies, 51 clinical features, 49–50, 49t cytopathologic features, 50–1, 50f, 50t, 51f differential diagnosis and pitfalls, 51 Hyaline cell myoepithelioma, 13 Hyalinizing trabecular adenoma, 59f Hydatid disease, 224–5 clinical features, 224t differential diagnosis and pitfalls, 225 pathologic features, 224–5, 225f, 225t Infectious mononucleosis, 77–8 ancillary studies, 77–8 clinical features, 77t cytopathologic features, 77t, 78f differential diagnosis and pitfalls, 78 Inflammatory myofi broblastic tumor, 231–2, 231t, 232f, 232t Insular carcinoma, 63–4 ancillary studies, 64 clinical features, 63t cytopathologic features, 63–4, 64f, 64t, 65f differential diagnosis and pitfalls, 64 Intraductal papillary mucinous neoplasm, 291–6 ancillary studies, 292 clinical features, 291t cytopathologic features, 291–2, 291t, 292f, 293f, 294f, 295f differential diagnosis and pitfalls, 292 Intrahepatic cholangiocarcinoma, 239–41 ancillary studies, 240–1 clinical features, 239t differential diagnosis and pitfalls, 241 pathologic features, 239–40, 239t, 240f Kidney, 299–327 angiomyolipoma, 320–1 cystic lesions, 321–4, 322f, 322t, 323f, 323t benign, 321–3 malignant, 323–4 lymphoma, 325–6 metastatic neoplasms, 326–7 nephroblastoma (Wilms tumor), 317–18 oncocytoma, 316–17 renal cell carcinoma, 299–315 chromophobe type, 308–11 clear cell type, 302–5 collecting duct type, 311–13 medullary type, 313–14 papillary type, 305–6 sarcomatoid type, 314–15 rhabdoid tumor, 318–20 urothelial carcinoma of renal pelvis, 324–5 Kuttner tumor, 2

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Lactation, breast changes, 130–2, 130t, 131f, 131t, 132f Large cell carcinoma, 190–1, 190t, 191f Leiomyosarcoma, 112–13 ancillary studies, 112–13 clinical features, 112t differential diagnosis and pitfalls, 113 pathologic features, 112, 112f, 113f Lipoma, 93–4 ancillary studies, 94 clinical features, 93t differential diagnosis and pitfalls, 94 pathologic features, 94f, 94t Liposarcoma, 94–7 ancillary features, 96 clinical features, 94–5, 95t dedifferentiated, 96f differential diagnosis and pitfalls, 96 myxoid, 96f pathologic factors, 95–6, 95t, 96f, 97f pleomorphic, 97f Liver, 219–50, 220f benign tumors, 226–32 bile duct adenoma, 229–30 hemangioma, 226–8 hepatobiliary cystadenoma, 230–1 hepatocellular adenoma, 228–9 inflammatory myofi broblastic tumor, 231–2 contraindications to fine needle aspiration, 221t cystic lesions, 224–6 ciliated hepatic foregut cyst, 225–6 hydatid disease, 224–5 metastatic tumors, 246–9, 246t, 247f, 247t, 248f, 248t, 249f needle contamination, 220f, 220t non-neoplastic diseases, 219–24 focal nodular hyperplasia, 222–4 macroregenerative nodule, 219–22 normal cytology, 220t parasitic cysts, 224t primary malignant epithelial tumors, 232–42 fi brolamellar hepatocellular carcinoma, 237–9 hepatoblastoma, 241–2 hepatocellular carcinoma, 232–7 intrahepatic cholangiocarcinoma, 239–41 primary malignant mesenchymal tumors, 242–6 angiosarcoma, 243–4 epithelioid hemangioendothelioma, 242–3 primary hepatic lymphoma, 244–6 Lung, 159–99 benign neoplasms, 178–81 clear cell (sugar) tumor, 180–1 hamartoma, 178–80 carcinoid tumor, 191–3 metastases, 193–8, 194f, 194t, 195f, 196f, 197f, 198f non-neoplastic conditions, 159–78 actinomycosis, 176–8 fungal infections, 165–76 sarcoidosis, 159–63 tuberculosis, 163–5 normal constituents, 159 primary malignant tumors, 181–91 adenocarcinoma, 185–6 bronchioloalveolar carcinoma, 186–9 large cell carcinoma, 190–1 pleomorphic carcinoma, 190–1 small cell carcinoma, 189–90 squamous cell carcinoma, 181–4 Lymph nodes, 71–92 granulomatous lymphadenopathy, 74–7 ancillary studies, 76f clinical features, 74–5, 75t cytopathologic features, 75–6, 75t, 76f differential diagnosis and pitfalls, 76–7 Hodgkin lymphoma, 78–81 ancillary features, 79–80, 80t clinical features, 78–9t

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350 cytopathologic features, 79t, 80f, 81f differential diagnosis and pitfalls, 80–1 infectious mononucleosis, 77–8 ancillary studies, 77–8 clinical features, 77t cytopathologic features, 77t, 78f differential diagnosis and pitfalls, 78 non-Hodgkin lymphoma large-cell, 86–9 pediatric, 89–91 small-cell, 81–6 reactive lymphoid hyperplasia, 71–4 ancillary studies, 73–4 clinical features, 71t cytopathologic features, 71–3, 71t, 72f, 73f differential diagnosis and pitfalls, 74 Lymphoepithelial cysts, 260t, 261f Lymphoepithelial sialadenitis, 4 Lymphoma follicular, 83, 84f hepatic, 244–6 ancillary studies, 246 clinical features, 244–5, 245t differential diagnosis and pitfalls, 246 pathologic features, 245–6, 245f, 245t, 246f Hodgkin see Hodgkin lymphoma kidney, 325–6, 325t, 326f mantle, 83, 84f mediastinal, 210–13 ancillary studies, 212 clinical features, 210, 211t cytopathologic features, 210–12, 212f, 212t, 213f non-Hodgkin see Non-Hodgkin lymphoma salivary glands, 30–1 clinical features, 30t cytopathologic features, 30–1, 30f, 31f, 31t differential diagnosis and pitfalls, 31 small lymphocytic, 83–4, 84f thyroid gland, 68–9, 68t, 69f Macroregenerative nodule, 219–22 ancillary studies, 222 clinical features, 219–21, 219t differential diagnosis and pitfalls, 222 pathologic features, 221–2, 221f, 221t, 222f Malignant fi brous histiocytoma, 102–3 ancillary studies, 103 clinical features, 102t differential diagnosis and pitfalls, 103 pathologic features, 102–3, 103f, 103t Malignant melanoma, 90f Malignant mixed tumor of salivary glands, 10–12, 11f Malignant peripheral nerve sheath tumors, 108–9, 108t, 109f Mantle lymphoma, 83, 84f Marginal zone lymphoma, 84–5, 85f Masood Cytology Index, 137t, 138f Mastitis, 127–8, 127f, 127t, 128f Mediastinal lymphomas, 210–13 Mediastinum, 201–18, 202t differential diagnosis, 202t germ cell tumors, 206–9 location of mediastinal lesions, 202t mediastinal lymphomas, 210–13 metastatic lesions, 215–17 neurogenic tumors, 213–15 thymic carcinomas, 205–6 thymic follicular hyperplasia, 206 thymic neuroendocrine (carcinoid) tumors, 209–10 thymoma, 203–5 Medullary carcinoma, 60–3, 147–8, 147t, 148f, 148t breast, 147–8, 147t, 148f, 148t thyroid gland ancillary studies, 61–2 clinical features, 60t cytopathologic features, 60–1, 60t, 61f, 62f, 63f differential diagnosis and pitfalls, 62–3

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INDEX Medullary renal cell carcinoma, 313–14 ancillary studies, 314 clinical features, 313t cytopathologic features, 314f, 314t differential diagnosis and pitfalls, 314 Mesothelial cells, 159 Metastases adrenal gland, 334–6, 334t, 335f, 336f, 337f breast, 151–4, 151t, 152f, 152t, 153f kidney, 326–7 liver, 246–9, 246t, 247f, 247t, 248f, 248t, 249f lung, 193–8, 194f, 194t, 195f, 196f, 197f, 198f mediastinum, 215–17 Mucinous carcinoma, 145–6, 145f, 145t Mucinous cystic neoplasm, 285–90 ancillary studies, 289 clinical features, 285t cytopathologic features, 285–9, 286f, 286t, 287f, 288f, 289f differential diagnosis, 289, 290f Mucocele, 4–5, 6f Mucoepidermoid carcinoma, 9, 23–5 clinical features, 23–4, 23t cytopathologic features, 24f, 24t, 25f differential diagnosis and pitfalls, 24–5 Mycobacterial lymphadenitis, 76f Myelolipoma, 328–9, 328t, 329f Myoepithelioma, 12–13, 13f, 14f Myxoid liposarcoma, 96f Myxoma, 117–18, 117t, 118f Nasopharyngeal carcinoma, 89f Necrotizing sialometaplasia, 4 Nephroblastoma (Wilms tumor), 317–18 ancillary studies, 318 clinical features, 317t cytopathologic features, 317–18, 318t differential diagnosis and pitfalls, 318 Neural tumors, 104–9 granular cell tumor, 106–7 malignant peripheral nerve sheath tumors, 108–9 neurofi broma and schwannoma, 104–6 Neuroblastoma, 338, 341–2 ancillary studies, 341 clinical features, 338, 341t cytopathologic features, 341, 342f, 342t differential diagnosis and pitfalls, 341–2 Neurofi broma, 104–6 ancillary studies, 106 clinical features, 104t differential diagnosis and pitfalls, 106 pathologic features, 104–6, 104t, 105f Neurogenic tumors, 213–15 clinical features, 213t cytologic features, 213–15, 214f, 215t Nodular cortical hyperplasia and cortical adenoma, 329–31 ancillary studies, 330 clinical features, 329t cytopathologic features, 329–30, 330f, 330t differential diagnosis and pitfalls, 330–1 Nodular fasciitis, 97–8 ancillary studies, 98 clinical features, 97t differential diagnosis and pitfalls, 98 pathologic features, 97–8, 97t, 98f Nodular goitre, 41–6 ancillary studies, 46 clinical features, 41t cytopathologic features, 41–2, 42f, 42t, 43f, 44f, 45f, 46f differential diagnosis and pitfalls, 46 Non-Hodgkin lymphoma, 212f, 213f large-cell, 86–9 ancillary studies, 88 clinical features, 86–7, 86t, 87t cytopathologic features, 87–8, 87t, 88f differential diagnosis, 86–7, 87f, 88f, 89f, 90f

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351

INDEX pediatric, 89–91 ancillar studies, 91 clinical features, 89–90, 90t cytopathologic features, 90–1, 91f differential diagnosis and pitfalls, 91 small-cell, 81–6 ancillary studies, 85 clinical features, 81–3, 82t cytopathologic features, 83–5, 83t, 84f, 85f, 85t differential diagnosis and pitfalls, 85–6, 86f Oncocytic carcinoma, 16 Oncocytoma, 16, 316–17 ancillary studies, 316–17 clinical features, 316t cytopathologic features, 316f, 316t, 317f differential diagnosis and pitfalls, 317 Owl’s eye appearance, 269f Pancreas, 251–98 cystic neoplasms, 279–96 intraductal papillary mucinous neoplasm, 291–6 mucinous cystic neoplasm, 285–90 serous cystadenoma, 279–82 solid-pseudopapillary neoplasm, 282–5 non-epithelial and metastatic tumors, 296 non-neoplastic mass lesions, 253–60 chronic pancreatitis, 253–7 lymphoepithelial cysts, 260 pancreatic pseudocyst, 257–60 normal, 251–3, 252f, 253f solid neoplasms, 260–79 acinar cell carcinoma, 274–8 ductal adenocarcinoma, 260–70 pancreatic endocrine neoplasm, 270–4 pancreatoblastoma, 278–9 Pancreatic endocrine neoplasm, 270–4 ancillary studies, 273 clinical features, 270t cytopathologic features, 270–3, 270f, 271f, 272f, 273f differential diagnosis and pitfalls, 273–4, 274f Pancreatic pseudocyst, 257–60 ancillary features, 258–9 clinical features, 257–8, 258t cytopathologic features, 258, 259f, 259t differential diagnosis and pitfalls, 259–60 radiologic features, 258 Pancreatoblastoma, 278–9, 278t, 279f, 280f Papillary carcinoma, 51–9 ancillary studies, 58 clinical features, 51–2, 51t cytopathologic features, 52–8, 53f, 54f, 55f, 56f, 57f, 58f differential diagnosis and pitfalls, 58–9, 59f Papillary renal cell carcinoma, 305–6 ancillary studies, 305, 308, 309f clinical features, 305t cytopatologic features, 305, 306f, 307f, 308t differential diagnosis and pitfalls, 308 Parathyroid cyst, 46 Pheochromocytoma, 336–8 ancillary studies, 338, 341f clinical features, 336–8, 338t cytopathologic features, 338t, 339f, 340f differential diagnosis and pitfalls, 338 Plasmacytoma, 274f Pleomorphic carcinoma, 190–1, 190t, 191f Pleomorphic liposarcoma, 97f Polymorphous low-grade adenocarcinoma, 21–3, 21t, 22f differential diagnosis and pitfalls, 22–3 pathologic features, 23t Pregnancy, breast changes, 130–2, 130t, 131f, 131t, 132f Reactive lymphoid hyperplasia, 71–4 ancillary studies, 73–4

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clinical features, 71t cytopathologic features, 71–3, 71t, 72f, 73f differential diagnosis and pitfalls, 74 Reed-Sternberg cells, 80f, 81f, 82f Renal cell carcinoma, 299–315, 300f chromophobe type, 308–11 classification, 299, 300t clear cell type, 302–5 clinical features, 299t collecting duct type, 311–13 cytopathologic features, 301–2, 302t medullary type, 313–14 nuclear grading, 300–1, 301f, 302f papillary type, 305–6 sarcomatoid type, 314–15 Retention cyst, 4–5, 6f Rhabdoid tumor, 318–20 ancillary studies, 319, 320f clinical features, 318–19, 319t cytopathologic features, 319f, 319t differential diagnosis and pitfalls, 319 Rhabdomyosarcoma, 109–11 ancillary studies, 111 clinical features, 109–10, 109t differential diagnosis and pitfalls, 111 pathologic features, 110–11, 110f, 110t, 111f Salivary duct carcinoma, 28–9 clinical features, 28, 28t cytopathologic features, 28–9, 28t, 29f differential diagnosis and pitfalls, 29 Salivary glands, 1–36, 2f acinic cell carcinoma, 25–7 clinical features, 25–6, 26t cytopathologic features, 26–7, 26f, 26t, 27f differential diagnosis and pitfalls, 27 adenocarcinoma, 32 basaloid neoplasms, 17–23 adenoid cystic carcinoma, 19–21 basal cell adenocarcinoma, 18 basal cell adenoma, 17–18 polymorphous low-grade adenocarcinoma, 21–3 benign mixed tumor, 7–10 clinical features, 7–8, 7t cytopathological features, 7–8, 8f, 9f differential diagnosis and pitfalls, 8–10, 10f, 11f carcinosarcoma, 12f clear cell carcinoma, 32 lymphoepithelial carcinoma, 32, 33t malignant lymphoma, 30–1 malignant mixed tumor, 10–12, 11f mucoepidermoid carcinoma, 23–5 clinical features, 23–4, 23t cytopathologic features, 24f, 24t, 25f differential diagnosis and pitfalls, 24–5 myoepithelial neoplasms, 12–13, 13f, 14f non-neoplastic cystic lesions, 4–7 cytopathologic features, 5–6, 6f differential diagnosis and pitfalls, 6–7 non-neoplastic lesions, 1–7 sialadenitis, 1–4, 2t, 3f, 4f sialadenosis, 1 oncocytic neoplasms, 13–16 oncocytoma and oncocytic carcinoma, 16 Warthin tumor, 13–16 primary small cell carcinoma, 31–2, 32f salivary duct carcinoma, 28–9 sarcoma, 32 secondary tumors, 32–4, 34f squamous cell carcinoma, 32, 33t ‘Salt and pepper’ chromatin, 211f, 270, 271f Sarcoidosis, 76f, 159–63 ancillary studies, 162 clinical features, 159–61, 160f, 160t, 161f, 161t cytopathologic features, 161–2, 162f, 162t differential diagnosis and pitfalls, 162–3

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352 lung, 159–63 radiologic features, 161 Sarcoma alveolar soft part, 120–1, 120f, 120t, 121t epithelioid, 118–20 salivary gland, 32 synovial, 121–3 Sarcomatoid renal cell carcinoma, 314–15, 315f, 315t Schistosoma mansoni, 224t Schwannoma, 104–6, 213f ancillary studies, 106 clinical features, 104t differential diagnosis and pitfalls, 106 pathologic features, 104–6, 104t, 105f Seminoma, 89f, 207 Serous cystadenoma, 279–82 ancillary studies, 281 clinical features, 279–80, 279t cytopathologic features, 280–1, 280t, 281f differential diagnosis and pitfalls, 281–2 radiologic features, 280 Sialadenitis, 1–4 clinical features, 1–2t cytopathologic features, 2–4, 2t, 3f, 4f, 5f differential diagnosis and pitfalls, 4 Sialadenosis, 1 Sialolithiasis, 2 Signet-ring cell adenocarcinoma, 267f Signet-ring cell carcinoma, 146–7, 146t, 147f Sjögren syndrome, 4 Skeletal muscle tumors, 109–11 Small cell carcinoma, 189–90, 189f, 189t, 190f Small lymphocytic lymphoma, 83–4, 84f Smooth muscle tumors, 112–13 Soft tissue, 93–126 adipose tissue tumors, 93–7 lipoma, 93–4 liposarcoma, 94–7 alveolar soft part sarcoma, 120–1 epithelioid sarcoma, 118–20 fi broblastic/fi brohistiocytic tumors, 97–103 dermatofi brosarcoma protuberans, 100–1 fi bromatosis, 98–100 fi brosarcoma, 101–2 malignant fi brous histiocytoma, 102–3 nodular fasciitis, 97–8 gastrointestinal stromal tumor, 115–17 myxoma, 117–18 neural tumors, 104–9 granular cell tumor, 106–7 malignant peripheral nerve sheath tumors, 108–9 neurofi broma and schwannoma, 104–6 skeletal muscle tumors, 109–11 smooth muscle tumors, 112–13 synovial sarcoma, 121–3 vascular tumors, 113–15 Solid-pseudopapillary neoplasm, 282–5 ancillary studies, 285 clinical features, 282t cytopathologic features, 282–4, 282t, 283f, 284f differential diagnosis and pitfalls, 285 radiologic features, 282 Squamous cell carcinoma lung, 181–4 clinical features, 181t cytopathologic features, 182–3, 182f, 182t, 183f, 183t, 184f differential diagnosis and pitfalls, 183–4 radiologic features, 182 salivary glands, 32, 33t Squamous pearls, 205 Synovial sarcoma, 121–3 ancillary studies, 122 clinical features, 121t differential diagnosis and pitfalls, 123 pathologic features, 121–2, 122f, 122t, 123f

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INDEX Thymic carcinoma, 205–6, 205f, 206f Thymic follicular hyperplasia, 206 Thymic neuroendocrine (carcinoid) tumors, 209–10 ancillary features, 210 clinical features, 209–10, 209t cytopathologic features, 210f, 210t, 211f differential diagnosis and pitfalls, 210, 211f Thymoma, 203–5 ancillary studies, 205 clinical features, 203t cytopathologic features, 203–5, 203t, 204f differential diagnosis, 205, 205f Thyroid gland, 37–70, 38f anaplastic carcinoma, 64–7 ancillary studies, 66 clinical features, 64–5, 65t cytopathologic features, 65–6, 65t, 66f, 67f differential diagnosis and pitfalls, 67f follicular neoplasms, 47–9 ancillary studies, 48–9 clinical features, 47t cytopathologic features, 47–8, 47t, 48f, 49f differential diagnosis and pitfalls, 49 Hashimoto’s thyroiditis, 37–41 ancillary studies, 39 clinical features, 37–8, 38t cytopathologic features, 39f, 39t, 40f, 41f differential diagnosis and pitfalls, 39–40 Hürthle cell neoplasms, 49–51 ancillary studies, 51 clinical features, 49–50, 49t cytopathologic features, 50–1, 50f, 50t, 51f differential diagnosis and pitfalls, 51 insular carcinoma, 63–4 ancillary studies, 64 clinical features, 63t cytopathologic features, t, 63–4, 64f, 64t, 65f differential diagnosis and pitfalls, 64 lymphoma, 68–9, 68t, 69f medullary carcinoma, 60–3 ancillary studies, 61–2 clinical features, 60t cytopathologic features, 60–1, 60t, 61f, 62f, 63f differential diagnosis and pitfalls, 62–3 nodular goitre, 41–6 ancillary studies, 46 clinical features, 41t cytopathologic features, 41–2, 42f, 42t, 43f, 44f, 45f, 46f differential diagnosis and pitfalls, 46 papillary carcinoma, 51–9 ancillary studies, 58 clinical features, 51–2, 51t cytopathologic features, 52–8, 53f, 54f, 55f, 56f, 57f, 58f differential diagnosis and pitfalls, 58–9, 59f Tuberculosis, 163–5 ancillary studies, 165 clinical features, 163t cytopathologic features, 163–5, 163t, 164f, 165f differential diagnosis and pitfalls, 165 radiologic features, 163 Tubular carcinoma, 143–5, 144f, 144t Urothelial carcinoma of renal pelvis, 324–5, 324f, 324t Vascular tumors, 113–15 Warthin tumor, 4, 13–16 clinical features, 13, 14t cytopathological features, 14–15, 15f, 16f differential diagnosis and pitfalls, 15–16 Yolk sac tumor, 207, 208f, 209f Zygomycoses, 175–6 clinical features, 175t cytopathologic features, 176f, 176t radiologic features, 175

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