Part 1 book Atlas of anatomic pathology presentation of content: Reactive, developmental, inflammatory and tumorlike conditions, thymic epithelial neoplasms, neuroendocrine neoplasms of the thymus. Invite you to consult.
Saul Suster Editor Atlas of Mediastinal Pathology 123 Atlas of Anatomic Pathology Series Editor Liang Cheng For further volumes: http://www.springer.com/series/10144 Saul Suster Atlas of Mediastinal Pathology Saul Suster, MD Department of Pathology Medical College of Wisconsin Milwaukee, Wisconsin USA Atlas of Anatomic Pathology ISBN 978-1-4939-2673-2 ISBN 978-1-4939-2674-9 DOI 10.1007/978-1-4939-2674-9 (eBook) Library of Congress Control Number: 2015941333 Springer New York Heidelberg Dordrecht London © Springer Science+Business Media, LLC 2015 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made Printed on acid-free paper Springer Science+Business Media LLC New York is part of Springer Science+Business Media (www.springer.com) This book is dedicated to my wife, Jenny Suster, my best friend and partner, for always being there for me, and to our children, David Ilan and Dana Deborah, for bringing light and meaning to our lives (B’H’) Series Preface One Picture Is Worth Ten Thousand Words – Frederick Barnard, 1927 Remarkable progress has been made in anatomic and surgical pathology during the last 10 years The ability of surgical pathologists to reach a definite diagnosis is now enhanced by immunohistochemical and molecular techniques Many new clinically important histopathologic entities and variants have been described using these techniques Established diagnostic entities are more fully defined for virtually every organ system The emergence of personalized medicine has also created a paradigm shift in surgical pathology Both promptness and precision are required of modern pathologists Newer diagnostic tests in anatomic pathology, however, cannot benefit the patient unless the pathologist recognizes the lesion and requests the necessary special studies An up-to-date Atlas encompassing the full spectrum of benign and malignant lesions, their variants, and evidence-based diagnostic criteria for each organ system is needed This Atlas is not intended as a comprehensive source of detailed clinical information concerning the entities shown Clinical and therapeutic guidelines are served admirably by a large number of excellent textbooks This Atlas, however, is intended as a “first knowledge base” in the quest for definitive and efficient diagnosis of both usual and unusual diseases The Atlas of Anatomic Pathology is presented to the reader as a quick reference guide for diagnosis and classification of benign, congenital, inflammatory, nonneoplastic, and neoplastic lesions organized by organ systems Normal and variations of “normal” histology are illustrated for each organ The Atlas focuses on visual diagnostic criteria and differential diagnosis The organization is intended to provide quick access to images and confirmatory tests for each specific organ or site The Atlas adopts the well-known and widely accepted terminology, nomenclature, classification schemes, and staging algorithms This book Series is intended chiefly for use by pathologists in training and practicing surgical pathologists in their daily practice It is also a useful resource for medical students, cytotechnologists, pathologist assistants, and other medical professionals with special interest in anatomic pathology We hope that our trainees, students, and readers at all levels of expertise will learn, understand, and gain insight into the pathophysiology of disease processes through this comprehensive resource Macroscopic and histological images are aesthetically pleasing in many ways We hope that the new Series will serve as a virtual pathology museum for the edification of our readers Indianapolis, IN, USA Liang Cheng, MD vii Preface The subject of this volume on mediastinal pathology has not enjoyed the status of a separate subspecialty in pathology owing to the fact that, other than for thymomas and other rare forms of thymic pathology, no other specific type of pathological processes are restricted to the mediastinum As such, mediastinal pathology essentially has fallen in the realm of general pathology The pathology of the mediastinum has, thus, been historically somewhat neglected The contents of this volume are the result of personal experience and observations the author accrued over a period of more than 20 years, during which circumstances and opportunities allowed me to be exposed to a wealth of material from many sources on this topic My interest in mediastinal pathology was initially sparked during my fellowship at Yale University with Dr Juan Rosai, who introduced me to the study of thymic epithelial neoplasms and generously shared with me his vast collection of consultation cases accumulated over the years My interest in this topic was rekindled when I became an attending pathologist at the Mount Sinai Hospital of Greater Miami due to the opportunity to collaborate with Dr Cesar Moran, at the time the Director of Mediastinal Pathology at the Armed Forces Institute of Pathology in Washington, D.C., who generously made available to me the inexhaustible files of mediastinal pathology stored at that institution It is inevitable that in a work like this the personal bias of its author should be introduced It is also inevitable that the terminology and the specific approach to many of the entities discussed will change with time This volume expresses my current understanding of the field with the acknowledgement that newer discoveries or observations may require that we adjust our terminology or our point of view The book is intended as a text and pictorial atlas but does not presume to be comprehensive or to explore every topic in every detail; it is simply meant to provide guidance and assistance for practicing pathologists for the diagnosis of mediastinal conditions I am indebted to my teachers, colleagues, and students who have guided, taught, challenged, and stimulated me over the years I am also in debt to the many pathologists who have shared their difficult and challenging cases of mediastinal pathology with me in consultation I would also like to thank my Developmental Editor, Lee Klein from Springer for the patience exhibited during the production of this volume on account of many delays Finally, I must make public my appreciation to my wife, Jenny Suster, who patiently put up with my absenteeism and self-absorption during the writing of this book and selflessly stimulated me to complete it Milwaukee, WI, USA Saul Suster, MD ix 3.2 Moderately Differentiated Neuroendocrine Carcinoma 73 Fig 3.55 This variation on the diffuse pattern of growth in neuroendocrine carcinoma of the thymus is characterized by sheets of monotonous tumor cells punctuated by prominent stromal vessels Fig 3.57 In this example of moderately differentiated thymic neuroendocrine carcinoma with a diffuse growth pattern, the vascular spaces are more subtle Fig 3.56 Higher magnification shows a monotonous population of small tumor cells with round nuclei and a scant rim of pink cytoplasm; these cells seem to be arranged around dilated small vessels, resembling perivascular rosettes Fig 3.58 Higher magnification from the same case as Fig 3.57 shows sheets of round to oval tumor cells with a stippled nuclear chromatin pattern and an eccentric rim of eosinophilic cytoplasm There are numerous scattered apoptotic cells and occasional mitoses 74 Neuroendocrine Neoplasms of the Thymus Fig 3.59 Higher magnification from the same case as Fig 3.57 shows a small vessel with prominent palisading of the tumor cells around the lumen, simulating a perivascular rosette Fig 3.61 Higher magnification from Fig 3.60 shows spindle cells with elongated nuclei displaying small nucleoli It may be difficult to identify these cells as neuroendocrine, particularly in the absence of an “organoid” growth pattern The use of immunohistochemical stains helps by showing positivity of the spindle cell for chromogranin and synaptophysin Fig 3.60 Another unusual variant of neuroendocrine carcinoma of the thymus is characterized by spindling of the tumor cells Fig 3.62 Well-differentiated neuroendocrine carcinoma of the thymus with a spindle-cell pattern Unlike the previous example, this one shows very well-developed, nested (“organoid”) architecture 3.2 Moderately Differentiated Neuroendocrine Carcinoma 75 Fig 3.63 This well-differentiated neuroendocrine carcinoma of the thymus shows well-defined, small nests of tumor cells (“tzellballen”) containing spindle cells alongside nests showing the more traditional round cell morphology Fig 3.65 Moderately differentiated neuroendocrine carcinoma of the thymus with spindle-cell morphology In contrast to Fig 3.64, the spindle-cell proliferation in this tumor is more dense and cellular Fig 3.64 Higher magnification of well-differentiated neuroendocrine carcinoma of the thymus with spindle-cell morphology shows nests composed of bland-appearing spindle cells without mitotic activity Fig 3.66 Higher magnification shows a striking neuroendocrine pattern of growth, with well-delimited nests of spindle tumor cells separated by fibrovascular septa 76 Neuroendocrine Neoplasms of the Thymus Fig 3.67 Higher magnification from the previous case shows streaming of cells with elongated nuclei and some stippling of the nuclear chromatin Scattered mitoses can be seen Fig 3.69 Cords and thin trabeculae of tumor cells are seen separated by vascular stroma The cords of these tumor cells are composed of cells with elongated, spindle nuclei Fig 3.68 Another example of spindle-cell thymic neuroendocrine carcinoma shows a trabecular pattern of growth instead of the nested, “tzellballen” pattern seen in Fig 3.66 Fig 3.70 Higher magnification of spindle-cell neuroendocrine carcinoma of the thymus with trabecular growth pattern shows palisading of spindled nuclei; note the stippled chromatin pattern displayed by the tumor cells 3.2 Moderately Differentiated Neuroendocrine Carcinoma Fig 3.71 In another variation on thymic neuroendocrine carcinoma with spindle cells, tumors can closely resemble medullary carcinoma of the thyroid, not because of amyloid-like stroma but because of a prominent nested pattern of growth composed of solid sheets of spindle cells Fig 3.72 Higher magnification shows solid nests of spindle cells with small nuclei and an abundant rim of eosinophilic cytoplasm Thin, compressed strands of fibrovascular tissue separate the nests This image is very similar to the spindle-cell variant of medullary carcinoma of the thyroid 77 Fig 3.73 Higher magnification of medullary thyroid carcinoma-like neuroendocrine carcinoma of the thymus shows nests of blandappearing spindle cells with small nuclei showing the characteristic stippled pattern of nuclear chromatin of neuroendocrine neoplasms Fig 3.74 Immunohistochemical staining in medullary carcinoma-like neuroendocrine carcinoma of the thymus shows cytoplasmic positivity of the tumor cells for synaptophysin Stains for calcitonin and pCEA were negative in this case 78 Fig 3.75 Another unusual variant of thymic neuroendocrine carcinoma is characterized by a monotonous population of cells with abundant eosinophilic, granular cell cytoplasm resembling an oncocytic tumor Fig 3.76 Higher magnification from the oncocytic variant of neuroendocrine carcinoma of the thymus shows a monotonous population of tumor cells surrounded by an abundant rim of granular, eosinophilic cytoplasm Neuroendocrine Neoplasms of the Thymus Fig 3.77 Another example of the oncocytic variant of thymic neuroendocrine carcinoma shows well-delineated nests of tumor cells containing a uniform population of round cells with abundant eosinophilic cytoplasm Fig 3.78 Higher magnification of the oncocytic variant of thymic neuroendocrine carcinoma shows nests of round tumor cells with abundant granular cytoplasm, but the nuclei display the stippled chromatin pattern characteristic of neuroendocrine neoplasms 3.2 Moderately Differentiated Neuroendocrine Carcinoma Fig 3.79 Higher magnification from the case in Fig 3.78 shows cells with small, round nuclei with stippled chromatin surrounded by an ample rim of granular, eosinophilic cytoplasm Fig 3.80 Prominent cytoplasmic clearing of the tumor cells is a rare phenomenon that occasionally can be seen in neuroendocrine carcinoma of the thymus The tumors retain their low-power organoid architecture but show small, round nuclei surrounded by empty, water-clear cytoplasm 79 Fig 3.81 Higher magnification of neuroendocrine carcinoma of the thymus with clear cell features shows small nests of tumor cells with small, round nuclei displaying fine stippling of the nuclear chromatin and surrounded by abundant clear cytoplasm The tumors can superficially resemble metastatic clear cell renal cell carcinomas but are positive for neuroendocrine markers Fig 3.82 A cribriform pattern of growth can be sometimes seen in moderately differentiated neuroendocrine carcinomas of the thymus This pattern is caused by numerous luminal spaces dotting the nests of tumor cells 80 Neuroendocrine Neoplasms of the Thymus Fig 3.83 In another example of the cribriform growth pattern in moderately differentiated neuroendocrine carcinoma of the thymus, this island of tumor cells shows multiple irregular fenestrations, giving the appearance of fused glands Fig 3.85 Higher magnification shows cuffing of tumor cells around empty luminal spaces resembling rosettes Notice that the tumor cells retain the stippled nuclear chromatin pattern Fig 3.84 A microacinar pattern of growth is displayed in this example of neuroendocrine carcinoma of the thymus Multiple small, luminal spaces resembling microacinar structures are scattered throughout Fig 3.86 An immunohistochemical stain for chromogranin is positive in many of the tumor cells, supporting the neuroendocrine nature of the tumor cell population surrounding the microacinar structures 3.2 Moderately Differentiated Neuroendocrine Carcinoma 81 Fig 3.87 Another example of thymic neuroendocrine carcinoma with focal rosette-like arrangement of the tumor cells (arrows) Fig 3.89 Moderately differentiated neuroendocrine carcinomas can exhibit aggressive behavior and are usually infiltrative at the time of initial diagnosis, with invasion of surrounding structures and prominent lymphovascular invasion Irregular infiltration of the surrounding soft tissue is commonly seen in moderately differentiated cases Fig 3.88 Higher magnification from the same case as Fig 3.87 shows small, rosette-like structures with palisading of tumor cells around a central space Notice that the tumor cells are spindled and contain elongated nuclei Fig 3.90 Higher magnification from Fig 3.89 shows perineurial invasion by moderately differentiated neuroendocrine carcinoma of the thymus 82 3.3 Neuroendocrine Neoplasms of the Thymus Poorly Differentiated Neuroendocrine Carcinoma Fig 3.91 Spread to regional and distant lymph nodes is a common finding in primary neuroendocrine carcinoma of the thymus, even for cases with well-differentiated histology Fig 3.93 Poorly differentiated neuroendocrine carcinoma of the large cell type is a rare neoplasm characterized grossly by a lobulated cut surface with focal areas of necrosis and invasion Fig 3.92 Higher magnification of mediastinal lymph node metastasis from neuroendocrine carcinoma of the thymus shows almost complete effacement of the architecture by nests of monotonous tumor cells with a compressed rim of residual lymph node at the periphery Fig 3.94 Poorly differentiated neuroendocrine thymic carcinoma of the large cell type (large cell neuroendocrine carcinoma) is characterized by a vaguely neuroendocrine growth pattern composed of islands of tumor cells with peripheral palisading of nuclei 3.3 Poorly Differentiated Neuroendocrine Carcinoma 83 Fig 3.95 The cells in large cell neuroendocrine carcinoma show enlarged nuclei with abundant cytoplasm Foci of necrosis can be seen (arrow) Fig 3.97 Small cell neuroendocrine carcinoma of the thymus is a poorly differentiated type of primary thymic neuroendocrine carcinoma that is histologically indistinguishable from small cell neuroendocrine carcinomas from other organs For lesions in the mediastinum, particular care must be taken not to make a diagnosis of primary small cell carcinoma of the thymus until a primary origin in the lung has been properly ruled out by clinical and radiographic means The tumor is composed of sheets of relatively small, round blue cells Fig 3.96 On higher magnification, the tumor cells in large cell neuroendocrine carcinoma of the thymus contain enlarged nuclei with prominent nucleoli and numerous mitoses The diagnosis is established by the demonstration of a positive reaction for neuroendocrine markers Fig 3.98 Small cell neuroendocrine carcinoma of the thymus is characterized by a sheetlike growth pattern The neuroendocrine organization seen in better-differentiated tumors is lost, and extensive irregular areas of necrosis are seen 84 3.4 Neuroendocrine Neoplasms of the Thymus Mediastinal Paraganglioma Fig 3.99 A common feature of small cell neuroendocrine carcinoma of the thymus is extensive infiltration of surrounding structures and soft tissue The permeative pattern of infiltration of the mediastinal fat, with preservation of adipocytes, is very similar to that observed in mediastinal lymphomas Immunohistochemical stains are quite helpful for differential diagnosis, demonstrating negative staining for lymphoid markers and showing a positive reaction for cytokeratin and neuroendocrine markers Fig 3.101 Paragangliomas may arise from displaced paraganglia in the mediastinum The tumors are distinguished grossly from neuroendocrine carcinomas by their good circumscription and encapsulation Fig 3.100 In rare instances, transitions between well-differentiated or moderately differentiated neuroendocrine carcinoma with a welldeveloped organoid pattern and poorly differentiated, small cell neuroendocrine carcinoma can be observed in the same tumor In this image, well-differentiated neuroendocrine carcinoma (left) merges with a poorly differentiated small cell component (right) Fig 3.102 Cut section of a paraganglioma shows a well-circumscribed and encapsulated tumor with a homogeneous tan color and soft cut surface with foci of stromal hemorrhage 3.4 Mediastinal Paraganglioma 85 Fig 3.103 The histologic hallmark of mediastinal paraganglioma is a nested (“tzellballen”) pattern of growth Unlike neuroendocrine carcinomas of the thymus, paragangliomas not show trabecular, diffuse, microacinar, or ribbon-like patterns of growth Fig 3.105 The cells in mediastinal paragangliomas are most often characterized by abundant eosinophilic cytoplasm, but in some instances, they can be composed predominantly of cells with abundant clear cytoplasm Fig 3.104 One of the distinguishing features of paraganglioma is the presence of endocrine atypia, characterized by scattered large, atypical cells with nucleomegaly in the absence of mitotic activity Fig 3.106 Rare cases of mediastinal paraganglioma can also show prominent spindling of the tumor cells, which is most often a focal phenomenon The diagnosis can be made by identifying the more conventional components of the lesion 86 Fig 3.107 Mediastinal paragangliomas sometimes can undergo regressive changes of the stroma, including stromal sclerosis and angiectatic vessels These changes can sometimes be so extensive that they obscure the lesion, and ample sampling to identify the more conventional tumor component is required for the correct diagnosis Fig 3.108 An unusual variant of mediastinal paraganglioma is characterized by extensive stromal sclerosis that sometimes can obscure the underlying tumor Neuroendocrine Neoplasms of the Thymus Fig 3.109 Most mediastinal paragangliomas are characterized by strong expression of neuroendocrine markers This image shows cytoplasmic positivity for chromogranin in a mediastinal paraganglioma Unlike primary neuroendocrine carcinomas of the thymus, however, these tumors are negative for cytokeratin Suggested Reading Suggested Reading Cardillo G, Rea F, Lucci M, Paul MA, Margoritora S, Carleo F, et al Primary neuroendocrine tumors of the thymus: a multicenter experience of 35 patients Ann Thorac Surg 2012;94:241–5 Chetty R, Batitang S, Govender D Large cell neuroendocrine carcinoma of the thymus Histopathology 1997;11:274–6 Crona J, Bjorklund P, Welin S, Kozlovacki G, Oberg K, Granberg D Treatment, prognostic markers and survival in thymic neuroendocrine tumors A study from a single tertiary referral centre Lung Cancer 2013;79:289–93 Economopoulus GC, Lewis Jr JW, Lee MW, Silverman NA Carcinoid tumors of the thymus Ann Thorac Surg 1990;50:58–61 Floros D, Dosios T, Tsourdis A, Yiatromanolakis N Carcinoid tumor of the thymus with multiple endocrine adenomatosis Pathol Res Pract 1982;175:404–9 Gal AA, Kornstein MJ, Cohen C, Duarte IG, Miller JI, Mansour KA Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study Ann Thorac Surg 2001;72:1179–82 Klemm KM, Moran CA, Suster S Pigmented thymic carcinoids A clinicopathological and immunohistochemical study of cases Mod Pathol 1999;12:946–8 Montpreville VT, Machiarini P, Dulmet E Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of 14 cases J Thorac Cardiovasc Surg 1996;111:134–41 Moran CA, Suster S Angiomatous neuroendocrine carcinoma of the thymus: report of a distinctive morphological variant of neuroendocrine tumor of the thymus resembling a vascular neoplasm Hum Pathol 1999a;30:635–9 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 1999b;12:587–91 Moran CA, Suster S Neuroendocrine carcinoma (carcinoid) of the thymus: A clinicopathologic analysis of 80 cases Am J Clin Pathol 2000a;114:100–10 Moran CA, Suster S Primary neuroendocrine carcinoma (carcinoid) of the thymus with prominent oncocytic features: clinicopathologic study of 22 cases Mod Pathol 2000b;13:489–94 87 Moran CA, Suster S Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma: a clinicopathologic and immunohistochemical study of 11 cases Am J Clin Pathol 2000c;113:345–50 Moran CA, Suster S Cystic well-differentiated neuroendocrine carcinoma (carcinoid tumor) A clinicopathologic and immunohistochemical study of two cases Am J Clin Pathol 2006a;126:377–80 Moran CA, Suster S Spectrum of pathologic features in neuroendocrine neoplasms of the mediastinum Pathol Case Rev 2006b;11:199–205 Moran CA, Suster S, Fishback N, Koss MN Mediastinal paragangliomas: a clinicopathologic and immunohistochemical study of 16 cases Cancer 1993;72:2358–64 Olson JL, Salyer WR Mediastinal paragangliomas (aortic body tumor): A report of four cases and a review of the literature Cancer 1978;41:2405–12 Rosai J, Levine G, Weber WR, Higa E Carcinoid tumors and oat cell carcinomas of the thymus Pathol Annu 1977;2:33–62 Saito T, Kimoto M, Nakai S, Ikoma A, Toyoshima H, Kawakami M, et al Ectopic ACTH syndrome associated with large cell neuroendocrine carcinoma of the thymus Intern Med 2011;50:1471–5 Suster S, Moran CA Thymic carcinoid with prominent mucinous stroma: report of a distinctive morphologic variant of thymic neuroendocrine neoplasm Am J Surg Pathol 1995;19:1277–85 Suster S, Moran CA Neuroendocrine neoplasms of the mediastinum Am J Clin Pathol 2001;115(S):17–27 Suster S, Rosai J Thymic carcinoma A clinicopathologic study of 60 cases Cancer 1991;67:1025–32 Tiffet O, Nicholson AG, Ladas G, Sheppard MN, Goldstraw P A clinicopathologic study of 12 cases of neuroendocrine tumors arising in the thymus Chest 2003;124:141–6 Valli M, Fabris GA, Dewar A, Chikte S, Fisher C, Corrin B, Sheppard MN Atypical carcinoid tumor of the thymus: a study of eight cases Histopathology 1994;24:371–5 Wick MR, Carney JA, Bernatz PE, Brown LR Primary mediastinal carcinoid tumors Am J Surg Pathol 1982;6:195–205 Wick MR, Scheithauer BW Oat cell carcinoma of the thymus Cancer 1982;49:1652–7 ... (ed.), Atlas of Mediastinal Pathology, Atlas of Anatomic Pathology, DOI 10 .10 07/978 -1- 4939-2674-9_2, © Springer Science+Business Media, LLC 2 015 19 20 Table 2 .1 Current histologic classifications of. .. College of Wisconsin Milwaukee, Wisconsin USA Atlas of Anatomic Pathology ISBN 978 -1- 4939-2673-2 ISBN 978 -1- 4939-2674-9 DOI 10 .10 07/978 -1- 4939-2674-9 (eBook) Library of Congress Control Number: 2 015 9 413 33.. .Atlas of Anatomic Pathology Series Editor Liang Cheng For further volumes: http://www.springer.com/series /10 144 Saul Suster Atlas of Mediastinal Pathology Saul Suster, MD Department of Pathology