Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances

Aejaz Nasir • Domenico Coppola Editors

Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances

Editors Aejaz Nasir Diagnostic & Experimental Pathology Lilly Research Laboratories, Eli Lilly & Co. Indianapolis Indiana USA

Domenico Coppola University of South Florida H. Lee Moffitt Cancer Ctr & Res Tampa Florida USA

ISBN 978-1-4939-3424-9 ISBN 978-1-4939-3426-3 DOI 10.1007/978-1-4939-3426-3

(eBook)

Library of Congress Control Number: 2016943073 © Springer Science+Business Media, LLC 2016 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 This Springer imprint is published by Springer Nature The registered company is Springer Science+Business Media LLC New York

This book is dedicated With love to: My dear mother, Bilqis Jehan, and late father, Muhammad Anwar, for nurturing and supporting me to become a healer With honor and gratitude to: Prof. A. H. Nagi and Prof. Hans E. Kaiser, my role models, who profoundly influenced my career Prof. Julia M. Polak and Prof. Larry Kvols, who inspired me to learn and practice Neuroendocrine Tumor Pathology for patients Aejaz Nasir, MD, MPhil, FCAP With love to: My wife Beverly and to my family – Stefano, David, Jennifer, Marc, and Christina for their continuous support Domenico Coppola, MD, FCAP

Preface

Neuroendocrine neoplasms involve many different organs in the human body and are characterized by diverse biology, unusual clinicopathologic and molecular profiles, and a number of unique challenges in their clinical management. With the exception of specialized centers, most institutions do not deal with these in sufficient frequency. Until recently, there has been lack of uniformly agreed diagnostic schemes and treatment guidelines for managing these patients. When dealing with these unusual neoplasms, some of the major challenges faced by the practicing pathologists include reference to internationally agreed, diagnostically reproducible, and clinically relevant classification schemes; unique patterns of tumor histology; and differentiation and patient outcomes. In recent years, there has been an unprecedented progress in diagnosis, prognostication, and treatment of these neoplasms both in the United States and Europe. In addition to efforts at standardization of histopathologic classification and grading schemes, recent advances in molecular pathology, diagnostic methodologies, and targeted therapeutics have also contributed a great deal to the recent progress in this field. At the H. Lee Moffitt Cancer Center and Research Institute (Tampa, FL, USA), neuroendocrine tumor pathology has been practiced for many years by dedicated subspecialty pathologists, who serve a critical role not only in providing the highest standards in pathologic evaluation and diagnosis but they have also been an integral part of a large multidisciplinary NET patient management team led by worldrenowned neuroendocrine oncologists, Professor Larry Kvols, M.D., and Jonathan Strosberg, M.D. Collaborative team efforts by pathologists, oncologists, surgeons, radiologists, and advanced researchers have led to a model of service excellence, which has made tremendous contribution to improve the quality of diagnostic service and patient care at this global center of excellence. Members of the clinical and subspecialty pathology team have also made major contributions to the recent development of comprehensive diagnostic and clinical guidelines by the North American Neuroendocrine Tumor Society (NANETS), the European Neuroendocrine Tumor Society (ENETS), and the World Health Organization (WHO). In order to address some of the variations in the earlier NET classification schemes, the WHO has published revised histologic classifications of neuroendocrine neoplasms vii

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of the gastrointestinal tract and lung, including clinical, histopathologic, and molecular genetic features of these neoplasms. Furthermore, to help modern pathologists play an active role in the diagnosis, prognostication, and management of NET patients, a multidisciplinary team of experts in NETs proposed a consensus statement (Klimstra et al. 2010) on minimal data to be included in the NET pathology reports to ensure consistent patient management and reproducibility of data from clinical trials. It was heartening that agreement was reached among the members of the expert panel about the importance of tumor grading, staging landmarks, prognostic factors assessable by routine histology, the potential for tumors to metastasize, and the current status of advanced immunohistochemical and molecular testing for treatment-related biomarkers. This consensus statement could serve as an important resource for pathologists in their NET pathology practice. Another important advance in recent years is the addition of NET staging to the seventh edition of the AJCC Cancer Staging Handbook. The TNM staging for NETs of the GI tract and pancreas was proposed in line with the adenocarcinomas of these sites. With the current progress in the practice of NET pathology, neuroendocrine markers, tissue-specific transcription factors (TTF1, CDX2), and other emerging immunohistochemical and molecular markers will need to be used more effectively by incorporating their use in the overall patient management plan. This will provide pathologists with more effective approaches to identify neuroendocrine differentiation in human cancer tissues, to workup metastatic neuroendocrine carcinomas (NECs) with unknown primaries, and to validate and assess newer molecular biomarkers of prognostic or therapeutic relevance. By implementation of these approaches, pathologists will make substantial contributions to advance the field of personalized oncology for NET patients. Because of the differences in biology and clinical course of pancreatic, thoracic, and gastrointestinal NETs, advanced imaging and molecular diagnostic approaches will play an important role in the pathologic classification of NETs in the future. Although it is conventional to classify NETs based on embryologic origin (foregut, midgut, hindgut), anatomic location (lung, pancreas, GI tract), and their secreted products (insulin, glucagon, gastrin, others), the anatomic site of origin (pancreatic vs. nonpancreatic) is now being recognized as a key determinant decision regarding patient management because of important differences in NET biology and clinical course at these sites. Some NETs actively secrete hormones resulting in well-recognized clinical syndromes (functional NETs like insulinomas, VIPomas, etc.). In order to provide clinical teams with comprehensive surgical pathology reports for patient management, pathologists need to workup NET cases to be able to render both histopathologic and clinical classification in a given case of NET. With improved understanding of the diverse biology and clinical course of NE malignancies, it is also becoming evident that NETs need to be separated into pancreatic and nonpancreatic NETs both for enrollment in clinical trials and treatment in the clinic. Until recently, there were only a few therapeutic options for patients with low- and intermediate-grade NETs. Promising clinical advances are being made to delay NET growth and improve patient survival. Recognition of PI3K/Akt/ mTOR pathway, angiogenesis, and other biologic pathways as important “druggable” therapeutic targets offers further hope for NET patients in the future. A number

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of targeted therapies are under investigation and will offer additional therapeutic choices for NET patients in the future. In order to personalize therapies for individual NET patients, robust methodologies for predictive and prognostic biomarkers will need to be validated and implemented, so that newer targeted therapies may be tailored for specific subsets of NET patients. Emerging data suggest clinical relevance to assess methylguanine-methyltransferase (MGMT), PTEN, and TSC2 and other emerging biomarkers – findings that need to be validated in future studies. In recent years, we offered a subspecialty training course in NET pathology for practicing pathologists and pathology residents and fellows titled “Diagnosis and Prognostication of Gastro-entero-pancreatic Neuroendocrine Neoplasms: A Multidisciplinary Approach” at the Joint American Society for Clinical Pathology (ASCP) Annual Meeting/World Association of Societies of Pathology and Laboratory Medicine (WASPaLM) XXVI World Congress in Las Vegas (NV, USA) (2011) and at the 2012 ASCP Annual Meeting in Boston (MA, USA). With the outstanding reviews and feedback from the audience, we felt the need for a more comprehensive reference book with a well-integrated subspecialty diagnostic pathology content, including a balanced review of recent advances in molecular aspects and targeted therapies for NET patients. In this regard, we are highly appreciative of the Anatomic Pathology faculty at Moffitt Cancer Center and at other institutions for sharing their advanced expertise in NET pathology. By providing a fully updated state of the science in NET pathology, this book is aimed to empower the practicing pathologists involved in NET diagnosis in their service work and the pathology residents, fellows, oncologists, radiologists, and NET researchers with the latest advances in the field. Recent developments will serve as a landmark in the future progress in neuroendocrine tumor pathology and oncology and will set higher standards and uniformity both in the diagnostic services and patient care. In the near future, the field is also going to move closer to its twenty-first century goal of implementation of personalized oncology in order to maximize benefit to these patients. Some of the key areas of advancement for pathologists, who are actively engaged in the multidisciplinary management of NET patients, include more unified pathologic classification, histologic grading, reporting schemes, and molecular characterization, especially for development of promising biomarkers and diagnostics to predict response or resistance of NETs to more effective and safer targeted therapeutics. We are confident that this comprehensive reference book with state of the science in cutting-edge advances in NET pathology will enable our fellow pathologists to take on a proactive role in application of recent NET pathologic typing, grading, and staging guidelines and integrate these with molecular and targeted therapeutic advances as part of a multidisciplinary model of NET oncology in the clinic. We envision that by doing so, pathologists can become major contributors to the forthcoming advancements not only in the diagnosis of NETs but also in the clinical management of neuroendocrine tumor patients in the twenty-first century. Indianapolis, IN, USA Tampa, FL, USA

Aejaz Nasir Domenico Coppola

Contents

Part I

General Topics in Neuroendocrine Tumor Pathology

Neuroendocrine Tumor Classification Systems: Grading . . . . . . . . . . . . . . . . 3 Shabnam Seydafkan and Domenico Coppola Neuroendocrine Tumor Classification Systems: Staging . . . . . . . . . . . . . . . 21 Shabnam Seydafkan and Domenico Coppola Differential Diagnosis of Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . 31 Kun Jiang and Domenico Coppola Role of Immunohistochemistry and Molecular Genetics in Neuroendocrine Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Kun Jiang, Ujalla Sheikh, Aejaz Nasir, and Domenico Coppola Gastroenteropancreatic: Poorly Differentiated Neuroendocrine Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Mulazim H. Bukhari, Ujalla Sheikh, Jalil Muhammad, Domenico Coppola, and Aejaz Nasir Part II

Systemic Aspects of Neuroendocrine Tumor Pathology

Neuroendocrine Neoplasms of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Yuan Frank Shan, Fulin Wang, Changshu Ke, and Meng Yan Medullary Thyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Pablo Valderrabano, Stacey Simons, Jaime Montilla-Soler, Tuya Pal, Victor Zota, Kristen Otto, Bryan McIver, Domenico Coppola, and Marino E. Leon Neuroendocrine Tumors (NETs) of the Mediastinum and Thymus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Sameer Al Diffalha and Farah Khalil

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Neuroendocrine Tumors of the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Farah Khalil Breast Carcinomas with Neuroendocrine Features (Neuroendocrine Carcinomas of the Breast) . . . . . . . . . . . . . . . . . . . . . . . . 179 Marilin Rosa, Ujalla Sheikh, and Aejaz Nasir Neuroendocrine Tumors of the Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Shabnam Seydafkan and Domenico Coppola Neuroendocrine Neoplasms of the Stomach . . . . . . . . . . . . . . . . . . . . . . . . . 217 Evita Henderson-Jackson, Ujalla Sheikh, Jalil Muhammad, Domenico Coppola, and Aejaz Nasir Neuroendocrine Neoplasms of the Pancreas . . . . . . . . . . . . . . . . . . . . . . . . 245 Michael Markow and Barbara Ann Centeno Neuroendocrine Neoplasms of the Small Intestine . . . . . . . . . . . . . . . . . . . 273 Shabnam Seydafkan and Domenico Coppola Neuroendocrine Neoplasms of the Appendix . . . . . . . . . . . . . . . . . . . . . . . . 289 Ujalla Sheikh, Evita Henderson-Jackson, Jalil Muhammad, Domenico Coppola, and Aejaz Nasir Neuroendocrine Neoplasms of the Colon and Rectum . . . . . . . . . . . . . . . . 309 Masoumeh Ghayouri, Shabnam Seydafkan, Aejaz Nasir, and Domenico Coppola Adrenal Neuroendocrine Tumors: Pheochromocytoma and Neuroblastic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Carmen M. Perrino and Debra L. Zynger Neuroendocrine Tumors of the Urinary Bladder and Molecular Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Jasreman Dhillon Neuroendocrine Tumors of the Prostate and Molecular Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 Jasreman Dhillon Neuroendocrine Tumors of the Female Genital Tract . . . . . . . . . . . . . . . . . 379 Ozlen Saglam and Ardeshir Hakam Pathology of Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of the Skin) . . . . . . . . . . . . . . . . . . . 393 Carlos N. Prieto-Granada and Jane L. Messina Extraskeletal Ewing Sarcoma/Primitive Neuroectodermal Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 Rania Shamekh, Vicky Pham, and Marilyn M. Bui

Contents

Part III

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Molecular & Therapeutic Advances in Neuroendocrine Tumor Pathology

Molecular Pathology of Neuroendocrine Tumor: The Era of Targeted Therapeutics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 Anthony M. Magliocco Somatostatin Receptors in Human Neuroendocrine Tumors . . . . . . . . . . . 445 Aejaz Nasir, Ujalla Sheikh, Jalil Muhammad, and Domenico Coppola Pathologic Angiogenesis in Neuroendocrine Tumors. . . . . . . . . . . . . . . . . . 457 Aejaz Nasir, Ujalla Sheikh, Jalil Muhammad, and Domenico Coppola Molecular Targets in Human Neuroendocrine Tumors. . . . . . . . . . . . . . . . 471 Ujalla Sheikh, Jalil Muhammad, Domenico Coppola, and Aejaz Nasir Recent Advances in Molecular Pathology of Neuroendocrine Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487 Aejaz Nasir, Ujalla Sheikh, Kevin G Neill, Kun Jiang, Jalil Muhammad, and Domenico Coppola Targeted Therapies for Neuroendocrine Neoplasms . . . . . . . . . . . . . . . . . . 505 Heloisa Prado Soares and Jonathan Strosberg Future Prospects in Neuroendocrine Tumor Pathology . . . . . . . . . . . . . . . 517 Aejaz Nasir and Domenico Coppola Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525