Neuropathology of Brain Tumors with Radiologic Correlates [1st ed.] 9789811571251, 9789811571268

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Neuropathology of Brain Tumors with Radiologic Correlates Meghana Chougule

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Neuropathology of Brain Tumors with Radiologic Correlates​

Meghana Chougule

Neuropathology of Brain Tumors with Radiologic Correlates​

Meghana Chougule Shanti Pathology Laboratory Kolhapur Maharashtra India

ISBN 978-981-15-7125-1    ISBN 978-981-15-7126-8 (eBook) https://doi.org/10.1007/978-981-15-7126-8 © Springer Nature Singapore Pte Ltd. 2020 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, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

I am extremely pleased to present the first edition of “Neuropathology of Brain tumors with Radiologic Correlates.” Just over the last decade or so, the practice of neuropathology has undergone an extensive evolution far beyond traditional intraoperative consultation (crush smears and frozen section), histopathology, and immunohistochemistry (IHC), to include new molecular entities defined by massively parallel next-generation sequencing (NGS). Further advances in companion diagnostics, prognostic and therapeutic markers continue to be made. This was reflected in the most recent WHO classification of tumors of the central nervous system (2016). I have been fortunate to receive brain tumors regularly as a part of intraoperative consultation and surgical pathology for the past several years. Over the years, my collection of brain tumors has continued to accumulate in my practice located in South-Western Maharashtra, India. Frozen sections are not avalaible at all the laboratory setups. In the earlier peroid of my practice, I did crush smear cytology for intraoperative consultation. At inception, this was planned to be an atlas of intraoperative cytology alone but I realized very early on that this was an opportunity to present an integrated profile of brain tumors reflecting their radiologic, intraoperative cytology along with histopathology and immunohistochemistry to help readers understand closely the practical workflow of diagnostic neuropathology. To my knowledge, this is the first such book “Neuropathology of Brain tumors with Radiologic Correlates” to be published by an Indian author. In the practice of neuropathology, the importance of a clear understanding of the radiologic findings of brain tumors and the value of communication with the neurosurgeon cannot be overemphasized. I attempt to present a collection of carefully selected radiologic, intraoperative (crush smear cytology), histopathology, and immunohistochemistry images of tumors from my practice along with valuable contributions from very respected pathologists and radiologists in the field to present a full coverage of the speciality. The book begins with a normal anatomical graphic depicting the major brain tumors with their common locations. I have included a chapter on normal neuroimaging which introduces the readers to the MRI scans of the brain. I am convinced that neuroradiology forms the basic foundation for a better understanding of brain tumors which goes a long way to help the pathologist during intraoperative consultation of brain tumors. Although the goal of intraoperative cytology is not necessarily arriving at the exact diagnosis and grade of the tumor but it definitely provides valuable v

Preface

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information and guidance to the neurosurgeon in the operating room. Intraoperative cytology images included in the book are from crush smears stained with a rapid modification of field stain. This method is simpler, easier, reproducible, and cost-effective for IOC and yields the slide for microscopic interpretation within 2 minutes. The differential diagnosis of tumors is discussed at the level of radiology, histopathology along with the IHC findings that closely follow the actual workup to arrive at a precise diagnosis. A large number of microscopic images of crush smears, histopathology, and immunohistochemistry are the main strengths of this book. Illustrations of some genetic diseases are included. I have chosen to make stringent presentation of the text in the bullet form and a tabular form for immunohistochemical findings that make the understanding easy. Each chapter concludes with a summary of the genetic profile and prognosis of the disease. An attempt is made at presenting the complete profile of brain tumors at a glance. It is my sincere hope that practicing pathologists, neurosurgeons, radiologists along with trainees and residents in the specialities of pathology, neurosurgery, radiology, find this book as a quick reference on their bookshelves. I hope that the readers will benefit from the contents packaged in the “Neuropathology of Brain tumors with Radiologic Correlates” and find it an enjoyable and educational experience. Personally, this book is a work of passion for me. In the words of Steve Jobs, “you have got to find what you love. And this is as true for your work as it is for your lover. Your work is going to fill a large part of your life and the only way to be truly satisfied is to do what you believe is a great work. The only way to do great work is love what you do. If you have not found it yet, keep looking. Do not settle.” Kolhapur, India

Meghana Chougule

Acknowledgments

This atlas was my dream project which has come alive because of so many good persons I met in life. I am extremely grateful to the world-renowned neuropathologist, Professor Dr. Marc Rosenblum, from Memorial Sloan Kettering Cancer Center, New York who is an author for CNS chapters in many textbooks of pathology and WHO classification of CNS tumors. He taught me the finer aspects of neuropathology and contributed pictures of rare tumors. He always responded timely to my queries despite his busy schedule. Dr. Umesh K. Bhanot, Scientific Head and Senior Scientist, Biobanking, Dept. of Pathology at Memorial Sloan Kettering Cancer Center, New York needs a special mention for his constructive criticism and advice throughout the development of this book. I am extremely grateful to him for his valuable time and efforts which helped me immensely in the configuration of this book. I am particularly thankful to Dr. B.  N. Nandeesh, Assistant Professor, National Institute of Mental Health and Neurosciences, Bengaluru for his contribution and timely guidance in difficult cases. I am greatly indebted to my clinical colleagues, the neurosurgeons, Prof. Dr. Vinayak Raje, Dr. Virendrasinh Pawar, Dr. S. Prabhakar, Dr. P. Patankar, Dr. S. M. Kulkarni, Dr. Uday Ghate, Dr. Ravindra Patil, Dr. Arihant Patil, Dr. Abhinandan Patil, Dr. Narendra Bhagwat, and Dr. Amol Degaonkar who believed in me by sending the tumors for many years. My sincere thanks to Dr. Atul Goel and Dr. Naina Goel for their guidance. I am very thankful to Dr. Dattatray Mujumdar, Professor, K.E.M. Hospital and Seth G.S. Medical College, Mumbai for his contribution of MR images. This is the right opportunity to appreciate and acknowledge the contribution of radiologists, Dr. Prashant Kittad of Sai diagnostic, Dr. Manjeet Kulkarni of Shrutika Scans, Dr. Mahesh Shettennavar of S. M. Diagnostic, Dr. Pramod Nagure of Eureka Diagnostic, who have gone an extra mile to search for good-quality, classical radiological images of the lesions I have seen microscopically. I express my gratitude to Dr. Yanming Zhang, M.D., Attending Cytogeneticist and Member, Director of Cytogenetics Laboratory, Department of Pathology, Molecular Diagnostic Service, Memorial Sloan Kettering Cancer Center, MSKCC, New  York for making an image contribution to molecular genetics.

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I am thankful to all my laboratory staff, especially Mr. Sagar Pawar, an ingenious person who took relentless efforts right from making all the slide blocks available to digging up interesting cases and retrieving all the needed data. He always went out of the way to conclude the task. Dr. Atul Ranade deserves special thanks for the support and for having relieved me from the routine work of the department. I would also like to take this opportunity to thank my teachers from Krishna Institute of Medical Science, Karad, Tata Memorial Hospital, Mumbai and National Institute of Mental Health and Neurosciences, Bengaluru, who helped me during my training in neuropathology. I owe a deep debt of gratitude to my parents, Dr. Shantikumar Chivate and Mrs. Jayashree for cultivating the habit of perseverance and hard work. The writing of this book would have never been possible without their support. My elder son Aditya (MBBS student) contributed at every stage of its preparation, writing, compilation, and verification. Finally, I would like to thank my beloved husband Dr. Vinay Chougule and my younger son Yashraj who always boosted my venture and morally stood by me.

Acknowledgments

Contents

1 Brain Anatomy and Anatomical Distribution of Major Brain Tumors ������������������������������������������������������������������   1 2 Normal Neuroimaging ��������������������������������������������������������������������   3 3 Introduction to WHO Classification of Tumors of the Central Nervous System, 2016 ��������������������������������������������   9 3.1 New Nomenclature ������������������������������������������������������������������   9 3.2 Some Major Updates in WHO Classification of Tumors of the CNS, 2016 ����������������������������������������������������   10 Reference ������������������������������������������������������������������������������������������  13 4 Diffuse Astrocytic and Oligodendroglial Tumors��������������������������  15 4.1 Introduction to Diffuse Astrocytic and Oligodendroglial Tumors ��������������������������������������������������  15 4.2 Diffuse Astrocytoma, WHO Grade II ��������������������������������������  16 4.2.1 Diffuse Astrocytoma, IDH-Mutant ������������������������������  16 4.2.2 Diffuse Astrocytoma, IDH-­Wild Type��������������������������  22 4.2.3 Diffuse Astrocytic Glioma, IDH-Wild Type, with Molecular Features of Glioblastoma, WHO Grade IV ������������������������������������������������������������  22 4.2.4 Granular Cell Astrocytoma ������������������������������������������  23 4.2.5 Gemistocytic Astrocytoma, IDH-Mutant WHO Grade II��������������������������������������������������������������  24 4.3 Anaplastic Astrocytoma, WHO Grade III��������������������������������  26 4.4 Glioblastoma, WHO Grade IV��������������������������������������������������  30 4.4.1 Presence of Epithelioid Cells/Epithelioid Glioblastoma, IDH-Wild Type��������������������������������������  38 4.4.2 Giant Cell Glioblastomas, IDH-Wild Type, WHO Grade IV ������������������������������������������������������������  47 4.4.3 Gliosarcoma, IDH-Wild Type, WHO Grade IV�����������  50 4.5 Diffuse Midline Glioma, WHO Grade IV, H3 K27M Mutant����������������������������������������������������������������������  53 4.6 Oligodendroglial Tumors����������������������������������������������������������  56 4.6.1 Oligodendroglioma, IDH-Mutant, and 1p/19q Codeleted ��������������������������������������������������  56 4.6.2 Anaplastic Oligodendroglioma, IDH-Mutant and 1p/19q-­Codeleted ��������������������������������������������������  61 ix

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4.7 Oligoastrocytoma, NOS������������������������������������������������������������  66 References������������������������������������������������������������������������������������������  70 5 Other Astrocytic Tumors ����������������������������������������������������������������  73 5.1 Introduction������������������������������������������������������������������������������  73 5.2 Pilocytic Astrocytoma, WHO Grade I��������������������������������������  73 5.3 Pilomyxoid Astrocytoma����������������������������������������������������������  79 5.4 Subependymal Giant Cell Astrocytoma, WHO Grade I ����������  80 5.5 Pleomorphic Xanthoastrocytoma, WHO Grade II��������������������  85 5.6 Anaplastic Pleomorphic Xanthoastrocytoma, WHO Grade III ������������������������������������������������������������������������  90 References������������������������������������������������������������������������������������������  93 6 Ependymal Tumors��������������������������������������������������������������������������  95 6.1 Introduction������������������������������������������������������������������������������  95 6.2 Subependymoma, WHO Grade I����������������������������������������������  95 6.3 Myxopapillary Ependymoma, WHO Grade I ��������������������������  97 6.4 Ependymoma, WHO Grade II�������������������������������������������������� 100 6.5 Papillary Ependymoma, WHO Grade II ���������������������������������� 107 6.6 Clear Cell Ependymomas �������������������������������������������������������� 107 6.7 Tanycytic Ependymoma, WHO Grade II���������������������������������� 110 6.8 Anaplastic Ependymoma, WHO Grade III ������������������������������ 111 References������������������������������������������������������������������������������������������ 119 7 Other Gliomas���������������������������������������������������������������������������������� 121 7.1 Introduction������������������������������������������������������������������������������ 121 7.2 Chordoid Glioma of Third Ventricle, WHO Grade II �������������� 121 7.3 Angiocentric Glioma, WHO Grade I���������������������������������������� 123 References������������������������������������������������������������������������������������������ 124 8 Choroid Plexus Tumors ������������������������������������������������������������������ 127 8.1 Choroid Plexus Papilloma, WHO Grade I�������������������������������� 127 8.2 Choroid Plexus Carcinoma, WHO Grade III���������������������������� 133 References������������������������������������������������������������������������������������������ 137 9 Neuronal and Mixed Neuronal-­Glial Tumors������������������������������� 139 9.1 Introduction������������������������������������������������������������������������������ 139 9.2 Dysembryoplastic Neuroepithelial Tumor, WHO Grade I���������������������������������������������������������������������������� 139 9.3 Gangliocytoma, WHO Grade I ������������������������������������������������ 141 9.4 Ganglioglioma�������������������������������������������������������������������������� 144 9.4.1 Ganglioglioma, WHO Grade I�������������������������������������� 144 9.4.2 Anaplastic Ganglioglioma, WHO Grade III ���������������� 146 9.5 Dysplastic Cerebellar Gangliocytoma (Lhermitte–Duclos Disease), WHO Grade I���������������������������� 148 9.6 Papillary Glioneuronal Tumor�������������������������������������������������� 150 9.7 Rosette-Forming Glioneuronal Tumor, WHO Grade I ������������ 152 9.8 Diffuse Leptomeningeal Glioneuronal Tumor�������������������������� 153 9.9 Central Neurocytoma, Extraventricular Neurocytoma, and Cerebellar Liponeurocytoma, WHO Grade II�������������������� 154

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9.10 Atypical Neurocytoma�������������������������������������������������������������� 157 9.11 Paraganglioma, WHO Grade 1 ������������������������������������������������ 159 References������������������������������������������������������������������������������������������ 166 10 Tumors of the Pineal Region ���������������������������������������������������������� 167 10.1 Pineal Tumors ������������������������������������������������������������������������ 167 10.1.1 Introduction���������������������������������������������������������������� 167 10.2 Pineocytoma, WHO Grade I �������������������������������������������������� 167 10.3 Pineal Parenchymal Tumor of Intermediate Differentiation (PPTID)���������������������������������������������������������� 172 10.4 Papillary Tumor of Pineal Region������������������������������������������ 174 10.5 Pineoblastoma, WHO Grade IV���������������������������������������������� 175 References������������������������������������������������������������������������������������������ 179 11 Embryonal Tumors�������������������������������������������������������������������������� 181 11.1 Introduction���������������������������������������������������������������������������� 181 11.2 Medulloblastoma, WHO Grade IV ���������������������������������������� 181 11.2.1 Four Histologically Defined Groups and Four Genetically Defined Groups [3]���������������������������������� 184 11.2.2 Medulloblastomas, NOS �������������������������������������������� 185 11.3 Embryonal Tumor with Multilayered Rosettes, WHO Grade IV ���������������������������������������������������������������������� 189 11.4 Embryonal Tumor with Multilayered Rosettes, NOS������������ 192 11.5 Other CNS Embryonal Tumors���������������������������������������������� 192 11.5.1 Medulloepithelioma���������������������������������������������������� 192 11.5.2 CNS Neuroblastoma �������������������������������������������������� 194 11.5.3 CNS Ganglioneuroblastoma �������������������������������������� 196 11.5.4 CNS Embryonal Tumors, NOS���������������������������������� 198 11.6 Atypical Teratoid/Rhabdoid Tumor WHO Grade IV�������������� 199 11.7 CNS Embryonal Tumors with Rhabdoid Features, WHO Grade IV ���������������������������������������������������������������������� 203 References������������������������������������������������������������������������������������������ 203 12 Tumors of the Cranial and Paraspinal Nerves������������������������������ 205 12.1 Introduction of Cranial and Spinal Nerve Tumors������������������ 205 12.2 Schwannoma, WHO Grade-I (Neurilemoma/Neurinoma)���������������������������������������������������� 205 12.2.1 Cellular Schwannoma ������������������������������������������������ 212 12.2.2 Plexiform Schwannoma (PS)/Multinodular Pattern ������������������������������������������������������������������������ 214 12.3 Melanotic Schwannoma���������������������������������������������������������� 215 12.4 Epithelioid Schwannoma�������������������������������������������������������� 217 12.5 Neurofibroma WHO Grade I�������������������������������������������������� 217 12.5.1 Atypical Neurofibroma ���������������������������������������������� 219 12.5.2 Plexiform Neurofibroma �������������������������������������������� 219 12.6 Malignant Peripheral Nerve Sheath Tumor (MPNST) ���������� 221 12.7 Hybrid Nerve Sheath Tumor �������������������������������������������������� 224 References������������������������������������������������������������������������������������������ 225

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13 Meningioma�������������������������������������������������������������������������������������� 227 13.1 Introduction���������������������������������������������������������������������������� 227 13.2 Meningothelial Meningioma, WHO Grade I�������������������������� 230 13.3 Fibrous Meningioma, WHO Grade I ������������������������������������ 234 13.4 Transitional Meningioma, WHO Grade I ������������������������������ 236 13.5 Angiomatous Meningioma, WHO Grade I (Vascular Meningioma)�������������������������������������������������������������������������� 237 13.6 Psammomatous Meningioma, WHO Grade I ������������������������ 239 13.7 Microcystic Meningioma, WHO Grade I������������������������������� 239 13.8 Secretory Meningioma, WHO Grade I ���������������������������������� 241 13.9 Lymphoplasmacyte-Rich Meningioma, WHO Grade I���������� 243 13.10 Metaplastic Meningioma, WHO Grade I�������������������������������� 244 13.11 Atypical Meningioma, WHO Grade II ���������������������������������� 245 13.12 Chordoid Meningioma, WHO Grade II���������������������������������� 248 13.13 Clear Cell Meningioma, WHO Grade II�������������������������������� 248 13.14 Rhabdoid Meningioma, WHO Grade III�������������������������������� 249 13.15 Papillary Meningioma, WHO Grade III��������������������������������� 250 13.16 Anaplastic Meningioma, WHO Grade III������������������������������ 251 13.17 Primary Extradural Meningioma (PEM)�������������������������������� 254 References������������������������������������������������������������������������������������������ 255 14 Mesenchymal, Non-meningothelial Tumors���������������������������������� 257 14.1 Introduction of Mesenchymal, Non-­meningothelial Tumors������������������������������������������������������������������������������������ 257 14.2 Solitary Fibrous Tumor/Hemangiopericytoma ���������������������� 257 14.3 Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, WHO Grade IV������������������������������ 262 14.4 Chondroma������������������������������������������������������������������������������ 264 14.5 Chondrosarcoma �������������������������������������������������������������������� 267 14.6 Mesenchymal Chondrosarcoma���������������������������������������������� 269 14.7 Chordoma�������������������������������������������������������������������������������� 272 14.8 Hemangioblastoma, WHO Grade I���������������������������������������� 275 14.9 Hemangioma, WHO Grade I�������������������������������������������������� 281 14.10 Cavernous Hemangioma/Cavernoma�������������������������������������� 283 14.11 Lipoma������������������������������������������������������������������������������������ 284 References������������������������������������������������������������������������������������������ 286 15 Melanocytic Tumors������������������������������������������������������������������������ 287 15.1 Meningeal Melanocytosis ������������������������������������������������������ 287 15.2 Meningeal Melanomatosis������������������������������������������������������ 287 15.3 Meningeal Melanocytoma������������������������������������������������������ 288 15.4 Meningeal Melanoma ������������������������������������������������������������ 289 Reference ������������������������������������������������������������������������������������������ 290 16 Lymphomas�������������������������������������������������������������������������������������� 291 16.1 Introduction���������������������������������������������������������������������������� 291 16.2 WHO Classification of Primary Lymphomas of the Central Nervous System, 2016 ������������������������������������ 291 16.3 Primary CNS Lymphoma�������������������������������������������������������� 292

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16.3.1 Diffuse Large B-cell Lymphoma�������������������������������� 292 16.3.2 Intravascular Large B-Cell Lymphoma���������������������� 295 References������������������������������������������������������������������������������������������ 299 17 Plasmacytoma���������������������������������������������������������������������������������� 301 References������������������������������������������������������������������������������������������ 305 18 Germ Cell Tumors���������������������������������������������������������������������������� 307 18.1 Introduction���������������������������������������������������������������������������� 307 18.2 Germinoma ���������������������������������������������������������������������������� 307 18.3 Non-germinomatous Germ Cell Tumors (NGCT)������������������ 309 18.3.1 Embryonal Carcinoma������������������������������������������������ 309 18.3.2 Yolk Sac Tumor���������������������������������������������������������� 310 18.3.3 Choriocarcinoma�������������������������������������������������������� 311 18.3.4 Teratomas�������������������������������������������������������������������� 312 18.4 Mixed Germ Cell Tumors ������������������������������������������������������ 312 References������������������������������������������������������������������������������������������ 313 19 Craniopharyngioma������������������������������������������������������������������������ 315 19.1 Adamantinomatous Craniopharyngioma (ADC)�������������������� 315 19.2 Papillary Craniopharyngioma (PCP)�������������������������������������� 315 References������������������������������������������������������������������������������������������ 322 20 Pituitary Adenoma �������������������������������������������������������������������������� 323 20.1 Introduction���������������������������������������������������������������������������� 323 References������������������������������������������������������������������������������������������ 331 21 Metastatic Tumors �������������������������������������������������������������������������� 333 21.1 Case Studies of Metastatic Tumors to Brain and Spine���������� 335 References������������������������������������������������������������������������������������������ 343 22 Benign Cysts of CNS������������������������������������������������������������������������ 345 22.1 Cysts of CNS Origin �������������������������������������������������������������� 345 22.1.1 Arachnoid Cyst ���������������������������������������������������������� 345 22.1.2 Glioependymal Cyst��������������������������������������������������� 346 22.2 Cysts of Non-CNS Origin������������������������������������������������������ 347 22.2.1 Epidermoid Cyst �������������������������������������������������������� 347 22.2.2 Dermoid Cyst�������������������������������������������������������������� 348 22.2.3 Rathke’s Cleft Cyst ���������������������������������������������������� 349 22.2.4 Colloid Cysts�������������������������������������������������������������� 350 22.2.5 Teratoma �������������������������������������������������������������������� 351 22.2.6 Pineal Cysts���������������������������������������������������������������� 354 References������������������������������������������������������������������������������������������ 354 23 Intra-axial/Extra-axial Brain Tumors�������������������������������������������� 357 24 Intramedullary/Extramedullary Spinal Tumors�������������������������� 359 25 Intraoperative Cytology Staining Technique�������������������������������� 361 25.1 Modified Field Stain �������������������������������������������������������������� 361

About the Author

Meghana  Chougule holds an MD in Pathology with a gold medal from Shivaji University. She is the chief consultant at Shanti Pathology Laboratory, Maharashtra. She was also an Associate Professor of Pathology at D.Y. Patil Medical College, Maharashtra. She gained neuropathology experience at NIMHANS (National Institute of Mental Health and Neurosciences), Bangalore; TATA Memorial Hospital, Mumbai; Bombay Hospital; and Memorial Sloan Kettering Cancer Center (MSKCC), New York. Her areas of interest include neuropathology and immunohistochemistry. She has been a speaker at various conferences and has published papers in peer-reviewed international journals. She is a member of the Neuropathology Society of India and Indian Association of Pathology and Microbiology.

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1

Brain Anatomy and Anatomical Distribution of Major Brain Tumors

Brain anatomy & anatomical distribution of major brain tumors Aditya Chougule

Medical student, T N Medical College & Nair Charitable Hospital, Mumbai.

Meninges

Cerebral hemispheres

Meningioma SFT/ Hemangiopericytoma Ewing sarcoma Metastatic tumors

Diffuse astrocytic and oligodendroglial tumors (low & high grade) Metastatic tumors

Ventricle Ependymoma, Subependymoma, SEGA, Central neurocytoma, Choroid plexus tumors, Meningioma, Colloid cyst.

Corpus callosum Glioblastoma Anaplastic astrocytoma Oligodendroglioma Lymphoma Lipoma

Pineal gland Pineocytoma Pineoblastoma Pineal parenchymal tumors Germ cell tumors, Germinoma Teratoma, Arachnoid cyst

Optic nerve Pilocytic astrocytoma Meningioma

4th ventricles Cerebellum

Sellar region

Medulloblastoma Hemangioblastoma Pilocytic astrocytoma Metastasis

Pituitary adenoma Craniopharyngioma Germinoma Meningioma

Cerebello-pontine angle Schwannoma Meningioma Epidermoid cyst Glomus tumor

Brainstem Diffuse midline glioma, Glioblastoma, pilocytic astrocytoma

Extramedullary intradural Schwannoma, Meningioma Metastasis

Ependymoma, Medulloblastoma Choroid plexus papilloma & cysts, metastasis

Foramen magnum Schwannoma Meningioma Neurofibroma

Spinal cord (intramedullary) Ependymoma Astrocytoma

Extradural Chordoma Metastatic carcinoma Hematopoetic tumor Bone tumor

Cauda equina region Schwannoma Myxopapillary ependymoma Paraganglioma Chordoma (extradural) Lipoma Teratoma Dermoid cyst

Sagittal view of normal brain and spinal cord with major tumors and their locations.

© Springer Nature Singapore Pte Ltd. 2020 M. Chougule, Neuropathology of Brain Tumors with Radiologic Correlates​, https://doi.org/10.1007/978-981-15-7126-8_1

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Normal Neuroimaging

The initial diagnosis of brain tumors involves mainly two diagnostic specialities: radiology and pathology. Their collective findings and interventions are responsible for subsequent patient treatment and outcomes. A patient with radiological findings is subjected to surgery and the biopsy is sent to confirm or to negate the diagnosis.

Knowing the radiology of a tumor becomes helpful to a pathologist in quick and efficient intraoperative diagnosis. Here are a few normal axial, sagittal, and coronal sections through various levels which can help a pathologist to understand the tumor locations (Figs. 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, and 2.8).

AXIAL T2 WEIGHTED

GLOBE ETHMOID AIR CELLS

MEDIAL RECTUS

LATERAL RECTUS ORBITAL APEX SPHENOID SINUS BASILAR ARTERY

TEMPORAL LOBE

PONS

FOURTH VENTRICLE

CEREBELLAR HEMISPHERE

CEREBELLAR VERMIS

Fig. 2.1  Axial T2W MR at the level of the pons © Springer Nature Singapore Pte Ltd. 2020 M. Chougule, Neuropathology of Brain Tumors with Radiologic Correlates​, https://doi.org/10.1007/978-981-15-7126-8_2

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2  Normal Neuroimaging

4 AXIAL T2 WEIGHTED

FRONTAL LOBE INTERHEMISHERIC FISSURE

SYLVIAN FISSURE

MAMILLARY BODIES INTERPEDUNCULAR CISTERN

MIDBRAIN

CEREBRAL AQUEDUCT

INFERIOR COLLICULUS

OCCIPITAL LOBE

Fig. 2.2  Axial T2W MR at the level of the midbrain AXIAL T2 WEIGHTED

FALX CEREBRI FRONTAL LOBE FRONTAL HORN OF LATERAL VENTRICLE CAUDATE HEAD PUTAMEN FORAMEN OF MONRO SYLVIAN FISSURE

GLOBUS PALLIDUS EXTERNAL CAPSULE THIRD VENTRICLE THALAMUS

ATRIUM OF LATERAL VENTRICLE

OCCIPIAL LOBE SUPERIOR SAGITTAL SINUS

Fig. 2.3  Axial T2W MR at the level of basal ganglia

2  Normal Neuroimaging

5 AXIAL T2 WEIGHTED

INTERHEMISPHERIC FISSURE

FRONTAL LOBE

GENU OF CORPUS CALLOSUM CAUDATE NUCLEUS BODY OF LATERAL VENTRICLE CORONA RADIATA

CHOROID PLEXUS IN LATERAL VENTRICLE

SPLENIUM OF CORPUS CALLOSUM

PARIETAL LOBE

OCCIPITAL LOBE SUPERIOR SAGITTAL SINUS

Fig. 2.4  Axial T2W MR at the body of lateral ventricle SAGITTAL T1 WEIGHTED

FRONTAL LOBE

CENTRAL SULCUS

BODY, CORPUS CALLOSUM PARIETAL LOBE GENU, CORPUS CALLOSUM FORNIX

SPLENIUM, CORPUS CALLOSUM

THALAMUS MAMILLARY BODY

OCCIPITAL LOBE

PITUITARY GLAND

TENTORIUM CEREBELLI

SPHENOID SINUS

MEDULLA

CEREBELLAR HEMISPHERE MID BRAIN PONS

CERVICAL CORD

Fig. 2.5  Sagittal T1W MR at the level of the brainstem

2  Normal Neuroimaging

6 CORONAL FAT SUPRESSED POST CONTRAST T1 WEIGHTED

FRONTAL LOBE

FRONTAL HORN OF LATERAL VENTRICLE

SYLVIAN FISSURE TEMPORAL LOBE OPTIC CHIASMA PITUITARY GLAND

INFUNDIBULUM

CAVERNOUS PORTION OF INTERNAL CAROTID ARTERY

CAVERNOUS SINUS

SPHENOID SINUS

Fig. 2.6  Post-contrast fat-suppressed T1W MR at the level of the pituitary gland

HIGH RESOLUTION AXIAL T2 WEIGHTED

TEMPORAL LOBE BASILAR ARTERY PRE PONTINE CISTERN 7TH AND 8TH NERVE COMPLEX CEREBELLO-PONTINE ANGLE CISTERN

INTERNAL ACOUSTIC CANAL PONS MIDDLE CEREBRAL PEDUNCLE

FOURTH VENTRICLE

CEREBELLAR VERMIS

Fig. 2.7  Axial high-resolution T2W MR at the level of the lower pons

CEREBELLAR HEMISPHERE

2  Normal Neuroimaging

7 HIGH RESOLUTION AXIAL T2 WEIGHTED TEMPORAL LOBE

MECKEL CAVE BASILAR ARTERY 5TH

PRE PONTNE CISTERN

NERVE

PONS FOURTH VENTRICLE

CEREBELLAR VERMIS

Fig. 2.8  Axial high-resolution T2W MR at the level of the upper pons

CEREBELLAR HEMISPHERE

3

Introduction to WHO Classification of Tumors of the Central Nervous System, 2016

The World Health Organization classification (WHO) of CNS tumors is considered a gold standard and followed worldwide. The previous version (2007) of WHO classification of CNS tumors was epicentered on histological features of the tumor [hematoxylin–eosin staining (HE)], immunohistochemical (IHC) lineage-­ associated proteins, and ultrastructural characteristics with different putative cells of origin and level of differentiation. 2016 WHO classification update includes both phenotypic and genotypic parameters, making it more objective than the previous classification. In the past few decades, extensive evolvement of molecular studies followed by clinically proven trials provided a prognostic and a predictive data within diagnostic categories. In 2014, a meeting was held in Haarlem, the Netherlands, by the International Society of Neuropathology to formulate and incorporate the molecular findings into CNS tumor classification and diagnosis. This meeting was attended by 117 eminent contributors from 20 countries. Finally, the WHO classification of CNS tumors was updated in 2016 based on histological classification, the grade, and molecular information [1]. The WHO 2016 classification of CNS tumors implemented new nomenclature, WHO grades, their molecular genetics profile, the addition of newer entities along with the omission of certain entities.

3.1

New Nomenclature

Standard terminology was introduced by combining histopathological, molecular features and the grade: • Histopathological name of the tumor followed by the genetic features or status of the molecular marker, e.g., diffuse astrocytoma, isocitrate dehydrogenase (IDH)-mutant. This is followed by the WHO grade. • For tumors with more than one genetic determinant: histopathological name of the tumor followed by the multiple molecular features are included, e.g., oligodendroglioma, IDH-­ mutant, and 1p/19q-codeleted and followed by the grade. • The term wild type has been designated for a tumor lacking a specific genetic mutation. For example, a glioblastoma without IDH mutation is glioblastoma, IDH-wild type. • The term not otherwise specified (NOS) can be designated to tumors lacking access to molecular diagnostic testing or to the tumors, in which genetic assay testing has been found to be inconclusive. The NOS designation implies that there is insufficient information to assign the most specific code to the tumor.

© Springer Nature Singapore Pte Ltd. 2020 M. Chougule, Neuropathology of Brain Tumors with Radiologic Correlates​, https://doi.org/10.1007/978-981-15-7126-8_3

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3.2

3  Introduction to WHO Classification of Tumors of the Central Nervous System, 2016

 ome Major Updates in WHO S Classification of Tumors of the CNS, 2016

Major changes have been introduced in the classification of two categories of tumors, based on molecular markers. These are diffuse gliomas (astrocytic, oligodendroglial, and glioblastoma tumors) and embryonal tumors, particularly medulloblastoma: • Diffuse gliomas: The 2007 classification grouped all astrocytic and oligodendroglial tumors together under the category of diffuse gliomas. Taking into consideration the growth pattern, behavior, and IDH mutation status, the new classification (2016) categorizes diffuse gliomas into the astrocytic tumors (WHO grade II and III), oligodendrogliomas (WHO grade II and III), oligoastrocytoma (WHO grade II and III), and glioblastomas (WHO grade IV). This classification sharply delineates astrocytomas that have more circumscribed growth, lack IDH gene alteration, and which may demonstrate BRAF mutation from the category of diffuse astrocytoma. These are categorized into other astrocytic tumors. The tumors in this category are pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma. • Embryonal tumors –– Medulloblastoma: addition of four molecular genetically defined groups, such as WNT-activated, SHH-activated, and non-­ SHH/non-WNT, the numerically designated “group 3 and group 4” was done. These histological and genetic variants are associated with significant prognostic and therapeutic significance. –– The term “primitive neuroectodermal tumor” PNET is eliminated. –– In the 2016 WHO classification of CNS tumors, the embryonal tumors with the presence of C19MC amplification should be designated as an embryonal tumor with multilayered rosettes (ETMR), C19MC-altered. In absence of C19MC amplification, a tumor with histological features conforming to ETANTR (embryonal tumors with abundant

•

•

•

•

•

•

•

neuropil and true rosettes)/ETMR (embryonal tumor with multilayered rosettes) should be diagnosed as embryonal tumors with multilayered rosettes, NOS. A tumor with histological features of medulloepithelioma should be diagnosed as medulloepithelioma (recognizing that some apparently bona fide medulloepitheliomas do not have C19MC amplification). –– Atypical teratoid/rhabdoid tumor (AT/RT) is diagnosed by alterations of either INI1 or very rarely BRG1. A genetically defined variant of ependymomas RELA fusion-positive [v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA)], characterized by its peculiar supratentorial location and the worst outcome has been included. Earlier entities such as gliomatosis cerebri and variants such as protoplasmic and fibrillary astrocytoma, and cellular ependymomas have been omitted. Updated profiles of the hematopoietic/lymphoid tumors of the CNS (lymphomas and histiocytic tumors) as per the updates made in hematopoietic/lymphoid WHO classifications have been incorporated. Inclusion of brain invasion along with mitotic count >4 mitoses /10 high power field (hpf) to be as a criterion for the diagnosis of atypical meningioma. A combined terminology of solitary fibrous tumor and hemangiopericytoma (SFT/HPC) into a single entity was incorporated into tumors sharing inversions at 12q13, fusing the NAB2 and STAT 6 genes leading to nuclear STAT 6 expressions on IHC. A grading system was also added. Change in the classification of nerve sheath tumors, with the inclusion of hybrid nerve sheath tumors and separation of melanotic schwannoma from other schwannomas. Newer entities included were: –– Diffuse midline glioma, H3 K27M-mutant: a midline tumor –– Diffuse leptomeningeal disease –– Multinodular and vacuolating neuronal tumor of cerebrum (MVNT)

3.2  Some Major Updates in WHO Classification of Tumors of the CNS, 2016

–– Epithelioid glioblastoma and glioblastoma with neuroectodermal component The WHO 2016 Classification of CNS tumors is depicted in the following table: The WHO 2016 classification of CNS tumors Diffuse astrocytic and oligodendroglial Grade tumors • Diffuse astrocytoma, IDH-mutant   – Gemistocytic astrocytoma, II IDH-mutant • Diffuse astrocytoma, IDH-wild type II • Diffuse astrocytoma, NOS II • Anaplastic astrocytoma, IDH-mutant III • Anaplastic astrocytoma, IDH-wild type III • Anaplastic astrocytoma, NOS III • Glioblastoma, IDH-wild type IV   – Giant cell glioblastoma IV   – Gliosarcoma IV   – Epithelioid glioblastoma IV • Glioblastoma, IDH-mutant IV • Glioblastoma, NOS IV IV • Diffuse midline glioma, H3K27M-mutant II • Oligodendroglioma, IDH-mutant and 1p/19q-codeleted • Oligodendroglioma, NOS II • Anaplastic oligodendroglioma, IDHIII mutant and 1p/19q-codeleted • Anaplastic oligodendroglioma, NOS III • Oligoastrocytoma, NOS II • Anaplastic oligoastrocytoma, NOS III Other astrocytic tumors • Pilocytic astrocytoma I • Pilomyxoid astrocytoma NA • Subependymal giant cell astrocytoma I • Pleomorphic xanthoastrocytoma II • Anaplastic pleomorphic III xanthoastrocytoma Ependymal tumors • Subependymoma I • Myxopapillary ependymoma I • Ependymoma II   – Papillary ependymoma   – Clear cell ependymoma   – Tanycytic ependymoma • Ependymoma, RELA fusion-positive II or III • Anaplastic ependymoma III Other gliomas • Chordoid glioma of the third ventricle II • Angiocentric glioma I • Astroblastoma NA

The WHO 2016 classification of CNS tumors Chordoid plexus tumors • Choroid plexus papilloma I • Atypical choroid plexus papilloma II • Choroid plexus carcinoma III Neuronal and mixed neuronal-glial tumors • Dysembryoplastic neuroepithelial tumor I • Gangliocytoma I • Ganglioglioma I • Anaplastic ganglioglioma III • Dysplastic cerebellar gangliocytoma I (Lhermitte-Duclos disease) • Desmoplastic infantile astrocytoma and I ganglioglioma • Papillary glioneuronal tumor I • Rosette-forming glioneuronal tumor I • Diffuse leptomeningeal glioneuronal NA tumor • Central neurocytoma II • Extraventricular neurocytoma II • Cerebellar liponeurocytoma II • Paraganglioma I Tumors of the pineal region • Pineocytoma I • Pineal parenchymal tumor of II or III intermediate differentiation • Pineoblastoma IV • Papillary tumor of the pineal region II or III Embryonal tumors IV • Medulloblastoma • Medulloblastoma, NOS • Medulloblastomas, genetically defined   – Medulloblastoma, WNT-activated   – Medulloblastoma, SHH-activated and TP53-mutant   – Medulloblastoma, SHH-activated and TP53-wildtype   – Medulloblastoma, non-WNT/ non-SHH • Medulloblastoma, histologically defined   – Medulloblastoma, classic   – Desmoplastic/nodular medulloblastoma   – Medulloblastoma with extensive nodularity   – Large cell anaplastic medulloblastoma • Embryonal tumor with multilayered IV rosettes, C19MC-altered IV • Embryonal tumor with multilayered rosettes, NOS • Other CNS Embryonal tumors   – Medulloepithelioma IV   – CNS neuroblastoma IV

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3  Introduction to WHO Classification of Tumors of the Central Nervous System, 2016

The WHO 2016 classification of CNS tumors   – CNS ganglioneuroblastoma IV   – CNS Embryonal tumor, NOS IV   – Atypical teratoid/rhabdoid tumor IV   – CNS embryonal tumor with rhabdoid IV features Tumors of the cranial and paraspinal nerves • Schwannoma I   – Cellular schwannoma   – Plexiform schwannoma   – Melanotic schwannoma • Neurofibroma I   – Atypical neurofibroma   – Plexiform neurofibroma • Perineurioma I • Hybrid nerve sheath tumors • Malignant peripheral nerve sheath tumors II, III or (MPNST) IV   – MPNST with divergent differentiation   – Epithelioid MPNST   – MPNST with perineurial differentiation Meningiomas • Meningothelial meningioma I • Fibrous meningioma I • Transitional meningioma I • Psammomatous meningioma I • Angiomatous meningioma I • Microcystic meningioma I • Secretory meningioma I • Lymphoplasmacyte-rich meningioma I • Metaplastic meningioma I • Chordoid meningioma II • Clear cell meningioma II • Atypical meningioma II • Papillary meningioma III • Rhabdoid meningioma III • Anaplastic (malignant) meningioma III Mesenchymal, non-meningothelial tumors • Solitary fibrous tumor/ I or II or hemangiopericytoma III • Hemangioblastoma • Hemangioma I • Epithelioid hemangioendothelioma I • Angiosarcoma • Kaposi sarcoma • Ewing sarcoma/peripheral primitive neuroectodermal tumor • Lipoma • Angiolipoma • Hibernoma

The WHO 2016 classification of CNS tumors • Liposarcoma • Desmoid-type fibromatosis • Myofibroblastoma • Inflammatory myofibroblastic tumor • Benign fibrous histiocytoma • Fibrosarcoma • Undifferentiated pleomorphic sarcoma (malignant) • Fibrous histiocytoma • Leiomyoma • Leiomyosarcoma • Rhabdomyoma • Rhabdomyosarcoma • Chondroma • Chondrosarcoma • Osteoma • Osteochondroma • Osteosarcoma Melanocytic tumors NA • Meningeal melanocytosis • Meningeal melanomatosis • Meningeal melanocytoma • Meningeal melanoma Lymphomas NA • Diffuse large B cell lymphoma of the CNS   – Corticoid-mitigated lymphoma   – Sentinel lesions • Immunodeficiency-associated CNS lymphomas   – AIDS-related diffuse large B cell lymphoma   – EBV+ diffuse large B cell lymphoma, NOS   – Lymphomatoid granulomatosis • Intravascular large B cell lymphoma • Low-grade B cell lymphoma • T cell and NK/T cell lymphomas • Anaplastic large-cell lymphoma (ALK+/ ALK−) • MALT lymphoma of the dura Histiocytic tumors NA • Langerhans cell histiocytosis • Erdheim–Chester disease • Rosai–Dorfman disease • Juvenile xanthogranuloma • Histiocytic sarcoma Germ cell tumors NA • Germinoma • Embryonal carcinoma • Yolk sac tumor • Choriocarcinoma

Reference The WHO 2016 classification of CNS tumors • Teratoma   – Mature teratoma   –Immature teratoma   –Teratoma with malignant transformation • Mixed germ cell tumor Familial tumor syndromes • Neurofibromatosis type 1 • Neurofibromatosis type 2 • Schwannomatosis • von Hippel–Lindau disease • Tuberous sclerosis • Li–Fraumeni syndrome • Cowden syndrome • Turcot syndrome • Mismatch repair cancer syndrome • Familial adenomatous polyposis • Naevoid basal cell carcinoma syndrome • Rhabdoid tumor predisposition syndrome Tumors of the sellar region • Craniopharyngioma I   – Adamantinomatous I craniopharyngioma   – Papillary craniopharyngioma I

13 The WHO 2016 classification of CNS tumors • Granular cell tumor of the sellar region I • Pituicytoma I • Spindle cell oncocytoma I Metastatic tumors NA IDH isocitrate dehydrogenase; NA Not assigned; NOS not otherwise specified; RELA v-rel avian reticuloendotheliosis viral oncogene homolog A; MALT mucosa- associated lymphoid tissue; EBV Epstein-Barr virus

Reference 1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison DW, Branger FD, et al., editors. WHO classification of tumours of the central nervous system. 4th Rev ed. Lyon: International Agency for Research Centre; 2016. p. 12–17.

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Diffuse Astrocytic and Oligodendroglial Tumors

4.1

Introduction to Diffuse Astrocytic and Oligodendroglial Tumors

Glial cells or neuroglia are non-neuronal supporting cells in the central nervous system (CNS) and peripheral nervous system required to maintain homeostasis, myelin production, and provide support and protection for neurons. The glial cells include astrocytes, oligodendrocytes, ependymal cells, and microglia. Gliomas are thought to originate from glial (progenitor) cells or stem cells that develop glial features upon transformation into neoplasia. Gliomas are the largest category of primary CNS tumors, a heterogeneous group of neoplasms that affect patients of all age groups. Until recently, gliomas have been classified based on their histologic features and malignancy grade alone. The previous WHO classification (2007) graded glial tumors based on St. Anne–Mayo grading system. These included four grades, grade I to grade IV. Grade I and II were considered as low-grade astrocytomas and III and IV were high-grade astrocytomas. The 2016 WHO Classification categorizes diffuse gliomas (astrocytic and oligodendroglial) that infiltrate the CNS parenchyma and are further classified as astrocytic, oligodendroglial, and rare mixed oligodendroglial–astrocytic. The diffuse glioma grades are Grade II (low grade), Grade III (anaplastic), and Grade IV (glioblas-

toma). Gliomas with a more circumscribed growth pattern most frequently are pilocytic astrocytoma (WHO grade I), subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma and are categorized as other astrocytic tumors [1, 2] The ependymal tumors have WHO grade I, II, or III. Diffuse astrocytomas have an intrinsic capacity for malignant progression to IDH-mutant anaplastic astrocytoma grade III and ultimately progressing to IDH-mutant glioblastoma grade IV [3]. Astrocytic tumors demonstrate IDH1 mutations most commonly and are associated with a TP53 mutation [4]. These tumors rarely exhibit loss of chromosomes 1p and 19q. The most frequent mutation is the R132H (CGT to CAT) found in 83–91% of astrocytic and oligodendroglial tumors. IDH mutations have a definite effect on prognosis and may be predictive of response to radiation and/or alkylating chemotherapy. IDH1 mutations are observed in a high percentage of grade II and III astrocytomas, oligodendrogliomas, and secondary glioblastomas [5–7]. Mutations in IDH2 have been found in fewer than 3% of glial tumors. Interestingly, IDH mutations found in astrocytomas that developed in Li– Fraumeni syndrome are caused by mutations in TP53 suppressor gene [8]. All oligodendrogliomas demonstrate IDH1 mutation along with the characteristic 1p and 19q

© Springer Nature Singapore Pte Ltd. 2020 M. Chougule, Neuropathology of Brain Tumors with Radiologic Correlates​, https://doi.org/10.1007/978-981-15-7126-8_4

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codeletion, and these tumors rarely demonstrate p53 mutation [6]. Another pathway starts with IDH mutation followed by a loss of 1p/19q, which is associated with mutation in the capicua(CIC)gene. These alterations result in the development of grade II oligodendrogliomas, which can then acquire other genetic alterations to transform into its malignant counterpart, i.e., anaplastic oligodendroglioma grade III [9]. The third pathway includes IDH-wild type gliomas. Such gliomas appear to rapidly acquire multiple complex genetic alterations, to become glioblastomas very early in their development due to amplification or mutation of EGFR, and loss of the PTEN gene [4]. It should be noted that the cell of origin for some tumors remains unknown, and it also remains unclear whether there is a common cell of origin or different cells of origin for the different lineage and molecular subtypes [9]. These tumors are classified according to their pure or mixed histology (oligoastrocytoma), the grade, and molecular basis. Reinforcing the latest WHO classification (2016) which integrates the phenotypic and genotypic status based on the IDH status, gliomas have been classified as follows:

4  Diffuse Astrocytic and Oligodendroglial Tumors

Main molecular makers in gliomas are IDH 1/2, 1p/19q deletion, MGMT, TERT, ATRX, and p53, EGFR, PDGF, PDGFR, and H3 K27M-­mutation, which are of diagnostic significance. Details have been discussed in the following chapters.

4.2

Diffuse Astrocytoma, WHO Grade II

Diffuse astrocytoma: based on their IDH (isocitrate dehydrogenase) status are: • Diffuse astrocytoma, IDH-mutant –– Gemistocytic astrocytoma, IDH-mutant • Diffuse astrocytoma, IDH-wild type • Diffuse astrocytoma, NOS

Definition Diffuse astrocytoma, IDH-mutant—A diffusely infiltrating astrocytoma with a mutation in either the IDH1 or IDH2 gene [10]. These are low-grade glial tumors, having slow growth, characterized by increased cellular differentiation, moderate pleomorphism, supported by the presence of ATRX and TP53 mutation, lacking 1p/19q codeletion and carry intrinsic potential for malignant progression [11]. Astrocytic Tumors Diffuse astrocytoma, IDH-wild type—A 1. Diffuse astrocytoma, IDH-wild type, or IDH-­ diffusely infiltrating astrocytoma but without mutant, or NOS, WHO grade II mutations in the IDH genes. 2. Anaplastic astrocytoma, IDH-wild type, or Diffuse astrocytoma, NOS—A tumor with IDH-­mutant, or NOS, WHO grade III morphological features of diffuse infiltrating 3. Glioblastoma, IDH-wild type, or IDH-mutant, astrocytoma, but in which IDH status has not or NOS, WHO grade III been fully assessed. Diffuse midline glioma H3K27M-mutant WHO grade IV

4.2.1 Diffuse Astrocytoma, IDH-Mutant

Oligodendroglial Tumors 1. Oligodendroglioma IDH-mutant, and 1p/19q codeleted or NOS, WHO grade II 2. Anaplastic oligodendroglioma IDH-mutant, and 1p/19q codeleted or NOS, WHO grade III

IDH-mutant diffuse astrocytomas have the intrinsic potential for malignant progression to IDH-­ mutant anaplastic astrocytoma and eventually to IDH-mutant glioblastoma.

Mixed Histology 1. Oligoastrocytoma, NOS (WHO grade II) 2. Anaplastic oligoastrocytoma, NOS (WHO grade III)

Epidemiology Accounts for 11–15% of all astrocytic tumors. Age—affects young adults in the third decade. Male:female—1.3:1.

4.2 Diffuse Astrocytoma, WHO Gr II

17

Localization • Most commonly found in the supratentorial region affecting the cerebral hemisphere with a predilection for frontal and temporal lobes. However, maybe present throughout CNS. • One-third of tumors are seen in the infratentorial compartment, frequently in the pons and medulla. • Deep gray matter structures, thalamus, and basal ganglia are involved in 20% of cases. Clinical Features Seizure is the most common presenting feature in cerebral tumors. Difficulty in speech, changes in sensation or vision, and some form of motor change may be early symptoms. Frontal lobe tumors manifest as personality and behavioral changes. Imaging (Figs. 4.1 and 4.2) Imaging Findings • On MRI, diffuse astrocytoma presents either as a circumscribed or diffusely infiltrating, non-enhancing white matter mass. T1W images show them as a homogeneous hypointense mass, that may expand into the white matter and adjacent cortex and T2W images as a homogeneous, hyperintense mass. On

a

b

Fig. 4.1  Case1: A 29 year old man presented with headache and seizures prompted MR study and revealed diffuse astrocytoma of thalamus. (a) T2W MRI shows a lobulated, focal hyperintense mass involv-

post-contrast T1W images, the mass shows no enhancement. Enhancement suggests progression to higher-grade tumors. DW images typically show no restricted diffusion in mass. MR spectroscopy shows high choline and low NAA [12]. • Differential diagnoses include oligodendroglioma, anaplastic astrocytoma, and cerebral abscess [13]. Herpes encephalitis, cerebritis, acute/subacute infarct, active seizures, or encephalitis may mimic diffuse astrocytoma. Macroscopy • Ill-defined, infiltrating tumor with indistinct margins in gray or white matter. • Appearance: focal spongy to gelatinous areas (due to multiple cysts of varying sizes). • Tumors with prominent gemistocytes may have a single, smooth-walled large cyst. • Calcification is rare. Intraoperative Cytology (IOC) Microphotographs of Case 2 (Fig. 4.3) Intraoperative Cytology • Astrocytic tumor with low to moderate cellularity. • On low power, the neoplastic astrocytes are arranged in irregular clusters around thin-­walled

c ing the left thalamus (b) T1W MRI shows a hypointense mass causing significant compression of left lateral and third ventricles. (c) Diffuse weighted image shows no significant restriction of diffusion

4  Diffuse Astrocytic and Oligodendroglial Tumors

18

c a Fig. 4.2  Case 2: A 32 year old man presented with seizures. MRI study revealed a left temporal diffuse astrocytoma: (a) Axial FLAIR and (b) Post contrast T1 weighted images and perfusion images revealed an ill

a

• •

•

defined poorly enhancing hyperintense cortical based mass (arrow) in the left temporal region with (c) poor perfusion

b

Fig. 4.3  Case 2: Diffuse astrocytoma IOC smears (a) Moderately cellular tumor composed of uniform neoplastic astrocytes on fibrillary background (low power) (b)

•

b

blood vessels. In some tumors, the cells are less cohesive and smear out individually. The nuclei may be round to oval, sometimes elongated with coarsely stippled chromatin and scant cytoplasm. Nuclear atypia or coarse cytoplasmic process may be noted. Background is fibrillary. Smears are taken from the diffusely infiltrating margins may show neoplastic astrocytes scattered among neurons and oligodendrocytes with finely textured neuropil on background as compared to coarser fibrillary background taken for smears from the tumor proper. No mitoses or necrosis.

Fibrillary astrocytes have hyperchromatic nuclei. Background appears mucoid (magnified view of (a)) (Modified field stain)

Histology Microphotographs of Case 2 (Figs. 4.4, 4.5, and 4.6) Histology Findings • A low-grade glioma with moderate cellularity than normal white matter. • The tumor is composed of well-differentiated neoplastic fibrillary astrocytic cells. Nuclear atypia distinguishes it from the reactive a­strocytes. The tumor nuclei are enlarged, round or ovoid, hyperchromatic and have scanty to moderate cytoplasm with fibrillary processes giving rise to fibrillary background.

4.2 Diffuse Astrocytoma, WHO Gr II

19

a Fig. 4.4  Diffuse astrocytoma of the same patient: (a, b) Moderately cellular tumor composed of uniform neoplastic fibrillary astrocytes with hyperchromatic nuclei.

a

b Numerous microcysts give cobweb-like appearance. Mucoid degeneration is noted. (b) Higher magnification of (a). (H&E)

b

Fig. 4.5  Diffuse astrocytoma (a) Nuclear hyperchromasia and atypia is noted (low power) (b) higher magnification of (a). (H&E)

a

b

Fig. 4.6 (a) High power magnification showing minigemistocyte component (H&E) (b) GFAP positive with minigemistocytic component

20

4  Diffuse Astrocytic and Oligodendroglial Tumors

• Mitotic activity is generally absent (a single mitosis in large biopsy does not indicate a higher-grade lesion). • Necrosis and microvascular proliferation are absent. • Other features: microcyst formation, extensive mucoid degeneration, cobweb-like appearance, and calcification may be present.

tively. IDH 1 mutations are heterozygous, involving an amino acid substitution (arginine to histidine) in the active site of the enzyme in codon 132 (R132H). This mutation results in the abnormal production of 2-hydroxyglutarate which causes histone and DNA hypermethylation, G-CIMP hence promoting tumorigenesis. IDH 2 mutations occur in codon 172 and are associated with 2-hydroxyglutaric aciduria (D-2-hydroxyglutaric aciduria [D-2-­ HGA], L-2-HGA, and combined D, L-2-­HGA), which results in seizures, weak muscle tone (hypotonia), and progressive damage to the cerebrum. IDH1 mutations are observed in a high percentage of grade II and III astrocytomas, oligodendrogliomas, and secondary glioblastomas (only 10%) than IDH 2 mutations [4]. Interpretation: IDH1 or IDH2 mutation can be demonstrated by immunohistochemistry

Immunohistochemistry Microphotographs of Case 2 (Figs. 4.7, 4.8, and 4.9; Table 4.1) Differential Diagnosis • Reactive astrocytosis: IDH negative. • Pilocytic astrocytoma: young patients with typical radiological features of solid with cystic nodule. Histology shows Rosenthal fibers and eosinophilic granular bodies. IDH negative and maybe BRAF V600E positive. • Oligodendroglioma: Typical cellular morphology of uniform oligodendrocytes with perinuclear halos and 1p/19q codeleted. • Demyelinating diseases: non-infiltrative lesions with the presence of numerous foamy macrophages. Genetic Profile • Isocitrate dehydrogenase (IDH) IDH is a most important diagnostic marker as it can differentiate glioma from gliosis. IDH 1 and IDH 2 are the two enzymes in the Krebs cycle that catalyze the conversion of isocitrate to alpha-ketoglutarate. IDH1 and IDH2 proteins are present in cytosol and mitochondria respec-

a

Fig. 4.8  Low Mib-1 index (low power)

b

Fig. 4.7  Diffuse astrocytoma (a) GFAP positive (low power) (b) p53-mutant (positive) (low power)

4.2 Diffuse Astrocytoma, WHO Gr II

a

21

b

Fig. 4.9  Diffuse astrocytoma: IDH-1 R132H mutant from (a) microcystic areas (b) cellular areas (low power) Table 4.1  IHC features Marker name GFAP, S100, Vimentin IDH 1-R132

IDH1/2 P53

Expression Positive Positive (90% cases) It is a (stronger) cytoplasmic and (weaker) nuclear stain Nonmutant Positive (94% cases)

ATRX (Alpha thalassemia mental retardation X-linked syndrome)

Immunonegativeor lost (86% cases)

Mib1 (Ki-67)

20% of tumor cells [19]. Epidemiology • Account for approximately 10% of all WHO Grade II diffuse astrocytomas. • Median age group is 40 years. • Male:female = 2:1. Localization Most frequently found in frontal and temporal lobes. However, can develop throughout the CNS.

Histology Microphotographs of the Same Patient (Fig. 4.13) Histology • Neoplastic gemistocytes should account for >20% of all tumor cells. • The neoplastic gemistocytes are large, angulated cells with glassy eosinophilic cytoplasm. The tumor nuclei are eccentric with clumped chromatin some contain distinct nucleoli. • Small cell component with dark nuclei and scanty cytoplasm indicate the proliferating component with a high Mib1 (ki-67) index. • Rare or no mitosis. • Perivascular lymphocyte cuffing is present. Immunohistochemistry Microphotograph of the Same Patient (Fig. 4.14)

Imaging (Fig. 4.12) Macroscopy A firm to soft consistency granular tumor with indistinct boundaries and microcystic change. Intraoperative Cytology • Smears composed of numerous gemistocytes characterized by large, plump cells that have

a

eccentric nuclei with densely clumped chromatin containing small distinct nucleoli. The cytoplasm is typically glassy and eosinophilic cytoplasm. • Background fibrillary.

b

Fig. 4.12  Case 1: A 40 year old woman presented with headache, vomiting, memory loss, prompted MR study. (a and b) A large, well defined, oval, intra-axial, solid-cystic mass seen in right frontal region extending into the right

Immunohistochemistry (IHC) (Table 4.3) Differential Diagnoses • Gliosis—presence of reactive astrocytes that resemble gemistocytes, are IDH1-negative. • Oligodendroglioma with prominent gemistocytic component—shows 1p/19q codeletion.

c half of body of corpus callosum. Cystic component appears hyperintense on T2 weight images with solid component showing heterogenous intermediate signal intensity, better seen on coronal flair sequence image (c)

4.2 Diffuse Astrocytoma, WHO Gr II

25

• Ganglioglioma—Shows the presence of neoplastic ganglion cells which are positive for synaptophysin and MAP 2. • Subependymal giant cell astrocytoma— SEGA is an intraventricular, non-infiltrative, and IDH1-nonmutant, while gemistocytic astrocytoma is intraparenchymal and IDH-mutant. Genetic Profile • IDH mutation present. • TP53 mutations are observed in >80% of cases [21]. Prognosis Gemistocytic astrocytoma is associated with early progression to anaplastic astrocytoma [21].

Fig. 4.14  Gemistocytic astrocytoma GFAP positive (low power)

a

b

c

d

Fig. 4.13  Gemistocytic astrocytoma of the same patient (a) Tumor composed of sheets of neoplastic gemistocytes (low power) (b) Perivascular lymphocytic infiltration (low power) (c, d) Enlarged tumor cells with

glassy, eosinophilic cytoplasm, and stout cytoplasmic processes, eccentric nuclei with distinct nucleoli. Background is fibrillary (high power) (H&E)

4  Diffuse Astrocytic and Oligodendroglial Tumors

26 Table 4.3  IHC findings of Gemistocytic astrocytoma Marker GFAP IDH1, R132H p53

Mib-1 (ki-67)

4.3

Result Strongly positive Positive [20] Positive in gemistocytic and non-­gemistocytic component, thus indicating the gemistocytes are neoplastic in nature and not reactive Low proliferation index is seen in the gemistocytic component than in intermingled small cell component

Anaplastic Astrocytoma, WHO Grade III

Definition Anaplastic astrocytoma based on their IDH (isocitrate dehydrogenase) status are: • Anaplastic astrocytoma, IDH-mutant— Diffusely infiltrating astrocytoma with focal or dispersed anaplasia, significant proliferative activity, and a mutation in either IDH1 or IDH2 gene. • Anaplastic astrocytoma, IDH-wild type—A diffusely infiltrating astrocytoma with focal or dispersed anaplasia, significant proliferative activity but without mutation in IDH genes. • Anaplastic astrocytoma, NOS—A tumor with morphological features of anplastic

a

b

Fig. 4.15  Case 1 Anaplastic astrocytoma: A 50 year old woman presented with confusion, difficulty in speaking and personality changes prompted MR study. (a) Axial T2 and (b) FLAIR and (c) Coronal T2 weighted

astrocytoma, but in which IDH status has not been fully assessed. Patients with IDH-mutant anaplastic astrocytoma are more frequent than the IDH-wild type (6/10 hpf). • Necrosis and microvascular proliferation absent.

Genetic Profile • IDH 1 (R132) mutations—occur in 80% of anaplastic astrocytoma. • ATRX mutation with p53 mutation—present. • Genetic alterations involved in tumor progression from grade II to III are by retinoblastoma pathway, with alterations in the CDKN2A/p 16, CDK4, Rb 1 genes [26]. • Loss of long arm of chromosome 19 also plays a role in tumor progression.

Immunohistochemistry Microphotographs (Fig. 4.21; Table 4.4)

Prognosis • IDH-mutant anaplastic astrocytoma has a better prognosis than IDH-wild type. • Alterations in the CDKN2A/p 16, CDK4, Rb 1 genes exhibit poor prognosis [26].

4  Diffuse Astrocytic and Oligodendroglial Tumors

30

a

b

c

d

Fig. 4.21  Anaplastic astrocytoma (a) GFAP positive (b) p-53 positive (c) High Mib 1(Ki-67) (d) IDH 1(R132H)-mutant Table 4.4  Immunohistochemistry expressions and its interpretations Marker IDH 132

Expression Positive

IDH 132

Negative

IDH 132

Cannot be assessed Positive Strongly positive Nuclear staining lost 5–10%

GFAP P53 ATRX Mib 1 (Ki-67 index)

Remark Anaplastic astrocytoma, IDH-mutant Anaplastic astrocytoma, IDH-wild type Anaplastic astrocytoma, NOS type Glial origin p53 mutation ATRX mutation

4.4

Glioblastoma, WHO Grade IV

Meghana V. Chougule and Umesh K. Bhanot Glioblastoma is a highly aggressive primary brain tumor. They constitute approximately 15% of all intracranial neoplasms and 45–50% of all primary malignant brain tumors. Adults are commonly affected; however, glioblastoma also occurs in the pediatric age group. Glioblastoma in the pediatric age group differs from adult counterpart in their genetic constitution. Glioblastoma based on their IDH (isocitrate dehydrogenase) status are: • Glioblastoma IDH-wild type

4.4 Glioblastoma, WHO Grade IV

• Glioblastoma IDH-mutant • Glioblastoma, NOS Definition Glioblastoma, IDH-wild type A high-grade glioma with predominantly astrocytic differentiation; featuring nuclear atypia, cellular pleomorphism (in most cases), mitotic activity, and typically a diffuse growth pattern as well as microvascular proliferation and/or necrosis and which lacks mutation in the IDH genes. The variants of glioblastoma IDH-wild type are: • Giant cell glioblastoma • Gliosarcoma • Epithelioid glioblastoma Glioblastoma, IDH-mutant A high grade glioma with predominantly astrocytic differentiation; featuring nuclear atypia, cellular pleomorphism (in most cases), mitotic activity, and typically a diffuse growth pattern, as well as microvascular proliferation and /or necrosis; with a mutation in either the IDH1 or IDH2 gene.(WHO 2016). Glioblastoma, NOS A high-grade glioma with predominantly astrocytic differentiation;featuring nuclear atypia, cellular pleomorphism(in most cases), mitotic activity, and typically a diffuse growth pattern, as well as microvascular proliferation and/or necrosis; in which IDH mutation status has not been fully assessed.(WHO 2016) Epidemiology • Glioblastoma, IDH-wild type: IDH1-wild type accounts for 90% of all glioblastomas; they arise de novo and not from a preexisting lower grade precursor lesion. • IDH-mutant glioblastomas account for 10% of all glioblastomas and arise from a lower grade glial tumor [27]. • Age: The IDH-wild type occurs at 55–85 years. IDH-mutant occurs at an earlier age, the mean age being 45 years. • Sex: Males are more affected than females in both types.

31

Clinical Features These are rapidly growing tumors, symptoms depend on tumor location, primarily manifesting as focal neurological deficits (e.g., hemiparesis and aphasia) and tumor-associated edema with increase intracranial pressure. Half of the patients are diagnosed after a seizure. Median survival is 1 year. The length of clinical history is longer in patients with secondary glioblastomas compared to the primary. Location and Morphology • IDH-wild type: centered in the subcortical white matter and deeper gray-matter of cerebral hemisphere; however, these have a widespread anatomical distribution. In children, more commonly it affects basal ganglia and thalamus. • IDH-mutant: Supratentorial deep cerebral white matter is the most common location particularly frontal lobes. • Tumor typically crosses the corpus callosum tracts to involve contralateral hemispheres; it is called butterfly glioma. • Rarely, they can be multifocal and multicentric. Imaging (Figs. 4.22, 4.23, and 4.24) Imaging Findings • On MRI, glioblastoma presents as a large, heterogeneous, poorly defined, diffusely infiltrating white matter mass with central necrosis, thick irregular shaggy wall, and increased vascularity. Intra-tumoral hemorrhage, necrosis, and flow voids (blood vessels) are common with marked peritumoral edema and mass effect. The tumor typically crosses white matter tracts to involve contralateral hemi­ spheres (butterfly glioma). • T1W image shows an irregular, heterogeneous, isointense, or hypointense mass. Subacute hemorrhage may be seen as hyperintense areas. T2W/FLAIR images show a heterogeneous, hyperintense mass with adjacent tumor infiltration and vasogenic edema. On diffusion-­ weighted image tumor typically shows no diffusion restriction. Post-contrast T1W images typically show thick, irregular ring enhancement with a central necrotic area.

4  Diffuse Astrocytic and Oligodendroglial Tumors

32

a

b

Fig. 4.22 Glioblastoma: (a) post contrast axial MR image shows a large, solid-cystic mass in the right frontal lobe with heterogeneously enhancing peripheral solid areas (arrowhead) and central non-enhancing cystic-­

a Fig. 4.23  Glioblastoma: (a) T2 weighted axial and (b) post gadolinium T1 weighted axial show large lobulated soft tissue mass involving the splenium and posterior body of corpus callosum spanning across midline into

necrotic area (arrow). There is mass effect in the form of effacement of frontal sulcal spaces and right lateral ventricle. (b) MR Spectroscopy shows elevated choline peak and reduced NAA peak

b both cerebral hemispheres (giving “butterfly appearance”) more on right side which shows heterogeneous moderate enhancement with non-enhancing necrotic areas

4.4 Glioblastoma, WHO Grade IV

a

33

b

Fig. 4.24  Glioblastoma: (a) T2W axial and (b) post gadolinium T1W axial reveal large lobulated soft tissue mass involving genu and body of corpus callosum with

extension into left frontal white matter showing heterogeneous moderate enhancement (arrowhead) with nonenhancing necrotic areas (arrow)

MR spectroscopy shows elevated choline peak and decreased NAA [28]. • Differential diagnoses on MRI includes primary CNS lymphoma, metastases, tumefactive demyelination, and abscess [29]: –– Primary CNS lymphoma present as enhancing solitary mass or multiple lesions in periventricular region, basal ganglia, thalami, and corpus callosum. Extension along corpus callosum and ependymal surface is often seen. –– Metastases are perceived as multiple round lesions at gray-white matter junction with disproportionate surrounding edema. A single metastatic lesion may be indistinguishable from glioblastoma. –– Tumefactive demyelination shows incomplete or open ring enhancement, open toward the cortex. –– Abscess shows typically diffusion restriction, T2 hypointense wall, thin regular wall

enhancement, and central non-enhancing necrotic area. Macroscopy • Large, infiltrative tumors, typically stippled with red and brown foci of remote and recent hemorrhages (Fig. 4.25). • Cut-surface is variable in color due to heterogeneous components, peripheral grayish tumor with central yellowish necrosis from myelin breakdown. Macroscopic cysts when present contains turbid fluid as a result of liquefied tumor tissue. Intraoperative Cytology (IOC) Microphotographs (Figs. 4.26, 4.27, 4.28, 4.29, and 4.30) IOC Findings • High-grade glial tumor with dense cellularity in comparison with the low-grade astrocytoma.

4  Diffuse Astrocytic and Oligodendroglial Tumors

34

• Palisading of the tumor cells around necrosis is noted. • Morphology of the neoplastic cells varies from malignant astrocytic cells, bipolar cells to poorly differentiated cells.

• Pleomorphic nuclei, multinucleated tumor giant cells, and bizarre cells noted. • Increased endothelial proliferation is a defining feature of glioblastoma. The malignant astrocytic cells with abundant cytoplasmic processes smear around the vasculature. • Brisk mitoses are present. • Other features: neoplastic oligodendroglial component, undifferentiated cells, rhabdoid cells, carcinoma-like cells, etc. Histology Microphotographs (Figs. 4.31, 4.32, 4.33, and 4.34)

Fig. 4.25  Gross image showing left parietal lobe glioblastoma infiltrating into surrounding parenchyma and having typical stippled appearance of red and brown foci of remote and recent hemorrhage with necrotic foci

Histology • A densely cellular glial tumor composed of poorly differentiated, sometimes pleomorphic cells, nuclear atypia, bizarre cells, and multinucleated tumor giant cells may be present. • Necrosis: Palisading coagulative necrosis (irregular zones of necrosis surrounded by tumor cells) may exhibit a serpiginous pattern and/or area of confluent necrosis may be present. A mandatory feature to diagnose glioblastomas and differentiate it from other astrocytic tumors. More areas of necrosis are observed in wild-type than IDH-mutant. • Microvascular proliferation: Prominent microvascular proliferation is an essential feature. Glomeruloid vasculature (glomeruloid tufts of multilayered mitotically active endothelial cells together with smooth muscle

N E

a

N E

b

Fig. 4.26  Glioblastoma (a, b) Dense cellularity, pleomorphism and necrosis (NE) with peripheral palisading of tumor cells (Modified field stain, (a): Scanner view, (b): Higher magnification of the same)

4.4 Glioblastoma, WHO Grade IV

a

N E

35

N E b

Fig. 4.27  Glioblastoma (a) neoplastic astrocytes around thick walled blood vessels (arrow) and necrosis (NE) (low power), (b) elongated bipolar cells with nuclear atypia around blood vessels (high power) (Modified field stain)

a

b

c

d

Fig. 4.28  Glioblastoma: (a–d) Endothelial hyperplasia and tumor cells smearing around the blood vessels. (c) Spindle tumor cells around blood vessels. (d) Mitotic figure (arrow) and pleomorphic cells (Modified field stain)

4  Diffuse Astrocytic and Oligodendroglial Tumors

36

a

b

Fig. 4.29  Glioblastoma: (a, b) Pleomorphic astrocytes, mono and multinucleated tumor giant cells (arrowhead). The pleomorphic cells have scanty cytoplasm. At a times

a

b

Fig. 4.30  Glioblastoma: (a) showing proliferation of oligodendroglial component on fibrillary background (low power) (b) showing presence of rhabdoid-like/epithelioid-­

• • • •

becomes difficult to identify the astrocytic nature. ((b): Higher magnification of (a)) (Modified field stain)

cells forming multiple lumina resembling a glomerulus) are present. Another less common type is hypertrophic proliferating endothelial cells within medium-sized vessels. Microvascular proliferation is usually noted in the vicinity of necrosis. Tumors show brisk mitotic activity with atypical mitoses. Thrombosed blood vessels are noted. Apoptotic bodies may be found. A small number of glioblastomas may show perivascular cuffing of lymphocytes along with gemistocytic component.

like/gemistocytic-like cells (higher magnification of the same) (Modified field stain)

Histologic Patterns or Cellular Composition • Oligodendroglioma-like component: is more common in mutant glioblastomas than wild type (54% vs. 20%) (Fig. 4.35). • Small cell component/Small cell glioblastoma, IDH-wild type—composed of densely packed monomorphic small cells, which exhibit mild nuclear atypia and frequent mitosis. IDH mutations—absent (Fig. 4.36). • Presence of primitive neuronal cells, ganglion cells (Fig. 4.37). • Adenoid glioblastoma/adenocarcinoma-­ like component (Fig. 4.38)

4.4 Glioblastoma, WHO Grade IV

37

NE NE

a

b

NE NE

c

d

Fig. 4.31  Glioblastoma: (a, b) focus of ischaemic necrosis (NE) surrounded by palisading tumor cells and presence of microvascular proliferation. Serpiginous pattern is

noted (scanner view) (c) tumor with increased cellularity (arrow) and confluent necrosis (NE) (low power) (d) Endothelial proliferation (arrowhead) (low power) (H&E)

• Rhabdoid-like/epithelioid-like/gemistocytic component (Fig. 4.39). • Granular cell component or granular cell glioblastoma-wild type (Fig. 4.40)

• Nuclei are eccentric, oval to bean-shaped, containing dispersed chromatin and a single prominent eosinophilic nucleolus. • Reticulin stains show a distinct network between neoplastic cells [30]. • Necrosis, microvascular proliferation, and brisk mitotic activity.

Presence of Granular Cells or Granular Cell Glioblastoma Histology: • Large, round to oval granular cells (60–100 μm in diameter) in sheets or interspersed within the Differential Diagnosis of Granular Cell tumor. The eosinophilic granules are entirely Glioblastoma distributed in the cytoplasm or distributed • Reactive lesion—Aggregates or sheet-like toward the cell periphery leaving a central pale arrangement of macrophages (CD68 positive). to clear zone (“targetoid” appearance) [30]. The macrophages have clear or only finely • Granules are lysosomes which are PAS-­ vacuolated cytoplasm, often concentrated positive and diastase resistant. around blood vessels. • Multiple sclerosis • Progressive multifocal leukoencephalopathy

38

a

4  Diffuse Astrocytic and Oligodendroglial Tumors

Immunohistochemistry: Granular Cell Glioblastoma • GFAP and S-100 protein-positive. Cytoplasmic GFAP immunoreactivity can be either uniform or peripheral, a circular rim of staining being seen beneath the cell membrane. • IDH mutations-absent. • MIB-1 proliferation rates are significantly higher in the conventional infiltrating astrocytoma cells that are interspersed than in the large granular cells. • Ultrastructural studies show intermediate filaments in the same peripheral cytoplasmic distribution as GFAP immunoreactivity. Thus, GFAP staining is most likely neither artifact nor nonspecific cross-reactivity. Gliosarcoma, IDH-Wild Type A sarcomatous component in a preexisting glioblastoma, should prompt the diagnosis of gliosarcoma.

b

Metaplasia Adenoidmetaplasia, squamous metaplasia, the formation of bone and cartilage are more common in gliosarcoma than in ordinary glioblastomas [31].

4.4.1 P  resence of Epithelioid Cells/ Epithelioid Glioblastoma, IDH-Wild Type

c Fig. 4.32  Glioblastoma: (a) Spindle cell morphology with brisk mitotic activity (arrow) (low power) (b) Relatively monomorphic cytology with atypical mitotic figure (arrow) and a large tumor giant cell (low power) (c) Bizarre pleomorphic mono and multinucleated giant cells (high power) (H&E)

Definition A high-grade diffuse astrocytic tumor variant with a dominant population of closely packed epithelioid cells, some rhabdoid cells, mitotic activity, microvascular proliferation, and necrosis. These are IDH-wild type and BRAFV600E mutation is found in more than 50% of tumors. It is frequently found in children and young adults (Figs. 4.41 and 4.42).

4.4 Glioblastoma, WHO Grade IV

39

a

b

c

d

e

f

Fig. 4.33  Glioblastoma: Microvascular proliferation (a–c) Garland of proliferated tumor blood vessels with a thrombosed vein is noted in (c). (d) Hyalinised vascular proliferation (e, f) Glomeruloid microvascular proliferation (H&E)

4  Diffuse Astrocytic and Oligodendroglial Tumors

40

a

b

Fig. 4.34  Glioblastoma: (a) Glioblastoma with large thrombosed blood vessels (arrow) and necrosis. (b) Perilymphocytic cuffing (H&E)

• Cytokeratin (AE1/AE3) or EMA—may be focally positive. • BRAF V600E—mutation is noted in 50%. • Negative for Melan-A, myoglobin, Desmin, and SMA. • SMARCB1—retained throughout the tumor cell population.

Fig. 4.35  Glioblastoma: with oligodendroglial component with microvascular endothelial proliferation (H&E)

Histology: Epithelioid glioblastoma Tumor is composed of a focally discohesive population of epithelioid cells. The uniform tumor cells with eccentric nuclei and a moderate amount of dense eosinophilic cytoplasm. Necrosis is present. Immunohistochemistry of Epithelioid Glioblastoma • S100, GFAP, Vimentin-positive.

Differential Diagnosis of Epithelioid Glioblastoma • Pleomorphic xanthoastrocytoma shows the presence of Rosenthal fibers and eosinophilic granular bodies which is not a feature of epithelioid glioblastoma. • Atypical teratoid/rhabdoid tumor (AT/RT) shows a cell population of rhabdoid cells and necrosis mimicking epithelioid glioblastoma. SMARCB1(INI-1) loss in tumor cells is diagnostic of ATRT [32]. BRAF V600E-mutation is found in 50% of cases of epithelioid glioblastomas [33]. • Lipidized cells: presence of lipidized cells and or heavily lipidized glioblastoma: tumor composed of foamy tumor cells (D.D. Anaplastic PXA—BRAF V600 positive while glioblastoma—BRAF V600-negative).

4.4 Glioblastoma, WHO Grade IV

a Fig. 4.36  Glioblastoma: (a, b) with small cell component monomorphic round to oval, mild hyperchromatic nuclei with bland chromatin, small inconspicuous nucle-

41

b oli minimal discernable cytoplasm. Brisk mitotic activity D.D. lymphoma. (b): Higher magnification of (a) (H&E)

a

b

Fig. 4.37  Glioblastoma: (a, b) With primitive cell component. Courtesy: Dr. M. Rosenblum (H&E, (a): scanner view, (b): medium power)

a

b

Fig. 4.38  Glioblastoma: (a, b) Adenoid glioblastoma: Small epithelioid cells arranged in nests and ill-formed glandular pattern. Background shows mucinous stroma (H&E). Courtesy by Dr. M. Rosenblum

4  Diffuse Astrocytic and Oligodendroglial Tumors

42

a

b

Fig. 4.39  Presence of glioblastoma: (a) Glioblastoma with rhabdoid-like/epithelioid-like/gemistocytic features (H&E) (b) IDH-1 R132H mutation present

a

b

c

d

Fig. 4.40  Presence of granular cells or granular cell glioblastoma: (a) Diffuse sheets of granular cells with mitotic activity. (b, c) Large granular cells with eosinophilic cyto-

plasm showing central clearing leaving peripheral rim of granular cytoplasm (arrow) (H&E) (d) GFAP positive. Courtesy: Dr. M. Rosenblum

4.4 Glioblastoma, WHO Grade IV

43

NE

a

b

a

b

c c Fig. 4.41  Epithelioid glioblastoma: (a) Necrosis (NE) surrounded by epithelioid cells. (scanner view) (b, c) The cells are relatively uniform with eccentrically placed nuclei and dense eosinophilic cytoplasm, and abundant mitotic figures. Rosenthal fibers and eosinophilic granular bodies are not features of glioblastoma (higher magnifcation of (a)) (H&E). Courtesy: Dr. M Rosenblum

Fig. 4.42 Glioblastoma: (a) Epithelioid-like features (H&E) (b) GFAP positive (c) Cytokeratin focally positive

4  Diffuse Astrocytic and Oligodendroglial Tumors

44

Immunohistochemistry Microphotographs: Glioblastoma (Table 4.5; Figs.  4.43 and 4.44; Table 4.6)

• Lymphoma: Diffuse large-cell B cell lymphoma shows CD45 and CD20 positivity and are immuno-negative for GFAP and OLIG2. Very high Mib 1 index. Differential Diagnosis of Glioblastoma • Metastatic disease: Negative for GFAP, • Anaplastic oligodendroglioma are IDH1-­ OLIG2, and S100. The immuno-positivity of mutant, exhibit 1p/19q codeletion by molecuthe tumor depends on the site of origin of the lar study. primary tumor. Table 4.5 Glioblastoma: immunohistochemistry and interpretation Marker name GFAP, S100 OLIG 2 IDH1 (R132H) or IDH2 (R172) IDH1 (R132H) or IDH2 (R172) ATRX

ATRX

Cytokeratin (AE1/AE3)

Expression Positive

Remark Glial origin

Positive

Glioblastoma, IDH-mutant

Negative

Glioblastoma, IDH-wild type

Loss of expression (mutant)

Typically present with IDH and Tp53 mutation in IDH-mutant WHO grade IV glioblastoma IDH-wild type

Retained (no mutation) May be positive focally

Tp53

Positive

Nestin

Positive

EGFR

WT1 Mib-1 (Ki-67) proliferation index

Expressed (40–90%) in wild type [5] and rare in IDH-­ mutant Maybe expressed 15–20%, may go upto >50% in some of the cases

• Cross-reactivity with GFAP • Due to epithelial differentiation Strong and diffuse immunohistochemical overexpression Frequently expressed in glioblastoma. Helpful diagnostically to distinguish between glioblastomas and high-grade gliomas Amplification is noted in primary glioblastoma

GFAP

a

S100

b

IDH1

c

In low- and high-grade tumors as well

Fig. 4.43  Glioblastoma (a) GFAP positive (b) S-100 positive (c) IDH 1 R-132H mutant

4.4 Glioblastoma, WHO Grade IV

45

Oilg2

a

Cytokeratin

b

p53

c

Ki-67

d

Fig. 4.44  Glioblastoma (a): OLIG 2 positive (b): focal cytokeratin positive (c) p53 positive (d) High Mib-1 (Ki-67) index

Genetic Profile (rare). It acts by causing increased DNA tran• Cytogenetic abnormalities scription angiogenesis, cellular proliferation, Primary glioblastoma demonstrates the gain and antiapoptosis by RAS/MAPK and P13/ of chromosome 7 and loss of chromosomes 9, AKT pathways. EGFR—targeted therapy may 10, and 13 are frequently encountered. The be beneficial to a specific subset of patients. combination of gain 7p and loss of 10q is also • Alterations in receptor tyrosine kinase P13/ frequently noted. EGFR amplification and PTEN/AKT/mTOR pathway: Alterations in PTEN deletion are associated with 7p+/10q-is receptor tyrosine kinase pathway occurs in more frequent in primary glioblastoma than 90% of primary glioblastomas. Mutations and the secondary. amplifications in P13 gene (PIK3CA and • IDH mutations: IDH mutation is the diagnosPIK3R1) occur in less than 10% of cases. The tic molecular marker for secondary glioblastoPTEN mutations are seen in 15–40% of cases mas derived from the lower grade of primary glioblastomas and are exceptional IDH1-mutant, diffuse astrocytoma, or IDH1-­ in secondary glioblastomas. PTEN mutations mutant, anaplastic astrocytoma. Details have are involved in cell proliferation, tumor cell been discussed in the diffuse astrocytoma, migration, and tumor cell invasion. IDH-mutant. • TERT (Telomerase reverse transcriptase pro• Epidermal growth factor receptor amplificamoter mutations): tion and mutation is most commonly encounThese are commonly found in 70–80% pritered in primary glioblastoma (35%) and other mary glioblastoma and also in oligodendrowild type gliomas than secondary glioblastoma glioma. They often involve C228T and C250T

46

4  Diffuse Astrocytic and Oligodendroglial Tumors

Table 4.6  Epidemiology, radiology, histology, immunohistochemistry, and molecular genetic features of primary (IDH-wild type) and secondary glioblastomas (IDH-­ mutant) are contrasted

glioblastoma patients, but it is not a diagnostic marker. The O6-methylguanine-DNA methyltransferase (MGMT) gene encodes a DNA repair enzyme that can nullify the effects of alkylating chemotherapy such as temozolomide. The alkylating chemotherapy damages DNA by adding methyl groups. Therefore, a tumor with a high degree of MGMT activity will be resistant to chemotherapies that target DNA at this location [35]. Tp53 mutation Tp53 mutations along with IDH and ATRX are characteristics of diffuse and anaplastic astrocytoma, secondary glioblastomas (81%), giant cell glioblastomas. These are less common in primary glioblastomas (27%). CDKN2A deletion and RB1 alterations are mutually exclusive in glioblastomas. Inactivation of genes occurs in both primary and secondary glioblastomas. Platelet-derived growth factor receptor (PDGF)-α: Increased expression is indicative of a gene inactivation. It is noted in the mesenchymal subgroup of glioblastoma. Its presence may help in angiogenesis, a feature of malignancy. Neurofibromatosis type 1 (NF1) gene inactivation: Approximately 20% of glioblastomas show NF1 gene mutation. It is most commonly noted in the mesenchymal subgroup of glioblastoma. The tumor suppressor gene (NF1) encodes neurofibromin, which negatively regulates Ras and (mTOR) signaling in astrocytes causing in antitumorigenic effect. It is an indicator for targeted therapy.

Cell of origin

Frequency

Median age Location

Radiology

Necrosis with palisading IHC

Glioblastoma, IDH wild type Arises de-novo

Approx. 90% of all glioblastomas Around 62 years Supratentorial

Large areas of central necrosis present Enhancing tumor More edema Extensive (90%) No-IDHmutations

Molecular study Present (72%) TERT promoter mutations TP53 Present (27%) mutations ATRX Exceptional EGFR Present (35%) amplification PTEN Present (24%) mutations

Glioblastoma, IDH-mutant Arises from preexisting low-grade tumors Approx. 10%

Around 44 years

•

Preferentially frontal lobe along the rostrum of lateral ventricles Lesser areas of central necrosis

•

Most commonly non-enhancing tumor Less edema Limited (54%)

•

IDH-mutant (IDH1 > IDH2) Present (26%)

Present (81%) Present (71%) Rare Rare

mutations of the promoter region and inhibit apoptosis. They are inversely correlated to TP53 mutations within IDH-wild type adult diffuse gliomas. TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas [34]. • O6-methylguanine-DNA methyltransferase methylation (MGMT) Methylation of the MGMT gene promoter is a favorable prognostic and predictive factor in

•

Prognosis • Glioblastoma is known for its fatal outcome. The mortality occurs after 15–18 months of diagnosis. • Favorable prognosis has been observed in –– Patients under 50 years and complete macroscopic resection. –– Genetic alterations such as MGMT promoter methylation and IDH mutations. –– Giant cell glioblastoma.

4.4 Glioblastoma, WHO Grade IV

• The extent of necrosis is associated with reduced survival [36].

4.4.2 G  iant Cell Glioblastomas, IDH-Wild Type, WHO Grade IV Definition Rare histological variant of IDH-wild type glioblastoma, histologically characterized by bizarre, multinucleated giant cells, and occasionally abundant reticulin network. Epidemiology Account for 20). • Angulated giant cells, with large, pleomorphic nuclei that contain prominent nucleoli and abundant eosinophilic cytoplasm. • Large ischemic necroses. • Brisk mitoses with atypical forms. • Perivascular accumulation of tumor cells may mimic ependymoma. • Lymphocyte aggregates are usually present. Immunohistochemistry Microphotographs (Fig. 4.48; Table 4.7)

b

Fig. 4.45  IOC Giant cell glioblastoma: (a, b) Extremely bizarre, pleomorphic, mono and multinucleated tumor giant cells(arrowhead). Atypical mitotic figures (arrow). (Modified field stain)

4  Diffuse Astrocytic and Oligodendroglial Tumors

48

a

b

c

d

Fig. 4.46  Giant cell glioblastoma: (a–c) numerous multinucleated tumor giant cells (arrowhead), bizarre cells, atypical mitotic figure (arrow) and interspersed lymphocytes. (a, b: low power) (c) Bizarre cells have hyperchro-

a Fig. 4.47  Giant cell glioblastoma (a, b) numerous mono and multinucleated tumor giant cells, bizarre cells, atypical mitotic figures. Tumor nuclei have prominent

matic nuclei and fusiform cells. (c, d) large mononucleated cells with abundant eosinophilic cytoplasm (High power) (H&E)

b nucleoli. Lymphocytic aggregates noted (Courtesy by Dr. M. Rosenblum) (H&E, low power)

4.4 Glioblastoma, WHO Grade IV

Differential Diagnosis • Metastatic carcinoma: CK positive. • Anaplastic pleomorphic xanthoastrocytoma: Large pleomorphic astrocytes with sheets of foamy cells, eosinophilic granular bodies, and Rosenthal fibers, atypical nuclei with pseudoinclusions. BRAF fusion proteins noted [39–41]. • Glioblastoma, IDH-mutant: molecular study differentiates the two. Glioblastoma, IDH-­ mutant and giant cell glioblastoma both have high frequency of TP53 mutations [38, 42]. However, giant cell glioblastoma exhibits increased AURKB expression and rarely show EGFR amplification than the conventional glioblastoma. Genetic Profile • IDH mutations are absent—IDH-wild type [14]. • TP53 mutation in >80% cases. • PTEN mutations in 33%.

49

• Lack EGFR amplification/overexpression and homozygous CDKN2A deletion. Prognosis Despite a high degree of anaplasia, giant cell glioblastoma is more circumscribed and is known to have a better prognosis than ordinary glioblastoma [14]. Table 4.7  IHC findings Markers GFAP, Nestin Tp53 Mib1 (Ki-67) index CK

IDH1/2 mutation

a

b

c

d

Expression Positive Positive (>80% cases) ref [38] High

Negative (Metastatic carcinomas are rare in children. In adults, CK-negative tumor rules out metastatic carcinoma) Absent (IDH-wild type)

Fig. 4.48  Giant Glioblastoma: (a) GFAP- expression is variable (b) S-100 positive. (c, d) High Mib 1(Ki-67) index

4  Diffuse Astrocytic and Oligodendroglial Tumors

50

4.4.3 Gliosarcoma, IDH-Wild Type, WHO Grade IV

the location of the tumor and increase intracranial pressure.

Definition A variant of IDH wild type glioblastoma characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. It is most commonly associated with classic (astrocytic) glioblastoma. However, it may be found with ependymoma (ependymosarcoma), oligodendroglioma (oligosarcoma). Gliosarcomas can present de novo or appear during the post-treatment phase of glioblastoma.

Localization Cerebral hemisphere involving temporal, frontal, parietal, and occipital lobe in decreasing order of frequency.

Epidemiology Account for approximately 2% of all glioblastomas. Affects adults most commonly in 40–60 years of age. Male:female = 1.8:1. Clinical Features Clinical profile is similar to IDH1-wild type glioblastoma with short duration symptoms reflecting

a

Imaging (Figs. 4.49 and 4.50) Imaging Findings It is a peripherally located heterogeneous necrotic infiltrative mass with invasion of dura and adjacent skull. • On T1W MRI: appears as a heterogeneous hypointense mass. • On T2W images: mass is heterogeneous hyperintense with necrosis and hemorrhage. Marked vasogenic white edema is seen around the mass. • Post-contrast T1W image shows heterogeneous thick, irregular enhancement with central necrosis. Dural invasion and skull involvement can be appreciated on contrast images.

b

Fig. 4.49  Frontal gliosarcoma in a 55 year male patient: MR study (a) Axial and (b) coronal T2 weighted images show a large heterogeneous T2 hyperintense mass

in the frontal lobe with marginal cystic areas with erosion of the cribriform plate and extension into the nasal cavity

4.4 Glioblastoma, WHO Grade IV

a

51

b

Fig. 4.50  Recurrent frontal gliosarcoma in the same patient after 4 years: (a) Axial T2 and (b) T1 weighted images show a large heterogeneous T2 hyperintense mass in the left frontal lobe with marginal cystic areas

• Differential diagnosis includes glioblastoma, metastasis, hemangiopericytoma, and abscess. Macroscopy Firm, well-circumscribed (high connective tissue content) mass that resembles metastasis or a meningioma when attached to dura. Intraoperative Cytology • Highly cellular smears showing neoplastic astrocytic cells and mesenchymal spindle cells. Other components such as chondroid or muscle or adipose tissue may be present. • Cellular pleomorphism and nuclear atypia. • Mitotic activity noted. Histology Microphotographs (Figs. 4.51 and 4.52) Histology • Biphasic pattern—an admixture of gliomatous and sarcomatous tissue [14].

• Glial component typically shows features of glioblastoma. However, oligodendroglioma and ependymomas may be rarely noted. • Sarcomatous component resembles fibrosarcoma or malignant fibrous histiocytoma exhibiting nuclear atypia, mitotic activity, and necrosis. Mesenchymal differentiation such as the formation of cartilage, bone, osteoid– chondroid tissue, smooth and striated tissue, and lipomatous features [43]. • Epithelial differentiation in form of carcinomatous features with gland-like or adenoid formations and squamous metaplasia may be noted. • Primitive neuronal components may occur rarely. • Collagen deposition may be present in the mesenchymal part. This can be confirmed by trichrome stain and the same is negative for GFAP. Immunohistochemistry Microphotographs (Fig. 4.53; Table 4.8)

4  Diffuse Astrocytic and Oligodendroglial Tumors

52

a

b

c

d

Fig. 4.51  Gliosarcoma (a) Primary gliosarcoma and (b–d) recurrent tumor in frontal lobe. (a, b) Biphasic tumor composed of glial and sarcomatous component. The glial component is astrocytic in nature. The sarcomatous component is in form of spindle cells arranged in

a Fig. 4.52  Gliosarcoma (a) Fibrosarcoma-like sarcomatous component (arrowhead). (low power) (b) Magnified view of the microvascular proliferation and glial compo-

fascicles and bundles. Microvascular proliferation noted. (c) Predominantly sarcomatous component with scant interspersed glial component. (d) Foci of undifferentiated or primitive cells noted (H&E, scanner view)

b nent showing nuclear atypia and increased mitotic activity (arrow) (Higher magnification of same) (H&E)

4.5 Diffuse Midline Glioma, WHO Grade IV, H3 K27M Mutant

4.5

53

 iffuse Midline Glioma, WHO D Grade IV, H3 K27M Mutant

Definition An infiltrative midline high-grade glioma with predominantly astrocytic differentiation and a K27M mutation in either H3F3A or HIST1H3F3B/C.

Fig. 4.53  Gliosarcoma: GFAP positivity in gliomatous areas and negativity in sarcomatous areas

Table 4.8  IHC findings Markers GFAP

Reticulin

IDH1 (R132H) p53 EGFR overexpression

Expression Positive in glial component and negative in the sarcomatous component Positive in sarcomatous component and negative in the glial component Negative (IDH-wild type) Positive in glial and sarcomatous component Absent (helps to differentiate from IDH-wild type glioblastoma) [44]

Genetic Profile • Tp53 and PTEN mutations are observed. • Gains of chromosomes 7,9q and 20q; losses of chromosomes 10,9p and 13q and alterations of chromosome 3. • Expression of SNA12, TWIST, MMP2, and MMP6 have been demonstrated in mesenchymal areas [45]. Prognosis • Gliosarcoma carries a poor prognosis. • Skull invasion and systemic metastasis have been reported in some cases [45].

Epidemiology Affects mostly children of 5–11 years but can be found in adults as well. No gender specificity noted. Location Brainstem, thalamus, and spinal cord. Clinical Features Short history of clinical features related to CSF obstruction or brainstem dysfunction such as cranial nerve abnormalities, ataxia, and long tract symptoms. Imaging (Fig. 4.54) Imaging Findings On MRI, usually T1-hypointense and T2-hyperintense, large, expansile mass most commonly arising in pons. Contrast enhancement, hemorrhage, and necrosis may be seen. Infiltration into surrounding structures may be noted. Macroscopy Infiltration of the tumor into the surrounding structures causes distortion and enlargement of the anatomical structures such as the cerebellar peduncles, the cerebellar hemispheres, the midbrain, and the medulla. Histology Microphotographs (Figs. 4.55 and 4.56)

4  Diffuse Astrocytic and Oligodendroglial Tumors

54

a

b

c Fig. 4.54  Pontine glioma: (a) Axial T2 (b) FLAIR images (c) sagittal T2 weighted images show a large infiltrating heterogeneous T2 hyperintense mass lesion in the pons with pontine bulge

Histology • Tumor is composed of neoplastic astrocytes which range from small and monomorphic in some tumors to large and pleomorphic in the others. Oligodendroglial morphology may also be present. • Generally, the tumor exhibits features of cellular pleomorphism, atypia with or without necrosis and microvascular proliferation. Ten

percent of tumors are histologically consistent with grade II as they lack typical features of high-grade tumor such as mitotic figures, microvascular proliferation, and necrosis. Despite the cellular features, the presence of H3 K27M-mutant grade IV and midline location is mandatory to designate the tumor as diffuse midline glioma, WHO grade IV [46] (Table 4.9).

4.5 Diffuse Midline Glioma, WHO Grade IV, H3 K27M Mutant

a

b

c

d

Fig. 4.55  Diffuse midline glioma: (a) Cellular tumor composed of neoplastic astrocytes. Microvascular proliferation is noted. (b, c) Malignant features such as nuclear pleomorphism, tumor giant cells, microvascular prolifera-

Differential Diagnosis • Diffuse astrocytoma, IDH-mutant • Diffuse astrocytoma, IDH-wild type • Anaplastic astrocytoma • Glioblastoma • Small cell carcinoma metastasis Genetic Profile • H3 K27M mutation-specific immunostain— positive A heterozygous mutation at K27 position encoding the H3F3A, HIST1H3B, HIST1H3C genes. H3F3A gene encoding for histone

55

tion, increased mitoses are noted. (d) Strong nuclear immunoreactivity for K27M-mutant H3 in the tumor cells and absent in blood vessels (H&E) (Courtesy by Dr. B. N. Nandeesh)

H3.3 is most commonly demonstrated in diffuse midline gliomas. The lysine is replaced by methionine at 27th position, results in a decrease in H3K27me3, thought to be due to inhibition of PRC2 activity in histone variant H3.3 (H3.3-K27M). This mutation leads to a global reduction of H3K27 trimethylation by sequestering an enzymatic subunit of the polycomb repressive complex 2. As a consequence, the epigenetic setting of the cell including DNA methylation is altered and drives gene expression toward tumorigenesis [47, 48].

56

4  Diffuse Astrocytic and Oligodendroglial Tumors Table 4.9  Immunohistochemistry findings Markers H3 K27M-mutant S100, NCAMI, and OLIG 2 GFAP IDH-1/2 ATRX P53

a

c Fig. 4.56  Diffuse midline glioma (a, b) diffuse midline glioma with oligodendroglial morphology with few mitotic figures (H&E) (c) Strong nuclear immunoreactivity for K27M-mutant H3 in the glioma cells and absent in blood vessels. (Courtesy by Dr. B. N. Nandeesh)

• Mutations in PDGFRA, PIK3CA, PIK3R1 of PTEN occur in 50% of cases. Prognosis Prognosis of these tumors remains uniformly lethal as compared to the IDH-wild type tumors.

Variable Negative 10–15% of tumors show mutation (i.e., loss of nuclear expression) Positive in 50% of cases

The median survival of these patients is around 1 year from the time of diagnosis [49, 50].

4.6

b

Expression Nuclear positive-specific immunostain Positive

Oligodendroglial Tumors

Introduction Oligodendrogliomas are types of gliomas that are believed to originate from the oligodendrocytes of the brain or from a glial precursor cell. Oligodendrocytes are large glial cells producing the myelin sheath insulating neuronal axons (analogous to Schwann cells in the peripheral nervous system), although some oligodendrocytes (called satellite oligoden­ drocytes) are not involved in myelination. Oligodendrogliomas arise most frequently in the cerebral hemispheres. They occur primarily in adults than in children, presenting with headache and seizures. They are grade II (lowgrade, slow-growing) and grade III (anaplastic). They are differentiated from other gliomas on the basis of their unique genetic characteristics (IDH mutation and 1p/19q codeletion) and better response to chemotherapy. As a result of combined treatment with surgery, chemotherapy, and radiotherapy, survival rates in patients without recurrence are also good, even for patients with malignant (anaplastic) tumors.

4.6.1 Oligodendroglioma, IDHMutant, and 1p/19q Codeleted Definition Oligodendroglioma, IDH-mutant, and 1p/19q codeleted: A diffusely infiltrating, slow-growing glioma with IDH1 or IDH2

4.6 Oligodendroglial Tumors

57

mutation and codeletion of chromosomal arms 1p and 19q. Oligodendroglioma, NOS type: A diffusely infiltrating, glioma with classical oligodendroglial histology in which molecular testing for combined IDH mutation and 1p/19q codeletion could not be completed or was inconclusive. Loss of heterozygosity of 1p/19q occurs in 60–80% of oligodendroglioma [51]. It is an established genetic marker of glioma with predominant oligodendroglial morphology [52]. Codeletion of 1p/19q has also been demonstrated to be a prognostic marker [53] as well as predictive of responsiveness to PCV chemotherapy and radiation [54, 55]. Epidemiology Oligodendroglial tumors account for 1.7% of all brain tumors (Oligodendroglioma grade II constitutes 1.2% and anaplastic oligodendroglioma 0.5%). • Age: Peak incidence is in 35–44 years. • Rare in children below 18 years. • Pediatric oligodendrogliomas frequently lack IDH mutation and exhibit 1p/19q codeletion [55]. • Male:female = 1.3:1 Clinical Features Most common presentation is seizures, headache, increased intracranial pressure, focal neurological deficits, cognitive or mental changes. Localization IDH-mutant and 1p/19q-codeleted oligodendroglioma is most frequently found in cortex and white matter of cerebral hemispheres with a predilection for frontal lobe (>50% of all patients), followed by temporal, parietal, and occipital lobes. Primary oligodendrogliomas of the spinal cord are rare and account for 2% of all spinal cord tumors. Imaging (Figs. 4.57 and 4.58) Imaging Findings Oligodendroglioma presents as a heterogeneous, circumscribed mass, typically located in subcor-

Fig. 4.57  Case 1: A 22 year old boy presented with seizures, behavioral and emotional change, prompted MR study. T2 axial image revealed a right frontal mass involving the cortex and subcortical white matter with T2 hypointense areas corresponding to calcification (arrow). There is moderate perifocal edema with effacement of adjacent sulcal spaces

tical white matter and cortex causing expansion of involved cortex, most frequently in the frontal lobe. Other commonly observed features are calcification (70–90% of tumors) and cystic degeneration, whereas hemorrhage and peritumoral edema are uncommonly responsible for heterogeneity. Mass may cause adjacent calvarial remodeling or erosion. • T1W images: heterogeneous, hypointense, or isointense mass that expands white matter and adjacent cortex. • T2W images: heterogeneous, hyperintense mass expanding overlying cortex. • DW images typically show no restricted diffusion in mass. • On post-contrast T1W images mass appears heterogeneously enhancing. • MR spectroscopy shows elevated choline and reduced NAA in mass [56]. Differential Diagnosis • Anaplastic oligodendroglioma, astrocytomas, pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNET), ganglioglioma.

4  Diffuse Astrocytic and Oligodendroglial Tumors

58

a

b

Fig. 4.58  Oligodendroglioma: A 30 year old man presented with behavioral changes, memory loss, and seizures. On MR study (a) Diffuse, ill-defined, lobulated, infiltrative mass was seen in the right anterior frontal region with involvement of the ordering cortex as well as

c subcortical white matter appearing hyperintense on T2W images and (b) hypointense on T1W images with no significant diffusion restriction. It is seen compressing frontal horns of both lateral ventricles. (c) Post contrast T1W image

–– Anaplastic oligodendroglioma: Indistin- • Other features—areas of cystic degeneration, guishable from oligodendroglioma on intratumoral hemorrhages are commonly imaging [57]. noted. Exceptional tumors may exhibit exten–– Diffuse astrocytoma may be indistinguishsive mucoid degeneration giving rise to gelatiable from oligodendroglioma on imaging. nous appearance. Usually, a cortical mass with relative sparing of the cortex and generally lesser Intraoperative Cytology (IOC) no calcification is seen. Micro Photographs of Case 1 (Fig. 4.59) –– DNET: a well-circumscribed wedge shape multicystic intracortical mass with typical Intraoperative Cytology Findings “bubbly” appearance, usually non-­• Most of the oligodendrogliomas smear well enhancing with minimal or no mass effect. due to their soft consistency. –– Ganglioglioma: a cortical-based well-­ • A low power view shows a moderately cellular circumscribed, cystic mass with a mural tumor with cellular aggregation around fine nodule or a solid tumor in the hemisphere, branching capillary network. The neoplastic which is often not dural based. Calcification cells spread with little cohesion away from the is common. No enhancing dural tail noted. blood vessels forming monolayered sheets. • The tumor cells are round, with rounded Macroscopy monotonous nuclei, speckled chromatin, • A relatively well-circumscribed tumor located inconspicuous nucleoli, and scanty pale cytoin cortex and white matter. plasm. Some of the cells have eccentric • Soft, grayish-pink mass with blurring of gray-­ nuclei. white junction. • Grade II tumor typically lacks nuclear pleo• Calcification is frequently present giving rise morphism, mitotic figures, endothelial hyperto gritty sensation. plasia, and necrosis.

4.6 Oligodendroglial Tumors

a Fig. 4.59  IOC Oligodendroglioma: (a) moderately cellular smears composed of monomorphic round cells in monolayered sheets. Foci of calcification (arrow) (b) Little cohesion between the tumor cells is noted. The

a

59

b tumor nuclei are relatively uniform, small, round, with inconspicuous nucleoli and scanty cytoplasm. Background is gliofibrillary (Higher magnification of (a)) (Modified field stain)

b

Fig. 4.60  Oligodendroglioma, grade II: (a, b) moderately cellular tumor composed of monomorphic cells with uniform, rounded nuclei ,variable perinuclear halos and chicken-wire network of branching capillaries (arrow) (H&E)

• Background appears gliofibrillary. • Foci of calcification may be noted on smears. D.D. on IOC • Lymphoma: absence of gliofibrillary matrix may be mistaken for lymphoma. • Intraventricular oligodendroglioma may be mistaken for central neurocytoma. • Reactive astrocytosis—when tissue is obtained from the margin of tumor and cortex.

Histology Microphotographs of Case 1 (Figs. 4.60, 4.61, 4.62, and 4.63) Histology • Moderately cellular tumor, diffusely infiltrating into the surrounding brain parenchyma. • Monomorphic neoplastic cells have uniform, round nuclei with increased chromatin density/salt-pepper-like appearance and variable perinuclear haloes due to cytoplasmic retraction. These formalin fixation artifacts are seen

4  Diffuse Astrocytic and Oligodendroglial Tumors

60

a

b

Fig. 4.61 (a, b) Typical honey-comb or fried egg appearance with cytoplasmic clearing (tissue fixation artefact) (H&E, (b): high power)

on paraffin sections giving a honeycomb or fried-egg appearance. • A dense network of delicate branching capillaries is seen as a chicken-wire appearance. • Mitotic activity is low or absent, with no necrosis and endothelial proliferation. • Other features: minigemistocytes (the rounded belly of eccentrically GFAP-positive eosinophilic cytoplasm), microcalcifications, mucoid or cystic degeneration, and granular cells may be seen. Immunohistochemistry Microphotographs of Case 1 (Figs. 4.64 and 4.65; Table 4.10) Genetic Profile • IDH mutation: IDH1 (R 132) mutations occur in more than 90% of oligodendrogliomas. • 1p/19q codeletion: Complete deletion of both the short arms of chromosome 1 (1p) and the long arm of chromosome 19 (19q) is definitive for the

diagnosis of Grade II and Grade III (anaplastic) oligodendroglioma.1p/19q codeletion can be demonstrated by fluorescent in situ hybridization (FISH), polymerase chain reaction, chromogenic in situ hybridization, or molecular genetic testing. It is a strong prognostic factor associated with improved survival and also a predictive factor for response to chemotherapy as well as radiotherapy [59]. • TERT promoter mutations are encountered in approximately 78% and are associated with favorable prognosis [60]. Prognosis • IDH-mutant and 1p/19q codeleted patients when treated with adjuvant radiotherapy and/ or chemotherapy exhibit a favorable prognosis in contrast to those undergone only surgery. • 1p/19q is a predictive biomarker for response to procarbazine–lomustine–vincristine and temozolomide treatment in low-grade oligodendroglioma [60].

4.6 Oligodendroglial Tumors

61

4.6.2 Anaplastic Oligodendroglioma, IDHMutant and 1p/19q-Codeleted

a

Definition An IDH-mutant and 1p/19q codeleted oligodendroglioma with focal or diffuse histological features of anaplasia (in particular, pathological microvascular proliferation and/or brisk mitotic activity). Incidence Three percent of adult supratentorial malignant gliomas. Age: Mean age is 49 years. Male:female = 1.2:1. Localization Preferentially located in frontal lobe followed by temporal lobe.

b

Imaging (Fig. 4.66) Macroscopy Similar to grade II, may show necrotic areas. Intraoperative Cytology (IOC) Microphotographs (Fig. 4.67)

c Fig. 4.62  Oligodendroglioma grade II: (a) with microcysts (b) monomorphic small, round tumor cells show perinuclear halos and foci of calcification marked by arrows typical honey-comb or fried egg appearance due cytoplasmic clearing (tissue fixation artefact) (c) presence of interspersed granular/foamy cells(arrow) (H&E)

IOC Findings • Densely cellular smears than grade II oligodendroglioma show aggregation of tumor cells around blood vessels. The cellular density becomes less away from the blood vessels. • The neoplastic cells are large, have round to oval, hyperchromatic nuclei with high ­nucleo-­cytoplasmic ratio. Pleomorphism and tumor giant cells may be noted. • Mitotic activity and increased microvascular proliferation (marked by arrow). • Necrosis with inflammatory cells. • Foci of calcification noted.

4  Diffuse Astrocytic and Oligodendroglial Tumors

62

a

b

Fig. 4.63  Oligodendroglioma (a) presence of minigemistocytes (H&E) (b) with small globular paranuclear GFAP positivity (High power)

a

b

c

d

e

f

Fig. 4.64  Oligodendroglioma grade II (a) GFAP positive (b) S-100 positive (c) OLIG 2 positive (d) ATRX-retained (e) IDH1 (R-132) (f) Low Mib-1 (Ki-67)

4.6 Oligodendroglial Tumors

63

a

b

Fig. 4.65  Oligodendroglioma: (a) Fluorescent in situ hybridization (FISH) shows one nil orange two green signals in most interphase nuclei of tumor cells, demonstrating loss of 1p relative to 1q. (b) FISH shows one or nil

orange and two green signals in most interphase nuclei of tumor cells, demonstrating loss of 19q relative to 19p. Picture courtesy Dr. Zhang Yanming, MSKCC, New York

Table 4.10  Immunohistochemistry findings Markers GFAP, MAP2, S100, and LEU7 OLIG2 IDH1R132H-­mutant P53 ATRX Mib1 (Ki-67) proliferation index Mib1 (Ki-67) proliferation index

a

Expression Positive Positive (not specific for oligodendroglioma) [58] Immunoreactivity is noted in other glial tumors as well Positive IDH-mutant and 1p/19q codeleted oligodendrogliomas usually lack widespread p53 staining Retained (typical finding in IDH1 mutant and 1p19q codeleted oligodendrogliomas) 5%. In grade III

b

Fig. 4.66  Anaplastic oligodendroglioma: MRI of a 42 year old female shows a large focal lobulated, oval, intra-­ axial soft tissue mass in the left fronto-temporal region with extension into the left periopercular region. (a) It shows heterogenous mixed hyperintense signal on

c T2-weighted images and (b) iso to hypointense signal on T1-weighted images. (c) A large eccentric nodular moderately enhancing component is noted on dynamic post gadolinium study

4  Diffuse Astrocytic and Oligodendroglial Tumors

64

a

b

c

d

e

f

Fig. 4.67  Anaplastic oligodendroglioma: (a) Densely cellular smears composed of neoplastic oligodendroglial cells with foci of calcification (arrow) (b–d) Hypercellular smears with aggregation of neoplastic cells around the blood vessels. The cells tend to be less cohesive away from the blood vessels. Cellular pleomorphism, nuclear

atypia and few multinucleated tumor giant cells noted. Endothelial hyperplasia is noted. (e, f) large, round to oval neoplastic cells, hyperchromatic nuclei. Prominent endothelial cell proliferation is noted (arrow). Background is gliofibrillary. However, mitotic figures are not seen in F. (Modified field stain)

4.6 Oligodendroglial Tumors

Histology Microphotographs (Figs. 4.68, 4.69, 4.70, 4.71, and 4.72) Histology • Tumor with dense cellularity than grade II and with features of anaplasia. • Tumor nuclei are rounded, hyperchromatic with perinuclear haloes (fried egg appearance) and few cellular processes. Nuclear atypia and multinucleated tumor giant cells present. • Mitotic activity >6 mitoses/10 hpf [61]. • Increased microvascular proliferation. • Necrosis present (with or without palisading). Other Features • Gliofibrillary oligodendrocytes and minigemistocytes are frequent. • Eosinophilic granular cells may be occasionally found [62]. • Focal microcalcification. Immunohistochemistry Microphotographs (Fig. 4.73) Immunohistochemistry Same as oligodendroglioma grade II except the Mib1 (Ki-67) proliferation index more than 5%.

a Fig. 4.68  Anaplastic oligodendroglioma: (a) Dense cellularity and honeycomb cells with typical perinuclear halos giving fried-egg appearance (b) Tumor with mitotic

65

Differential Diagnosis • Lymphoma—LCA-positive. • Small cell glioblastoma, IDH- wild type, lacks 1p/19q codeletion [63]. • Metastatic clear cell tumors—appropriate antibody profile workup. Genetic Profile • IDH mutations and 1p/19 q codeletions: are diagnostic molecular markers. • TERT promoter mutations associated with CIC gene alterations are more common than FUBP1 mutations. • Others: overexpression of EGFR, PDGF, and PDGFR are noted. • Presence of MGMT methylation may be of favorable prognosis. Prognosis • The prognosis appears to be unfavorable in tumors with a higher Mib1 index. Molecular markers which exhibit favorable prognosis are the presence of MGMT methylation and TERT promoter mutations and the absence of CDKN2A loss.

b figures and thin delicate branching vasculature (chicken-­ wire appearance) (Higher magnification of (a)) (H&E)

66

4  Diffuse Astrocytic and Oligodendroglial Tumors

4.7

a

Oligoastrocytoma, NOS

Definition Oligoastrocytoma, NOS, Grade II: A diffusely infiltrating, slow-growing glioma composed of a conspicuous mixture of two distinct neoplastic cell types morphologically resembling tumor cells with either oligodendroglial or astrocytic features and in which molecular testing could not be completed or was inconclusive. Anaplastic oligoastrocytoma grade III: is an oligoastrocytoma with focal or diffuse microscopic features of anaplasia, including increased cellularity, nuclear atypia, pleomorphism, and brisk mitotic activity (WHO2016). Age Most frequently affects adults. Localization Predilection for cerebral hemispheres.

b

Clinical Features Seizures, headache, personality changes. Other symptoms depending on the location and size of the tumor. Difficulty in speech, changes in vision or some form of motor change may present earlier and frontal lobe tumors may present with changes in behavior or personality. Histology Microphotographs (Figs. 4.74 and 4.75)

c Fig. 4.69  Anaplastic oligodendroglioma: (a, b) Densely cellular glioma with cellular pleomorphism, multinucleated giant cells(arrowhead) hyperchromatic nuclei, mitotic figures(arrow ) and presence of gliofibrillary oligodendrocytes. (c) Less cellular density focus with mitotic activity (arrow) and thin delicate vasculature (H&E)

Histology Oligoastrocytoma, NOS, WHO grade II: • Tumor is composed of two distinct histological entities, i.e., the oligodendroglial features and astrocytic features. These components may be either diffusely intermingled or present as distinct entities.

4.7 Oligoastrocytoma, NOS

67

a

b

c

d

Fig. 4.70  Anaplastic oligodendroglioma: (a) Necrosis (NE) with microvascular proliferation (MVP) and tumor (T). (b) High grade glioma with pleomorphism, nuclear atypia and multinucleated tumor giant cells and marked

a Fig. 4.71  Anaplastic oligodendroglioma: (a) Focus of gliofibrillary oligodendrocytes in a case of recurrent oligodendroglioma evolved from a low grade oligodendro-

microvascular endothelial proliferation (c) tumor with endothelial hyperplasia (d) MVP in form of glomeruloid tuft with mitotic ally active endothelial cells. (H&E)

b glioma. (b) Prominent microvascular proliferation noted in the same case (H&E)

4  Diffuse Astrocytic and Oligodendroglial Tumors

68

a

a

b b

c Fig. 4.73 Anaplastic oligodendroglioma shows (a) GFAP positive (b) IDH1 mutation (c) High Mib1 (Ki-67)

c Fig. 4.72  Anaplastic oligodendroglioma: (a, b) Resembles lymphoma (c) brisk mitotic activity and presence of numerous granular cells with dense eosinophilic cytoplasm (Courtesy Dr. M. Rosenblum) (H&E)

4.7 Oligoastrocytoma, NOS

• Essential features: Oligoastrocytoma, NOS is a glioma composed of two distinct types of neoplastic cells morphologically resembling with either oligodendroglial or astrocytic features and in which molecular testing cannot be completed or was inconclusive. Anaplastic oligoastrocytoma, NOS, WHO grade III with focal or diffuse microscopic features of anaplasia, including increased cellularity, nuclear atypia, pleomorphism, and increased mitotic activity. Diagnosis • WHO 2016 discourages diagnosis of oligoastrocytoma or mixed glioma: the diagnosis of oligoastrocytoma, NOS should remain rare and restricted to diffuse gliomas in which histology does not allow for unequivocal categorization into either astrocytic or oligodendroglial lineage tumors and that cannot be subjected to appropriate molecular testing or in which molecular findings are inconclusive [10]. • Tumors with combined IDH mutation and 1p/19q codeletion are classified as IDH-­ mutant and 1p/19q codeleted oligodendrogliomas, irrespective of mixed or ambiguous histology. • Tumors with combined IDH mutation and without 1p/19q codeletion are classified as IDH-mutant astrocytomas, irrespective of mixed or ambiguous histology.

a

69

• Rare cases of true oligoastrocytomas do exist, with phenotypic and genotypic evidence of spatially distinct oligodendroglioma and astrocytoma components in the same tumor [64]. • WHO supports a diagnostic algorithm for diagnosing gliomas starting with immunohistochemistry for IDH, ATRX, p 53, and TERT promoter mutations followed by testing for 1p/19q codeletion and then followed by IDH1 sequencing of tumors that are negative for R132H mutant IDH1 immunohistochemistry. Differential Diagnosis Astrocytoma, glioblastoma, oligodendroglioma.

Fig. 4.75 Anaplastic oligoastrocytoma, grade III: admixed astrocytic and oligodendroglial components with microvascular endothelial proliferation (H&E)

b

Fig. 4.74  Oligoastrocytoma grade II: (a, b) tumor shows two distinct components-astrocytic and oligodendroglial (H&E)

70

References 1. Velázquez Vega JE, Brat DJ. Incorporating advances in molecular pathology into brain tumor diagnostics. Adv Anat Pathol. 2018;25(3):143–71. 2. McLendon RE, Adesina AM.  Pathology of diffuse astrocytomas definition and overview. Updated: 4 Nov 2015. 3. Juratli TA, Kirsch M, Robel K, et  al. IDH mutations as an early and consistent marker in low grade astrocytomas WHO grade II and their consecutive secondary high grade gliomas. J Neurooncol. 2012;108(3):403–10. 4. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S. Riggins GJ IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73. 5. Parsons DW, Jones S, Zhang X, Lin JC, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12. 6. Watanabe T, Nobusawa S, Kleihues P, Ohagaki H.  IDH 1 mutations are early events in development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53. 7. SongTao Q, Lei Y, Si G, et  al. IDH mutations predict longer survival and response to temozolomide in secondary glioblastomas. Cancer Sci. 2012;103(2):269–73. 8. Cohen A, Holmen S, Colman H.  IDH1and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 2013;13(5):345. 9. Labussiere M, Idbaih A, Wang XW, et  al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology. 2010;74(23):1886–90. 10. Loius DN, Ohgaki H, Weister O. WHO Classification of Tumors of the Central Nervous System (medicine). 4th Rev ed. 2016. 11. Kleihues P, Soylemezoglu F, Schäuble B, Scheithauer BW, Burger PC.  Histopathology, classification, and grading of gliomas. Glia. 1995;15(3):211–21. 12. Osborn A. Osborn’s brain. 2nd ed. Salt Lake City, UT: Amirsys; 2013. p. 528–9. 13. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 435. 14. Louis DN, Perry A, Reifenberger G, et  al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–20. https://doi. org/10.1007/s00401-016-1545-1. 15. Wiestler B, Capper D, Holland-Letz T, Korshunov A, von Deimling A, Pfister SM, Platten M, Weller M, Wick W.  ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol. 2013;126(3):443–51. 16. Weller M, Weber RG, Willscher E, Riehmer V, Hentschel B, Kreuz M, et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using

4  Diffuse Astrocytic and Oligodendroglial Tumors genome-and transcriptomewide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol. 2015;129:679–93. 17. Brat DJ, Aldape K, Colman H, Holland EC, Louis DN. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol. 2018;136(5):805–10. 18. Brat DJ, Scheithauer BW, Medina-Flores R, Rosenblum MK, Burger PC.  Infiltrated astrocytoma with granular cell features (granular cell astrocytomas): a study of histopathologic features, grading and outcome. Am J Surg Pathol. 2002;26(6):750–7. 19. Krouwer HG, Davis RL, Silver P, Prados M. Gemistocytic astrocytomas: a reappraisal. J Neurosurg. 1991;74(3):399–406. 20. Capper D, Weissert S, Balss J, et al. Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol. 2010;20:245–54. 21. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK.  World Health Organization Classification of Tumors of the Central Nervous System, IARC 2016. Gemistocytic astrocytoma. p. 23. 22. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M, Herold-Mende C, Unterberg A, et  al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–74. 23. Wick W, Stoffels M, Engel C, et al. NOA-04 randomized phase III study of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol. 2009;27(35):5874–80. 24. Osborn A. Osborn’s brain. 2nd ed. Salt Lake City, UT: Amirsys; 2013. p. 533–6. 25. Osborn A, Salzman K, Jhaveri M. Diagnostic imaging: brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 438. 26. Reis GF, Pekmezci M, Hansen HM, et al. CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas. J Neuropathol Exp Neurol. 2015;74(5):442–52. 27. Houillier C, Wang X, Kaloshi G, et  al. IDH1 or IDH2 mutations predict longer survival ad response to temozolomide in low-grade gliomas. Neurology. 2010;75(17):1560–6. 28. Osborn A. Osborn’s brain. 2nd ed. Salt Lake City, UT: Amirsys; 2013. p. 536–8. 29. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 443. 30. Brat D, Scheithauer B, Medina-Flores R, Rosenblum M, Burger P.  Infiltrative astrocytomas with granular cell features (granular cell astrocytomas): a study of histopathologic features, grading, and outcome. Am J Surg Pathol. 2002;26:750–7. 31. Louis DL, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumors of the Central Nervous System. Lyon: IARC; 2016.

References 32. Judkins AR, Mauger J, Ht A, Rorke LB, Biegel JA.  Immunohistochemical analysis of hSNF5 / INI1 in pediatric CNS neoplasms. Am J Surg Pathol. 2004;28(5):644–50. 33. Hartmann C, Hentschel B, Tatagiba M, et al. Molecular markers in low grade gliomas: predictive or prognostic? Clin Cancer Res. 2011;17(13):4588–99. 34. Gao K, Li G, Qu Y, Wang M, Cui B, Ji M, Shi B, Hou P. TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas. Oncotarget. 2016;7(8):8712–25. 35. Håvik AB, Brandal P, Honne H, Dahlback HS, Scheie D, Hektoen M, Meling TR, Helseth E, Heim S, Lothe RA, Lind GEJ.  MGMT promoter ­ methylation in gliomas-­ assessment by pyrosequencing and quantitative methylation-specific PCR.  Transl Med. 2012;10:36. 36. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World Health Organization Classification of Tumors of the Central Nervous System, IARC 2016. Glioblastoma. p. 42, 43. 37. Kozak KR, Moody JS.  Giant cell glioblastoma: a glioblastoma subtype with distinct epidemiology and superior prognosis. Neuro Oncol. 2009;11(6):833–41. 38. Takami H, Yoshida A, Fukushima S, Arita H, Matsushita Y, Nakamura T, Ohno M, Miyakita Y, Shibui S, Narita Y, Ichimura K.  Revisiting TP53 mutations and immunohistochemistry—a comparative study in 157 diffuse gliomas. Brain Pathol. 2015;25(3):256–65. 39. Hilda M-D, Kleinschmidt-DeMasters BK, Powell SZ, Yachnis AT. Giant cell glioblastoma and pleomorphic xanthoastrocytoma show different immunohistochemical profiles for neuronal antigens and p53 but share reactivity for class III β-tubulin. Arch Pathol Lab Med. 2003;127(9):1187–91. 40. Lohkamp LN, Schinz M, Gehlhaar C, Guse K, Thomale UW, Vajkoczy P, Heppner FL, Koch A. MGMT promoter methylation and BRAF V600E mutations are helpful markers to discriminate pleomorphic xanthoastrocytoma from giant cell glioblastoma. PLoS One. 2016;6:e17948. 41. Murakami C, Yoshida Y, Yamazaki T, Yamazaki A, Nakata S, Hokama Y, Ishiuchi S, Akimoto J, Shishido-­ Hara Y, Yoshimoto Y, Matsumura N, Nobusawa S, Ikota H, Yokoo H.  Clinicopathological characteristics of circumscribed high-grade astrocytomas with an unusual combination of BRAF V600E, ATRX, and CDKN2A/B alternations. Brain Tumor Pathol. 2019;36(3):103–11. 42. Peraud A, Watanabe K, Kreth FW, Schwechheimer K, Yonekawa Y. Genetic profile of giant cell glioblastoma. Lab Invest. 1999;79(2):123–9. 43. Borota OC, Scheie D, Bjerkhagen B, Jacobsen EA, Skullerud K. Gliosarcoma with liposarcomatous component, bone infiltration and extracranial growth. Clin Neuropathol. 2006;25(4):200–3. 44. Cachia D, Kamiya-Matsuoka C, Mandel JJ, et  al. Primary and secondary gliosarcomas: clinical, molec-

71 ular and survival characteristics. J Neuro-Oncol. 2015;125(2):401–10. 45. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK.  World Health Organization Classification Of Tumors Of The Central Nervous System, IARC 2016, Gliosarcoma. p. 49. 46. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, et  al. World Health Organization Classification of Tumors of the Central Nervous System IARC 2016. Diffuse midline glioma, H3K27M mutant. p. 58. 47. Buczkowicz P, Hoeman C, Rakopoulos P, et  al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet. 2014;46(5):451–6. https://doi.org/10.1038/ng.2936. 48. Reynolds N, Salmon-Divon M, Dvinge H, Hynes-­ Allen A, Balasooriya G, Leaford D, et  al. NuRD-­ mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression. EMBO J. 2012;31:593–605. https://doi.org/10.1038/emboj.2011.431. 49. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Europathol. 2012;124:439–47. https:// doi.org/10.1007/s00401-012-0998-0. 50. Grimm SA, Chamberlain MC.  Brainstem glioma: a review. Curr Neurol Neurosci Rep. 2013;13:346. https://doi.org/10.1007/s11910-013-0346-3. 51. Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, Sure U, Wrede K, Nakazato Y, Tanaka Y, Vital A, Mariani L, Stawski R, et  al. Molecular classification of low-grade diffuse gliomas. Am J Pathol. 2010;177:2708–14. 52. Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, Flynn H, Passe S, Felten S, Brown PD, Shaw EG, Buckner JC. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006;66:9852–61. 53. Erdem-Eraslan L, Gravendeel LA, de Rooi J, Eilers PH, Idbaih A, Spliet WG, den Dunnen WF, Teepen JL, Wesseling P, SillevisSmitt PA, Kros JM, Gorlia T, van den Bent MJ, et al. Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. J Clin Oncol. 2013;31:328–36. 54. Van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344–50. 55. Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L,

72 Laperriere N, Curran W, Mehta M. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337–43. 56. Osborn A. Osborn’s brain. 2nd ed. Salt Lake City, UT: Amirsys; 2013. p. 553–7. 57. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 468–71. 58. Rodrigue FJ, Tihan T, Burger PC. Clinico pathologic features of peadtric oligodendroglioma. Am J Surg Pathol. 2014;38(8):1058–70. 59. Wesseling P, van den Bent M, Perry A. Oligodendroglioma: pathology, molecular mechanism makers. Acta Neuropathol. 2015;129(6):809–27. 60. Louis DN, von Deimling A, Cavenee WK.  Diffuse astrocytic and oligodendroglial tumours. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison

4  Diffuse Astrocytic and Oligodendroglial Tumors DW, Branger FD, et al., editors. WHO classification of tumours of the central nervous system. 4th Rev ed. Lyon: International Agency for Research Centre; 2016. p. 15 61. Giannini C, Scheithauer BW, Weaver AL, Burger PC.  Oligodendrogliomas: reproducibilty and prognostic value of histologic diagnosis and grading. J Neuropathol Exp Neurol. 2001;60:248. 62. Takei Y, Mirra SS, Miles ML. Eosinophilic granular cells in oligodendrogliomas. An ultrastructural study. Cancer. 1976;38(5):1968–76. 63. Takashi K, Tsuda M, Kanno H, Murata J, Mahabir R.  Differential diagnosis of small glioblastoma and anaplastic Oligodendroglioma: a case report. 64. Huse JT, Diamond EL, Wang L, et al. Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true “oligoastrocytoma”? Acta Neuropathol. 2015;129:151–3.

5

Other Astrocytic Tumors

5.1

Introduction

Gliomas with a more circumscribed growth pattern most frequently are pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma and are categorized as other astrocytic tumors.

5.2

Pilocytic Astrocytoma, WHO Grade I

Definition An astrocytoma classically characterized by biphasic pattern with variable proportions of compacted bipolar cells with Rosenthal fibers and loose, textured multipolar cells with microcysts and occasional granular bodies. Pilocytic means hair-like due to the presence of long bipolar processes. Epidemiology • Accounts for 5.4% of all gliomas. • Children and young adults (10% [14, 15].

Imaging (Fig. 10.10)

Immunohistochemistry (Table  10.3)

Imaging findings • On MRI, it presents as moderate to large relatively well-circumscribed, often partially cystic mass located in the pineal region causing obstructive hydrocephalous. Mass arises from the posteroinferior wall of the third ventricle. CSF dissemination is common. The imaging appearance of mass is nonspecific.

Genetic Profile Distinct DNA methylation profiles differentiating papillary tumors of the pineal region from ependymomas have been studied [16]. Prognosis Known to have local recurrence [16].

10.5  Pineoblastoma, WHO Grade IV

a

175

b

Fig. 10.10  Papillary tumor of pineal region: (a) Axial T2W MR shows well-defined heterogeneous mass (arrow) in the pineal region causing compression over posterior third ventricle with resultant obstructive hydrocephalus.

a

(b) Axial post-contrast fat-suppressed T1W MR shows peripheral enhancement of the mass (arrow). (Courtesy: Dr. Shrinivas Desai, Jaslok Hospital and Research Centre, Mumbai)

b

Fig. 10.11  Papillary tumor of pineal region: (a) exhibits prominent papillary architecture with vascular axes harboring multiple capillaries (arrowhead). Resembles epen-

dymal pseudorosetts. (b) Higher magnification of (a) (H&E) (arrow) (Courtesy: Dr. M. Rosenblum)

Table 10.3  Immunohistochemistry findings

10.5 Pineoblastoma, WHO Grade IV

Markers Keratins: (CK 18, KL1, AE1/AE3, NCAM 1), S 100, NSE, vimentin Mib1 (Ki-67) Cadherin-1, claudin−2, KIR 7.1

Expression Positive in epithelial-like neoplastic cells and perivascular areas Grade II: 10% Absent (helps to differentiate from choroid plexus)

Definition A poorly differentiated, highly cellular malignant embryonal neoplasm arising in the pineal gland (WHO 2016).

10  Tumors of the Pineal Region

176

Epidemiology • Pineoblastomas are rare, highly cellular, accounting for approximately 35% of all pineal parenchymal tumors. • Age—First two decades of life. More common in children. • Male:Female = 0.7:1. Localization • It arises from the pineal gland and frequently extends into corpus callosum, thalamus, midbrain, and vermis. It is usually large in size, greater than 3  cm at the time of presentation. Clinical Features • Raised intracranial pressure causes mainly headache and vomiting. Ocular symptoms and Parinaud syndrome may be present. • Similar to other pineal region tumors. Imaging (Figs. 10.12 and 10.13) Imaging Findings • On MRI, it presents as a large, heterogeneous, irregular pineal mass, usually greater than 3 cm, with poorly defined margins, with foci of hemorrhage and necrosis, causing compression of adjacent structures, midbrain, and

a

b

Fig. 10.12  Pineoblastoma: (a) Post-contrast T1 fat saturation axial, (b) Sagittal, and (c) Coronal images show a large lobulated intensely and heterogeneously enhancing mass (arrow) in the region of the pineal gland with small

• • •

•

•

cerebral aqueduct resulting in obstructive hydrocephalus. Diffuse CSF seeding with spinal metastasis is seen in 15% cases. Peripheral “exploded” calcification is classic for pineoblastoma. On T1W and T2W MRI, it appears as a heterogeneous mass with a solid portion appearing isointense on T1W images and hypointense on T2W images. Mild peritumoral edema usually seen. T2* GRE images show calcification and hemorrhage as areas of blooming (very low signal). Post-contrast T1W images show moderate heterogeneous enhancement. MR spectroscopy shows increased choline and ­ reduced NAA [17]. Differential diagnosis includes pineocytoma, germinoma, teratoma, tectal glioma, and meningioma [18].

Macroscopy • Poorly demarcated invasive masses, soft friable, pinkish-gray mass. • Hemorrhage and necrosis may be present. Intraoperative Cytology (IOC) Microphotograph of the Second Case (Fig. 10.14)

c non-­enhancing necrotic areas (arrow in b). The lesion is seen causing obstruction of the aqueduct and third ventricle with resultant moderate obstructive hydrocephalus

10.5  Pineoblastoma, WHO Grade IV

a Fig. 10.13 A 19-year-old male presented with short duration complaints of headache, vomiting, and decreased visual acuity, which prompted an MRI. The study revealed a large, well-defined, lobulated, oval mass (arrow) in the region of the pineal gland with bulging into the posterior

a

177

b aspect of the third ventricle. It shows intermediate signal intensity on T1 (image a) as well as T2-weighted images (image b) with patchy hypointense areas on the GRE sequence to suggest intralesional micro-hemorrhages

b

Fig. 10.14  IOC pineoblastoma: (a, b) Densely cellular smears composed of undifferentiated cells with high nucleo-­ cytoplasmic ratio and scanty cytoplasm. Brisk mitotic activity (arrow) (Modified field stain)

Intraoperative Cytology • Cellular smears composed of round cells with hyperchromatic nuclei, high nucleo-­cytoplasmic ratio, and scanty amount of cytoplasm. The neoplastic cells tend to smear away from numerous thickened vasculatures in a diffuse monolayer.

• Mitotic activity and necrosis frequently found. • Pineoblastic rosetts are difficult to identify in smears. Histology Microphotographs of the Second Case (Figs. 10.15, 10.16, and 10.17)

10  Tumors of the Pineal Region

178

a

b

Fig. 10.15  Pineoblastoma: (a, b) With necrosis (H&E)

a

b

Fig. 10.16  Pineoblastoma: (a, b) Sheets of undifferentiated blue cells with high nucleo-cytoplasmic ratio. The nuclei are irregular, hyperchromatic, and show molding. Mitotic figures are noted (H&E)

Fig. 10.17  Pineoblastoma with Homer-Wright rosetts (H&E, low power)

Histology • A highly cellular tumor composed of sheets of densely packed small blue cells. • The neoplastic cells have a high nucleo-­ cytoplasmic ratio, hyperchromatic nuclei with occasional small nucleolus, and scanty eosinophilic cytoplasm. Focal nuclear folding and irregularly shaped nuclei may be seen. • Pineocytomatous rosetts found in low-grade tumors are absent while Homer-Wright or Flexner–Wintersteiner rosetts (retinoblastic differentiation) may be seen. • High mitotic activity and necrosis are noted. • Biphasic pattern exhibiting pineocytoma– pineoblastoma may be seen.

References

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a

b

Fig. 10.18  Pineoblastoma: (a) Synaptophysin positive (b) High Mib1 (Ki-67) Table 10.4  IHC findings Markers SMARCB 1 (INI-1) Synaptophysin Chromogranin-A NFP, NSE Mib-1 (Ki-67) proliferation index

Expression Positive [19] Variable positivity [20] May be positive [20] Positive [20] 23.5–50.1%

Pineal Anlage Tumors • Extremely rare. Characterized by a combination of neuroectodermal and heterologous ectomesenchymal components. • Neuroepithelial component—Characterized by pineoblastoma-like sheets or nests of small blue round cell neuronal ganglionic/ glial differentiation or melanin-containing epithelioid cells. • The ectomesenchymal component—rhabdomyoblast striated muscle or cartilaginous islands. Immunohistochemistry Microphotographs of the Same Patient (Fig. 10.18; Table 10.4) Differential Diagnosis • PNET— CD99 positive. • Medulloblastoma: synaptophysin and molecular studies are helpful. • Glial tumor—Glial markers and IDH status. • Pineocytoma—low MIB 1 index.

Genetic Profile No specific genetic alteration noted. Prognosis • Aggressive clinical behavior. • The mitotic count and proliferative activity are more important factors in determining the prognosis [21].

References 1. Osborn A.  Osborn’s brain. 2nd ed. Salt Lake City, Utah: Amirsys Pub; 2013. p. 612–4. 2. Osborn A, Salzman K, Jhaveri M. Diagnostic imaging: brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 525. 3. Fevre-Montange M, Szathmari A, Champier J, Mokhtari K, Chretien F, Coulon A, et al. Pineocytoma and pineal parenchymal tumors of intermediate differentiation presenting cytologic pleomorphism: a multicenter study. Brain Pathol. 2008;18:354–9. 4. Jouvet A, Saint-Pierre G, Fauchon F, Privat K, Bouffet E, Ruchoux MM, et al. Pineal parenchymal tumors: a correlation of histological features with prognosis in 66 cases. Brain Pathol. 2000;10:49–60. 5. Coca S, Vaquero J, Escandon J, Moreno M, Peralba J, Rodriguez J.  Immunohistochemical characterization of pineocytomas. Clin Neuropathol. 1992;11:298–303. 6. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK.  World Health Organization classification of tumors of the central nervous system. Lyon: IARC; 2016. Pineocytoma, page 172 7. Osborn A.  Osborn’s brain. 2nd ed. Salt Lake City, Utah: Amirsys Pub; 2013. p. 528–9.

180 8. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 614–5. 9. Jouvet A, Nakazato Y, Vasiljevic A. Pineal parenchymal tumour of intermediate differentiation. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of Tumours of the central nervous system. 4th ed. Lyon: International Agency for Research on Cancer; 2016. p. 173–5. 10. Fevre-Montange M, Vasiljevic A, Frappaz D, Champier J, Szathmari A, Aubriot Lorton MH, et al. Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study. Neuropathol Appl Neurobiol. 2012;38:87–94. 11. Wu X, Wang W, Lai X, Zhou Y. CD24 and PRAME are novel grading and prognostic indicators for pineal parenchymal tumors of intermediate differentiation. Am J Surg Pathol. 2020;44:11–20. 12. Osborn A.  Osborn’s brain. 2nd ed. Salt Lake City, Utah: Amirsys Pub; 2013. p. 618–9. 13. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 534–5. 14. Jouvet A, Vasiljevic A, Nakazato Y, Paulus W, Hasselblatt M. Papillary tumour of pineal region. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of Tumours of the central

10  Tumors of the Pineal Region nervous system. 4th ed. Lyon: International Agency for Research on Cancer; 2016. p. 180–182. 15. Heim S, Beschorner R, Mittelbronn M, Keyvani K, Riemenschneider MJ, Vajtai I, et al. Increased mitotic and proliferative activity are associated with worse prognosis in papillary tumors of the pineal region. Am J Surg Pathol. 2014;38:106–10. 16. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK.  World Health Organization classification of tumors of the central nervous system. Lyon: IARC; 2016. Papillary tumor of pineal region,page 180-181 17. Osborn A.  Osborn’s brain. 2nd ed. Salt Lake City, Utah: Amirsys Pub; 2013. p. 616–7. 18. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: Brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 530. 19. Miller S, Ward JH, Rogers HA, Lowe J, Grundy RG.  INI1 loss in CNS PNETs. Brain Pathol. 2013;23:19–27. 20. Fevre-Montange M, Vasiljevic A, Champier J, Jouvet A.  Histopathology of tumors of the pineal region. Future Oncol. 2010;6:791–809. 21. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK.  World Health Organization classification of tumors of the central nervous system. Lyon: IARC; 2016. Gliosarcoma, page 49

11

Embryonal Tumors

11.1

Introduction

Embryonal tumors (ET) of the central nervous system (CNS) include a heterogeneous group of immature-appearing neoplasms that occur most commonly in children; however, cases in adults have also been reported. Embryonal tumors occurring in children younger than 2 years of age constitute approximately 10–15% of all childhood nervous system tumors that are thought to be congenital in origin. ETs are highly cellular and mitotically active malignant tumors which not only invade nervous tissue but also can disseminate in the cerebrospinal fluid (CSF) and subarachnoid space. Improvements in neuroimaging have led to the earlier diagnosis of intracranial neoplasms. With the wider utilization of immunohistochemical and molecular genetic techniques, the complexity of some infantile tumors is now being recognized which has helped obscure the unique nature of these tumors and possibly their differing responses to therapy. Embryonal Tumor Classification • Medulloblastoma: –– Genetically defined –– Histologically defined

• Embryonal tumor with multilayered rosettes: –– Embryonal tumor with multilayered rosettes, C19MC-altered Embryonal tumor with abundant neuropil and true rosettes (ETANTR) Ependymoblastoma Medulloepithelioma –– Embryonal tumor with multilayered rosettes, NOS • Atypical teratoid/rhabdoid tumor • CNS embryonal tumor with rhabdoid features • Other embryonal tumors: –– CNS neuroblastoma –– CNS ganglioneuroblastoma –– CNS embryonal tumor, NOS

11.2

Medulloblastoma, WHO Grade IV

Definition An embryonal neuroepithelial tumor arising in the cerebellum or dorsal brain stem, presenting mainly in childhood, and consisting of densely packed small, round undifferentiated cells with mild to moderate nuclear pleomorphism and high mitotic count (WHO 2016).

© Springer Nature Singapore Pte Ltd. 2020 M. Chougule, Neuropathology of Brain Tumors with Radiologic Correlates​, https://doi.org/10.1007/978-981-15-7126-8_11

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Epidemiology Most common malignant CNS tumor of childhood, accounting for 25% of intracranial tumors. Peak incidence: 3–7  years Male:Female = 1.7:1 Clinical Features Those arising in the fourth ventricle cause raised intracranial tension. Localization • Classic variant and medulloblastoma with extensive nodularity are typically located in the midline. • Desmoplastic/nodular medulloblastoma: Frequently occur in cerebellar hemisphere and the vermis. Imaging (Figs. 11.1, 11.2, and 11.3) Imaging • Classic medulloblastoma arises in the midline, roof of the fourth ventricle, and seen as spherical solid mass filling and expanding the

a Fig. 11.1  Medulloblastoma: (a) T2W coronal and (b) Axial images show a large well-defined heterogeneous predominantly hyperintense mass (arrow) in the region of

fourth ventricle and usually causes obstructive hydrocephalus. Small intratumoral cyst/necrosis and calcification can be seen in tumors, hemorrhage is rare. On T2W MR, gray matter intensities are noted. Contrast MR shows mild heterogeneous enhancement. Sagittal MR is very useful to demonstrate the indistinct interface of tumors with the roof of the fourth ventricle. Contrast-enhanced MR of entire neuraxis is essential to detect CSF dissemination of tumors [1]. • Differential diagnoses include: ependymoma, pilocytic astrocytoma, and brain stem glioma [2]. Macroscopy • Fourth ventricle medulloblastoma: Pink or gray, friable expansile mass, small foci of necrosis may be seen. • Cerebellar vermis medulloblastoma: Circumscribed and firm. Intraoperative Cytology (IOC) Microphotographs (Figs. 11.4 and 11.5)

b the fourth ventricle with few cystic areas resulting into obstructive hydrocephalus

11.2  Medulloblastoma, WHO Grade IV

183

a

b

Fig. 11.2  Medulloblastoma: (a) Sagittal (b) Axial images of the same patient show moderate and heterogenous enhancement of the mass (arrow) on post-contrast T1 fat saturation sequence

a

b

Fig. 11.3  Medulloblastoma of the same patient. (a, b) The mass (arrow) shows restriction on diffusion-weighted images

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a

b

Fig. 11.4  IOC Medulloblastoma: (a, b) Densely cellular smears composed of round to oval cells arranged in sheets around thin-walled blood vessels (Modified field stain)

a

b

Fig. 11.5  IOC Medulloblastoma: (a, b) The cells have a high nucleo-cytoplasmic ratio with a scanty amount of eosinophilic cytoplasm. Mitotic activity is noted (arrowhead) (Modified field stain)

Intraoperative Cytology • Medulloblastomas are soft to smear forming monolayered sheets. • High cellularity tumor with densely packed small uniform cells. The tumor nuclei are oval or carrot-shaped with finely granular chromatin and scanty cytoplasm. Occasionally nuclear molding is noted. • Nuclear pleomorphism increases with higher grades. • Dense vascularity with crowding of tumor around the vessels and increased mitotic activity is noted. • Other features: neuroblastic rosetts, ganglion cells, necrosis may be noted.

11.2.1

 our Histologically Defined F Groups and Four Genetically Defined Groups [3]

Histologically Defined • Medulloblastoma classic • Medulloblastoma desmoplastic/nodular • Medulloblastoma with extensive nodularity • Large cell or anaplastic medulloblastoma New variants: • Medulloblastoma with myogenic differentiation • Medulloblastoma with melanotic differentiation

11.2  Medulloblastoma, WHO Grade IV

Genetically Defined  umors in Wingless and Sonic Hedgehog T Activation WNT-activated and sonic hedgehog active groups show activation cell signaling pathways which lead to tumorigenesis in medulloblastoma. In the 2016 WHO classification of tumors of the CNS update, medulloblastoma is classified according to molecular characteristics as well as histological features. Molecular classification is based on transcriptome, microRNA (miRNA), and methylome profiling for clinical treatment and histological classification has also been retained due to its clinical utility when molecular analysis is not feasible: • Medulloblastoma, WNT-activated • Medulloblastoma, SHH-activated and TP53-mutant • Medulloblastoma, SHH-activated and TP53wild type • Medulloblastoma, non-WNT/non-SHH: –– Medulloblastoma group 3 • Medulloblastoma group 4

11.2.2

Medulloblastomas, NOS

Medulloblastoma Histopathology Microphotographs (Figs. 11.6, 11.7, 11.8, and 11.9) Histology Common features in all histologic variants: Dominant population of undifferentiated cells with high nucleo-cytoplasmic ratio, mitotic figures. Histological Variants 1. Medulloblastoma classic: Located in midline: • Small round cell tumor composed of densely packed undifferentiated embryonal cells in syncytia. • Absence of desmoplasia. • Mitotic activity and apoptotic bodies present.

185

• Homer-Wright rosetts present (40%). • Genetic study: Non-WNT/non-SHH tumors. 2. Desmoplastic or nodular medulloblastoma: Located in cerebellar hemispheres and midline: • Densely packed undifferentiated cells in nodular pattern. • Pleomorphic, hyperchromatic nuclei with dense intercellular reticulin fiber network with nodular reticulin-free zones (pale islands) of neurocytic differentiation between narrow desmoplastic strands of proliferating embryonal cells. • Other features: Bimodal age group, associated with Naevoid basal cell carcinoma syndrome. • Genetic study-SHH activated. • Favorable outcome in young children [4]. 3 . Medulloblastoma with extensive nodularity: Most commonly located in the cerebellar vermis: • Tumor exhibits expanded lobular architecture as the reticulin free zones or nodules are enlarged and composed of small, round neurocytic cells set in fibrillary (rich in neuropil-like) background. • Mitotic activity is low or absent in these nodules. • Genetic study: SHH-activated. • Excellent prognosis. 4 . Large cell or anaplastic medulloblastoma: • Anaplasia with marked nuclear pleomorphism. • High mitotic and apoptotic count. • Nuclear molding and cell wrapping. • Genetic study: more commonly SHHactivated or group 3. • More aggressive than others Differential Diagnosis of Medulloblastoma • High-grade small cell gliomas. • Some ependymomas having embryonal-like cytology. • Embryonal tumor with multinodular rosetts or AT/RT.

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a

b

c

d

e

f

Fig. 11.6  Medulloblastoma: (a) Nodular areas. (b, c) Nodular areas of neurocytic differentiation. (d) Nodular areas of neurocytic differentiation with variable desmoplasia. (e) Showing infiltration by a nodule of primitive-­

looking cells exhibiting focal neurocytic differentiation. (f) Homer-Wright rosettes (H&E) (Courtesy: Dr. B.  N. Nandeesh)

11.2  Medulloblastoma, WHO Grade IV

187

a

b

c

d

Fig. 11.7  Medulloblastoma: (a, b, c) Densely cellular tumor with elongated carrot-shaped nuclei with mitotic activity. (d) Presence of nuclear pleomorphism and absence of desmoplasia (H&E)

a

b

Fig. 11.8  Large cell/anaplastic medulloblastoma: (a, b) Densely packed tumor with anaplastic morphology, (H&E) (Courtesy: Dr. M. Rosenblum)

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a

b

Fig. 11.9  Large cell/anaplastic medulloblastoma: (a) Large cells with high nucleo-cytoplasmic ratio and prominent nucleoli necrotic zones. (b) Tumor cell wrapping (arrow) (Courtesy Dr. M. Rosenblum)

a

b

Fig. 11.10  Medulloblastoma: (a) Synaptophysin positive. (b) High Mib 1 (Ki-67)

Other Rare Variants 1. Medulloblastoma with myogenic differentiation—previously called medullomyoblastoma. 2. Medulloblastoma with melanotic differentiation—previously called melanocytic medulloblastoma. Immunohistochemistry Microphotographs (Fig. 11.10; Tables 11.1 and 11.2)

Table 11.1  IHC findings Markers Synaptophysin, NeuN class III tubulin, NSE, MAP2. SMARCB1 (INI 1) and SMARCA4 Desmin and myogenin Alpha-SMA HMB45, Melan-A Cytokeratin Mib1 index

Expression Positive in undifferentiated embryonal cells [5] Retained (lost in AT/RT) Positive in myogenic component Negative Positive in melanotic component Positive in epithelioid cells with melanin pigment Significantly higher in the internodular areas [6]

11.3  Embryonal Tumor with Multilayered Rosettes, WHO Grade IV

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Table 11.2  The epidemiological features, location, immunohistochemistry (IHC), genetic profile, and prognosis [6]

Incidence Age group

Location Microscopy

Classic medulloblastomas Approx. 70% More common in children than adults Midline • Small round blue cell tumor • Homer-Wright rosetts • Lacks intratumoral desmoplasia

IHC

Synaptophysin, NeuN-positive

Genetic profile

Shows all molecular subgroups

Prognosis

Variable

11.3

Desmoplastic/nodular medulloblastomas 20% Bimodal age group. Higher incidence in young children and adolescence. Midline and lateral • Pale nodular (cells with neurocytic maturation) areas surrounded by densely packed, undifferentiated cells with hyperchromatic and pleomorphic nuclei • Internodular desmoplasia noted • Neuroblastic rosetts absent Synaptophysin, NeuN-positive. Mib1 index: Low in pale areas and high in cellular area. SHH-activated group, mutation, PTCH1, SUFU, SMO, SHH, GLI2, or MYCN are detected in 85% of tumors. TERT mutations Excellent outcome in children

Embryonal Tumor with Multilayered Rosettes, WHO Grade IV

Definition • Embryonal tumor with multilayered rosettes, C19MC-altered: (ETMR) An aggressive CNS embryonal tumor with multilayered rosettes and alterations (including amplification and fusions) in the C19MC locus at 19q13.42(WHO 2016). Patterns of ETMR: (a) Embryonal tumor with abundant neuropil and true rosettes (ETANTR) (b) Ependymoblastoma (c) Medulloepithelioma

Medulloblastoma with extensive nodularity 3.5% Infants

Large cell or anaplastic medulloblastoma 10% Infancy to adulthood

Midline vermis • Expanded lobular architecture with neurocytic cells exhibit a streaming pattern. • Internodular component is markedly reduced.

Midline • Large cells with anaplasia, nuclear molding, nuclear wrapping. • High mitotic and apoptotic count.

Synaptophysin, NeuN-positive. Mib1 index high in internodular areas.

Synaptophysin, NeuN-positive.

Activation of SHH pathway. SUFU mutation

Group 3 (MYC overexpression) or SHH-activated (GLI2 and MYCN amplification), p53 mutation Aggressive behavior

Excellent prognosis

• Embryonal tumor rosettes, NOS:

with

multilayered

An aggressive CNS embryonal tumor with multilayered rosettes, in which copy number at the 19q13 C19MC locus either shows no alteration or has not been tested (WHO 2016). Epidemiology • Most commonly affects children less than 4 years of age. • Male:Female = 1:1. Localization Supratentorial (frontal and parieto-temporal) is more common than infratentorial (cerebellum and brain stem).

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a

b

Fig. 11.11  ETMR: (a) Axial contrast-enhanced CT shows large heterogeneously enhancing left-hemispheric mass with cystic component (straight arrow), solid component (arrowhead), and calcification (lower white arrow). (b) Axial T2W MR shows a complex heterogeneous mass with cystic (straight arrow) and solid component (arrow-

a

c head). Note no peritumoral edema. (c) Axial post-contrast fat-suppressed T1W MR shows marked heterogeneous enhancement of solid portion (arrowhead) and non-­ enhancing cystic portion (straight arrow). Courtesy: Dr. Shrinivas Desai, Jaslok Hospital and Research Centre, Mumbai

b

Fig. 11.12  ETMR: (a, b) Dense clusters of small cells with round to polygonal nuclei, scant cytoplasm. True rosetts and neuropil-like areas (H&E) (Courtesy: Dr. M. Rosenblum)

Clinical Features Signs and symptoms of raised intracranial tension. Imaging (Fig. 11.11) Macroscopy • Well circumscribed, grayish-pink, with areas of necrosis and hemorrhage. • Cyst formation and calcification may be noted. Histology Microphotographs (Figs. 11.12 and 11.13)

Histology of Embryonal tumor with multilayered rosettes: • Broad histologic spectrum characterised by true ependymoblastic rosettes. • Multilayered rosettes with central round or slit-like lumen. • Nuclei of rosette-forming cells are aligned away from the lumen. Three Variants (1) Embryonal tumor with abundant neuropil and true rosettes (ETANTR):

11.3  Embryonal Tumor with Multilayered Rosettes, WHO Grade IV

a

191

b

Fig. 11.13  ETMR: (a, b) True rosettes, perivascular rosettes (arrowhead) neuropil-like areas, and sheets of large cells. The lumen of the rosette may be slit-like or empty (arrow). Brisk mitotic activity (H&E) (Courtesy: Dr. M. Rosenblum)

• Biphasic tumor composed of: • Hypercellular areas: dense clusters of small cells with round or polygonal nuclei, scanty cytoplasm, and indistinct cell borders. • Paucicellular areas, fibrillar or neuropil-­ like areas, containing neoplastic neurocytic and ganglion cells occasionally. • Apoptotic bodies and brisk mitotic activity are noted. • Multilayered rosettes present. (2) Ependymoblastoma: • The presence of numerous multilayered rosettes intermixed with poorly differentiated embryonal cells is characteristic. • Poorly differentiated, small- to medium-­ sized embryonal cells arranged in nests and sheets. The cells have a high nuclear– cytoplasmic ratio. • Lacks neuropil-like matrix and ganglion cells. ( 3) Medulloepithelioma • A distinct cerebral mass in young children. • Tumor composed of neoplastic pseudostratified epithelium arranged in papillary, tubular, and trabecular patterns that resemble the primitive neural tube. • Luminal surface of the tubule lacks cilia and blepharoblasts. • Abundant mitotic figures which tend to be located near the luminal surface.

• Poorly differentiated cells with high nucleo-cytoplasmic ratio and hyperchromatic nuclei are noted away from the tubular or papillary structures. Clusters of multilayered rosetts may be seen here. Tumor cells range from embryonal cells to mature neurons and astrocytes. • Other features: rarely mesenchymal differentiation or melanin pigmentation. ETMR Immunohistochemistry • Primitive neuroepithelial cells are positive for nestin and vimentin. • Patchy cytokeratin positivity, CD 99, EMA in small-cell areas, and true rosetts. • Neuropil-like areas positive for synaptophysin, NFPs, and NeuN. • Mib1 Ki-67 high—20 to 80%. • LIN28A—strong and diffuse cytoplasmic positivity. It is considered as a diagnostic marker [7].

ETMR Molecular and Cytogenetic Study • Medulloepithelioma and ependymoblastoma share similar molecular features including diffuse expression of LIN28A. • Amplicon at 19q13.42 is a sensitive and specific diagnostic marker for medulloepithelioma with C19MC alteration [7, 8]. This is associated with an upregulation of the oncogenic miRNA cluster.

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Prognosis • Poor prognosis may be related to some tumor cells expressing pluripotent stem cell phenotypes.

11.4

Embryonal Tumor with Multilayered Rosettes, NOS

Definition An aggressive CNS embryonal tumor with multilayered rosettes, in which copy number at the 19q13 C19MC locus either shows no alteration or has not been tested (WHO 2016). Localization Cerebrum, brain stem, and cerebellum. Histology may resemble ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes. Medulloepithelioma in which copy number at the 19q13 C19MC locus either shows no alteration or has not been tested are considered separately because they are considered genetically distinct (In the chapter “Other CNS embryonal tumors”).

11.5

11.5.1

Medulloepithelioma

Definition A CNS embryonal tumor with a prominent pseudostratified neuroepithelium that resembles the embryonic neural tube in addition to poorly differentiated neuroepithelial cells (WHO 2016). Genetic analysis shows no C19MC alterations. Epidemiology Age—most commonly affects children below 5 years with equal incidence in males and females. Localization • Most common in the ciliary body of eyes. • In CNS, it occurs supratentorially in cerebral hemispheres with a predilection for periventricular regions (70%) and infratentorial in the cerebellum and brainstem (30%). Imaging (Fig. 11.14)

 ther CNS Embryonal O Tumors

Definition A group of rare, poorly differentiated embryonal neoplasms of neuroectodermal origin that lack the specific histopathological features or molecular alterations that define other CNS tumors (WHO 2016): • • • •

Medulloepithelioma CNS neuroblastoma Ganglioneuroblastoma CNS embryonal tumors, NOS

Fig. 11.14  Axial T2W MR of a 2-year-old girl shows large ill-defined heterogeneous solid and cystic mass in left temporal lobe causing severe compression over adjacent structures

11.5  Other CNS Embryonal Tumors

Imaging findings On MRI, a huge, very heterogeneous mass that replaces a significant portion of the affected hemisphere (most commonly temporo-parietal lobe) and causes severe mass effect over adjacent structures. Cysts, calcifications, and intratumoral hemorrhages are commonly seen [9]. Intraoperative Cytology (IOC) Microphotographs of the Same Patient (Figs. 11.15 and 11.16)

a

193

Intraoperative Cytology Findings • Highly cellular smears show neoplastic cells arranged in tubules, papillary pattern, and sheets. Pseudostratification of neuroepithelium is noted. • Poorly differentiated neoplastic cells have high nucleo-cytoplasmic ratio, and hyperchromatic nuclei. • Mitotic figures noted. • Mature neurons and astrocytes may be present.

b

Fig. 11.15  Medulloepithelioma: (a, b) Densely cellular smears exhibit papillary and tubular architecture of pseudostratified neoplastic cells resembling neural tube (Modified field stain)

a Fig. 11.16  Medulloepithelioma: (a) Papillary and tubular structures along with sheets of discohesive primitive cells neoplastic cells. (b) Round to oval neoplastic cells

b with large hyperchromatic nuclei and moderate to scanty amount of cytoplasm (Modified field stain)

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Histology Microphotographs of the Same Patient (Figs. 11.17, 11.18, and 11.19) Histology • Tumor is composed of neoplastic pseudostratified epithelium that resembles embryonic neural tube arranged in papillary, tubular, trabecular pattern, multilayered rosettes may be seen. Sheets of large poorly differentiated embryonal cells with hyperchromatic nuclei with high nucleo-­ cytoplasmic ratio. The external limiting membrane is PAS-positive and its luminal surface lacks cilia and blepharoblasts [7]. • Brisk mitotic activity is noted toward the luminal surface. • Other features—astrocytic or mature neurons, mesenchymal differentiation may be found.

Fig. 11.17  Medulloepithelioma: Sheets and trabeculae of poorly differentiated cells with hyperchromatic nuclei. The cells have a high nuclear–cytoplasmic ratio and scanty cytoplasm (H&E)

Immunohistochemistry Microphotographs of the Same Patient (Figs. 11.20; Table 11.3) Genetic Profile • Lacks C19MC amplification [10]. Prognosis Poor.

11.5.2

CNS Neuroblastoma

Fig. 11.18  Medulloepithelioma: Multilayered rosettes (H&E)

Definition A CNS embryonal tumor characterized by poorly differentiated neuroepithelial cells, groups of neurocytic cells, and a variable neuropil-rich stroma (WHO 2016). Epidemiology Very rare tumor. Histology Microphotographs (Figs. 11.21 and 11.22) Histology • The tumor is composed of primitive embryonal cells and neurocytic differentiation cells on the fibrillary matrix. Occasionally, Schwannian stroma may be present.

Fig. 11.19  Medulloepithelioma: Sheets of poorly differentiated cells with hyperchromatic nuclei. No cilia in the lumen (H&E)

11.5  Other CNS Embryonal Tumors

195

a

b

c

d

Fig. 11.20  Medulloepithelioma: (a) Vimentin positive, (b) Cytokeratin positive, (c) EMA positive focally, (d) High Mib1 (Ki 67)

• Neurocytic cells have larger nuclei and variably distinct cytoplasm as compared to the primitive embryonal cells. IHC Findings of Medulloepithelioma: (Table 11.3) Other features: Homer-Wright rosettes, palisading patterns of cells, necrosis, and calcification may be present in variable proportions. Three variants: Classical Variant Resembles the peripheral neuroblastoma and is characterized by a high frequency of Homer-­ Wright rosettes and ganglionic differentiation. Desmoplastic Variant Typically shows intense connective tissue stroma.

Table 11.3  IHC findings of Medulloepithelioma Marker Cytokeratin, EMA and CD99 Synaptophysin LIN28A

Mib1 index

Expression Positive in small-cell areas and true rosettes May be absent or weakly positive in neuropil-like areas Diagnostic marker and prominent in multilayered rosettes and undifferentiated cells 20–80%

Transitional Variant In which both the classical and the desmoplastic features may be present within the same case, either concurrently or consecutively. Both the desmoplastic and the transitional forms are less likely to exhibit differentiation to mature ganglion cells, but the importance of identifying the primitive cell elements as neuroblasts is emphasized [11].

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a

b

Fig. 11.21  Neuroblastoma: (a, b) Lobular pattern of tumor cells with zones of neurocytic cells among sheets of densely packed primitive embryonal cells (H&E)

a

b

Fig. 11.22  Neuroblastoma: (a, b) Homer-Wright roettes with pink neuropil in the center. Small blue cells (Inset) (H&E) Table 11.4  IHC findings Markers Synaptophysin

Expression May be occasionally or weakly positive in embryonal cells GFAP Negative in embryonal cells Synaptophysin, NFPs, Positive in neurocytic or MAP2, and NeuN ganglion cells Mib1 index High

Immunohistochemistry: (Table 11.4) Genetic Profile • Genomic aberrations that occur more frequently in CNS neuroblastoma include 13q telomeric deletion, 14q deletion, homozygous deletion of 9p21.3 spanning the CDKN2A and CDKN2B loci, and 19q gain [12–14]. • RASSF1A promoter methylation, transcriptional silencing of the DLC1 gene, and expression of Neuro D family genes.

• TP53 mutations were not observed in these tumors, although a few samples of adult CNS neuroblastoma revealed mutation of IDH1 [15]. Prognosis Recurrence and metastasis are known to occur after surgical removal. The overall clinical behavior of these tumors is that of malignant neuroepithelial neoplasms [16].

11.5.3

CNS Ganglioneuroblastoma

Definition A CNS embryonal tumor characterized by poorly differentiated neuroepithelial cells and groups of neurocytic and ganglion cells (WHO 2016).

11.5  Other CNS Embryonal Tumors

Localization Extracranial and rarely found in cerebral hemispheres (Fig. 11.23). Imaging (Fig. 11.23) Imaging findings • On MRI, spinal ganglioneuroblastoma presents as a large, ill-defined infiltrative mass in the paraspinal region which extends into the spinal canal through neural foramina and may cross the midline, causing variable cord compression. Fine stippled calcifications, hemorrhage, and necrosis are usually seen in mass. T1W images mass appear hypo- to isointense. On T2W images, it is hypo- to hyperintense. On post-contrast T1W images mass

197

shows heterogeneous enhancement is seen [17, 18]. • Differential diagnosis of spinal ganglioneuroblastoma includes Ewing’s sarcoma, lymphoma, nerve sheath tumor, and vertebral metastasis [17]. Histology Microphotographs (Figs. 11.24 and 11.25) Histology • Tumor shows the presence of sheets of primitive embryonal cells, neurocytic cells, and ganglion cells. • The ganglion cells may be binucleated and found in clusters. • Varying degree of maturation in the neuronal component.

a

b Fig. 11.23 (a) Axial T2W MR shows large heterogeneous mixed signal intensity left paraspinal mass (arrow) with intraspinal extension through left neural foramina. (b) Axial and (c) Coronal post-contrast fat-suppressed T1W MR shows intense heterogeneous enhancement of

c the mass (arrow). Courtesy: Dr. Raghu Ramakrishnaiah MBBS, FRCR, Program Director (Pediatric Radiology Fellowship), University of Arkansas for Medical Sciences, Little Rock

11  Embryonal Tumors

198

a

b

Fig. 11.24  Ganglioneuroblastoma: (a, b) Tumor composed of neurocytic cells interspersed with ganglion cells (H&E) (Courtesy: Dr. Umesh K.Bhanot)

11.5.4

CNS Embryonal Tumors, NOS

Definition A rare, poorly differentiated embryonal neoplasm of neuroectodermal origin that lacks the specific histopathological features or molecular alterations that define other CNS tumors (WHO 2016).

Fig. 11.25 Poorly differentiated neuroepithelial cells with bi- and multinucleated ganglion cells on the fibrillary background (H&E) (Courtesy: Dr. Umesh K. Bhanot)

• Mitotic activity and apoptotic bodies are commonly found in the embryonal component. • Other features: Homer-Wright rosettes, palisading patterns of cells, and regional necrosis with granular calcification. Immunohistochemistry • Embryonal cells may be negative for GFAP or synaptophysin. Some may show weak expression of synaptophysin. • Neurocytic or ganglion cells express synaptophysin, NFPs, MAP 2, and NeuN. • Mib1 Ki-67 is high in embryonal areas and lower elsewhere [19].

Histology • Poorly differentiated neuroepithelial cells which may show a diversified differentiation along neuronal, astrocytic, myogenic, or melanocytic lines. • The tumor cells are round to oval with a high nucleo-cytoplasmic ratio. Densely packed areas show angular or molded cells. HomerWright rosettes may be found. • Numerous mitotic figures and apoptotic bodies are found. • Necrosis and hemorrhage is common. • Cystic change may be noted. Immunohistochemistry • Neuroepithelial cells may show variable expression depending on differentiation: • GFAP for glial differentiation. • Synaptophysin, NFP, and NeuN for neuronal differentiation. • Mib 1 (Ki −67) proliferation index > 50%.

11.6  Atypical Teratoid/Rhabdoid Tumor WHO Grade IV

11.6

199

Atypical Teratoid/ Rhabdoid Tumor WHO Grade IV

Definition A malignant CNS embryonal tumor composed predominantly of poorly differentiated elements and frequently including rhabdoid cells with inactivation of SMARCB 1 (INI1) or (extremely rare) SMARCA4 (BRG1) (WHO 2016). Epidemiology • 1–2% of all pediatric brain tumors. • Age group affected is children less than 3 years and rarely found in adults. • Sex—Male predominance, Male:Female = 1.6 to 2:1.

Clinical Features More specific problems such as head tilt and cranial nerve palsy affecting the sixth and seventh nerve. Children more than 3 years present with headache and hemiplegia. Infants manifest with lethargy, vomiting, and failure to thrive.

Fig. 11.26  Atypical teratoid rhabdoid tumor (AT/RT): A 1-year-old baby boy presented with lethargy, vomiting, failure to thrive, and increased head circumference. Axial T1W MR revealed a large heterogenous fairly well-­defined mixed signal intensity mass (arrow) in the right frontal lobe causing severe compression over the adjacent structures

Localization More commonly located in supratentorial than the infratentorial region. Supratentorial tumors are located in cerebral hemispheres and less frequently in the ventricular system, suprasellar region, and pineal gland. The cerebral hemisphere is the most common site in adults. Infratentorially in cerebellar hemispheres, cerebellopontine angle, and brainstem. Imaging (Figs. 11.26 and 11.27) Imaging Findings • On MRI, AT/RT is perceived as a large, heterogeneous, roughly spherical, ill-defined mass that contains cysts, hemorrhage, and necrosis. CSF dissemination is seen in 15–20% cases. • On T1W images the mass appears heterogeneous and isointense. Hyperintense foci are

Fig. 11.27  AT/RT: A 3-year-old girl presented with vomiting, irritability, and delayed milestones. Axial post-­ contrast T1W MR image shows large heterogeneously enhancing left cerebellar mass (arrows)

200

•

•

• •

•

•

seen in mass on T1W images due to hemorrhage. On T2W images, the mass shows heterogeneous mixed signal intensity. Marked hypointense foci on T2W images represent hemorrhage and hyperintense foci represent cystic/necrotic areas. Contrast images are also helpful to detect leptomeningeal metastasis. Contrast-enhanced MR of the entire neuraxis (brain and spine) is needed to detect drop metastasis. MR spectroscopy shows elevated choline and reduced NAA [20]. Differential diagnosis of cerebellar AT/RT includes medulloblastoma, ependymoma, and pilocytic astrocytoma [21]. Differential diagnosis of cerebral hemispheric AT/RT includes ependymoma, glioblastoma, oligodendroglioma, and tumefactive multiple sclerosis. Differential diagnosis of suprasellar AT/RT includes pilomyxoid astrocytoma and teratoma.

11  Embryonal Tumors

IOC Findings • Tumor composed of heterogeneous population of cells: rhabdoid cells, undifferentiated cells, spindle-shaped cells. • Background shows necrosis and hemorrhage. • Mitotic figures are noted. Histology Microphotographs (Figs. 11.31, 11.32, 11.33, and 11.34) Histology • Diagnostic feature—Tumor composed of a heterogeneous population of cells with a predominance of rhabdoid cells arranged in nests, sheets, or jumbled appearance [22].

Intraoperative Cytology (IOC) Microphotographs of Case 1 (Fig. 11.28, 11.29, and 11.30)

Fig. 11.29  AT/RT: Undifferentiated cells with pale to clear cytoplasm (Modified field stain)

Fig. 11.28  AT/RT: Densely cellular smears with a heterogeneous population of cells composed of rhabdoid cells, undifferentiated cells, small round cells (Modified field stain)

Fig. 11.30  AT/RT: Predominantly rhabdoid cells and small cells (Modified field stain)

11.6  Atypical Teratoid/Rhabdoid Tumor WHO Grade IV

a

201

b

Fig. 11.31  AT/RT: (a) Tumor composed of sheets of undifferentiated cells, rhabdoid cells, brisk mitotic activity. (b) Extensive areas of necrosis and hemorrhage (H&E)

a

b

Fig. 11.32  AT/RT: (a) High power of the same: undifferentiated cells with rhabdoid cells (b) Brisk mitotic activity (H&E, high power)

–– Rhabdoid cells have a well-defined cell border, eccentric vesicular nuclei with prominent eosinophilic nucleoli. Abundant eosinophilic, granular cytoplasm with eosinophilic globular inclusion, and cytoplasmic vacuolation (artifact). –– Abundant mitotic figures found. Extensive geographical necrosis and hemorrhage are commonly found. Other components: Fig. 11.33  AT/RT sheets of rhabdoid cells, with eccentric vesicular nuclei, prominent nucleoli, and abundant eosinophilic to pale cytoplasm (H&E)

• Primitive neuroectodermal component: composed of small round cells exhibiting nuclear molding.

11  Embryonal Tumors

202

a

b

Fig. 11.34  AT/RT: (a, b) Glandular architecture and primitive component along with rhabdoid cells (H&E)

a

b

Fig. 11.35  AT/RT: (a, b) Loss of INI1 in tumor cells whereas retained nuclear expression of endothelial cells in the blood vessels and inflammatory cells serve as an internal positive control

• Undifferentiated large cells with large vesicular nuclei, inconspicuous to prominent nucleoli, and pale eosinophilic cytoplasm. • Mesenchymal differentiation: spindle cells on myxoid background. • Epithelial differentiation: epithelial-like cells in papillary or glandular architecture.

Immunohistochemistry Microphotographs (Figs. 11.35, 11.36, 11.37, and 11.38; Table 11.5)

Differential Diagnosis • Choroid plexus carcinoma: presence of papillary structures, adenomatous component, myxoid matrix is uncommon but distinction from choroid plexus carcinoma becomes challenging. INI1-retained. • Medulloblastoma: INI-1—retained. Genetic Profile INI-1 loss, mutation or loss of SMARCB1 at 22q11.2 is commonly found. Prognosis Poor prognosis.

References

203 Table 11.5  IHC findings Markers EMA, SMA, and Vimentin Cytokeratin, GFAP, NFP, and synaptophysin Desmin, Myogenin, and MyoD1 INI1

Fig. 11.36  AT/RT: Focal EMA positivity

11.7

Expression Positive in rhabdoid cells May show positivity Negative Loss of nuclear expression confirmatory [23]

CNS Embryonal Tumors with Rhabdoid Features, WHO Grade IV

Definition A highly malignant CNS embryonal tumor composed predominantly of poorly differentiated elements and including rhabdoid cells, either with an expression of SMARCB1 (INI1) or SMARCA4 (BRG1) or in which SMARCB1 and SMARCA4 status cannot be confirmed (WHO 2016).

Fig. 11.37  AT/RT: Focal cytokeratin positivity

Histology similar to AT/RTs. Due to the rarity of the tumor, no data is available to determine its epidemiology or clinical significance.

References 1. Osborn A.  Osborn’s brain. 2nd ed. Salt Lake City, Utah: Amirsys Pub; 2013. p. 638–40. 2. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: Brain. 3rd ed. Philadelphia: Elsevier; 2016. p. 536. 3. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D.  The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016 Jun; 131(6): \-20. doi:https://doi.org/10.1007/s00401016-1545-1.Epub. Fig. 11.38  AT/RT: Vimentin positivity

204 4. Skolyszewski J, Glinski B.  Results of postoperative irradiation of group (POG 9031). Int J Radiat Oncol Biol Phys. 2001;51:120–1. 5. Yachnis AT, Perry A.  Embryonal (primitive) neoplasms of the central nervous system. In: Practical surgical neuropathology. Philadelphia, PA: Elsevier; 2010. p. 165–84. 6. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, et  al. World Health Organization classification of tumors of the central nervous system. Lyon, France: IARC; 2016. Medulloblastoma, page no. 194-200 7. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, et  al. World Health Organization classification of tumors of the central nervous system. Lyon, France: IARC; 2016. Medulloepithelioma, page no. 207 8. Korshunov A, Sturm D, Ryzhova M, Hovestadt V, Gessi M, Jones DT, Remke M, Northcott P. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathol. 2014 Aug;128(2):279–89. 9. Wang YZ, Chen J, Fang Y-L, Cai C-Q.  Intracranial medulloepithelioma in a child: a case report. Turk Neurosurg. 2018;29(6):957–60. https://doi. org/10.5137/1019-5149.jtn.22225-17.2. 10. Spence T, Sin-Chan P, Picard D, Barszczyk M, Hoss K, et  al. CNS PNETs with C19MC amplification and/or LIN28A expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol. 2014;128(2):291–303. 11. Horten BC, Rubinstein LJ.  Primary cerebral neuroblastoma: a clinicopathological study of 35 cases. Brain. 1976;99:735–56. 12. MG MC, Ichimura K, Liu L, Plant K, Bäcklund LM, Pearson DM.  High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermaltumors. Collins VPJ Neuropathol Exp Neurol. 2006 Jun;65(6):549–61. 13. Pfister S, Remke M, Toedt G, Werft W, Benner A, Mendrzyk F, et  al. Supratentorial primitive neuroectodermal tumors of the central nervous system

11  Embryonal Tumors frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastomas. Genes Chromosomes Cancer. 2007 Sep;46(9):839–51. 14. Russo C, Pellarin M, Tingby O, Bollen A, Lamborn K, Mohapatra G, Collins V, Feuerstein B.  Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer. 1999;86:331–9. 15. Hayden J, Frühwald M, Hasselblatt M, Ellison D, Bailey S, Clifford S.  Frequent IDH1 mutations in supratentorial primitive neuroectodermal tumors (sPNET) of adults but not children. Cell Cycle. 2009;8:1806–7. 16. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, et  al. World Health Organization classification of tumors of the central nervous system. Lyon, France: IARC; 2016. Medulloepithelioma, page no. 207 17. Ross J, Brant-Zawadzki M, Chen M, Moore K, Salzman K. Diagnostic Imaging: Spine. 1st ed. Salt Lake City, UT: Amirsys; 2004. p. 70–3. 18. Gasparetto EL, Rosemberg S, Matushita H, Leite CDC. Ganglioneuroblastoma of the cerebellum: neuroimaging and pathological features of a case. Arq Neuropsiquiatr. 2007;65(2A):338–40. 19. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, et  al. World Health Organization classification of tumors of the central nervous system. Lyon, France: IARC; 2016. Ganglioneuroblastoma, page no. 207. 20. Osborn A.  Osborn’s brain. 2nd ed. Salt Lake City, Utah: Amirsys Pub; 2013. p. 528–9. 21. Osborn A, Salzman K, Jhaveri M.  Diagnostic imaging: brain 3rd ed. Philadelphia: Elsevier; 2016. p. 652–6. 22. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK.  World Health Organization classification of tumors of the central nervous system. Lyon, France: IARC; 2016. Atypical teratoid/rhabdoid tumor, page 4209–212 23. Biegel JA, Zhou J-Y, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Germ-line and acquired mutations of INI1 in atypical Teratoid and Rhabdoid tumors. Cancer Res. 1999 Jan 1;59(1):74–9.

Tumors of the Cranial and Paraspinal Nerves

12.1 I ntroduction of Cranial and Spinal Nerve Tumors Nerve sheath tumors are derived from the neuroectoderm or neural crest tissue of the developing embryo. Knowing the normal nerve architecture helps to understand the specific derivation of nerve sheath tumors. The normal nerve consists centrally of axons, surrounded by Schwann cells. The connective tissue of the axons, including the Schwann cells, fibroblasts, mast cells, capillaries, and collagen, is called the endoneurium. Groups of these axons with their Schwann cells are surrounded by perineurium, forming a fascicle. Groups of fascicles are surrounded by epineurium. Schwannomas arise from Schwann cells, which encase and insulate cranial nerves and other nerves, and therefore, the tumor can be extracted without damaging the involved nerve (axons are not usually found within schwannoma). These account for 8% of all CNS tumors and most of them being benign and affect the eighth cranial nerve near the cerebellum (vestibular schwannomas or acoustic neuromas) leading to hearing loss and imbalance. They may exhibit variation in morphology such as degenerative atypia (ancient schwannoma), cellular schwannoma, atypical schwannoma, and plexiform schwannoma. Spinal schwannomas cause weakness, sensory loss, and bowel and bladder problems. Neurofibromas arise from within the nerve or axon (demonstrating residual axons within neu-

12

rofibroma), and the nerve must be taken to excise the lesion. Its variants are atypical neurofibroma, plexiform neurofibromas. Other variants of nerve sheath tumors, perineurioma, and hybrid nerve sheath tumors. The nerve sheath tumors may be a sporadic solitary lesion or associated with syndrome (familial), neurofibromatosis type 1 (NF1) or NF2. Malignant peripheral nerve sheath tumors are the malignant counterparts and are associated with NF1 in 50% of cases, which often arises in a preexisting deep-seated plexiform or a large intraneural neurofibroma. Another important variant is melanotic schwannoma, which commonly affects the spinal and paraspinal nerves of young adults. Fifty percent of cases are associated with Carney complex and 10% follow a malignant course. Histologically, these show the presence of melanin pigment, which may be psammomatous or non-psammomatous. Differentiation from melanoma is important.

12.2 Schwannoma, WHO Grade-I (Neurilemoma/Neurinoma) Definition A benign, typically encapsulated nerve sheath tumor composed entirely of well-differentiated Schwann cells with loss of merlin (the NF2 gene product) expression in conventional forms (WHO 2016).

© Springer Nature Singapore Pte Ltd. 2020 M. Chougule, Neuropathology of Brain Tumors with Radiologic Correlates​, https://doi.org/10.1007/978-981-15-7126-8_12

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12  Tumors of the Cranial and Paraspinal Nerves

Epidemiology and General Features Incidence • Accounts for 8% of all intracranial tumors, and frequently occur in adults with a female predominance. • Schwannomas are a component of NF2. Bilateral vestibular schwannoma is the pathognomonic diagnostic feature of NF2 caused by inactivating alterations in the NF2 gene product, merlin on chromosome 22q12.2 [1]. • However, population-based studies revealed that such lesions do not develop in all NF2 patients (41% lack) and other diagnostic criteria become essential [2]. Other characteristic lesions frequently encountered in NF2: multiple schwannomas of cranial, spinal, or peripheral nerves, meningiomas, ependymomas, and ocular lesions. Localization • Intracranial location: accounts for 85% of cerebellopontine (CP) angle tumors, majority arise from the vestibular branch of eighth cranial nerve, commonly referred to as acoustic neuroma, which is a double misnomer, as it arises from the vestibular branch and not acoustic nor is it a neuroma. Rarely periventricular location. • 29% of spinal nerve root tumors. Clinical Features • Slow growing, benign lesions mainly affect the sensory nerve, making motor symptoms uncommon. • Spinal nerve tumor presents with radicular pain and signs of nerve root/spinal cord compression. • Eighth cranial nerve tumors present with hearing loss, tinnitus, loss of balance, pressure in the ear, and occasional vertigo. • Patients with NF2 present with bilateral vestibular tumors and pain is the most common symptom in patients with schwannomatosis. • Complete surgical removal is curative. Imaging (Figs. 12.1, 12.2, and 12.3)

Fig. 12.1  Schwannoma: A 44-year-old male patient presented with loss of hearing and tinnitus. MRI: T2W axial image revealed a lobulated, solid cystic (arrowhead) extra-axial mass in right cerebellopontine angle cistern extending into the right internal auditory canal (arrow)

Imaging Findings • On MRI, cranial nerve schwannoma presents as extra-axial mass (a CSF vascular “cleft” between mass and brain parenchyma), displacing the cortex. Intratumoral cyst and hemorrhage are seen less commonly. Vestibular schwannoma has an ice cream on cone appearance while trigeminal schwannoma looks like a dumbbell shape. • On T1W cranial nerve schwannoma usually shows intermediate signal and T2W presents as isointense or mix signal. • On contrast, it shows strong enhancement. • Differential diagnosis for acoustic schwannoma is meningioma, epidermoid cyst, arachnoid cyst [3]. • Spinal nerve schwannoma presents as well-­ circumscribed “dumbbell”-shaped intradural extramedullary mass causing variable cord compression. • Iso- to hypointense on T1W images and hyperintense on T2W images.

12.2  Schwannoma, WHO Grade-I (Neurilemoma/Neurinoma)

207

Fig. 12.2  Schwannoma: A 9-month-old baby boy hyperintense enhancing vestibulo-cochlear schwannoma brought by parents for hearing loss and excessive crying (arrow) in the right CP angle extending into the internal prompted MRI: Axial high-resolution T2 and post-­ acoustic canal with an “ice cream on cone” appearance contrast T1 weighted images revealed a lobulated, nodular

• Differential diagnosis for spinal nerve schwannoma is neurofibroma, meningioma, lateral meningocele, sequestered disc. • Intracerebral schwannoma is seen as a cyst with nodule. Cyst shows a hypointense signal on T1W images and hyperintense signal on T2W images while nodule is isointense on both T1W and T2W image [5]. • Nodule shows strong enhancement on post-­ contrast T1W images. • Differential diagnosis for intracerebral schwannoma is pleomorphic xanthoastrocytoma, pilocytic astrocytoma, ganglioglioma, and hemangioblastoma.

Fig. 12.3  Trigeminal schwannoma: Axial post-contrast fat-suppressed T1W MR shows well-circumscribed heterogeneous dumbbell-shaped mass in right cerebellopontine angle cistern extending into middle cranial fossa through Meckel’s cave. Mass shows enhancing solid (arrowhead) and non-enhancing cystic component (arrow)

• Target sign can be seen occasionally, which is peripheral high signal and central low signal on T2W images. Cystic change and hemorrhage can be seen in mass [4].

Localization • Peripheral nerves in skin and subcutaneous tissue are most often affected. • Intracranial schwannomas show a strong predilection for the vestibular division of the eighth cranial nerve in the cerebellopontine angle in NF2 patients. • Intraspinal schwannomas show a strong predilection for sensory nerve roots. Macroscopy • Encapsulated, globoid, or dumbbell-shaped mass ranging from 2  mm to 7  cm, found abutting the associated nerve that simplifies the surgical excision.

12  Tumors of the Cranial and Paraspinal Nerves

208

• The intraparenchymal tumors may be non-encapsulated. • Cut surface shows light-tan, glistening tissue with patchy bright yellow areas. • Other changes—Cystic areas, hemorrhages, and infarct-like necrosis in larger tumors. Intraoperative Cytology (IOC) Microphotographs of the First Case (Figs. 12.4 and 12.5) IOC Findings • The tissue is difficult to crush making smears thick due to fascicles of tumor cells from the dense cohesive Antoni A areas.

a

• The spindle cells have elongated wavy nuclei and a moderate amount of eosinophilic cytoplasm [6]. Histology Microphotographs of the Same Patient (Figs. 12.6, 12.7, 12.8, 12.9, 12.10, 12.11, and 12.12) Histology • Schwannoma is composed entirely of neoplastic Schwann cells and inflammatory cells (macrophages and lymphoid aggregates). • Typically a biphasic tumor is composed of: –– Antoni A: Densely packed spindle cells arranged in fascicles running in different directions.

b

Fig. 12.4  IOC: Schwannoma: (a) Neoplastic spindle cells arranged in bundles and fascicles leading to twisted rope appearance (scanner). (b) Higher magnification of (a) (Modified field stain)

a

b

Fig. 12.5  IOC: Schwannoma (a, b) The spindle cells have wavy nuclei and a moderate amount of eosinophilic cytoplasm (Modified field stain)

12.2  Schwannoma, WHO Grade-I (Neurilemoma/Neurinoma)

a Fig. 12.6  Schwannoma: (a, b) Two basic architectural patterns in varying proportion are typically present, Antoni A—Areas of compact elongated cells with nuclear

a

209

b palisades, Antoni B—Less cellular loosely textured cells with indistinct processes and variable lipidization (arrow) and pericellular reticulin (arrow) (H&E)

b

Fig. 12.7  Schwannoma: (a, b) Striking palisades resulting from stacked arrays of nuclei alternating with anucleate zones composed of cell processes. (b) Nuclear palisades with acellular Verocay bodies (arrow) (H&E, low power)

a

b

Fig. 12.8  Schwannoma: (a, b) Verocay bodies, (b) Central acellular fibrillar area composed of the cell processes (higher magnification of Verocay body) (H&E)

12  Tumors of the Cranial and Paraspinal Nerves

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a

b

Fig. 12.9  Degenerative changes in schwannoma: (a) Hyalinization of blood vessels, (b) Perivascular accumulation of hemosiderin-laden macrophages (H&E)

Fig. 12.10 Schwannoma containing lipid-laden cells (foamy macrophages) resemble stromal cells of hemangioblastoma (H&E)

a

Fig. 12.11 Schwannoma with cystic degeneration (H&E)

b

Fig. 12.12  Schwannoma: (a) Edematous stroma and medium- to small-sized hyalinized blood vessels along with lymphocytic aggregates. (b) Lipidization is seen in Antoni B areas with the focus of ossification (rare finding) (H&E)

12.2  Schwannoma, WHO Grade-I (Neurilemoma/Neurinoma)

•

• • • •

•

Cellular areas often show nuclear palisading around acellular fibrillary processes (Verocay bodies). –– Antoni B: Myxoid, hypocellular areas with indistinct processes and variable lipidization. The tumor cells in this area have smaller, often round-to-ovoid nuclei. Loosely arranged collections of lipid-laden cells may be present in both Antoni A and B areas. Foci of vacuolation are noted at the periphery. Mitosis is rarely noted. Pericellular reticulin is present in all schwannomas. Vasculature—Thick walled, hyalinized, dilated vessels surrounded by hemorrhage are usually found in Antoni B areas. Thrombi may be present. Predominance of Antoni A tissue, whorl formation and lobular grape-like growth pattern is most often noted in Neurofibromatosis type 2 (Table 12.1).

211

Immunohistochemistry Microphotographs of the Same Patient (Fig. 12.13) (Tables 12.2 and 12.3) Differential Diagnosis • Fibroblastic meningioma—May be misleading in cases that exhibit S100-positivity. However, these are EMA and SSRT2 positive. • Astrocytoma—no parenchymal reticulin. • SFT—STAT6 positive. • Subependymoma/tanycytic ependymomas— GFAF, S100, EMA-positive. Ancient Schwannoma These are long duration tumors with no clinical significance. Histology Microphotographs (Fig. 12.14) Histology • Tumors with marked degenerative atypia. • Schwann cell nuclei are often large, hyperchromatic, and multilobated.

Table 12.1  Comparison between Antoni A and Antoni B areas Histological features Antoni A areas Cellularity Compact and densely cellular areas of elongated cells arranged in fascicles. Commonly found in NF2 Nuclear features Normochromic spindle or elongated shaped nuclei with tapered ends Nuclear palisades Nuclear palisades present (stacked array of nuclei with anucleate zones) Verocay bodies Present Lipid collection

a

Present

b

Fig. 12.13  Schwannoma: (a) S-100 positive, (b) SOX 10 positive

Antoni B areas Hypocellular areas with loosely textured cells with indistinct processes Smaller, often round-to-oval nuclei. Somewhat degenerative appearance Not commonly found as the cells are loosely arranged. Present

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• Bizarre form with cytoplasmic inclusions. • Lack mitotic figures. • Usually show other degenerative changes including cyst formation, calcification, hemorrhage, and hyalinization. • May be misdiagnosed as malignancy. Immunohistochemistry • S-100 positive. • SOX10 is superior to S100  in differentiating schwannoma from meningioma [9]. • Mib1 (Ki-67) proliferation index is low. Table 12.2  Immunohistochemistry findings Markers S100 SOX 10

LEU 7, Calretinin GFAP

Expression Positive Positive (more specific than S100 in differentiating glial tumors from schwannomas) Often expressed

a

Localization Most common in paravertebral sites in the pelvis, retroperitoneum mediastinum, cranial nerves fifth and eighth.

Histology microphotographs (Figs. 12.16 and 12.17)

Focally positive. May lead to a misdiagnosis of ependymoma. The ependymomas are SOX10 negative and schwannomas SOX 10 positive.

Recurring group 2.28% (range 0.1–8.6) 8%

Definition Hypercellular schwannoma composed exclusively or predominantly of Antoni A areas and devoid of well-formed Verocay bodies (WHO 2016). These are benign tumors with more frequent recurrence.

Intraoperative Cytology (IOC) Microphotographs (Fig. 12.15)

Table 12.3  Depicting Mib1 (Ki-67) index in conventional and cellular schwannoma. Diagnosis of the case study 1: Melanotic Schwannoma Type Conventional [7] Cellular [8]

12.2.1 Cellular Schwannoma

Nonrecurring group 0.59% (range 0–1.5) 6%

Histology • Hypercellular tumor arranged in a fascicular pattern. • Composed of predominantly or exclusively Antoni A areas without Verocay bodies. • May be mitotically active, but usually   =  10 mitoses/10 hpf, may be misdiagnosed as malignancy, MPNST). • Lacks atypia.

b

Fig. 12.14  Ancient schwannoma: (a, b) Bizarre cells show hyperchromatic nuclei, multilobation, and degenerative atypia with no mitotic activity

12.2  Schwannoma, WHO Grade-I (Neurilemoma/Neurinoma)

a

213

b

Fig. 12.15  IOC cellular schwannoma: (a, b) Densely packed neoplastic Schwann cells in bundles and fascicles (Modified field stain)

Fig. 12.16  Cellular schwannoma: Schwannoma with increased cellularity, fascicular arrangement of spindle cells, and low mitotic activity. May mimic MPNST (H&E)

a Fig. 12.17  Cellular schwannoma: (a) Cerebellopontine angle fibrous meningioma: Tumor cells in bundles and fascicles having elongated nuclei and occasional palisades

b that mimic cellular schwannoma. (b) CP angle cellular schwannoma (H&E)

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Fig. 12.18  S100 positive in schwannoma

• Increased rate of recurrence is frequently found in intracranial, spinal, and sacral tumors but no malignant behavior. Immunohistochemistry Microphotographs (Fig. 12.18)

12.2.2 Plexiform Schwannoma (PS)/ Multinodular Pattern Definition It is a schwannoma growing in a plexiform or multinodular manner and can be of either conventional or cellular type (WHO 2016). • PS is associated with NF2 and schwannomatosis syndrome. Involvement of multiple nerve fascicles, requires complete resection to prevent recurrence. • Superficially located, arises in the skin or subcutaneous tissue of an extremity, the head and neck, or the trunk. On rare occasions, deeply situated. Histology Microphotographs (Fig. 12.19)

12  Tumors of the Cranial and Paraspinal Nerves

Fig. 12.19  Plexiform schwannoma: Multiple interlacing and interconnecting fascicles and nodules, composed predominantly of Antoni A-type (H&E)

Histology • Schwannoma with plexiform or nodular pattern grow intraneurally. • Often cellular exhibiting Antoni A areas, infrequent Antoni B. Immunohistochemistry • S-100 diffusely positive. • Low p 53 [9]. • SOX 10, calretinin—often positive. • Approximately half may show GFAP immunoreactivity [10]. Genetic Profile • NF2, tumor suppressor gene is a hallmark of sporadic schwannomas. Prognosis • Conventional schwannomas are benign, slow-­ growing tumors. Recurrence or malignancy is uncommon. • 30–40% of cases of cellular schwannomas (intracranial, spinal, and plexiform) undergo malignant transformation. • Plexiform schwannoma: May recur after incomplete surgical excision.

12.3  Melanotic Schwannoma

12.3 Melanotic Schwannoma Definition A rare, circumscribed but unencapsulated, grossly pigmented tumor composed of cells with ultrastructure and immunophenotype of Schwann cells but that contain melanosomes and are reactive for melanocytic markers (WHO 2016). Epidemiology • Affects a decade younger than conventional schwannoma. • 10% of all melanotic schwannomas follow a malignant course. Localization Spinal nerves and paraspinal ganglia are most commonly affected. One percent are intramedullary.

a

215

Histology Microphotographs (Figs. 12.20, 12.21, and 12.22) Histology: Melanotic Schwannoma • Composed predominantly of largely of fascicular Antoni A tissue. • Cytologically atypical cells with plump, epithelioid, or spindled cells. • Nuclear hyperchromasia, central prominent macronucleoli, and heavily pigmented cytoplasm. • Pronounced cellular elongation helps distinguish the lesion from melanocytoma (Table 12.4). Case Study 1 (Fig. 12.23)

b

Fig. 12.20  Melanotic schwannoma: (a, b) Cytological atypia, hyperchromatic nuclei, prominent nucleoli, and heavy cytoplasmic pigmentation (H&E) (Courtesy: Dr. M. Rosenblum)

Fig. 12.21  Epithelioid pigmented schwannoma: Epithelioid-looking plump Schwann cells with pigmented cytoplasm (Courtesy: Dr. M. Rosenblum)

Fig. 12.22  Psammomatous pigmented schwannoma: Psammoma bodies and melanin pigmentation in schwannoma (H&E) (Courtesy: Dr. M. Rosenblum)

12  Tumors of the Cranial and Paraspinal Nerves

216

a1

b

c2 Fig. 12.23 (a1, a2) A 24-year-old woman complained of backache which prompted MRI. A large, focal altered signal intensity tumor measures 3.5 × 2.5 × 1.3 cm was revealed in the spinal canal and right neural foramina at C4–5 level. The tumor appears hypointense on T2/STIR and FS images and hyperintense on T1W images. Heterogenous contrast enhancement noted on post-­ contrast. The lesion is seen

a2

c1

d causing compression on the spinal cord. The tumor was excised and sent for histopathological evaluation. (b) Gross: Black pigmented tumor. Histology: (c1) Pigmented spindle cell tumor (c2) Spindle cells with wavy elongated nuclei and dense cytoplasmic pigmentation. IHC: (d) S100 positive. HMB-45 and Melan A are negative. Diagnosis of case study 1: Melanotic Schwannoma

12.5 Neurofibroma WHO Grade I Table 12.4  Variants of melanotic schwannoma Psammomatous melanotic schwannoma Affects autonomic nerve viscera, e.g., intestine and heart 50% of patients have carney complex— Autosomal dominant disorder characterized by lentiginous facial pigmentation, cardiac myxoma, and endocrine hyperactivity (Cushing syndrome—Adrenal hyperplasia and acromegaly due to pituitary adenoma)

Non-psammomatous melanotic schwannoma Spinal nerves and paraspinal ganglia It needs to be differentiated from other pigmented lesions like pigmented neurofibroma, Bednar tumor, cellular blue nevus, and especially malignant melanoma, which has an obvious ominous prognosis

12.4 Epithelioid Schwannoma Often subcutaneous and have no clinical significance. Histology • Consists of predominantly round, epithelioid Schwann cells arranged singly and in clusters (Fig. 12.21). • Schwann cell origin confirmed by strong, diffuse S-100 immunoreactivity. • Antoni A and B areas and Verocay bodies may be absent or only focal. • Main differential diagnosis is MPNST. Small size, sharp circumscription, bland ­morphology, and low proliferative activity favor epithelioid schwannoma. • No clinical significance (Table 12.5).

12.5 Neurofibroma WHO Grade I Definition A benign, well-demarcated, intraneural or diffusely infiltrative extraneural nerve sheath tumor consisting of neoplastic, well-differentiated Schwann cell intermixed with non-neoplastic elements including perineural-like cells, fibroblasts, mast cells, a variably myxoid to collagenous matrix, and residuals axons or ganglion cells (WHO 2016).

217 Table 12.5  Depicts IHC findings: Melanotic and epithelioid schwannoma Markers Vimentin, S100 HMB 45, Melan-A

Expression Positive Negative in schwannoma and positive in melanoma.

Epidemiology Neurofibromas are common. Sporadically occur as solitary nodules unrelated to NF1 and those associated with NF1 mutations are multiple [11]. Patients of any age, sex can be affected. Clinical Features • Presents as a slow-growing painless mass. • Deeper tumors including paraspinal forms present with motor and sensory deficits attributable to nerve origin. Imaging (Fig. 12.24) Imaging Findings • On imaging, neurofibromas can be seen in three forms, a solitary localized mass, multiple localized masses, and a plexiform mass. • Solitary spinal neurofibroma presents as a single, intradural extramedullary “dumbbell”shaped mass, usually in the neural foramina and paraspinal region, causing variable cord compression. • Multiple spinal neurofibromas are commonly found in patients with neurofibromatosis type I and present as bulky multilevel, intradural extramedullary spinal nerve root masses/paraspinal masses, causing a variable degree of cord compression. • On T1W MR it appears isointense to cord. • On T2W it appears iso- to hyperintense and exhibits Target sign (peripheral high signal and central low signal). This is suggestive for neurofibroma, but not diagnostic. • On post-contrast T1W image, it shows relatively homogeneous mild to moderate enhancement. • Rapid growth of neurofibroma is suggestive of malignant transformation [12]. • Differential diagnosis for spinal neurofibroma is schwannoma, spinal meningioma, lateral

218

Fig. 12.24  Neurofibroma: T1 weighted post-GD images showing oval peripherally enhancing intradural lesion near the tip of conus with tiny solid nodular enhancing

meningocele, and chronic interstitial demyelinating polyneuropathy (CIDP) [12]. • Plexiform neurofibroma MRI: worm-like soft tissue mass infiltrating scalp, orbit, or parotid gland in the patient with neurofibromatosis type I. Isointense on T1W images and hyperintense on T2W images and shows strong heterogeneous enhancement on postcontrast T1W images. Hypointense septations throughout plexiform neurofibroma are seen on T2W images [13]. • The differential diagnosis for plexiform neurofibroma is a sarcoma, lymphoma, and metastasis [13]. Localization and Macroscopy • Neurofibromas involve the skin and subcutaneous tissue presenting as circumscribed or polypoidal nodule or fusiform masses. • They are usually unencapsulated, rubbery to firm in consistency. • Plexiform neurofibromas, usually deeply associated resembles as bag of worms or rope-­ like lesions, when multiple fascicles are involved. Cut section is firm, glistening and grayish-tan. Intraoperative Cytology Microphotographs (Fig. 12.25)

12  Tumors of the Cranial and Paraspinal Nerves

lesions in cauda equina. Similar nodular heterogeneously enhancing lesions seen adjacent to right-sided sacral neural foramina (arrow)

Fig. 12.25  IOC neurofibroma: Tissue is difficult to smear. Admixture of Schwann cells, fibroblasts, and collagen (Modified field stain)

IOC Findings • Firm consistency of the tumor makes it difficult to crush. • Tumor composed of an admixture of elongated Schwann cells with collagen fibers and fibroblasts. • D. D: Schwannoma. Histology Microphotographs (Fig. 12.26) Histology • Neurofibromas are composed predominantly of neoplastic Schwann cells with thin curved

12.5 Neurofibroma WHO Grade I

219 Table 12.6 Comparison between schwannoma and neurofibroma Schwannoma Encapsulated Biphasic (cellular Antoni A and hypocellular Antoni B), some areas of hypercellularity Palisading and Verocay bodies

a

b

Nuclei: Large Eccentric to nerve, axons generally absent within lesion Blood vessels: Hyalinization present Associated with NF2

Neurofibroma Non-encapsulated Monophasic, low to moderate cellularity. Collagen in the form of shredded carrot appearance Random pattern, only rare palisading, no well-­ formed Verocay bodies Smaller If nerve identified: Incorporates nerve, axons often present in the lesion Blood vessels lack hyalinization NF1 associated

• Unlike in schwannoma, blood vessels lack hyalinization. They may have Antoni B regions of schwannoma but they generally lack Antoni A region and Verocay bodies. • Other features: Large neurofibroma may contain pseudo-Meissner corpuscles and melanotic cells (Table 12.6). Ancient Neurofibroma • Degenerative nuclear atypia and should not be confused with atypical neurofibroma.

12.5.1 Atypical Neurofibroma

c Fig. 12.26  Neurofibroma: (a, b, c) Presence of Schwann cells have thin, curved to elongated, wavy nuclei with scanty cytoplasm interspersed with fibroblasts and collagen (shredded carrot appearance, high power) (H&E)

to elongated nuclei and scanty cytoplasm, fibroblasts in a matrix of collagen fibers (alcian blue—positive myxoid material.) • The nuclei of Schwann cells in neurofibroma are smaller than the nuclei of schwannoma. • Stromal collagen appears as dense refractory bundles giving rise to shredded carrot appearance.

• High cellularity tumor with cytological atypia and hyperchromatic nuclei. • Absence or scattered mitotic figures. The tumor is such that the histological features do not reach the diagnostic threshold of malignancy. • Fascicular growth in addition to cytological atypia may show premalignant features.

12.5.2 Plexiform Neurofibroma • A variant of neurofibroma defined by multiple fascicles that are expanded by tumor cells and collagen but commonly demonstrate bundled nerve fibers at the center. • These lesions are associated with NF1 and manifest early in life and tend to transform to

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220

a

b

Fig. 12.27  Plexiform neurofibroma: (a, b) Consists of nodular tumor composed of schwann cells, fibroblasts and mast cells (H&E) Table 12.7 Comparison between plexiform neurofibroma and schwannoma Plexiform neurofibroma Cells separated by collagen bundles Hypocellular with abundant mucinous matrix Associated with NF1

Plexiform schwannoma Infrequent extracellular collagen Infrequent hypocellular Antoni B areas (majority entirely hypercellular Antoni A) Associated with NF2

malignant peripheral nerve sheath tumors (MPNST). Malignant progression is generally considered the main cause of mortality, occurring in 2–16% of cases [14]. Histology Microphotographs (Fig. 12.27) Histology • May appear multinodular or diffuse, involving multiple fascicles. Hypocellular areas with myxoid stroma with the presence of Schwann cells, fibroblasts, and mast cells. The cells are separated by abundant collagen bundles (Table 12.7). Immunohistochemistry Microphotographs: Neurofibroma (Fig. 12.28) Immunohistochemistry • S100, SOX-10—positive.

Fig. 12.28  Neurofibroma: S-100 positive

Table 12.8  IHC findings Markers S 100, SOX 10 EMA EMA Mib1 (Ki-67)

Expression Positive Positivity noted in perineural cells in plexiform neurofibroma Negative in classical neurofibroma Low

• EMA—positivity noted in perineural cells in plexiform neurofibroma, negative in classical neurofibroma. • Mib-1 proliferation index is low (Table 12.8).

12.6 Malignant Peripheral Nerve Sheath Tumor (MPNST)

221

Genetic Study The neurofibromas associated with mutations in the NF1 gene, which is located at chromosome 17q11.2, characterized by multiple skin alterations such as café-au-lait macules and axillary freckling and by tumoral growth along nerves, called neurofibromas [11].

• In the case of spinal involvement, mass may show dumbbell shape, widening of ­intervertebral foramina, scalloping of the vertebral body, and erosion of pedicles [15]. • Differential diagnosis includes benign nerve sheath tumor, soft tissue sarcoma, and soft tissue hematoma [15].

Prognosis • Plexiform neurofibromas and neurofibromas of major nerves are considered potential precursors of MPNST.

Localization • Large and medium-sized nerves are more commonly affected than small nerves. • Frequently arise in the buttock and thigh, brachial plexus and upper arm, and paraspinal region. • Cranial nerve MPNSTs are rare and commonly arise from schwannoma [16]. • Sciatic nerve is most frequently involved.

12.6 M  alignant Peripheral Nerve Sheath Tumor (MPNST) Definition A malignant tumor with evidence of Schwann cell or perineurial cell differentiation, commonly arising in peripheral nerve or in extraneural soft tissue (WHO 2016). Epidemiology • Commonly affects the age group between 30 and 60  years and accounts for less than or equal to 5% of all malignant soft tissue tumors. • 50% are associated with neurofibromatosis (NF1). MPNST is induced in patients with radiation. Imaging • On MRI: a large (>5 cm) circumscribed or infiltrative mass related to the neurovascular bundle. It has a heterogeneous appearance due to areas of hemorrhage, necrosis, and calcification. Most commonly it is located in the paravertebral region (posterior mediastinum or retroperitoneum) and proximal portion of extremities. Rarely it is seen in intraspinal location. • On T1W images: isointense compared to muscle. • On T2W images: hyperintense compared to surrounding fat. • On post-contrast T1W images: heterogeneous marked enhancement. Infiltration of mass into the surrounding tissue is better appreciated on contrast images. Nerve entering and exiting into mass can be seen.

Clinical Features • The patient complains of a progressively enlarging mass in the extremities, with or without neurological symptoms. • Radicular pain is noted in patients with spinal tumors. Macroscopy • Size usually more than 5 cm. • Shape—an unencapsulated, fusiform, expansile, or globular masses. • Cut-surface is soft to hard in consistency with cream-colored or gray areas. • Foci of hemorrhages and necrosis are commonly noted. Histology Microphotographs (Figs. 12.29, 12.30, and 12.31) Histology • Tightly packed neoplastic spindle cells arranged in herring-bone or interwoven fasciculated pattern. • The spindle cells have wavy elongated nuclei with tapered ends. • Perivascular hypercellularity may be present. • Mitotic activity more than 4 mitoses/hpf. • Geographic necrosis present. • Other features: pigmentation, hemangiopericytoma-like features may be rarely present. • They often spread by local invasion, intraneural and hematogenous routes.

12  Tumors of the Cranial and Paraspinal Nerves

222

a Fig. 12.29  MPNST: (a) Hypercellular tumor with fasciculated or interwoven pattern. Nuclei are elongated with tapering ends, increased mitotic activity is noted. (b)

b MPNST resembles myxoid liposarcoma. Perivascular arrangement of tumor cells, necrosis, and hemorrhage noted (H&E)

Fig. 12.30  MPNST: Typically wavy, elongated nuclei with tapering ends, brisk mitotic activity (H&E) (Courtesy: Dr. Jaideep Pol, Deep Pathology Laboratory, Miraj)

a

b

Fig. 12.31  Pigmented MPNST: (a, b) Fibrosarcoma-­ Sushama R.  Desai, Ex Prof. and Head of the Dept of like pattern, pigmented spindle cells with elongated wavy pathology, KIIMS, Karad) nuclei. Mitotic figures are noted (H&E) (Courtesy: Dr.

12.6 Malignant Peripheral Nerve Sheath Tumor (MPNST)

223

Variants of MPNST 1. Malignant peripheral nerve sheath tumor with divergent differentiation (Synonyms—malignant triton tumor, glandular malignant peripheral nerve sheath tumor). Histology • Composed of a variety of mesenchymal elements like cartilage, bone, skeletal muscle, smooth muscle and angiosarcoma-like areas, and neuroendocrine features. • May show rhabodmyosarcomatous differentiation (60% of cases with NF1), glandular and neuroendocrine differentiation. 2. Epithelioid malignant peripheral nerve sheath tumor. • 5% are either partially or purely epithelioid. • Can arise from malignant transformation of schwannoma. • No association with NF1. 3. Malignant perineurinoma/MPNST with perineurial differentiation. • Shows histological features of perineurial differentiation. • S 100-negative and EMA-positive. Differential Diagnosis Cellular schwannoma, malignant fibrous histiocytoma, synovial sarcoma, dedifferentiated liposarcoma. Immunohistochemistry Microphotographs (Fig. 12.32) (Table 12.9) Complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity strongly favor malignant peripheral nerve sheath tumor. Taken together, immunohistochemistry is useful in the differential diagnosis of malignant peripheral nerve sheath tumor and cellular schwannoma [17]. Genetic Profile • Approximately 50% of patients of all MPNST manifest with NF1. • Patients with NF1 and plexiform neurofibromas are at the highest risk of developing MPNST.

Fig. 12.32  MPNST: Patchy S-100 positive Table 12.9  IHC findings Markers S100

Expression Positive (in only 50–70% of MPNST cases)

EGFR

Expressed in one-third MPNST [16] Loss in 75% of MPNST cases [16] Lost in MPNST [16] Positive in 75% cases Lost in 50% cases Negative in epithelioid MPNST

SOX 10

P 16 and neurofibromin P 53 SMARCB1 HMB 45 and Melan A

Mib1 (Ki-67)

More than 20%

Remark • S100 positivity is more patchy in MPNST and diffuse in cellular schwannoma. • In epithelioid MPNST, diffuse S-100 protein expression is common. Absent in cellular schwannoma Retained in cellular schwannoma Positive in cellular schwannoma

Differentiates MPNST from malignant melanoma Malignancy/ aggressive tumor

Prognosis Highly aggressively tumors with poor prognosis.

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224

12.7 Hybrid Nerve Sheath Tumor

Histology Microphotographs (Fig. 12.34)

Definition Benign peripheral nerve sheath tumors (PNSTs) with combined features of more than one conventional type (i.e., neurofibroma, schwannoma, and perineurioma) (WHO 2016).

Histology • Hybrid schwannoma/perineurioma shows predominantly a schwannian component along with perineurioma-like features. • Hybrid schwannoma/neurofibroma shows two distinct components of schwannoma and neurofibroma. • Hybrid neurofibroma/perineurioma: are uncommon shows two distinct components of neurofibroma and perineurioma.

Epidemiology • Neurofibroma/schwannoma is typically associated with schwannomatosis, neurofibromatosis type 1(NF1) or (NF2). • Schwannoma/perineurioma occur sporadically. Localization Digits are more commonly affected. The cranial or spinal nerves are rarely involved. Clinical Features • Depends on the site of origin. Imaging (Fig. 12.33) Macroscopy Are indistinguishable from schwannoma or neurofibroma.

a Fig. 12.33 (a, b, c) Case 1: A 30-year-old woman presented with giddiness, reduced hearing, imbalance, diminished vision of the left eye. MRI study revealed multiple schwannomas, meningiomas, neurofibromas, intraven-

IHC Findings S100 and EMA in varying proportions stain the components of hybrid PNSTs: • Schwannian component: S100, SOX10—positive, EMA—negative. • Neurofibroma component: Schwann cells: S100, SOX10—positive, perineural cells: EMA—positive, GLUT1—positive. • Perineurioma: EMA, GLUT1, Claudin 1-­ positive and negative for S100 and SOX10 [18].

b

c

tricular and intradiploic tumors. She also gave a history of CP angle tumor surgery 10 years back. Patient’s father and brother had similar tumors on screening. A typical case of NF2

References

a

225

b

Fig. 12.34  Hybrid nerve sheath tumor: Schwannoma/neurofibroma showing two distinct components. (a) Schwannoma, (b) Neurofibroma in a known case of neurofibromatosis in the same patient (H&E) 10. Kawahara E, Oda Y, Ooi A, Katsuda S, Nakanishi I.  Umeda S.; expression of glial fibrillary acidic protein (GFAP) in peripheral nerve sheath tumors. A comparative study of immunoreactivity of GFAP, 1. Rouleau GA, Merel P, Lutchman M, Sanson vimentin, S-100 protein, and neurofilament in 38 M, Zucman J, Marineau C, Hoang-Xuan K, schwannomas and 18 neurofibromas. Am J Surg et  al. Alteration in a new gene encoding a putaPathol. 1988 Feb;12(2):115–20. tive membrane-­ organizing protein causes neuro-­ 11. Evans DG, Howard E, Giblin C, et al. Birth incidence fibromatosis type 2. Nature. 1993;363:515–21. and prevalence of tumor-prone syndromes: estimates 2. Baser ME, Friedman JM, Wallace AJ, Ramsden from a UK family genetic register service. Am J Med RT, Joe H, Evans DG.  Evaluation of clinical diagGenet A. 2010;152A:327–32. nostic criteria for neurofibromatosis 2. Neurology. 12. Osborn A, Salzman K, Jhaveri M.  Diagnostic imag2002;59(11):1759–65. ing: brain 3rd ed. Philadelphia: Elsevier; 2016. 3. Osborn A, Salzman K, Jhaveri M.  Diagnostic imagp. 556–7. ing: Brain, vol. II-3. 1st ed. Philadelphia: Elsevier; 13. Ross J, Brant-Zawadzki M, Chen M, Moore K, 2004. p. 28–9. Salzman K. Diagnostic Imaging: Spine. 1st ed. Salt 4. Ross J, Brant-Zawadzki M, Chen M, Moore K, Lake City, UT: Amirsys; 2004. p. IV-1 90–3. Salzman K. Diagnostic Imaging: Spine, vol. IV-1. 1st 14. Sabatini C, Milani D, Menni F, et  al. Treatment of ed. Salt Lake City, UT: Amirsys; 2004. p. 86–7. neurofibromatosis type 1. Curr Treat Options Neurol. 5. Osborn A, Salzman K, Jhaveri M.  Diagnostic imag2015;17:355. ing: Brain, vol. I-6. 1st ed. Philadelphia: Elsevier; 15. Moore K, Ross J.  Diagnostic imaging. 1st ed. 2004. p. 108–9. Philadelphia: Elsevier. p. IV-1-94–7. 6. Moss TH, Nicholl JNR, et al. Intraoperative diagnosis 16. Scheithauer Bernd W, Sibel E, Rodriguez FJ, of CNS tumors. p. 123. et  al. Malignant peripheral nerve sheath tumors 7. Gwak HS, Hwang SK, Paek SH, Kim DG.  Jung of cranial nerves and intracranial contents: a HW.; long-term outcome of trigeminal neuriClinicopathologic study of 17 cases. Am J Surg nomas with modified classification focusing on Pathol. 2009;33(3):325–38. petrous erosion. Surg Neurol. 2003;60(1):39–48. 17. Pekmezci M, Reuss D, Hirbe A, et  al. Morphologic Discussion 48 and immunohistochemical features of malignant 8. Casadei GP, Scheithauer BW, Hirose T, Manfrini peripheral nerve sheath tumors and cellular schwanM, Van Houton C, Wood MR.  Cellular schwannomas. Mod Pathol. 2015;28:187–200. https://doi. noma: a clinicopathologic, DNA flow cytometric, org/10.1038/modpathol.2014.109. and proliferation marker study of 70 cases. Cancer. 18. Louis DN, Ohgaki H, Wiestler OD, Cavenee 1995;75:1109–19. WK.  World Health Organization classification of 9. Judith NG, Celebre A, Munoz DG, Keith JL, tumors of the central nervous system. Lyon, France: Karamchandani JR. Sox10 is superior to S100 in the IARC; 2016. Hybrid nerve sheath tumor, page diagnosis of meningioma. Appl Immunohistochem 224–225 Mol Morphol. 2014;23(3):3–9.

References

13

Meningioma

13.1 Introduction Meningiomas are slow-growing, extra-axial neoplasms arising from the “meningothelial (arachnoid) cells, typically attached to the inner surface of the dura mater.” Meningioma comprises about one-fourth of all primary tumors of the central nervous system (CNS). It is the most common primary intracranial neoplasm and the most diversified in histologic patterns among all primary tumors of the CNS with WHO grades I, II, and III. Primary extradural meningioma (PEM) denotes a different subset of meningioma arising outside the subdural compartment as the primary tumors and without containing any connection or extension into the underlying subdural compartment or contained structures [1, 2]. Definition A group of mostly benign, slow-growing neoplasms that most likely derive from meningothelial cells of arachnoid layer (WHO 2016). Epidemiology • Accounts for 30% of overall brain tumors. • Age: commonly found in adults, with 65 years being a median age. • 2.8% of pediatric primary brain tumors. • Female:Male  =  3.15:1  in cerebral meningiomas.

• 90% of spinal cord meningiomas occur in women. • Grade II and III are higher in males than grade I. • Primary extradural meningiomas rarely occur and account for less than 2% of all the meningiomas. Clinical Features • Generally slow growing, may grow rapidly during pregnancy. • Produces neurological signs and symptoms due to compression of adjacent structures; headache and seizures are common. Localization • Intracranial, intraspinal, or orbital location are most common. • Intraventricular and epidural examples are rare. • Intracranial: common sites include cerebral convexities, often located parasagittally in association with falx and venous sinus, olfactory grooves, sphenoid ridges, para−/suprasellar region, optic nerve sheath, petrous ridges, tentorium, and posterior fossa. • Spinal meningioma: 90% of spinal meningiomas occur in females in the thoracic region. • Atypical and anaplastic meningiomas: most common at convexities and other non-skull-­ based sites.

© Springer Nature Singapore Pte Ltd. 2020 M. Chougule, Neuropathology of Brain Tumors with Radiologic Correlates​, https://doi.org/10.1007/978-981-15-7126-8_13

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• Anaplastic meningioma: Metastasize most commonly into the lung, pleura, bone, or liver. • Primary extradural meningiomas are intraosseous and can originate in the paranasal sinus,

a

b

Imaging (Figs. 13.1, 13.2, and 13.3)

c

Fig. 13.1  MRI of a 58-year-old woman presented with headache, hearing loss in the right ear, and loss of balance. MRI (a) T2W, (b) CISS, and (c) DIFFUSION W images revealed an oval, lobulated, extra-axial meningioma

a

orbit, neck, salivary gland, calvaria, and along the perineural sheath of cranial nerves [3].

(arrow) in right cerebellopontine angle cistern based on the posterior surface of the right petrous temporal bone which shows intermediate signal intensity on T2W images and no significant restriction of diffusion

b

Fig. 13.2 (a) Post-contrast T1 fat-saturated axial and (b) homogeneous enhancement and a small central non-­ coronal images show a large well defined extra-axial mass enhancing area. An enhancing dural tail (arrow) is also along the left Sylvian fissure with intense near-­ noted along the posterior aspect of the mass

13.1 Introduction

229

a

b

Fig. 13.3  Tentorial meningioma: (a) Coronal and (b) axial T2W images show a large, well-defined T2 hyperintense mass (arrow) along the left tentorial leaflet extend-

ing into the suprasellar cistern causing mild obstructive hydrocephalus

a

b

Fig. 13.4  Gross: Meningioma with nodular appearance. Cut-section gray-white, homogeneous areas

Imaging Findings • A sharply circumscribed, spherical or lobulated, extra-axial mass with broad dural attachment; however, en plaque meningiomas are flatter, carpet-like lesions that infiltrates dura. Cortical buckling, a distinct cleft of arachnoid with trapped CSF and prominent vessels that surround the extra-axial mass is often observed. Calcification, necrosis, cyst, and hemorrhage can be seen. Hyperostosis of adjacent calvarial bone and irregular cortex can be seen.

• On T1W & T2W images, meningioma appears iso- to hypointense with cortex. T1W images are best to visualize gray matter buckling. T2W images are best to visualize trapped CSF clefts and vascular flow voids. • Post-contrast T1W images show intense homogeneous enhancement. The dural tail is seen in many cases. It is not specific for meningioma. Differential diagnosis of focal dural masses includes dural metastasis, pachymeningitis, neurosarcoid, and extramedullary hematopoiesis.

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Macroscopy (Fig 13.4) • Well-circumscribed, sometimes lobulated or rounded mass attached to dura which is separable from the brain. • Consistency—rubbery or firm, homogeneous areas. • Gritty sensation may be due to numerous psammoma bodies. • Bone formation is rare. • Hyperostosis occurs in cases of skull invasion (bone invasion) or in PEM. Table 13.1  WHO classification of histologic subtypes into three grades WHO grade I Meningothelial meningioma Fibrous meningioma Transitional meningioma Psammomatous meningioma Angiomatous meningioma Microcystic meningioma Secretory meningioma Lymphoplasmacyte-­ rich meningioma Metaplastic meningioma

WHO grade II Chordoid meningioma Clear-cell meningioma Atypical meningioma

WHO grade III Papillary meningioma Rhabdoid meningioma Anaplastic meningioma

a Fig. 13.5  Meningotheliomatous meningioma: (a, b) Soft consistency of meningioma readily smears the tumor into clusters with irregular margins. Unlike astrocytic

• Enplaque meningioma—meningiomas grow flat in carpet-like fashion, especially along the sphenoid bone [4, 5] (Table 13.1).

13.2 Meningothelial Meningioma, WHO Grade I Definition A classic and common variant of meningioma, with medium-sized epithelioid tumor cells forming lobules, some of which are partly demarcated by thin collagenous septa (WHO 2016). Intraoperative Cytology (IOC) Microphotographs (Figs.  13.5, 13.6, 13.7, 13.8, and 13.9) Intraoperative Cytology • Meningiomas are relatively soft to smear as compared to schwannomas. • Low power shows cells are arranged in irregular clumps or clusters with irregular margins and show no specific architectural arrangement around the blood vessels as the astrocytic tumors do. • The meningotheliomatous meningioma is composed of small- to medium-sized oval meningothelial cells arranged in syncytia, sheets, or lobules.

b tumors, the meningiomas are unrelated to blood vessels. (b) A small whorl formation is seen (arrow) (Modified field stain)

13.2 Meningothelial Meningioma, WHO Grade I

a

231

b

Fig. 13.6  Meningioma (a, b) Neoplastic meningothelial cells arranged in ill-formed, fascicles, and patternless sheets and a psammoma body is noted (Modified field stain)

a

b

Fig. 13.7  Meningioma: (a) Syncytia, (b) tumor cells around rich collagen band (Modified field stain)

a Fig. 13.8  Meningioma: (a, b) The nuclei are uniform, ovoid or round, with diffuse chromatin and inconspicuous nucleolus. The cytoplasm is indistinct with ill-defined

b boundaries. Psammoma body (arrowhead) in (a), (b) Nuclei with small prominent nucleoli (Modified field stain)

13 Meningioma

232

a

b

Fig. 13.9  Meningioma: (a, b) Nuclear holes (arrow) (Modified field stain)

a Fig. 13.10  Meningotheliomatous meningioma: (a) Meningothelial cells arranged in syncytia and lobular pattern separated by thin fibrous septa. The cells have poorly

b defined cell borders. (b) Presence of numerous psammoma bodies (H&E)

• The nuclei are uniform, oval with diffuse • Tumor cells have uniform, large, oval nuclei chromatin and with small or indistinct nuclewith delicate chromatin, variable nuclear oli. Some nuclei have grooves and intranuholes (i.e., empty-looking clear spaces.), and clear vacuoles (pseudoinclusions). These are nuclear pseudoinclusions (cytoplasmic not specific for meningiomas (differential invagination). The cytoplasm is abundant, ­ diagnosis melanoma). eosinophilic with indistinct cell borders. • The cytoplasm is usually indistinct with ill-­ • Psammoma bodies, whorls, and fibrous tissue defined boundaries. are typically scant in meningothelial • Variable psammoma bodies may be noted. meningioma. Histology Microphotographs (Figs. 13.10, 13.11, and 13.12)

Immunohistochemistry Microphotographs (Figs. 13.13 and 13.14)

Histology • Tumor is composed of neoplastic meningothelial cells arranged in syncytia, sheets, and lobules separated by thin fibrous septae.

IHC Findings • EMA—membranous positivity (Atypical and anaplastic meningiomas may show focal and patchy expression).

13.2 Meningothelial Meningioma, WHO Grade I

a Fig. 13.11  Meningotheliomatous meningioma: (a) Large, uniform tumor cells with oval nuclei have delicate chromatin and variable nuclear holes, i.e., empty-looking

233

b clear spaces and (b) nuclear pseudoinclusions (arrow) (H&E, high power)

Fig. 13.12  Meningotheliomatous meningioma: Fairly uniform cells with round to oval, clear nuclei and small prominent nucleoli. The cytoplasm is indistinct with ill-defined cell borders

a

b

Fig. 13.13  Meningioma: (a) EMA-positive, (b) Vimentin-positive, (c) Low MIB 1

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Fig. 13.14  Meningioma: Low MIB 1

• Somatostatin receptor 2A is the most sensitive and specific marker for all grades of meningiomas. • Vimentin—positive (nonspecific marker). • S-100 protein limited and variable expression in meningothelial meningiomas. • Progesterone receptor-positive. The intensity of expression reduces with a grade of tumor.Please note: Detail immunohistochemistry findings and their mimics have been discussed at the end of the chapter.

13.3 F  ibrous Meningioma, WHO Grade I Definition A variant of meningioma that consists of spindled cells, forming parallel, storiform, and interlacing bundles in collagen-rich matrix (WHO 2016). Imaging (Fig. 13.15) Intraoperative Cytology (IOC) Microphotographs (Fig. 13.16) IOC Findings • Smears are difficult to smear as compared to meningotheliomatous meningioma. • Cellular smears with elongated spindle cells arranged in ill-defined fascicles and have no resemblance to the arachnoidal nuclei of other

Fig. 13.15  Meningioma: Axial post-contrast T1W MR reveals a well-circumscribed, homogenously enhancing, extra-axial mass (arrow) with a dural tail in right cerebellopontine angle cistern

meningiomas (Differential diagnosis: a misdiagnosis of schwannoma may be made at cerebellopontine angle). • The nuclei are elongated and hyperchromatic. • A variable amount of intercellular collagen is present. Histology Microphotographs (Figs. 13.17 and 13.18) Histology • Cellular tumor composed of spindle-shaped cells arranged in parallel, storiform, and interlacing bundles set in the collagen-rich matrix. • The nuclei are more elongated and hyperchromatic than meningothelial meningioma. The cells have a moderate amount of cytoplasm. • Other features—Nuclear palisades may be present that resembles Verocay bodies. Immunohistochemistry Microphotographs (Fig. 13.19) • Differential diagnosis: –– Schwannoma: Fibrous meningioma is the differential diagnosis for schwannoma at the cerebellopontine angle (schwannoma constitutes 85%of CP angle tumors). Both

13.3 Fibrous Meningioma: WHO Grade I

a

235

b

Fig. 13.16  Fibrous meningioma: (a, b) Fascicles and bundles of spindle or elongated meningothelial cells with elongated nuclei and a moderate amount of cytoplasm, mimicking schwannoma (Modified field stain)

a

b

Fig. 13.17  Fibrous meningioma: (a, b) Bundles and fascicles of neoplastic meningothelial cells with elongated nuclei and indistinct cell borders (H&E)

a

b

Fig. 13.18  Fibrous meningioma: (a) Storiform pattern, (b) Variable amount of intercellular reticulin and collagen fibers (H&E)

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13.4 Transitional Meningioma, WHO Grade I

mimic histologically and may show immunoreactivity for S100. However, the expression for S 100 in meningioma is not as strong as schwannoma. SOX 10 positivity is expressed only in schwannoma [6]. –– Solitary fibrous tumor/hemangiopericytoma: Express nuclear STAT 6 positive.

Definition A common variant of meningioma that contains ­meningothelial and fibrous patterns as well as transitional features (WHO 2016). Intraoperative Cytology Microphotographs (Fig. 13.20) IOC Findings • Smears show prominent whorl formation, i.e., concentric arrangement of meningothelial cells. The cells show flattening. Histology Microphotographs (Fig. 13.21) Histology • Prominent lobular and fascicular foci appear adjacent with conspicuous tight whorls. The cells appear flattened.

Fig. 13.19  Fibrous meningioma—EMA positive

a

b

Fig. 13.20  IOC transitional meningioma: (a, b) Prominent whorl formation with flattened meningothelial cells (Modified field stain). (a) H&E, (b) Modified field stain

a

b

c

Fig. 13.21 (a, b, c) Transitional meningioma composed of prominent whorl formation with a psammoma body and variable fibrous tissue (H&E)

13.5 Angiomatous Meningioma: WHO Grade I (Vascular Meningioma)

237

Intraoperative Cytology (IOC) Microphotographs (Figs. 13.23 and 13.24)

• Psammoma bodies may be present. • Elongated fibroblast-like cells stream from periphery.

13.5 Angiomatous Meningioma, WHO Grade I (Vascular Meningioma) Definition A variant of meningioma that features numerous blood vessels, which often constitute a greater proportion of tumor mass than do the intermixed meningioma cells. Imaging (Fig.13.22)

a

Fig. 13.24  IOC Angiomatous meningioma: Prominent endothelial lined thin vascular channels surrounded by meningothelial cells (arrow) (Modified field stain)

b

c

Fig. 13.22 (a, b, c) T1W and T1 post-gadolinium fat saturation images reveal intensely enhancing extra-axial dural-based neoplasm with enhancing dural tail (arrow).

a

Coronal T2W image shows associated significant perifocal edema and mass effect

b

Fig. 13.23  IOC Angiomatous meningioma: (a, b) Meningothelial cells around thick-walled blood vessels (arrow) (Modified field stain)

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IOC Findings • Moderate to marked degenerative nuclear • Numerous endothelial lined thin- and thick-­ atypia is common. walled vascular channels surrounded by meningothelial cells. Immunohistochemistry Microphotographs (Fig. 13.28) Histology Microphotographs (Figs. 13.25, 13.26, and 13.27) Differential Diagnosis • Vascular malformations. Histology • Hemangioblastoma: Inhibin and NSE • Tumor is predominantly composed of blood positive. vessels, that accounts for more than 50% of • Solitary fibrous tumor/hemangiopericytoma: the tumor mass than the intermixed meningiSTAT6 positive. oma cells. • Blood vessels: may be small- to medium-­ Prognosis sized, thin- to thick-walled with variable Do not recur if complete resection is done. hyalinization.

a

b

Fig. 13.25  Angiomatous meningioma: (a) numerous thin-walled vascular channels. (b) Thick- and thin-walled blood vessels with variable hyalinization (H&E)

a

b

Fig. 13.26  Angiomatous meningioma: (a, b) Degenerative atypia in the intervening meningothelial cells (H&E)

13.7 Microcystic Meningioma, WHO Grade I

a

239

b

Fig. 13.27  Angiomatous meningioma: (a) Presence numerous foamy cells and a single psammoma body, (b) Presence of foamy cells resemble hemangioblastoma (High power, H&E)

Imaging (Fig. 13.29) Intraoperative Cytology (IOC) Microphotographs (Fig. 13.30) IOC Findings • Presence of numerous psammoma bodies predominating over the meningothelial component. Histology Microphotographs (Fig. 13.31)

Fig. 13.28  Angiomatous meningioma: EMA positive

13.6 Psammomatous Meningioma, WHO Grade I Definition A designation applied to meningiomas (usually of the transitional type) containing a predominance of psammoma bodies over tumor cells (WHO 2016). Localization • Characteristically occurs in the thoracic spine of middle-aged to elderly women with indolent behavior.

Histology • Tumor composed predominantly of psammoma bodies. In some tumors, intervening meningothelial cells are hardly detected.

13.7 Microcystic Meningioma, WHO Grade I Definition A variant of meningioma characterized by cells with thin, elongated processes encompassing microcysts and creating a cobweb-like background (WHO 2016). Imaging (Fig. 13.32) Histology Microphotographs (Fig. 13.33)

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a Fig. 13.29  Psammomatous meningioma: (a) T2W sagittal and (b) Post-contrast T1W MRI shows an extramedullary, intradural tumor with homogenous intense

a

b enhancement at D7-D8 intervertebral disc level causing compression over the cord in a 61-year-old female

b

Fig. 13.30  IOC of the same patient: (a, b) Numerous psammoma bodies intermixed with meningothelial cells (Modified field stain)

Histology • Hypocellular tumor with loose texture. • Tumor cells are stellate and spindle cells with long, thin interconnecting cytoplasmic processes arranged in a complex network

resulting in “sieve-like” or cobweb-like appearance. • Microcysts and macrocysts of varying sizes are present. • Fluid-filled intercellular spaces are noted.

13.8 Secretory Meningioma, WHO Grade I

a

241

b

Fig. 13.31  Histology of the psammomatous meningioma of the same patient (H&E)

IHC Findings • EMA, PR, and S-100 are positive. • Very rarely microcystic meningiomas may develop as primary extradural meningiomas arising intraosseously in calvarium. Differential Diagnosis • Hemangioblastoma—vascularity, foamy cells, and large scattered pleomorphic nuclei. Inhibin and NSE positive. • Hemangioma—CD31 positive. • Lipoma—EMA negative. • Fibrous dysplasia exhibits curvilinear trabaculae of woven bone surrounded by a storiform pattern of spindle cells with intervening collagen fibers. Negative for EMA, PR, and S100. • Chordoma—brachyury positive [7].

Fig. 13.32  Post-contrast T1 fat saturation axial image shows a large well-defined intensely and heterogeneously enhancing mass (arrow) in the trigone and temporal horn of left lateral ventricle with non-enhancing cystic areas (arrowhead). There is a mass effect in the form of compression of the midbrain and midline shift toward right

• Other changes: Vacuolated cells (with xanthomatous change) and focal nuclear atypia. (may resemble hemangioblastoma). Hyalinization may be noted. Immunohistochemistry Microphotographs (Fig. 13.34)

13.8 Secretory Meningioma, WHO Grade I Definition A variant of meningioma characterized by the presence of focal epithelial differentiation in the form of intracellular lumina containing periodic acid–Schiff-positive eosinophilic secretions called pseudopsammoma bodies (WHO 2016). Imaging • Peritumoral edema is prominent in some secretory meningiomas. Histology Microphotographs (Fig. 13.35)

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a Fig. 13.33  Histology of the same patient revealed microcystic meningioma. (a, b) Numerous microcysts of varying sizes noted between the tumor cells. The cells have

a

b thin elongated processes forming numerous microcysts giving cobweb-like appearance. Degenerative atypia is noted (H&E)

b

Fig. 13.34  Microcystic meningioma: (a) EMA positive (b) Progesterone positive

a

b

Fig. 13.35  Secretory meningioma: (a) Eosinophilic secretions called as pseudopsammoma bodies in meningioma (H&E). (b) PAS positive pseudopsammoma bodies (Courtesy: Dr. B Nandeesh)

13.9 Lymphoplasmacyte-Rich Meningioma, WHO Grade I

243

Histology • Tumor is composed of eosinophilic hyaline bodies called pseudopsammoma (periodic acid–Schiff positive) bodies. These bodies are CEA (carcinoembryonic antigen) positive [8] (Table 13.2). • Laboratory investigations: Elevated Sr. CEA [9].

13.9 Lymphoplasmacyte-Rich Meningioma, WHO Grade I

Immunohistochemistry • EMA-positive. • CEA-positive. • MIB1 (Ki-67)  = 4 up to 19 mitoses/10 hpf.

• Brain or bone invasion on histology (characterized by irregular, tongue-like protrusions of tumor cells infiltrating underlying parenchyma, without an intervening layer of leptomeninges). • At least three out of five the following features [14]: –– Increased cellularity. –– Small cells with high nucleocytoplasmic ratio. –– Prominent nucleoli.

13.11 Atypical Meningioma, WHO Grade II

247

a

b

Fig. 13.42  Atypical meningioma: (a) Small cell change with prominent nucleoli. (b) Bone invasion (H&E)

a

b

Fig. 13.43  Atypical meningioma: (a, b) Increased mitotic activity and no nuclear atypia in this case. (b) High power of (a) (H&E)

a

b

c

Fig. 13.44  Atypical meningioma: (a) Histology (H&E), (b) EMA positive, (c) High mib-1

–– Sheet formation (i.e., uninterrupted patternless or sheet-like growth). –– Foci of spontaneous or geographic (i.e., non-iatrogenically induced) necrosis.

Immunohistochemistry (Fig. 13.44) Prognosis Associated: with a high recurrence rate.

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13.12 Chordoid Meningioma, WHO Grade II Definition A rare variant of meningioma that histologically resembles chordoma, featuring cords or trabaculae of eosinophilic, often vacuolated cells set in an abundant mucoid matrix (WHO 2016). Location Large supratentorial tumors. Histology Microphotographs (Fig. 13.45) Histology • Tumor composed of cords or trabaculae of epithelioid cells with vacuolated or eosinophilic cytoplasm set in abundant mucoid or myxoid matrix (Differential diagnosis: chordoma). • Patchy lymphoplasmacytic inflammatory cell infiltrate may be present. • Most often occurs in combination with typical meningioma than pure form.

• Chondrosarcoma: S100 positive, EMA negative, and CK negative. • Chordoid glioma of the third ventricle: Typically of third ventricle. GFAP positive. Prognosis High recurrence rate after subtotal resection.

13.13 C  lear Cell Meningioma, WHO Grade II Definition A rare variant of meningioma with a patternless (commonly) or sheeting architecture and round to polygonal cells with clear, glycogen-rich cytoplasm and prominent blocky perivascular and interstitial collagen (WHO 2016). • Younger age group. • Aggressive behavior [15]. Localization • Commonly found in the posterior fossa (cerebellopontine angle) and spine (cauda equina). Histology Microphotographs (Fig. 13.46)

Differential Diagnosis • Chordoma: vacuolated or physaliphorous cells are brachyury positive, CK positive and EMA positive.

a

Histology • Tumor dispersed in diffuse sheets and in nests separated by thick fibrovascular septa.

b

Fig. 13.45  Chordoid meningioma: (a, b) Chords or trabaculae of epithelioid cells within bluish mucin rich or myxoid stroma with lymphoplasmacytic infiltrate (H&E)

13.14 Rhabdoid Meningioma WHO GR III

249

• Clear cell renal cell carcinoma: CK, PAX8 positive. • Oligodendroglioma: are GFAP, OLIG 2, IDH mutant 1p/19q codeleted. • Hemangioblastoma: Inhibin-positive. WHO Grade III Meningiomas • Rhabdoid meningioma. • Papillary meningioma. • Anaplastic meningioma.

Fig. 13.46  Clear cell meningioma: Sheets of round to polygonal cells with clear cytoplasm and increased perivascular and interstitial collagen (H&E, low power) (Courtesy: Dr. Rosenblum)

13.14 Rhabdoid Meningioma, WHO Grade III Definition An uncommon variant of meningioma that consists primarily of rhabdoid cells; plump cells with eccentric nuclei, open chromatin, a prominent nucleolus, and prominent eosinophilic paranuclear inclusions, appearing either as discernible whorled fibrils or compact and waxy (WHO 2016). Intraoperative Cytology Microphotographs (Fig. 13.48)

Fig. 13.47  Clear cell meningioma: EMA positive

• The tumor cells are round to polygonal in shape, with round nucleus, dispersed nuclear chromatin, inconspicuous nucleoli and moderate amount of clear glycogen-rich cytoplasm (periodic acid–Schiff-positive). • Prominent perivascular and interstitial collagen occasionally form large acellular zones of collagen or forms brightly eosinophilic amianthoid-like collagen. Immunohistochemistry (Fig. 13.47) Differential Diagnosis • Clear cell tumors: clear cell ependymomas: EMA-ring like positivity.

IOC Findings • Tumor composed of round to ovoid plump cells with eccentric nuclei, open chromatin, a prominent nucleolus, and an ample amount of dense eosinophilic cytoplasm. • The tumor may be entirely rhabdoid or intermixed with meningothelial components. Histology Microphotographs (Fig. 13.49) Histology • The tumor consists of loosely cohesive plump cells (rhabdoid cells) with eccentric nuclei, open chromatin, prominent nucleolus, and prominent eosinophilic paranuclear inclusions. • The tumor may be entirely rhabdoid or have intermixed meningothelial components. • Histologic malignancy (brain invasion or anaplasia) is observed in most of the cases.

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b

a

Fig. 13.48  IOC rhabdoid meningioma: (a, b) Clusters of rhabdoid cells with eccentric nuclei, some with prominent nucleoli and abundant eosinophilic cytoplasm (Modified field stain)

a

b

Fig. 13.49  Rhabdoid meningioma: (a) Loosely cohesive sheets of rhabdoid cells with eccentric vesicular nuclei and dense eosinophilic cytoplasm (H&E, low power), (b) EMA positivity in rhabdoid cells

• In the majority, increased cell proliferation was evidenced by a high mitotic rate or MIB 1 index. Immunohistochemistry (Fig 13.49b) • EMA, Vimentin—positive. • INI-1 is retained (differential diagnosis AT/ RT-­INI-­1: loss in tumor cells). • Mib-1 index is high. Genetic Profile These tumors retain SMARCB1 expression, have a high proliferation index and other histological features of malignancy.

13.15 Papillary Meningioma, WHO Grade III Definition A rare variant of meningioma defined by the presence of perivascular pseudopapillary pattern constituting most of the tumor (WHO 2016). Epidemiology Found in young adults and children. Localization Most common along cerebral convexities and some may be midline.

13.16 Anaplastic Meningioma, WHO Grade III

a

251

b

Fig. 13.50  Papillary meningioma: (a, b) Loose tumor cells arranged around fibrovascular cores in papillary structures (H&E) (Courtesy: Dr. M. Rosenblum)

Histology Microphotographs (Fig. 13.50) Histology • Tumor composed of cells arranged in a pseudopapillary pattern with loss of cellular cohesion away from central vascular cores. • Papillary meningioma may show features of classical and rhabdoid meningioma. • Perivascular nucleus free zone resembles pseudorosettes of ependymoma. Differential Diagnosis • Ependymoma: GFAP and EMA (paranuclear dot)—positive. • Metastatic papillary carcinoma from thyroid, gastrointestinal tract, female reproductive system, etc. Prognosis • Brain invasion is noted in 75% cases, recurrence in 55%, metastasis mostly in lung 20%, death in half cases. • Pseudopapillary architecture with rhabdoid cytology has aggressive behavior. This is associated with a higher recurrence rate.

13.16 Anaplastic Meningioma, WHO Grade III Definition A meningioma that exhibits overtly malignant cytology (resembling that of carcinoma, mela-

noma, or high-grade sarcoma) and/or markedly elevated mitotic activity (WHO 2016). Epidemiology Accounts for 1–3% of meningiomas. Localization Along cerebral convexity. Histology Microphotographs (Figs. 13.51 and 13.52) Histology • The cells of anaplastic meningioma exhibit resemblance to carcinoma, high-grade melanoma, and sarcoma. • And/or markedly elevated mitotic activity, i.e., > = 20 mitoses/10 hpf. • Extensive necrosis. • Other features: brain invasion may be present. –– Rare cases may show true epithelial or mesenchymal metaplasia. Immunohistochemistry Microphotographs (Figs. 13.53 and 13.54) Differential Diagnosis • Atypical meningioma. • Solitary fibrous tumor/hemangiopericytoma: STAT 6—positive. • Metastatic carcinoma: Cytokeratin—positive. • Melanoma: HMB45, Melan-A, S100—positive.

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a

b

Fig. 13.51  Anaplastic meningioma: (a, b) Carcinoma-like cells with high nucleo-cytoplasmic ratio and numerous mitotic figures (H&E)

NE

a

b

Fig. 13.52  Anaplastic meningioma: (a) Neoplastic cells with prominent nucleoli and brisk mitotic figures (High power), (b) Spontaneous necrosis (H&E)

a

b

Fig. 13.53  Anaplastic meningioma: (a) Vimentin—positive (b) EMA—positive

13.16 Anaplastic Meningioma, WHO Grade III

253

Prognosis Known to metastasize and average survival time 2–5 years. Rare Variant: (Figs. 13.55 and 13.56)

Fig. 13.54  Anaplastic meningioma: High Mib1 index

Fig. 13.55  Oncocytic meningioma: Sheets of large, polygonal cells with finely granular eosinophilic cytoplasm (H&E) (Courtesy: Dr. M. Rosenblum) [16]

a

Immunohistochemistry of Meningioma, WHO Grade I, II, and III (Table 13.3) • Vimentin, EMA—strongly positive. • Progesterone receptor (PR)—positive. PR has a lesser sensitivity than EMA and SSTR2A and shows decreasing expression from grade 1 to grade 3 meningiomas [18, 19]. • Somatostatin receptor 2A-positive is considered to be more sensitive and specific as compared to EMA alone. Certain studies have shown 100% accuracy in diagnosis when used in association with EMA.  The combination “EMA-positive and SSTR2A-positive” has shown the highest sensitivity and specificity. However, these two markers are not sufficient to differentiate meningioma from synovial sarcoma. In a study, AE1/AE3 was expressed by half of the synovial sarcomas assessed and was rarely expressed in meningiomas. Identification of the translocation t (X;18) (SS18-­SS1/2) is the most specific test for the diagnosis of synovial sarcoma and should be systematically performed when synovial sarcoma is suspected [20].

b

Fig. 13.56  Meningioma: (a) Eosinophilic cytoplasmic inclusions. (b) Cytoplasmic inclusions with spokes (H&E) (Courtesy: Dr. M. Rosenblum) [17]

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• Secretory meningioma, express AE1/AE3 along with CEA positivity and histology shows typical pseudopsammoma bodies [18]. Table 13.3  IHC findings Marker EMA, Vimentin SSTR2A (somatostatin receptor 2A) Progesterone receptor S100

AE1/AE3, CEA

Mib1 (Ki 67) index

Expression Positive Positive (more specific in comparison with EMA) Positive Positive in 50% of fibroblastic meningioma and microcystic (SOX10 is positive in schwannomas) Secretory meningiomas AE1/AE3 helpful in distinguishing synovial sarcoma Grade I—Less than 4% Grade II—More than 4%, up to 19% Grade III—More than or equal to 20%

Table 13.4  Genetic profile (the most commonly found) Monosomy 22 NF2 gene mutation

Chromosomal losses: 1p, 6q, 9p, 10, 14q, and 18q Chromosomal gains: 1q, 9q, 12q, 15q, 17q, and 20q Multiple polysomies, especially in 5, 13, and 20 Loss of CDKN2A and CDKN2B TERT promoter mutations

In most of meningiomas (Grade I, II, III) Associated with NF2 (occurs in multiple meningiomas with neurofibromas and other tumors) Transitional and fibroblastic type WHO grades II and III

WHO grades II and III

• Fibrous meningioma: fibrous meningiomas express S100 positivity. In such cases, “EMA–PR–SSRT2A” panel showed the best positivity in diagnosing a meningioma (Tables 13.3 and 13.4). Prognosis • Recurrence depends on the extent of gross total excision. • WHO grade I meningiomas have considerably low risk for recurrence than WHO grade II and III meningiomas. • Mib1 (Ki-67) proliferation index >4% have an increased risk of recurrence similar to that of atypical meningioma, whereas those with an index of >20% are associated with death rates analogous to those associated with anaplastic meningioma (Table 13.5).

13.17 Primary Extradural Meningioma (PEM) PEM are uncommon variants of meningiomas that account for less than 2%. These have no attachment to the dura [21, 22]. Localization Throughout the body, skull, scalp, spine. Most commonly arise in calvarium, more specifically in the frontoparietal convexity. They can also arise in paranasal sinuses, nasopharynx, jaw, neck, skin, spine, abdomen, peritoneum, arm, foot, and chest and in very unusual locations.

In angiomatous meningiomas

Anaplastic WHO grade III meningiomas In meningiomas associated with malignant progression and recurrence in both NF2 and non-NF2 meningiomas

Imaging Heterogenous and may have osteoblastic, osteolytic, or mixed appearances. Histologic variants of PEM are meningothelial followed by transitional, fibrous, and psammomatous types. Malignant are uncommon.

References

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Table 13.5  WHO categorizes histologic subtypes of meningioma into 3 grades, WHO grade I, WHO grade II, WHO grade III. Distinguishing salient features of histologic subtypes of meningioma are depicted in the table: WHO grade I Meningothelial meningioma Fibrous meningioma Transitional meningioma Psammomatous meningioma Angiomatous meningioma Microcystic meningioma Secretory meningioma Lymphoplasmacyte-rich meningioma Metaplastic meningioma Benign, most commonly occurring with low risk of recurrence Histology: • No/rare mitotic figures.

Mitotic activity: Absent or rare Mib 1 index: < 4%

WHO grade II Chordoid meningioma Clear cell meningioma Atypical meningioma

WHO grade III Papillary meningioma Rhabdoid meningioma Anaplastic meningioma

Incidence is around 6% with increased likelihood of recurrence At least 3 of 5 parameters: • Sheet-like or patternless growth (i.e., absence of whorling and fascicles). • Small cell formation with high N/C ratio. • Prominent large nucleoli. • Hypercellularity. • Spontaneous or geographic necrosis. Or brain invasion > = 4–19 mitoses/10 hpf > 4%

Rarely found (1–3%) with malignant potential, may metatstatize > = 20 mitoses/10 hpf Or Frank anaplasia (resembling sarcoma, carcinoma, or melanoma-­ like histology)

References 1. Liu Y, Wang H, Shao H, Wang C. Primary extradural meningiomas in head: a report of 19 cases and review of literature. Int J Clin Exp Pathol. 2015;8(5):5624–32. 2. Crawford TS, Kleinschmidt-DeMasters BK, Lillehei KO. Primary intraosseous meningioma. Case report. J Neurosurg. 1995;83(5):912–5. 3. Changhong L, Naiyin C, Yuehuan G. Lianzhong Z primary intraosseous meningiomas of the skull. Clin Radiol. 1997 Jul;52(7):546–9. 4. Akutsu H, Sugita K, Sonobe M, Matsumura A. Parasagittal meningioma en plaque with extracranial extension presenting diffuse massive hyperostosis of the skull. Surg Neurol. 2004;61:165–9. 5. Yamada S, Kawai S, Yonezawa T, Masui K, Nishi N, Fujiwara K.  Cervical extradural en-plaque meningioma. Neurol Med Chir (Tokyo). 2007;47:36–9. 6. Judith NG, Angela C, David M, Keith J, Jason K.  Sox10 is superior to S100  in the diagnosis of meningioma. Appl Immunohistochem Mol Morphol. 2014;23:215–9. 7. Vega JV, Rosenberg A.  Microcystic meningioma of the Calvarium: a series of 9 cases and review of the literature. Am J Surg Pathol. 2015;39(4):505–11.

> = 20 mitoses/10 hpf > 20%

8. Buhl R, Hugo HH, Mihajlovic Z, Mehdorn HM.  Secretory meningiomas: clinical and immunohistochemical observations. Neurosurgery. 2001;48(2):297–301. Discussion 301–2 9. Tsunoda S, Takeshima T, Sakaki T, Morimoto T, Hoshida T, Watabe Y. Goda K secretory meningioma with elevated serum carcinoembryonic antigen level. Surg Neurol. 1992 May;37(5):415–8. 10. Zhu H-D, Xie Q, Gong Y, Mao Y, Zhong P.  Lymphoplasmacyte-rich meningioma: our experience with 19 cases and a systematic literature review. Int J Clin Exp Med. 2013;6(7):504–15. 11. Kanno H, Nishihara H, Hara K, Ozaki Y, Itoh T, Kimura T, Tanino M, Tanaka S. A case of lymphoplasmacyte-­ rich meningioma of the jugular foramen. Brain Tumor Pathol. 2011;28:341–5. 12. Park KJ, Kang SH, Chae YS, Yu MO, Cho TH, Suh JK, Lee HK, Chung YG.  Influence of interleukin-6 on the development of peritumoral brain edema in meningiomas. J Neurosurg. 2010;112:73–80. 13. Hosler MR, Turbin RE, Cho ES, Wolansky LJ, Frohman LP. Idiopathic hypertrophic pachymeningitis mimicking lymphoplasmacyte-rich meningioma. J Neuroophthalmol. 2007 Jun;27(2):95–8. 14. David Louis, Hiroko Ohgaki, Otmar D.  Weister et  al WHO Classification of the central nervous

256 system, International agency for Research on Cancer Lyon 2016, Revised 4th edition, Meningiomas, 2016;231–244. 15. Zorludemir S, Scheithauer BW, Hirose T, Van Houten C, Miller G, Meyer FB.  Clear cell meningioma. A clinicopathologic study of a potentially aggressive variant of meningioma. Am J Surg Pathol. 1995 May;19(5):493–505. 16. Zheng J, Geng M, Shi Y, Jiang B, Tai Y, Jing H. Oncocytic meningioma: a case report and review of the literature. Surg Oncol. 2013 Dec;22(4):256–60. 17. Kawasaki K, Takahashi H, Kaneko H, Sato H, Ikuta F. Novel eosinophilic intracytoplasmic inclusions in a meningioma. Cancer. 1993 Nov 1;72(9):2675–9. 18. Boulagnonrombi C, Fleury C, et  al. Immunohistochemical approach to differential diagnosis of meningiomas and their mimics. J Neuropath Exp Neurol. 2017 April;76(4):289–98.

13 Meningioma 19. Mezmezian MB, Carassai MB, Dopazo V, et  al. Immunohistochemical expression of progesterone receptors in non meningothelial central nervous system tumors. Appl Immunohistochem Mol Morphol. 2016;25(6):439–44. 20. Foo WC, Cruise MW, Wick MR, Hornick JL.  Immunohistochemical staining for TLE1 distinguishes synovial sarcoma from histologic mimics. Am J Clin Pathol. 2011 June;135(6):839–44. 21. Lang FF, Macdonald OK, Fuller GN, DeMonte F. Primary extradural meningiomas: a report on nine cases and review of the literature from the era of computerized tomography scanning. J Neurosurg. 2000 Dec;93(6):940–50. 22. Liu Y, Wang H, Shao H.  Chuanwei Wang primary extradural meningiomas in head: a report of 19 cases and review of literature. Int J Clin Exp Pathol. 2015;8(5):5624–32.

Mesenchymal, Non-meningothelial Tumors

14.1 Introduction of Mesenchymal, Non-­ meningothelial Tumors Meninges are more commonly affected than the brain parenchyma. Supratentorial location is more commonly involved than the infratentorial. The histological features correspond to the extracranial soft tissue and bone tumors. The cell of origin could be meninges, vasculature, or osseous structures. The WHO classification of tumors of CNS, 2016 includes the spectrum of solitary fibrous tumor/hemangiopericytoma, hemangioblastoma, hemangioma, epithelioid hemangioendothelioma, angiosarcoma, Kaposi sarcoma, Ewing sarcoma/PNET, lipoma, liposarcoma, desmoid-type fibromatosis, myofibroblastoma, inflammatory myofibroblastic tumor, fibrosarcoma, undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteochondroma, and osteosarcoma. They range from benign grade I to highly malignant sarcoma, grade IV.

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14.2 Solitary Fibrous Tumor/ Hemangiopericytoma Definition A mesenchymal tumor of fibroblastic type, often showing a rich branching vascular pattern, encompassing a histological spectrum of tumors previously classified separately as meningeal solitary fibrous tumor and hemangiopericytoma (WHO 2016). • Mostly arising from meninges. • Detection of STAT6 nuclear expression or NAB2-STAT6 fusion is highly recommended to confirm the diagnosis of immunohistochemistry [1]. Epidemiology