Essentials of Diagnostic Surgical Neuropathology E-Book

• Herausgeber: Thieme Medical Publishers
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2024

Beschreibung

<p>Keeping abreast of the major strides made in the field of neuropathology, <cite>Essentials of Diagnostic Surgical Neuropathology</cite> brings out its second edition with the aim of keeping the neuroscience community updated with the new developments in neuropathology.</p> <p>This second edition comes close on the heels of the fifth edition of the WHO Classification of Central Nervous System Tumours (WHO CNS5) which was published in 2021. This new edition has retained the concise, point wise format of the earlier edition, making it a handy reference book. While the major changes in this edition are in neoplastic pathology, this book also provides updates in the pathology of non-neoplastic lesions that need surgical intervention.</p> <p><strong>The highlights of the neoplastic section are:</strong></p> <ul> <li>Description of new tumour types and subtypes included in the WHO CNS5</li> <li>Grading of tumours as per WHO CNS5</li> <li>Relevant immune profile and diagnostic molecular pathology for each tumour according to WHO CNS5. Essential and desirable diagnostic criteria, as defined by WHO CNS5, in a tabular form at the end</li> </ul> <p> </p> <p><strong>The salient features of the non-neoplastic section include:</strong></p> <ul> <li>New section on Therapy-related Neuropathology</li> <li>Recent classifications of vascular malformations and epilepsy related lesions</li> <li>New section on Infectious and Inflammatory Lesions Mimicking Neoplasms</li> <li>New chapter on Surgical Pathology of Spinal Dysraphism and Other Neural Tube Defects</li> <li>Another important feature includes the addition of a new chapter on techniques viz.</li> <li>Smears in the Rapid Diagnosis of Central Nervous System Lesions</li> <li>Challenges in the Interpretation of Stereotactic Biopsies</li> </ul> <p> </p> <p><strong>Publisher's Note: Products purchased from Third Party sellers are not guaranteed by the publisher for quality, authenticity, or access to any online entitlements included with the product.</strong></p>

Leseprobe

Essentials of Diagnostic Surgical Neuropathology

Edited by

Chitra Sarkar, MD, FRCPath, FICPath, FASc, FNASc, FAMS, FNAJ C Bose National Fellow Professor, Department of Pathology Former Dean (Research) Former Head, Department of Pathology All India Institute of Medical Sciences (AIIMS) New Delhi, Delhi

Vani Santosh, MD, FAMS, FICPath Senior Professor, Department of Neuropathology Dean, Neurosciences National Institute of Mental Health & Neurosciences (NIMHANS) Bengaluru, Karnataka

Geeta Chacko, MD, PhD Professor and Head Department of General Pathology Christian Medical College Vellore, Tamil Nadu

Anita Mahadevan, MD, DNB, FAMS Professor and Head Department of Neuropathology Coordinator, Human Brain Tissue Repository (Brain Bank) National Institute of Mental Health & Neurosciences (NIMHANS) Bengaluru, Karnataka

Co-editors: Vaishali Suri, Megha S. Uppin, and Shilpa Rao

ThiemeDelhi • New York • Stuttgart • Rio de Janeiro

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Managing Director & CEO: Ajit Kohli

© 2023. Neurological Society of India.

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ISBN: 978-93-95390-05-7

Also available as an e-book:

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This book is dedicated in loving memory of three stalwarts of Neuropathology: Professor Subimal Roy, Professor A. K. Banerjee, and Professor S. K. Shankar, who laid the foundations of this specialty in India. Neuropathology in this country has progressed by leaps and bounds and has its own standing and recognition internationally, because we stand tall on the shoulders of these giants. Their contributions will go down in history and they will remain treasured forever in our memory.

Contents

Foreword

V. V. Radhakrishnan

Foreword

V. P. Singh

Preface

Acknowledgments

Executive Committee of the Neurological Society of India: 2021–22

Contributors

1.Tumors of the Nervous System

1.1Introduction to the Fifth Edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5)

1.2Adult-Type Diffuse Gliomas

1.2.1Astrocytoma, IDH-mutant

1.2.2Oligodendroglioma, IDH-mutant and 1p/19q-codeleted

1.2.3Glioblastoma, IDH-wildtype

1.3Circumscribed Astrocytic Gliomas

1.3.1Pilocytic Astrocytoma

1.3.2High-Grade Astrocytoma with Piloid Features

1.3.3Pleomorphic Xanthoastrocytoma

1.3.4Subependymal Giant Cell Astrocytoma

1.3.5Chordoid Glioma

1.3.6Astroblastoma, MN1-Altered

1.4Pediatric-type Diffuse Low-Grade Gliomas

1.4.1Diffuse Astrocytoma, MYB- or MYBL1-altered

1.4.2Angiocentric Glioma

1.4.3Polymorphous Low-grade Neuroepithelial Tumor of the Young

1.4.4Diffuse Low-grade Glioma, MAPK Pathway-Altered

1.5Pediatric-type Diffuse High-grade Gliomas

1.5.1Diffuse Midline Glioma (DMG), H3K27-altered

1.5.2Diffuse Hemispheric Glioma, H3 G34-mutant

1.5.3Diffuse Pediatric-type High-grade Glioma, H3-wildtype and IDH-wildtype

1.5.4Infant-type Hemispheric Glioma

1.6Glioneuronal and Neuronal Tumors

1.6.1Dysembryoplastic Neuroepithelial Tumor

1.6.2Gangliocytoma and Ganglioglioma

1.6.3Dysplastic Cerebellar Gangliocytoma (Lhermitte–Duclos Disease)

1.6.4Desmoplastic Infantile Astrocytoma and Ganglioglioma

1.6.5Papillary Glioneuronal Tumor

1.6.6Rosette-Forming Glioneuronal Tumor

1.6.7Diffuse Leptomeningeal Glioneuronal Tumor

1.6.8Central Neurocytoma, Extraventricular Neurocytoma, and Cerebellar Liponeurocytoma

1.6.9Diffuse Glioneuronal Tumors with Oligodendroglioma-like Features and Nuclear Clusters

1.6.10Myxoid Glioneuronal Tumor

1.6.11Multinodular and Vacuolating Neuronal Tumor

1.7Ependymal Tumors

1.7.1Supratentorial Ependymomas

1.7.1.1Supratentorial Ependymoma

1.7.1.2Supratentorial Ependymoma, ZFTA Fusion-positive

1.7.1.3Supratentorial Ependymoma, YAP1 Fusion-positive

1.7.2Posterior Fossa Ependymomas

1.7.2.1Posterior Fossa Ependymoma

1.7.2.2Posterior Fossa Group A (PFA) Ependymoma

1.7.2.3Posterior fossa group B (PFB) ependymoma

1.7.3Spinal Ependymomas

1.7.3.1Spinal Ependymoma

1.7.3.2Spinal Ependymoma, MYCN-amplified

1.7.4Myxopapillary ependymomas

1.7.5Subependymoma

1.8Choroid Plexus Tumors

1.9Embryonal Tumors

1.9.1Medulloblastoma

1.9.1.1Medulloblastoma, Histologically Defined

1.9.1.2Medulloblastoma, Molecularly Defined

1.9.2Other CNS Embryonal Tumors

1.9.2.1Atypical Teratoid/Rhabdoid Tumor (AT/RT)

1.9.2.2Cribriform Neuroepithelial Tumor (CRINET)

1.9.2.3Embryonal Tumor with Multilayered Rosettes (ETMR)

1.9.2.4CNS Neuroblastoma, FOXR2-activated

1.9.2.5CNS Tumor with BCOR Internal Tandem Duplication

1.9.2.6CNS Embryonal Tumor NEC/NOS

1.10Pineal Tumors

1.10.1Pineocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, and Pineoblastoma

1.10.2Papillary Tumor of the Pineal Region

1.10.3Desmoplastic Myxoid Tumor of the Pineal Region, SMARCB1-mutant

1.11Meningioma

1.12Mesenchymal Non-meningothelial Tumors Involving the CNS

1.12.1Solitary Fibrous Tumor

1.12.2Hemangiomas and Vascular Malformations

1.12.3Hemangioblastoma

1.12.4Rhabdomyosarcoma

1.12.5Intracranial Mesenchymal Tumor, FET::CREB Fusion Positive

1.12.6CIC-rearranged Sarcoma

1.12.7Primary Intracranial Sarcoma, DICER1-mutant

1.12.8Ewing Sarcoma

1.12.9Mesenchymal Chondrosarcoma

1.12.10Chondrosarcoma

1.12.11Chordoma

1.13Cranial and Paraspinal Nerve Tumors

1.13.1Schwannoma

1.13.2Neurofibroma

1.13.3Perineurioma

1.13.4Hybrid Nerve Sheath Tumors

1.13.5Malignant Melanotic Nerve Sheath Tumor

1.13.6Malignant Peripheral Nerve Sheath Tumor

1.13.7Cauda Equina Neuroendocrine Tumor (Previously CNS Paraganglioma)

1.14Melanocytic Tumors

1.14.1Diffuse Meningeal Melanocytic Neoplasms: Meningeal Melanocytosis and Meningeal Melanomatosis

1.14.2Circumscribed Meningeal Melanocytic Neoplasms: Melanocytoma and Melanoma

1.15Hematolymphoid Tumors Involving the CNS

1.15.1CNS Lymphomas

1.15.1.1Primary Diffuse Large B-cell Lymphoma of the CNS

1.15.1.2Immunodeficiency-associated CNS Lymphoma

1.15.1.3Lymphomatoid Granulomatosis

1.15.1.4Intravascular Large B-cell Lymphoma

1.15.2Miscellaneous Rare Lymphomas in the CNS

1.15.2.1Mucosa-Associated Lymphoid Tissue Lymphoma of the Dura

1.15.2.2Other Low-grade B-cell Lymphomas of the CNS

1.15.2.3Anaplastic Large Cell Lymphoma (ALK+/ALK–)

1.15.2.4T-cell and NK/T-cell Lymphomas

1.15.3Histiocytic Tumors

1.15.3.1Erdheim–Chester Disease

1.15.3.2Rosai–Dorfman Disease

1.15.3.3Juvenile Xanthogranuloma

1.15.3.4Langerhans Cell Histiocytosis

1.15.3.5Histiocytic Sarcoma

1.16Germ Cell Tumors

1.16.1Germinoma

1.16.2Teratoma

1.16.2.1Mature Teratoma

1.16.2.2Immature Teratoma

1.16.2.3Teratoma with Somatic-type Malignancy

1.16.3Embryonal Carcinoma

1.16.4Yolk Sac Tumor

1.16.5 Choriocarcinoma

1.16.6Mixed Germ Cell Tumors

1.17Tumors of the Sellar Region

1.17.1Tumors of the Pituitary

1.17.2Adamantinomatous Craniopharyngioma

1.17.3Papillary Craniopharyngioma

1.17.4Pituicyte Tumor Family

1.17.5Pituitary Blastoma

1.18Genetic Tumor Syndromes Involving the CNS

1.18.1Neurofibromatosis Group

1.18.2Tuberous Sclerosis Complex (Bourneville Disease/Bourneville-Pringle Syndrome/Epiloia)

1.18.3Von Hippel–Lindau Syndrome

1.18.4Rhabdoid Tumor Predisposition Syndrome

1.18.5Constitutional Mismatch Repair Deficiency Syndrome

1.18.6Other Genetic Tumor Syndromes

1.19Metastases to the CNS

1.19.1Metastases to the Brain and Spinal Cord Parenchyma

1.19.2Metastases to the Meninges

1.20Tumors of the Spine

1.20.1Introduction

1.20.2Benign Tumors of the Vertebral Column

1.20.3Malignant Tumors of the Vertebral Column

1.20.4Extramedullary Spinal Cord Tumors

1.20.5Intramedullary Spinal Cord Tumors

1.20.6Tumor-like Lesions of the Spinal Cord

1.20.7Congenital malformations of the Spinal Cord

1.21Cysts of the Central Nervous System

1.22Therapy-related Neuropathology

1.22.1Radiation Necrosis (Radionecrosis, Radiation Necrosis, or Cerebral Radiation Damage)

2.Aneurysms and Vascular Malformations of the Nervous System

2.1Intracranial Aneurysms

2.2Vascular Malformations of the Brain

2.2.1Arteriovenous Malformation

2.2.2Cerebral Cavernous Malformation (CCM) or Cavernoma

2.2.3Venous Angioma/Developmental Venous Anomaly (DVA)

2.2.4Capillary Telangiectasia

2.2.5Arteriovenous Fistula

2.2.6Acquired Vascular Malformations

2.3Vascular Malformations of the Spinal Cord

2.4Syndromic Association with Vascular Malformations of CNS

3.Traumatic Brain Injury

3.1Classification of TBI by Severity of Injury

3.2Pathoanatomic Classification

3.3Classification by Physical Mechanism

3.4Classification by Pathophysiology

3.5Effects of TBI

4.Surgical Pathology of Drug-Resistant Epilepsy

4.1Introduction

4.2Hippocampal Sclerosis

4.3Malformations of Cortical Development

4.4Focal Cortical Dysplasia

5.Infectious and Inflammatory Lesions Mimicking Neoplasms

5.1Tuberculosis

5.2Fungal Infections

5.3Parasitic Infections

5.4Neurosarcoidosis

5.5Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS)

5.6IgG4-Related Disease

5.7Tumefactive Demyelination

6.Surgical Pathology of Spinal Dysraphism and Other Neural Tube Defects

6.1Embryology

6.2Incidence

6.3Etiopathogenesis

6.4Open Neural Tube Defects

6.4.1Anencephaly and Craniorachischisis Totalis

6.4.2Myelomeningocele and Meningocele

6.5Closed Neural Tube Defects

6.5.1Defect of Gastrulation

6.5.2Defect of Dysjunction

6.5.3Defect of Secondary Neurulation and Postneurulation

6.6Anterior Sacral Meningocele

7.Miscellaneous

7.1Smears in the Rapid Diagnosis of Central Nervous System Lesions

7.2Challenges in the Interpretation of Stereotactic Biopsies

Suggested Reading

Index

Foreword

I am indeed delighted to write the foreword for the second edition of Essentials of Diagnostic Surgical Neuropathology. It is heartening to see in this edition, significant contributions coming from the younger generation of our neuropathologists. This has brought a fresh perspective and augurs well for the future of neuropathology in this country.

Contrary to the conventional textbooks on neuropathology, the format used by the editors of this book is simple and user friendly. This book is an updated reference manual in neuropathology not only for pathologists but also for neurosurgeons, neurologists, neuro-oncologists, neuroradiologists, and research students.

During the past two decades, the range of diseases seen by neuropathologists has grown enormously. There are newer therapeutic options today and for accurate diagnoses, we need molecular and genetic markers. Further, we also need the ability to interpret the complexity of classifications and delineation of subgroups. These are now considered essential in ‘day to day’ clinical practice. This new edition contains a wealth of information to meet these new challenges. The reader will find it best emphasized in the section on Tumors of the Central Nervous System. Notably, up-to-date information of non-neoplastic lesions is also provided. One example is the Surgical Pathology of Drug-Resistant Epilepsy which is highlighted. Another very novel chapter is on infectious and immune mediated lesions mimicking neoplasms. Further, the importance of correlating clinical information with neuropathological features is a common theme notable throughout this book.

The publication of a newer edition is always an occasion for anticipation. During the past decade or so, advent of online publishing has taken center stage. Hence, for a book to succeed, it has to be not only relevant but also be meaningful. I can see that the editors and authors have responded to this challenge in a highly commendable manner. Within a short span of four years, they have brought out the second edition, a clear testimony of their untiring efforts.

I have no doubt that the editors, co-editors, and authors will be applauded by readers of this book, for promoting and disseminating knowledge among the neurosciences community.

With my best wishes.

V. V. Radhakrishnan, MD, FAMS

Formerly, Dean and Head of Department of Pathology

Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST)

Thiruvanathapuram, Kerala

Foreword

When I was the Secretary of the Neurological Society of India—the 2016 Update of the fourth edition of the WHO classification of brain tumors emerged—incorporating molecular data along with histopathological features to give an integrated diagnosis. The need was felt by clinicians like me to have a simple explanation of the nuances of pathology of brain tumors. The NSI initiated a project to publish a book of neuropathology for neurosurgeons, with practical and handy information available at a glance. The task was entrusted to the leading neuropathologists in our country: Dr. Chitra Sarkar from AIIMS, New Delhi; Dr. Vani Santosh from NIMHANS, Bengaluru; and Dr. Geeta Chacko from CMC, Vellore. They delivered in a short time and the book entitled Essentials of Diagnostic Surgical Neuropathology was released in the NSICON 2017 in Nagpur. The book became popular overnight. With more data available on the molecular pathology of tumors, the WHO has now released the full fifth edition of the classification of brain tumors in late 2021 .

In view of the tremendous success of the earlier book, NSI once again requested our distinguished team of neuropathologists to bring out a second edition of the book incorporating the latest changes. A fourth editor, Dr. Anita Mahadevan from NIMHANS, Bengaluru has also been added to the previous three. Even though the time given to them was extremely short, the editors have produced an excellent book showcasing the latest advances in surgical neuropathology.

The book is divided into seven chapters covering the pathology of all major surgical aspects. As expected, neuropathology of brain tumors forms the bulk of the chapters. There are also detailed discussions on the pathology of vascular lesions of the CNS, neural tube defects, and traumatic brain injury. Interestingly, they have also covered the neuropathological substrates of drug resistant epilepsy and of infectious and immune mediated lesions mimicking tumors.

The most endearing feature of the book is the lucid style of presentation which immediately captures the interest of the reader. The write-up in the point-wise bulleted format makes it easy for the reader to remember and retain in his/her memory. I am positive that this excellent book will swiftly attract the attention of neurosurgeons and it will soon become a “must have” for all specialists in the field whether they are trainees, junior neurosurgeons, or the senior established stalwarts.

I congratulate the four editors, the three co-editors, and all the other authors for their stupendous efforts in bringing out a much needed “par excellence” book in such a short time.

V. P. Singh

President

Neurological Society of India

Preface

In the past few years, we have witnessed rapid progress in the field of neuropathology. This has led to considerable advances in the diagnosis of neoplastic and non-neoplastic brain lesions with more refined diagnostic criteria and classification systems, with a goal to improve patient care. The emergence of personalized medicine has also led to a paradigm shift in the approach towards diagnostic neuropathology by both clinicians and pathologists.

This is the second edition of “Essentials of Diagnostic Surgical Neuropathology’’. Like the first edition, this book covers the vast subject of surgical neuropathology in a concise form, to serve as a quick reference guide. This edition aims to provide updated information on neoplastic and non-neoplastic surgical neuropathology. The purpose of this book is to offer a ready reckoner to aid clinicians and pathologists in their routine practice. The book will be useful for neurosurgeons, neurologists, neuro-oncologists, and neuroradiologists. It will also be a useful guide for general surgical pathologists, residents of pathology and researchers, who are not very familiar with the subspeciality of neuropathology. The standardized modular layout makes the book easily readable.

The book is divided into seven chapters. Chapter 1 is about tumors of the nervous system whilst Chapters 2 to 6 focus on non-neoplastic pathology. Chapter 7 is mainly on techniques and newly introduced in this edition. It deals with the importance of intraoperative smears for the rapid diagnosis of CNS lesions as well as challenges in the interpretation of small, stereotactic biopsies.

The section on neoplastic pathology is extensively revised from the previous edition, to incorporate the profound changes which have occurred in the diagnosis and classification of tumors of the central nervous system (CNS). The classification of CNS tumors has progressed significantly from the previous revised fourth edition of WHO 2016 to the fifth WHO edition published in late 2021 (WHO CNS5), with the incorporation of molecular parameters for diagnosis. The new WHO CNS5 classification is expected to help in more accurate diagnosis and prognostication of CNS tumors, better prediction of treatment response, risk stratification, improvement in management, design of more specific targeted therapies and analysis of clinical trials. Therefore, this book provides updated information on all tumors of the nervous system as per WHO CNS5. In doing so, this edition emphasises changes in CNS tumor nomenclature and grading, describes the new tumor types and subtypes, lays emphasis on layered reporting format and integrated diagnosis along with newer diagnostic technologies including DNA methylome profiling. Since ancillary techniques are a very important component for diagnosis, the book extensively covers immunohistochemistry(IHC) and molecular diagnostic parameters for all nervous system tumors. The information is provided in a bulleted point format under segments such as definition, grade, subtypes, localization, macroscopic features, histopathological features, immunophenotype, diagnostic molecular pathology and prognosis along with tables (wherever required), for ease of understanding.

It is pertinent to highlight here that we have obtained license from International Agency for Research on Cancer (IARC) / WHO for use of their selected material and hence the definitions as well as essential and desirable diagnostic criteria in this book are reproduced entirely from IARC/WHO publication (WHO CNS5). Also it is important to note that these essential and desirable diagnostic criteria have been included for all tumor types in a succinct tabular form at the end of their respective tumor chapter, which will serve as a ready reference to both clinicians and pathologists.

The non-neoplastic section restricts itself to illustrate the lesions amenable to surgical resections. The neuropathology of drug resistant epilepsy is challenging for both the surgeon and the pathologist. The field is an exquisite amalgamation of several fields of neuroscience – neurology, physiology, pharmacology, and developmental neurobiology. Awareness of the diversity of lesions associated with this condition is essential for an accurate diagnosis. The classification of these lesions has also been updated recently which is covered in this edition. The other chapters deal with overview of aneurysms and vascular malformations of the nervous system, and traumatic brain injury. The section on infections and immune mediated lesions mimicking neoplasms, has been expanded to include newly recognised lesions like IgG4 related disease and CLIPPERS. The pathology of spinal dysraphism and other neural tube defects, is an often-encountered biopsy for the pathologist, and is included in this edition. Often neglected by pathologists, it is important to understand the wide spectrum of these disorders in the context of embryology and development.

Since a great amount of neuropathological information comes from visual clues, both the neoplastic and non-neoplastic sections are supplemented by gross and/or photomicrographs including special stains, IHC and molecular test results. In fact, visual information is always the starting point for neuropathological evaluation and guides further testing. Therefore, every chapter is adequately illustrated with such photographs.

Finally the chapter wise consolidated listing of the suggested reading highlights important journal publications and reviews in the field. The most valuable resource for neuro-oncology being the WHO CNS5, this book has been referenced with details provided of the individual chapters. For those who wish to further explore any of the entities presented in the book, this section provides a list of important references for a quick overview.

The editors Chitra Sarkar, Vani Santosh, Geeta Chacko and Anita Mahadevan; co- editors Vaishali Suri, Megha S. Uppin, and Shilpa Rao, as well as more than 30 other contributors are distinguished neuropathologists at the forefront of diagnosis, teaching and research in the field. Notably they are from leading institutes across the country and members of the Neuropathology Society of India, which is a young vibrant society that has as its mandate the dissemination of knowledge in neuropathology to the wider community. The changes brought about in this book have involved enormous work on the part of all contributors, who have shown dignified politeness in responding to several requests to condense text, reorganise chapters and provide selected references.

This book has been the brain child of the Neurological Society of India (NSI), in its continuing endeavour to disseminate knowledge amongst its members and the medical community at large. NSI has given us an opportunity to update neuropathological information in this second edition and all the members of the Neuropathology Society of India (NPSI) are indebted to NSI for this support. We are particularly grateful to Dr. V. P. Singh, President of NSI and Dr. K. Sridhar, Secretary of NSI who facilitated this undertaking.

The editorial board is pleased to present the second edition of “Essentials of Diagnostic Surgical Neuropathology” and hopes that this will continue as a series to achieve the required standards for diagnosis and enable the translation of diagnostic research into clinical practice.

Chitra Sarkar

Vani Santosh

Geeta Chacko

Anita Mahadevan

Acknowledgments

The strength of the team is each member. The strength of each member is the team.

—Phil Jackson

I am extremely grateful to all my editors, co-editors, and contributors who have put in their valuable time and effort towards the completion of this vast project, despite their busy schedules. The group of authors that we could assemble to contribute to this book from across all parts of India is indeed impressive, and demonstrates that neuropathology is fast becoming an important super-speciality within pathology.

My deepest gratitude goes to Vani, Geeta, Anita, Vaishali, Megha and Shilpa, without whose unconditional help and unwavering support, I would never have been able to complete this project. They have been invaluable, seamlessly aligning their efforts with mine and putting in long hours even on holidays. They were always there for me and I have derived enormous strength from them. Their encouragement has always elevated my spirits and enthused me, especially in times of pressure to meet deadlines.

I gratefully acknowledge the support of the International Agency for Research on Cancer (IARC)/WHO, especially Prof. Ian Cree and his team for granting us the license to reprint and reproduce selected IARC/WHO published materials (definitions as well as essential and desirable diagnostic criteria).

I am indebted to my colleagues in neuropathology, Mehar Chand Sharma, Vaishali Suri, and Swati Mahajan as well as all my colleagues in the Department of Pathology, for allowing me to devote ample time for the compilation of this book. I would also like to take this opportunity to thank my teachers and mentors — Late Prof Subimal Roy, Prof P. N. Tandon, and Prof A. K. Banerjee for introducing me to the field of neuropathology. I am eternally grateful to Late Prof A. K . Banerjee and Late Prof S. K. Shankar for their constant inspiration and guidance in all my endeavours. It is extremely unfortunate that we lost these doyens of neuropathology a few months before the release of this book.

I would like to acknowledge all my technical staff, students, residents, and research scholars for being the backbone of all my scientific contributions. I am also immensely grateful to my secretarial associates Kamal Gulati and Sachin Mor for their help.

I would like to thank the Neurological Society of India and my long term friend Dr V.P. Singh for giving us this opportunity and entrusting us with a project of this magnitude. I commend my family, especially my daughter for tolerating the late nights, weekends, and missed family events spent in long writing and editing sessions. Last but not the least, I would also like to thank all the members of the Neuropathology Society of India for their constant support and encouragement. Special thanks to the staff at Thieme, especially Dr Nidhi Srivastava and Gaurav Prabhu for helping us at every step of this project.

Coming together is a beginning.Keeping together is progress.Working together is success.—Henry Ford

Chitra Sarkar

I am indebted to the Neurological Society of India for giving us an opportunity and supporting us to bring out the 2nd edition of “Essentials in Diagnostic Neuropathology”. Medicine is an ever-changing science, and newer research in neuropathology helps us understand the subject better, which is emphasized in this book. Writing and editing a book is harder than I thought and more rewarding than I could have imagined. None of this would have been possible, but for the sincere commitment by my very good friend Chitra Sarkar, the lead editor of this book. I am indebted to Chitra for her deep involvement and guidance at every step, starting with selection of topics and contributors up to the publication process. There have been innumerable phone calls and exchanges of mails with her during the past few months, only to ensure completion of the project in the stipulated time. I have enjoyed editing this book along with her and my dear colleagues, Geeta Chacko and Anita Mahadevan. I am very grateful to our co-editors, Vaishali Suri, Megha S. Uppin, and Shilpa Rao. They were incredibly helpful in detailed line editing and formatting the chapters. I am eternally grateful to all the authors of this book, who have put in enormous effort in contributing to the various chapters. I am indebted to our students and research staff at NIMHANS for providing photographs and illustrations for some of the chapters. I would like to acknowledge the staff at Thieme, especially Dr Nidhi Srivastava, in supporting us to publish this book on time. Finally, I am grateful to my teachers and mentors who have taught me different skills to impart knowledge in neuropathology.

Vani Santosh

I am grateful to the Neurological Society of India and Thieme for their support in the publication of the 2nd edition of, Essentials of Diagnostic Surgical Neuropathology. Dr Chitra Sarkar was the driving force behind recognizing the need for a new edition of this book, spearheading the interaction with the Neurological Society of India, recruiting contributors and ensuring its timely release with incisive editing. I am proud to be a member of the Neuropathology Society of India that enthusiastically urges its members to constantly update their knowledge in this ever-changing field and disseminate newer concepts amongst the wider Neuroscience community. This book stands testament to that endeavor and is a result of the wonderful cooperation we shared as editors, co-editors, and authors.

I am deeply indebted to Chitra, Vani, Anita, and the co-editors Vaishali, Megha and Shilpa who willingly provided help when I needed it. I salute my fellow co-authors for their contributions and for meeting deadlines despite their otherwise busy schedules. For giving me the time and space for this academic opportunity, I am grateful to my colleagues at CMC, Vellore especially Ranjani, Hemanth, Rima, Jonali, Nivetha, and Jones. I am very thankful to the staff of the Pathology department at CMC, and especially to the Neuropathology technicians, Janet and Sunitha, for always providing me with superb sections, crisp immunohistochemical staining and reliable molecular test results.

I wish to record my deepest gratitude to my mentors, parents, teachers, and students who inspire me to never cease learning. To my family, I am thankful every day for their unconditional love, support, and encouragement.

Geeta Chacko

I would like to dedicate the section on non-neoplastic neuropathology to Prof S.K. Shankar, doyen of neuropathology who made enormous contributions in the field and inspired many of us to take interest in it. Majority of the illustrations of autopsy specimens used throughout this edition are the specimens carefully and painstakingly dissected, preserved and mounted in the Neuropathology Brain Museum at National Institute of mental Health & Neurosciences (NIMHANS), Bangalore by Prof SK Shankar. I would also like to thank all the authors in this section for sharing their expertise and material that has enriched the content of this edition. The technical staff responsible for providing excellent histopathological slides is gratefully acknowledged. I would like to thank all the clinical colleagues who contributed radiology and clinical images to the chapters. The families of patients who consented to allow utilization of biopsy material of their kith and kin to enhance knowledge of clinicians with the sole aim of enhancing patient care is gratefully acknowledged.

Anita Mahadevan

Executive Committee of the Neurological Society of India: 2021-22

President:

Dr. V.P. Singh

President Elect:

Dr. Y.R. Yadav

Hon. Secretary:

Dr. K. Sridhar

Treasurer:

Dr. S.S. Kale

Editor, Neurology India:

Dr. P. Sarat Chandra

Members:

Dr. Abhidha Shah

Dr. Debashish Chowdhury

Dr. Deepak Gupta

Dr. Dhandapani SS

Dr. Dwarakanath S.

Dr. Manjul Tripathi

Dr. Rajshree Deopujari

Dr. S.V. Khadilkar

Dr. Sumit Sinha

Dr. VR Roopesh Kumar

Past Presidents:

Dr. Lokendra Singh

Dr. Atul Goel

Past Hon. Secretary:

Dr. N. Muthukumar

Past Hon. Treasurer:

Dr. Daljit Singh

Organizing Secretary, NSICON 2022:

Dr. Arvind Kumar Agarwal

Contributors

Abha Elizabeth John, MDAssistant Professor Department of General PathologyChristian Medical CollegeVellore, Tamil Nadu

Aditi Goyal, MDDM ResidentDepartment of NeuropathologyNational Institute of Mental Health and Neurosciences (NIMHANS)Bengaluru, Karnataka

Anita Mahadevan, MD, DNB, FAMSProfessor and HeadDepartment of NeuropathologyCoordinator, Human Brain Tissue Repository (Brain Bank)National Institute of Mental Health & Neurosciences (NIMHANS)Bengaluru, Karnataka

Aparna Govindan, MD, PDF (Neuropathology)Associate ProfessorDepartment of PathologyGovt. Medical CollegeKozhikode, Kerala

Ayushi Sahay, MDProfessorDepartment of PathologyTata Memorial Centre and Homi Bhabha National Institute (HBNI)Mumbai, Maharashtra

Bishan D. Radotra, MD, MAMS, FICPath, PhD (UK)Professor and HeadDepartment of HistopathologyPost Graduate Institute of Medical Education and Research (PGIMER) Chandigarh

Chitra Sarkar, MD, FRCPath, FICPath, FASc, FNASc, FAMS, FNAJ C Bose National FellowProfessor, Department of PathologyFormer Dean (Research)Former Head, Department of PathologyAll India Institute of Medical Sciences (AIIMS)New Delhi, Delhi

Debajyoti Chatterjee, MDAssistant Professor Department of HistopathologyPost Graduate Institute of Medical Education and Research (PGIMER)Chandigarh

Deepti Narasimhaiah, MD, PhDAdditional ProfessorDepartment of PathologySree Chitra Tirunal Institute for Medical Sciences and TechnologyThiruvananthapuram, Kerala

Geeta Chacko, MD, PhDProfessor and HeadDepartment of General PathologyChristian Medical CollegeVellore, Tamil Nadu

Hemanth Kumar R., MDAssistant Professor Department of General PathologyChristian Medical CollegeVellore, Tamil Nadu

Kiran Preet Malhotra, MD, DNB, PDCCProfessorDepartment of PathologyDr Ram Manohar Lohia institute of Medical Sciences Lucknow, Uttar Pradesh

Kirti Gupta,MDProfessorDepartment of HistopathologyPostgraduate Institute of Medical Education & Research (PGIMER) Chandigarh

Lateef Zameer, MDSenior ConsultantDepartment of HistopathologyTata Medical CentreKolkata, West Bengal

Mayur ParkhiSenior Research AssociateDepartment of HistopathologyPostgraduate Institute of Medical Education and Research (PGIMER)Chandigarh

Megha S. Uppin, MD, FICPathAdditional Professor Department of PathologyNizam’s Institute of Medical Sciences (NIMS)Hyderabad, Telangana

Mehar Chand Sharma, MD, FRCPath, FICPathProfessor and Head, NeuropathologyNeurosciences CentreAll India Institute of Medical Sciences (AIIMS)New Delhi, Delhi

Mou Das, MDAssociate ProfessorDepartment of PathologyInstitute of Post Graduate Medical Education and Research, SSKM HospitalKolkata, West Bengal

Nandeesh B. N., MD, DNBAdditional Professor Department of NeuropathologyNational Institute for Mental Health and Neurosciences (NIMHANS)Bengaluru, Karnataka

Nuzhat Husain, MD, FICPath, IFCAPDeanProfessor and Head, Department of PathologyFaculty In-charge Research CellOfficer In-charge State Referral Centre for Lab investigationsDr Ram Manohar Lohia Institute of Medical Sciences Lucknow, Uttar Pradesh

Rajalakshmi P., MD, PDF (Neuropathology)Associate ProfessorDepartment of PathologySree Chitra Tirunal Institute for Medical Sciences and TechnologyThiruvananthapuram, Kerala

Rakesh Kumar Gupta, MD, DNB, MNAMSAssistant ProfessorDepartment of PathologyAll India Institute of Medical Sciences (AIIMS)Raipur, Chhattisgarh

Ranjani Jayachandran, MD, PDF (Neuropathology)Assistant ProfessorDepartment of General PathologyChristian Medical CollegeVellore, Tamil Nadu

Ravindra Kumar Saran, MD, DNB, MNAMS, MBA (Healthcare)Director-Professor of PathologyG. B. Pant IPMER (Institute of Postgraduate Medical Education and Research)New Delhi

Rima S., MD, DNBAssistant Professor Department of General PathologyChristian Medical CollegeVellore, Tamil Nadu

Saumya Sahu, MDSenior Resident NeuropathologyNeurosciences CentreAll India Institute of Medical Sciences (AIIMS)New Delhi, Delhi 

Shilpa Rao, MD, DMAssociate Professor Department of NeuropathologyNational Institute for Mental Health and Neurosciences (NIMHANS)Bengaluru, Karnataka

Soumya Dey, MDSenior Resident Department of PathologyInstitute of Post Graduate Medical Education and Research, SSKM Hospital,Kolkata, West Bengal

Soutrik Das, MDConsultant NeuropathologistDepartment of Pathology and Laboratory MedicineInstitute of NeurosciencesKolkata, West Bengal

Sridhar Epari, MDProfessor Department of PathologyTata Memorial Centre and Homi Bhabha National Institute (HBNI)Mumbai, Maharashtra

Sundaram Challa, MD, FAMS, FICPathSenior Consultant, Advisor DNB PathologyDepartment of PathologyBasavatarakam Indo-American Cancer Hospital & Research InstituteHyderabad, Telangana

Sushama V. Patil MD, AB (Neuropathology)HeadDepartment of Laboratory ServicesApollo Proton Cancer CentreChennai, Tamil Nadu

Suvendu Purkait, MD Associate Professor of PathologyDepartment of Pathology & Lab MedicineAll India Institute of Medical Sciences (AIIMS)Bhubaneshwar, Odisha

Swati Mahajan, MD Senior Research Associate, NeuropathologyNeurosciences Centre All India Institute of Medical Sciences (AIIMS)New Delhi, Delhi 

Uttara Chatterjee, MDProfessorDepartment of PathologyInstitute of Post Graduate Medical Education and Research, SSKM HospitalKolkata, West Bengal

Vaishali Suri, MD Professor, Department of Neuropathology Neurosciences CentreAll India Institute of Medical Sciences (AIIMS)New Delhi, Delhi

Vani Santosh, MD, FAMS, FICPathSenior Professor, Department of NeuropathologyDean, NeurosciencesNational Institute of Mental Health & Neurosciences (NIMHANS)Bengaluru, Karnataka

Yasha T. C., MDProfessor Department of NeuropathologyNational Institute of Mental Health and Neurosciences (NIMHANS)Bengaluru, Karnataka

1

Tumors of the Nervous System

1.1Introduction to the Fifth Edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5)

Chitra Sarkar, Swati Mahajan, Vaishali Suri, and Mehar Chand Sharma

1.2Adult-Type Diffuse Gliomas

Vani Santosh and Shilpa Rao

1.3Circumscribed Astrocytic Gliomas

Vani Santosh and Shilpa Rao

1.4Pediatric-type Diffuse Low-Grade Gliomas

Shilpa Rao and Vani Santosh

1.5Pediatric-type Diffuse High-grade Gliomas

Ayushi Sahay, Saumya Sahu, and Vaishali Suri

1.6Glioneuronal and Neuronal Tumors

Suvendu Purkait, Swati Mahajan, Mehar Chand Sharma, Chitra Sarkar, and Vaishali Suri

1.7Ependymal Tumors

Rakesh Kumar Gupta, Ravindra Kumar Saran, and Mehar Chand Sharma

1.8Choroid Plexus Tumors

Aparna Govindan and Yasha T. C.

1.9Embryonal Tumors

Vaishali Suri, Swati Mahajan, Saumya Sahu, and Chitra Sarkar

1.10Pineal Tumors

Lateef Zameer and Megha S. Uppin

1.11Meningioma

Ranjani Jayachandran and Geeta Chacko

1.12Mesenchymal Non-meningothelial Tumors Involving the CNS

Hemanth Kumar R., Ranjani Jayachandran, and Geeta Chacko

1.13Cranial and Paraspinal Nerve Tumors

Yasha T. C. and Aditi Goyal

1.14Melanocytic Tumors

Shilpa Rao, Sridhar Epari, and Megha Uppin

1.15 Hematolymphoid Tumors Involving the CNS

Debajyoti Chatterjee, Mayur Parkhi, Kirti Gupta, and Bishan D. Radotra

1.16Germ Cell Tumors

Megha S. Uppin and Sundaram Challa

1.17Tumors of the Sellar Region

Geeta Chacko, Abha Elizabeth John, and Rima S.

1.18Genetic Tumor Syndromes Involving the CNS

Sushama V. Patil, Soutrik Das, Soumya Dey, and Uttara Chatterjee

1.19Metastases to the CNS

Kirti Gupta and Bishan D. Radotra

1.20Tumors of the Spine

Kiran Preet Malhotra and Nuzhat Husain

1.21Cysts of the Central Nervous System

Kirti Gupta and Bishan D. Radotra

1.22Therapy-related Neuropathology

Kirti Gupta and Bishan D. Radotra

1.1

Introduction to the Fifth Edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5)

Chitra Sarkar, Swati Mahajan, Vaishali Suri, and Mehar Chand Sharma

Introduction

The World Health Organization (WHO) classification is the well-accepted classification system for central nervous system (CNS) tumors globally. This classification system forms the foundation for neuropathologic diagnosis of CNS tumors and has prognostic and therapeutic significance. Until recently, there have been four editions of this classification, popularly known as the “Blue Books.” The first, second, third, and fourth editions were published in 1979, 1993, 2000, and 2007, respectively. In all these, the classification and grading have been based exclusively on histopathologic characteristics using the routine hematoxylin and eosin stains along with immunohistochemical markers as adjuncts to aid the diagnosis.

For the past two decades, there has been an upsurge of molecular data, from which clinically relevant molecular biomarkers have evolved and these have been found to have prognostic and predictive benefits within tumor groups. This augmented understanding of the molecular data on brain tumors led to the release of a prior “update” of the revised WHO CNS tumor classification, fourth edition, in 2016, rather than awaiting the fifth edition. A drastic transformation was observed in the 2016 WHO classification of tumors of the CNS that incorporated for the first time molecular information along with classic histological characteristics in an integrated diagnosis format, in an endeavor to define distinct tumor entities.

However, while the WHO 2016 revision was being compiled, the swift emergence of promising molecular biomarkers, novel distinct entities, and new therapeutic targets necessitated the formation of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT) to provide recommendations for future WHO classifications. Seven updates were published by cIMPACT, which contributed significantly to the preparation of the fifth edition of the WHO classification of CNS tumors released in 2021 (WHO CNS5). This edition has added important changes related to taxonomy, nomenclature, and grading of CNS tumors as well as introduced several newly recognized tumor types and subtypes.

This chapter provides a summary of the major changes introduced in the WHO CNS5.

1.1.1 CNS Tumor Taxonomy

Reorganization of Tumor Groups

A hybrid/mixed approach has been used for grouping of tumors viz.

•Grouping based on genetic changes that are essential for diagnosis, e.g., IDH and H3 status, MN1 alteration, etc.

•Grouping based on histological and histogenetic similarities (though molecular alterations are different), e.g., glione­uronal and neuronal tumors.

•Grouping based mainly on morphological features (molecular approaches rarely or never used), e.g., meningiomas.

Restructuring of Tumor Groups

•Diffuse gliomas have for the first time been divided into adult and pediatric types, based on their clinical and molecular parameters, despite sharing similar histomorphological features.

•Pediatric-type diffuse gliomas have been further classified into pediatric-type low- and high-grade gliomas.

•A new classification system has been introduced for ependymomas based on a combination of features, namely anatomic site, histopathology, and molecular alterations.

•Major tumor groups in WHO CNS5 are shown in Table 1.1.1.

Table 1.1.1 Major tumor groups in WHO CNS5

1.

Gliomas, glioneuronal, and neuronal tumors

•Adult-type diffuse gliomas

•Pediatric-type diffuse low-grade gliomas

•Pediatric-type diffuse high-grade gliomas

•Circumscribed astrocytic gliomas

•Glioneuronal and neuronal tumors

•Ependymal tumors

2.

Choroid plexus tumors

3.

Embryonal tumors

•Medulloblastoma, molecularly defined

•Medulloblastoma, histologically defined

•Other CNS embryonal tumors

4.

Pineal tumors

5.

Cranial and paraspinal nerve tumors

6.

Meningioma

7.

Mesenchymal, nonmeningothelial tumors

•Soft-tissue tumors

•Chondro-osseous tumors

•Notochordal tumors

8.

Melanocytic tumors

•Diffuse meningeal melanocytic neoplasms

•Circumscribed meningeal melanocytic neoplasms

9.

Hematolymphoid tumors

•Lymphomas

•Histiocytic tumors

10.

Germ cell tumors

11.

Tumors of the sellar region

12.

Metastases to the CNS

Introduction of the Terms “Type” and “Subtype”

•In WHO CNS5, the earlier terms “entity” and “variant” have been replaced by “type” and “subtype,” respectively.

•“Type” is used to define a neoplasm in which multiple parameters (e.g., clinical, anatomic, histopathologic, and/or molecular) differ from other types.

•“Subtype” defines a variant of a type in which a single or couple of parameters (clinical, anatomic, histopathologic, and/ or molecular) differ from other subtypes, thus making it essential to acknowledge the variant independently (e.g., three subtypes of glioblastoma, IDH wildtype).

•Only “types” are enumerated in the main classification, whereas “subtypes” are narrated under individual sections/chapters. For example, meningioma is a single type enlisted in the classification, whereas all the histological subtypes are discussed within the meningioma chapter.

1.1.2 Modifications in Grading of CNS Tumors

Use of the Term CNS WHO Grade

•Done to emphasize that the WHO grading criteria of CNS tumors are different from that of non-CNS neoplasms, e.g., glioblastoma, IDH wild type, CNS WHO grade 4.

Use of Arabic Numerals (1, 2, 3, 4) Instead of Roman Numerals (I, II, III, IV) for Grading

•Done to reduce the risk of transcriptional errors while using Roman numerals for grading (e.g., I mistaken for II or II mistaken for III), which could have grave clinical repercussions.

Grading within Individual Tumor Types

•Introduced in many groups of tumors in order to conform with the CNS WHO grading, e.g., astrocytoma, IDH-mutant can now be either CNS WHO grade 2 or 3 or 4 (instead of each grade of astrocytoma being a distinct tumor type as in the previous classifications).

•The terms “diffuse” and “anaplastic” are no longer used for grading.

Combined Histological and Molecular Grading

•WHO CNS5 has added molecular biomarkers in addition to histomorphological characteristics for grading of some tumors, e.g., in gliomas (1) presence of CDKN2A/B homozygous deletion in IDH-mutant astrocytoma makes the tumor grade 4 in spite of the presence of low-grade histology; (2) presence of TERT promoter (TERTp) mutation along with EGFR amplification and +7/-10 copy number changes allows for a diagnosis of glioblastoma, IDH wild-type, CNS WHO grade 4, even if the tumor is histologically of lower grade (i.e., molecular glioblastoma diagnosis without classical histologic features).

Clinicopathological Grading and Grades not Assigned to Some Tumors

•WHO CNS5 has retained the ranges of grades allotted to most of the tumors to predict survival as in prior editions.

•However, grades have not been assigned to some tumors:

○Wherein statistics on outcomes are still questionable, e.g., high-grade astrocytoma with piloid features, CNS tumor with BCOR internal tandem duplication, etc.

○Wherein predicting the natural history and survival is difficult owing to newer therapies available.

○Wherein assigning grades will lead to confusion in clinical management, e.g., astroblastoma, MN1-altered.

Expression of Mitosis

•Mitosis will be written as “per mm2” in addition to expression as “per 10 high-power fields.”

1.1.3 Changes in Nomenclature of CNS Tumors

•Names of tumors have been simplified as much as possible, and only location, age, or genetic markers/molecular alterations with clinical utility have been used in the name, e.g., extraventricular neurocytoma versus central neurocytoma; astroblastoma, MN1-altered; diffuse midline glioma; and H3K27M-altered.

•The terms like anaplastic astrocytoma, anaplastic oligodendro­glioma, and anaplastic pleomorphic xantho­astrocytoma are not used in the classification.

•Overall nomenclature of 13 tumors has been revised, which are enlisted in the classification (Table 1.1.2) and marked with a single asterisk (*).

Table 1.1.2 Classification of tumors of the central nervous system (WHO CNS5)

Type

Grade

GLIOMA, GLIONEURONAL TUMORS, AND NEURONAL TUMORS

Adult-type diffuse gliomas

•*Astrocytoma, IDH-mutant

2/3/4

•Oligodendroglioma, IDH-mutant and 1p/19q-codeleted

2/3

•Glioblastoma, IDH-wildtype

4

Pediatric-type diffuse low-grade gliomas

•**Diffuse astrocytoma, MYB or MYBL1-altered

1

•Angiocentric glioma

1

•**Polymorphous low-grade neuroepithelial tumor of the young

1

•**Diffuse low-grade glioma, MAPK pathway-altered

Not assigned

Pediatric-type diffuse high-grade gliomas

•*Diffuse midline glioma (DMG), H3 K27-altered

4

•**Diffuse hemispheric glioma, H3 G34-mutant

4

•**Diffuse pediatric-type high-grade glioma, H3-wildtype, and IDH-wildtype

4

•**Infant-type hemispheric glioma

Not assigned

Circumscribed astrocytic gliomas

•Pilocytic astrocytoma

1

•**High-grade astrocytoma with piloid features

Not assigned

•Pleomorphic xanthoastrocytoma

2/3

•Subependymal giant cell astrocytoma

1

•*Chordoid glioma

2

•*Astroblastoma, MN1-altered

Not assigned

Glioneuronal and neuronal tumors

•Ganglioglioma

1

•Desmoplastic infantile ganglioglioma/desmoplastic infantile astrocytoma

1

•Dysembryoplastic neuroepithelial tumor

1

•**Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters

Not assigned

•Papillary glioneuronal tumor

1

•Rosette-forming glioneuronal tumor

1

•**Myxoid glioneuronal tumor

1

•Diffuse leptomeningeal glioneuronal tumor

Not assigned

•Gangliocytoma

1

•**Multinodular and vacuolating neuronal tumor

1

•Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease)

1

•Central neurocytoma

2

•Cerebellar liponeurocytoma

2

•Extraventricular neurocytoma

2

Ependymal tumors

•Supratentorial ependymoma

2/3

•*Supratentorial ependymoma, ZFTA fusion-positive

2/3

•**Supratentorial ependymoma, YAP1 fusion-positive

2/3

•Posterior fossa ependymoma

2/3

•**Posterior fossa ependymoma, group PFA

2/3

•**Posterior fossa ependymoma, group PFB

2/3

•Spinal ependymoma

2/3

•**Spinal ependymoma, MYCN amplified

Not assigned

•Myxopapillary ependymoma

2

•Subependymoma

1

CHOROID PLEXUS TUMORS

•Choroid plexus papilloma

1

•Atypical choroid plexus papilloma

2

•Choroid plexus carcinoma

3

EMBRYONAL TUMORS

Medulloblastoma

•Medulloblastomas, molecularly defined

4

○Medulloblastoma, WNT activated

○Medulloblastoma, SHH activated and TP53-wildtype

○Medulloblastoma, SHH activated and TP53-mutant

○Medulloblastoma, non-WNT/non-SHH

•Medulloblastomas, histologically defined

4

•Other embryonal tumors

○Atypical teratoid/rhabdoid tumor

4

○**Cribriform neuroepithelial tumor

4

○*Embryonal tumor with multilayered rosettes (ETMR)

4

○**CNS neuroblastoma, FOXR2-activated

4

○**CNS tumor with BCOR internal tandem duplication

Not assigned

○CNS embryonal tumor, NEC/NOS

Not assigned

PINEAL TUMORS

•Pineocytoma

1

•Pineal parenchymal tumor of intermediate differentiation

2/3

•Pineoblastoma

4

•Papillary tumor of the pineal region

2/3

•**Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant

Not assigned

MENINGIOMAS

•Meningiomas

1/2/3

MESENCHYMAL, NONMENINGOTHELIAL TUMORS INVOLVING THE CNS

•Soft-tissue tumors

○Fibroblastic and myofibroblastic tumors

–*Solitary fibrous tumor

1/2/3

○Vascular tumors

–Hemangiomas and vascular malformations

Not assigned

–Hemangioblastoma

1

○Skeletal muscle tumors

–Rhabdomyosarcomas

Not assigned

○Tumors of uncertain differentiation

–**Intracranial mesenchymal tumor, FET-CREB fusion positive

Not assigned

–**CIC-rearranged sarcoma, DICER1-mutant

Not assigned

–**Primary intracranial sarcoma, DICER1-mutant

Not assigned

–Ewing’s sarcoma

Not assigned

•Chondro-osseous tumors

○Chondrogenic tumors

–*Mesenchymal chondrosarcoma

Not assigned

–Chondrosarcoma

Not assigned

○Notochordal tumors

–Chordoma (including poorly differentiated chordomas)

CRANIAL AND PARASPINAL NERVE TUMORS

•Schwannoma

1

•Neurofibroma

1

•Perineurioma

1

•Hybrid nerve sheath tumor

Not assigned

•*Malignant melanotic nerve sheath tumor

Not assigned

•Malignant peripheral nerve sheath tumor

Not assigned

•Cauda equina neuroendocrine tumor

1

HEMATOLYMPHOID TUMORS OF THE CNS

•Lymphomas

Not assigned

○CNS lymphomas

–Primary diffuse large B-cell lymphoma of the CNS

–Immunodeficiency-associated CNS lymphoma

–Lymphomatoid granulomatosis

–Intravascular large B-cell lymphoma

○Miscellaneous rare lymphomas in the CNS

–ALT lymphoma of the dura

–Other low-grade B-cell lymphomas of the CNS

–Anaplastic large cell lymphoma (ALK+/ALK–)

–T-cell and NK/T-cell lymphomas

•Histiocytic tumors

Not assigned

○Erdheim–Chester disease

○Rosai–Dorfman disease

○Juvenile xanthogranuloma

○Langerhans’ cell histiocytosis

○Histiocytic sarcoma

TUMORS OF THE SELLAR REGION

•*Adamantinomatous craniopharyngioma

1

•*Papillary craniopharyngioma

1

•*Pituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma

Not assigned

•*Pituitary adenoma/pituitary neuroendocrine tumor (PitNET)

Not assigned

•**Pituitary blastoma

Not assigned

MELANOCYTIC TUMORS

•Diffuse meningeal melanocytic neoplasms

Not assigned

○Meningeal melanocytosis and meningeal melanomatosis

•Circumscribed meningeal melanocytic neoplasm

Not assigned

○Meningeal melanocytoma and meningeal melanoma

GERM CELL TUMORS

•Mature teratoma

Not assigned

•Immature teratoma

Not assigned

•Teratoma with somatic type malignancy

Not assigned

•Germinoma

Not assigned

•Embryonal carcinoma

Not assigned

•Yolk sac tumor

Not assigned

•Choriocarcinoma

Not assigned

•Mixed germ cell tumor

Not assigned

METASTASIS TO THE CNS

•Metastasis to the brain and spinal cord parenchyma

–

•Metastasis to the meninges

–

Abbreviations: IDH, isocitrate dehydrogenase; NEC, not elsewhere classified; NOS, not otherwise specified; SHH, sonic hedgehog; WNT, Wingless.

1.1.4 Introduction of Newly Recognized CNS Tumor Types

•WHO CNS5 has introduced many new tumor types (total 22) based on distinct histopathological and/or molecular characteristics.

•The newly recognized tumors are enlisted under their respective tumor group in the classification (Table 1.1.2) and marked with a double asterisk (**).

•Some of these tumor types are still provisional (3) and are marked in Table 1.1.2 in italics. These tumors are distinct by way of clinicopathological features, molecular alterations, and/or methylation profile, but the current published literature is too scant to ascertain their true nature.

1.1.5 Use of Terms “Not Otherwise Specified (NOS)” and “Not Elsewhere Classified (NEC)”

•These terms can now be used for any tumor type (not reserved for specific tumor types).

•The suffix “NOS” implies that the complete molecular information required to diagnose a specific tumor type as per WHO CNS5 criteria is not available or not performed or not successful.

•The suffix “NEC” implies that the recommended diagnostic testing has been successfully performed, but the results do not allow for a standard WHO diagnosis because of the discrepancy between the clinical, histological, immunohistochemical, and molecular features. A descriptive diagnostic report can be rendered in such cases.

•For example, a tumor with histology and IHC typical of embryonal tumor with multilayered rosettes (ETMR) but:

○C19MC alteration or DICER1 mutation testing not performed:

￭Report as ETMR, NOS.

○Tested but did not have C19MC alteration or DICER1 mutation:

￭Report as ETMR, NEC.

1.1.6 Revisions in Nomenclature of Gene and Protein

The WHO CNS5 classification uses the following:

•For gene symbols and gene names: Hugo Gene Nomenclature Committee (HGNC) system.

•For sequence variants: Human Genome Variation Society (HGVS) recommendations.

•For reporting guidelines for chromosomal alterations: International System for Human Cytogenetic Nomenclature 2020.

•For histone sequence alterations: legacy protein numbering system in parenthesis after the protein level variant description (“prefix c” for sequence alteration and “prefix p” for protein sequence), e.g., H3–3A: c. 83 A >T p. Lys 28 Met (K27M).

•Italics to be used for gene symbols, but not for proteins and gene groups (e.g., the family of IDH genes are not italicized).

1.1.7 New Additions in the Text Section of Individual Tumor Types

Essential and Desirable Diagnostic Criteria

•Essential diagnostic criteria are considered to be the minimum prerequisites to establish the diagnosis.

•The desirable diagnostic criteria are the ones that will aid in arriving at a diagnosis but are not required by itself.

•For every tumor type in each chapter, a box describing the “Essential and desirable diagnostic criteria” is provided.

Diagnostic Molecular Pathology

•A paragraph on diagnostic molecular pathology has been added for each tumor type.

DNA Methylation Profiling

•DNA methylation profiling is emerging as a robust approach to CNS tumor classification and WHO CNS5 has advocated its use for diagnosis of various CNS tumor types and subtypes.

•Methylation profiling is especially reliable for identification of tumors with ambiguous morphological features as well as some rare tumor types and subtypes, e.g., high-grade astrocytoma with piloid features. Copy number profiles and O6-methylguanine-DNA methyltransferase (MGMT) gene methylation status can also be derived from methylation data.

•However, owing to problems related to methodology, cost, and inaccessibility of the test worldwide, WHO CNS5 does not propose methylome profiling as a primary or routine diagnostic test

•Therefore, WHO CNS5 has incorporated the details about methylation profiling either in the “definitions” or as “desirable diagnostic criteria” for the majority of tumors.

1.1.8 Integrated Diagnosis

•The layered reporting format is one of the key features of the 2016 and 2021 WHO classifications.

•The report should have integrated diagnosis at the top followed by diagnostic information, viz. histological features, CNS WHO grade, and molecular information as shown in Table 1.1.3.

Table 1.1.3 Example of layered report

Tumor site: Left frontal lobe

Layer 1

Integrated diagnosis (combined histopathological and molecular diagnosis)

Oligodendroglioma, CNS WHO grade 3, IDH-mutant and 1p/19q-codeleted

Layer 2

Histopathological classification

Oligodendroglioma with microvascular proliferation, mitosis, and necrosis

Layer 3

CNS WHO grade

3

Layer 4

Molecular information

IDH1 p.R132H positive, P53 negative, retained nuclear expression of ATRX (IHC); 1p/19q codeleted (FISH) (testing platform: IHC/FISH)

Abbreviations: FISH, fluorescence in situ hybridization; IDH, isocitrate dehydrogenase; IHC, immunohistochemistry.

1.2

Adult-Type Diffuse Gliomas

Vani Santosh and Shilpa Rao

In the WHO CNS5, adult-type diffuse gliomas include a group of genetically defined tumors. The classification of this group of tumors is simplified and includes three tumor types: astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and glioblastoma, IDH-wildtype.

•1.2.1 Astrocytoma, IDH-mutant

•1.2.2 Oligodendroglioma, IDH-mutant and 1p/19q-codeleted

•1.2.3 Glioblastoma, IDH-wildtype

1.2.1Astrocytoma, IDH-mutant

Definition

“A diffusely infiltrating IDH1- or IDH2-mutant glioma with frequent ATRX and/or TP53 mutation and absence of 1p/19q codeletion.” (WHO CNS5)

Grade

•CNS WHO grade 2, 3, or 4.

Subtype(s)

•Astrocytoma, IDH-mutant, CNS WHO grade 2.

•Astrocytoma, IDH-mutant, CNS WHO grade 3.

•Astrocytoma, IDH-mutant, CNS WHO grade 4.

Age and Gender Distribution

•Median age at presentation is 38 years for grade 2 and grade 3 tumors.

•Grade 4 tumors occur in slightly older patients.

•Reported male:female ratio is 1.3:1.

Localization

•Predominantly cerebral hemispheric tumors.

•Most common location is the frontal lobe.

•Rarely occurs in infratentorial region and spinal cord.

Macroscopic Features

•Diffusely infiltrative tumor invading normal anatomical structures with blurring of the gray–white junction.

•Microcyst or macrocyst formation, sometimes filled with gelatinous material, may be observed.

•Tumor is most often soft to firm in consistency, and calcification is rare.

•Grade 4 tumors may have yellowish necrotic and hemorrhagic areas.

Histopathological Features

Astrocytoma, IDH-mutant, CNS WHO Grade 2

•Low-grade diffusely infiltrating astrocytic glioma that is mild to moderately cellular.

•Composed of well-differentiated fibrillary, protoplasmic or gemistocytic astrocytes.

•Lacks features of anaplasia.

•Nil or low mitosis.

•Stroma is fibrillary with or without a microcystic change.

•Absence of microvascular proliferation and necrosis.

Astrocytoma, IDH-mutant, CNS WHO Grade 3

•Increased cell density with features of anaplasia.

•Significant mitosis.

•Absence of microvascular proliferation and necrosis.

Astrocytoma, IDH-mutant, CNS WHO Grade 4

A diffusely infiltrating IDH-mutant astrocytoma WITH

•Microvascular proliferation and/or necrosis

Or

•CDKN2A/2B homozygous deletion.

Or

•Any combination of these features.

Immunophenotype

•Diffuse OLIG2 positivity with the majority expressing glial fibrillary acidic protein (GFAP).

•IDH1 p.R132H mutation can be detected by immuno­histochemistry (IHC) with anti-IDH1 p.R132H antibody. The tumor cells exhibit cytoplasmic positivity for IDH1 p.R132H.

•Characterized by loss of alpha thalassemia mental retardation X-linked syndrome (ATRX) expression in the nuclei of the tumor cells, which is a surrogate for ATRX mutation.

•P53 expression is noted in the majority of astrocytomas, IDH-mutant, but it is neither a sensitive nor a specific marker for the diagnosis of astrocytoma, in view of false-positive and false-negative results.

•While grade 2 tumors have a low Ki-67 proliferation index of less than 4%, grade 3 tumors have a Ki-67 proliferation index between 4 and 10%.

Diagnostic Molecular Pathology

IDH1 and 2 Mutations

•These tumors are defined by IDH1 or IDH2 mutations.

•IDH1 mutation occurs at codon 132 and IDH2 mutation occurs at codon 172.

•IDH1 p.R132H (arginine to histidine) mutation is the most common, accounting for >90%.

•Other rare mutations at this position include R132C (arginine to cysteine), R132S (serine), R132L (leucine), R132G (glycine), and R132V (valine). All these mutations are missense and heterozygous mutations.

•Five other point mutations have been identified in IDH2, where arginine at 172 (R172) is replaced with glycine (R172G), methionine (R172M), lysine (R172K), serine (R172S), and tyrosine (R172Y).

•IHC for IDH1 p. R132H is very sensitive and specific for the IDH1 p.R132H mutation.

•While IHC serves as a surrogate for the IDH1 p.R132H mutation, the other uncommon IDH1 and IDH2 mutations are detected by DNA-sequencing methods.

ATRX Mutation

•Inactivating ATRX mutation is common.

•This usually co-occurs with TP53 mutation.

•ATRX mutation results in loss of ATRX protein expression.

•ATRX mutation is mutually exclusive with 1p/19q codeletion

•Loss of ATRX is also seen in H3-altered diffuse gliomas and therefore is not a surrogate for IDH mutation exclusively.

TP53 Mutation

•TP53 mutation is one of the most common mutations in adult-type diffuse gliomas, particularly astrocytomas, IDH-mutant.

•A strong, diffuse p53 immunostaining along with ATRX loss of expression supports the diagnosis of astrocytoma, IDH-mutant.

CDKN2A and/or CDKN2B Homozygous Deletion

•Associated with poor prognosis in patients with astrocytoma, IDH-mutant irrespective of histological grade.

•Astrocytoma, IDH-mutant with CDKN2A and/or CDKN2B homozygous deletion corresponds to CNS WHO grade 4.

•Most often detected by the fluorescent in situ hybridization (FISH) technique.

Prognosis

•Patients with grade 2 tumors have a median overall survival (OS) of >10 years, while thosewith grade 3 tumors have a typical median OS in the range of 5 to 10 years.

•Grade 4 tumors are associated with a poorer outcome.

Fig. 1.2.1 Astrocytoma, IDH-mutant, grades 2 and 3.

(a, b) Gross specimen of a diffusely infiltrating astrocytoma, IDH-mutant, grade 2, in the left cerebral hemisphere, where histology shows neoplastic astrocytes dispersed over a fibrillated microcystic stroma and exhibiting mild nuclear atypia. (c) Astrocytoma, IDH-mutant grade 3, exhibiting significant nuclear atypia and increased mitosis. Tumor cells are (d) immunopositive for IDH1 p.R132H, and (e) show loss of ATRX expression and (f) diffuse p53 immunoreactivity.

Fig. 1.2.1 Astrocytoma, IDH-mutant, CNS WHO grade 4.

(g) High-grade astrocytoma showing microvascular proliferation and necrosis. (h) Tumor cells are diffusely immunopositive for IDH1 p.R132H. (i) In an IDH1 p.R132H immunonegative astrocytoma, DNA sequencing shows uncommon IDH1 p.R132G mutation compared to an IDH-wildtype control. (j) In a grade 3 astrocytoma, IDH-mutant, FISH shows two chromosome 9 centromere signals (green) and no 9p signal (orange), suggestingCDKN2A/2B homozygous deletion, thus conforming to astrocytoma, IDH-mutant, CNS WHO grade 4.

Essential and Desirable Diagnostic Criteria

Refer Table 1.2.

Table 1.2 Essential and desirable diagnostic criteria (WHO CNS5)

Tumor type

Essential criteria

Desirable criteria

Astrocytoma, IDH-mutant

•A diffusely infiltrating glioma

AND

•IDH1 codon 132 or IDH2 codon 172 missense mutation

AND

•Loss of nuclear ATRX expression or ATRX mutation

OR

•Exclusion of combined whole-arm deletions of 1p and 19q

•TP53 mutation or strong nuclear expression of p53 in >10% of tumor cells

•Methylation profile of astrocytoma, IDH-mutant

•Astrocytic differentiation by morphology

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted

•A diffusely infiltrating glioma

AND

•IDH1 codon 132 or IDH2 codon 172 missense mutation

AND

•Combined whole-arm deletions of 1p and 19q

•DNA methylome profile of oligodendroglioma, IDH-mutant and 1p/19q-codeleted

•Retained nuclear expression of ATRX

•TERT promoter mutation

Glioblastoma, IDH-wildtype

•An IDH-wildtype, H3-wildtype, diffuse astrocytic glioma

AND

•One or more of the following:

○Microvascular proliferation

○Necrosis

○TERT promoter mutation

○EGFR gene amplification

○+7/−10 chromosome copy-number alterations

•DNA methylation profile of glioblastoma, IDH-wildtype

1.2.2Oligodendroglioma, IDH-mutant and 1p/19q-codeleted

Definition

“A diffusely infiltrating glioma with IDH1 or IDH2 mutation and codeletion of chromosome arms 1p and 19q.” (WHO CNS5)

Grade

•CNS WHO grade 2 or 3.

Subtype(s)

•Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2.

•Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3.

Age and Gender Distribution

•Occurs mainly in adults, rare in children.

•Median age of grade 2 tumors is 41 years and of grade 3 tumors is 47 years.

•Slight male preponderance.

Localization

•Commonly localized to the cerebral hemispheres.

•Most frequent location is the frontal lobe, followed by the temporal and other lobes.

•Rarely involves the posterior fossa, basal ganglia, and brainstem.

•Occasionally, a gliomatosis cerebri-like spread or a diffuse leptomeningeal spread is seen.

Macroscopic Features

•Soft, gray-tan tumor, usually seen to arise in the white matter and infiltrate the gray matter resulting in blurring of the gray–white junction.

•Frequent calcification gives a gritty feeling on cut section of the tumor.

•Cystic degeneration, mucoid change, and hemorrhage can be seen.

•Local invasion into leptomeninges may be seen occasionally.

Microscopic Features

•Composed of tumor cells arranged in lobules separated by thin-walled, branching capillaries (chicken-wire vasculature).

•Cells have round uniform nuclei and a perinuclear halo, which gives a “fried-egg” appearance.

•Perinuclear halo is seen as a result of fixation artifact; hence not seen on the frozen sections.

•Microcalcification, mineralized blood vessels, hemorrhage, and microcystic change are frequently noted.

•Tumors may also have varying proportions of minigemistocytes, gliofibrillary oligodendrocytes, granular cells, signet ring cells, and mucocytes. These are more often seen in CNS WHO grade 3 tumors.

•Some tumors can be composed of cells with fibrillary astrocyte or gemistocyte-like morphology.

•Other characteristic features include perineuronal satellitosis and subpial carpeting.

•In grade 2 tumors, nuclear atypia and mitotic activity are minimal. Microvascular proliferation or necrosis is absent.

•Mitosis is prominent in grade 3 tumors, which may have microvascular proliferation or necrosis.

Immunophenotype

•Immunopositive for OLIG2, S100, MAP2, and other markers, but there is no specific immunohistochemical marker for the diagnosis since these markers are also positive in astrocytomas.

•GFAP labels minigemistocytes and gliofibrillary oligodendro­cytes, whereas the classic oligodendroglioma cells exhibit minimal or negative expression.

•The underlying neuropil is usually positive for synaptophysin and does not indicate a neurocytic differentiation in the tumor.

•IDH1 p.R132H is uniformly positive in the majority of oligodendrogliomas.

•A proportion of oligodendrogliomas (<10%) that harbor rare IDH mutations are negative on IHC for IDH1 p.R132H.

•All tumors show retained nuclear expression of ATRX and are usually immunonegative for p53.

•Ki-67 proliferation index is less than 5% in grade 2 tumors and generally more than 10% in grade 3 tumors.

Diagnostic Molecular Pathology

•Characterized by IDH mutation and 1p/19q codeletion and hence the diagnosis is established only on demonstrating these two genetic alterations.

•IDH mutation is detected by IHC for IDH1 p.R132H, and when immunonegative, DNA sequencing of IDH1 or IDH2 genes is carried out to detect the other uncommon IDH1 or IDH2 mutations.

•Most common technique to test for 1p and 19q codeletion is FISH.

•Other techniques include chromogenic in situ hybridization, polymerase chain reaction (PCR) based loss of heterozygosity (LOH) studies, and other molecular genetic tests.

•A complete loss of whole chromosomal arms 1p and 19q is the diagnostic alteration.

•Lack ATRX mutation and therefore show retained ATRX expression.

•The majority of tumors harbor TERT promoter mutations, whereas TP53 mutations are rare.

•A small proportion of grade 3 tumors harbor CDKN2A/2B homozygous deletion, which is not seen in grade 2 tumors.

Prognosis

•Associated with a favorable treatment response with a median survival of more than 10 years.

•Younger patients, presentation with seizures, tumor location in the frontal lobe, gross total tumor resection, and a high postoperative Karnofsky score have a better prognosis.

•Higher mitotic count and proliferation index are associated with shorter survival times.

•Presence of polysomy 1q and/or 19p or homozygous deletion of CDKN2A/2B is associated with poor prognosis.

Essential and Desirable Diagnostic Criteria

Refer Table 1.2.

Fig. 1.2.2 Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2.

(a) The tumor shows neoplastic oligodendrocytes exhibiting mild nuclear atypia with thin-walled branching vessels in the background. (b)