Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2: The Path to Bedside Management (Advances in Experimental Medicine and Biology, 1405) [1st ed. 2023] 3031237048, 9783031237041

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Advances in Experimental Medicine and Biology 1405

Nima Rezaei Sara Hanaei   Editors

Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2 The Path to Bedside Management

Advances in Experimental Medicine and Biology Volume 1405

Series Editors Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS and University of Bordeaux, Pessac Cedex, France Haidong Dong, Departments of Urology and Immunology, Mayo Clinic, Rochester, MN, USA Heinfried H. Radeke, Institute of Pharmacology and Toxicology, Clinic of the Goethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany Nima Rezaei , Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Ortrud Steinlein, Institute of Human Genetics, LMU University Hospital, Munich, Germany Junjie Xiao, Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, China

Advances in Experimental Medicine and Biology provides a platform for scientific contributions in the main disciplines of the biomedicine and the life sciences. This series publishes thematic volumes on contemporary research in the areas of microbiology, immunology, neurosciences, biochemistry, biomedical engineering, genetics, physiology, and cancer research. Covering emerging topics and techniques in basic and clinical science, it brings together clinicians and researchers from various fields. Advances in Experimental Medicine and Biology has been publishing exceptional works in the field for over 40 years, and is indexed in SCOPUS, Medline (PubMed), EMBASE, BIOSIS, Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway Studio. 2021 Impact Factor: 3.650 (no longer indexed in SCIE as of 2022)

Nima Rezaei • Sara Hanaei Editors

Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2 The Path to Bedside Management

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Editors Nima Rezaei Department of Immunology School of Medicine Children’s Medical Center Hospital Tehran University of Medical Sciences Tehran, Iran Universal Scientific Education and Research Network (USERN) Tehran, Iran

Sara Hanaei Department of Neurosurgery Tehran University of Medical Sciences Tehran, Iran Universal Scientific Education and Research Network (USERN) Tehran, Iran

ISSN 2214-8019 (electronic) ISSN 0065-2598 Advances in Experimental Medicine and Biology ISBN 978-3-031-23704-1 ISBN 978-3-031-23705-8 (eBook) https://doi.org/10.1007/978-3-031-23705-8 © Springer Nature Switzerland AG 2023 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 Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

We would like to dedicate the book to our families, whose staunch encouragement and support made this whole work possible. May this book, through the joint collaboration of expert senior and junior scientists, light the path to better understanding and approaching the CNS tumors, leading to more favorable survival outcomes and quality of lives of patients.

Foreword by Prof. Karl Schaller

One may ask the question Why another book on brain and spinal cord tumors? Here, the answer lies in the question itself partially: There is no other such timely and comprehensive overview on these two entities, which share so many common features due to their intrinsically and ontologically common grounds from genetics and embryology to morphology—and to diagnosis and treatment. The two volumes of “Human Brain and Spinal Cord Tumors: From Bench to Bedside” are providing a joint regard of both brain and spinal cord tumors. That makes sense from a merely biological point of view already. Despite frequent clinically disparate behavior of certain intrinsic tumors, such as, i.e., low-grade gliomas of the brain vs. astrocytomas of the spinal cord, it does not make sense to separate a scholarly view on both at the level of the foramen magnum. The brainstem is a natural extension from brain central nervous tissue to the spinal cord. What is happening at this transitional zone? What makes some biological and oncological aspects differing between intracranial and intraspinal CNS tumors? In addition, at this very junction a whole variety of extrinsic and intrinsic tumors can be found, which require familiarity with combined cranial and spinal surgical approaches to this area of complex anatomical relationships. Volume 1 is dedicated to Immunology and Genetics of tumors of the brain and the spine. Emerging technologies in tumor treatment, such as nanotechnology and medico-economic aspects, are equally included in Volume 1. Volume 2 is covering The Path to Bedside Management. Hence, the intrinsic logic of the present book reflects this spirit of coherence. Internationally renowned experts, and with specific fields of expertise, are following the same order and internal organization of their chapter, from epidemiology and biology to diagnostics and treatment. That includes sections on modern adjuvant therapy and complementary and experimental therapeutic modalities for each specific tumor entity and a section on neuropsychological aspects in addition. The inherent logic of these two volumes eludes on important steps in pre-surgical diagnostics and surgical treatment as well: Tissue imaging is following similar principles for cranial and spinal tumors. Both organs of interest are surrounded by thick layers of bone, and modern MRI sequences provide important structural and functional and metabolic information with high spatial resolution. In addition, white matter tract imaging and spectroscopy are of great relevance for tumors affecting either the brain or the spinal cord. vii

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Foreword by Prof. Karl Schaller

Higher cerebral functions, as well as afferent and efferent somatosensory functioning, are at stake frequently, due to the intricate anatomical relationship between tumor tissue and healthy CNS tissue. Meningeal and other extrinsic tumors may be attached to the dural sheath and adjacent bones, with subsequent encasement of peripheral cranial or spinal nerves. That may require complex surgical approaches in order to get the best angle of attack for surgical resection and thorough techniques for dural closure in order to avoid CSF leakage. Similar techniques and tools are required for optimal surgical treatment, be that gentle tissue handling or monitoring and mapping of neural integrity and functional preservation. Hence, by treating both cranial and spinal tumors together in a two-volume comprehensive book that endeavor is serving an important educational purpose in addition: to maintain and to promote the expertise in the hands of dedicated teams with interest in surgical neuro-oncology and related neuro-scientific fields. I am confident that many young and advanced neurosurgeons and doctors from related fields will acquire this book as a reference for their practice. The book stands for a sound intellectual and for a holistic approach to these complex pathologies. It also shows that brain and spine surgeons have common roots and interests and are one of a kind. The editors are to be commended for its internal organization and for the selection of authors. I am sure that this book will serve as a reference in its field. Karl Schaller Co-founder of the SFITS (Swiss Foundation for Innovation and Training in Surgery) Professor and Chairman of the Department of Neurosurgery Faculty of Medicine, Geneva University Medical Center Geneva, Switzerland

Foreword by Prof. Charlie Teo

If cancer is considered the “Emperor of all Maladies” then the Grand Duke of all Emperors is brain cancer. It is considered the deadliest of all cancers. It kills more children in developed countries than any other disease. It kills more young adults than any other cancer. It ranks number 1 on all metrics for its socioeconomic impact on society. Despite these abominable statistics, it universally receives the least amount of funding by governments. Furthermore, it is considered the least desirable of all oncological sub-specialties and rightly so, given the paucity of therapeutic options. One of the tragedies of neuro-oncology is the isolation of the disciplines involved in the care of these patients. Multi-disciplinary units are few and far between and offer little by way of treatment algorithms. Surgeons are guilty of operating, often just a biopsy, and then relinquishing care to another team. These teams are not as well funded as many of the multi-disciplinary teams of the more common cancers and lack the staff to coordinate the treatment, rehabilitation, financial support and palliative care of patients with brain cancer. The end-result is a disease characterized by nihilism, short life expectancy and poor quality of life throughout their last months. This 2-volume book by Rezaei and Hanaei does a commendable job to bridge that knowledge gap. It has brought together the leaders in all the established and burgeoning fields of neuro-oncology. It is comprehensive, current, progressive (it even has a chapter on the role of nutrition in the management of patients with brain cancer!!) and multi-disciplinary in its content. Many of the authors are the Who’s Who of brain cancer research, and others are less well-known but who will undoubtedly become the leading lights of the future. When I read the List of Chapters and Authors I was excited to receive my copy so that I could sit back in a comfortable chair, lock out the kids, put on some comfy clothes and update my knowledge base with accurate and comprehensive information on a subject that is regrettably neglected far too

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often. This book was a long-time coming, and I thank the authors for their diligence and dedication in compiling a beautiful reference book on brain and spinal cord tumors, from bench to bedside. Charlie Teo AM M.B.B.S., FRACS Director Centre for Minimally Invasive Neurosurgery, Australia Consulting Professor of Neurosurgery Duke Medical College, USA Visiting Professor of Neurosurgery National University Hospital, Singapore Professor Honoris Causa, Hanoi Medical University, Vietnam Founder, Charlie Teo Foundation for Brain Cancer Research

Preface

Ever since I was a medical student, I was deeply concerned and curious about CNS tumors and the lives of patients with brain tumors. Although not very common in comparison to some other cancers, the tumors of CNS are considered as one of the most critical cancers since they influence almost every aspect of the patients’ lives. Most of these patients, who are affected by brain or spinal cord tumors, were healthy people with active productive lives, and sadly the disease may often result in their mortality and morbidity due to the irreversible sequels to the CNS. As the CNS tissue is characterized by very low regenerative abilities, most of the tumor-caused insults, whether direct or indirect, are permanent, which widely affect the personal, social and financial lives of the patients, in addition to undeniable financial burden to the societies. Therefore, the importance of this matter was a driving force to me to put an effort in this field, primarily as a student, as a researcher and then as a resident and clinician. Facing some of these patients at final stages of disease and their families, it is always hard to tell how little can be practically done for their treatment, and despite all the hope they may expect to hear from us, it is always a painful conversation to say we have come to a standstill to cure them. Although one may think there is nothing more to be done for these kinds of diseases, or everything has already been studied, I believe that there is always something to be done, no matter how little, but it might be a light in the darkness! Accordingly, the current book was planned to gather the knowledge about brain and spinal cord tumors in almost every aspect. As highly concerned to provide a comprehensive reference in the field, we invited senior expert scientists, neurosurgeons and clinicians to cover different chapters of this 2-volume book. The first volume, Human Brain and Spinal Cord Tumors: Neuroimmunology and Neuro-genetics, is mainly focused on the basic science aspects and economic impact of these tumors. Considering the importance of brain and spinal cord tumors, many centers organized registries for surveillance of the CNS tumors, which has been an invaluable effort in determining the epidemiologic aspects of these tumors. However, it should be noted that despite all of these advancements, there is still much to be done in many parts of the world to organize surveillance systems for CNS tumors. Therefore, the reported rates on incidence and prevalence of these tumors may underestimate the true epidemiology of brain and spinal cord tumors. The second chapter of this book discusses the epidemiology of brain and spinal cord tumors (Chapter 2). xi

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In brief, the occurrence of human brain and/or spinal cord tumors starts in molecular levels involving different genetic and immunologic pathways. While the innate immunity has non-specific and general roles in occurrence and progression of these tumors, the acquired immunity acts more specifically and therefore is considered as a more suitable target for immunotherapy of CNS tumors. The roles of innate and acquired immunity are discussed in detail in Chapters 3 and 4. Accordingly, and in addition to the standard therapeutic modalities, including surgery, chemotherapy and radiotherapy, the immune-based therapies have opened a new era in treatment of CNS cancers. The role of immunotherapy including non-specific immunotherapy, specific active immunotherapy (cancer vaccines), specific passive immunotherapy (monoclonal antibodies, oncolytic virus therapy and CAR T cell therapy) are the main outlines in Chapter 5. Considering different types of CNS tumors, one might wonder where these tumors come from, or which cells may undergo cancerous changes to create each type of these tumors. Interestingly, different types of CNS tumors are originated from different primary cells. Neural stem cells, committed precursor cells and mature cells are responsible for creation of different CNS tumors. The cell of origin for CNS tumors is extensively discussed in Chapter 6. In addition to the role of genetic alterations in pathophysiology of CNS cancers, epigenetic changes such as Histon methylation and modification, CpG island DNA methylation and other epigenetic changes are responsible for occurrence of these tumors as well, which are the main discussed outlines in Chapter 8. The tumor stem cells have been widely studied in creation of different cancers as well as their role in possible therapeutic options, which have been discussed in Chapter 9. Moreover, nutritional supplements and diet may be considered as either risk factors or preventive factors for brain cancer. Also, diet may play a therapeutic role in treatment of brain tumors. The role of nutrition in brain and spinal cord tumors is discussed in Chapter 10. Importantly, not only the scientists of biological and medical sciences, but also the scientists of mathematical and physical sciences are widely involved in research for CNS cancers. This importance has resulted in advancements in bioinformatic studies in the area to better understand the nature of CNS tumors, as well as proposing possible therapeutic plans. A good example of the role of bioinformatics in CNS cancer research is discussed in Chapter 7. Besides, the interdisciplinary combination of physical and biological sciences has resulted in advancements in application of nanotechnology in treatment of brain and spinal cord tumors, which are separately discussed in Chapters 11 and 12. And, the last but not the least, Chapter 13 of the first volume discussed the economic aspects of CNS tumors and the socioeconomic burden of these tumors. The second volume, Human Brain and Spinal Cord Tumors: The Path to Bedside Management, focuses on clinical aspects of brain and spinal cord tumors and extensively discusses different types of these tumors. Purposing on providing comprehensive chapters in addition to have them in a unified pattern, the structure of all chapters was designed as: (1) Background and Epidemiology, (2) Genetics, Immunology and Molecular Biology, (3) Histopathology and Morphology, (4) Imaging and Radiologic Features,

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(5) Clinical Manifestations, (6) Therapeutic Approaches, (7) Prognosis and Follow-up and (8) Conclusion, with minor modifications wherever necessary. As one of the most common CNS tumors, benign and malignant gliomas affect almost every age group, with the benign ones more common in pediatrics and youth and the malignant tumors more frequent in older ages compared to low-grade gliomas. Considering the extensive research on glioma, different aspects of these tumors were of interest to many scientists, and in addition to advancements in imaging and histopathologic characteristics, new therapeutic modalities were proposed for gliomas as well. Malignant and benign gliomas are extensively discussed in Chaps. 1 and 2, respectively. Meningiomas comprise one-third of the CNS tumors, often occurring in adults with female predominancy. The majority of meningiomas are slow-growing tumors, often grade I, but their critical locations may be responsible for their mortality and morbidity. On the other hands, atypical and anaplastic meningiomas are associated with less favorable outcomes. The route of treatment for meningiomas is based on surgery, radiosurgery and radiotherapy. Meningiomas and other meningeal tumors are discussed in detail in Chap. 3. Ependymomas and medulloblastomas are both more common in pediatric patients than in adults. As most of these tumors are high grades at the time of diagnosis, post-operative adjuvant therapy is often required as part of the treatment. In the past few decades, there was advancements in molecular characteristics of these tumors, which are all discussed in Chaps. 4 (ependymomas) and 5 (medulloblastomas). Although the pineal region is a small territory in the brain, about five categories of tumors arise from this region including benign pineal tumors, glial tumors, germ cell tumors, papillary tumors and pineal parenchymal tumors. Most of them represent signs of raised intracranial pressure due to hydrocephalus with imaging and biopsy considered as primary diagnostic approaches for them. Similar to most of other CNS tumors, surgery and post-operative adjuvant therapy (based on pathology) are considered in treatment of these tumors, which are explained in detail in Chap. 6. The choroid plexus could be the origin of some brain tumors arising from the ventricular system. Due to their location and large sizes at diagnosis, the treatment of such tumors was always a challenge. Chapter 7 has discussed these tumors as well as other ventricular system tumors. The embryonal tumors were long discussed as a category of brain tumors, until different subtypes of this category were introduced in the 2016 WHO classification of CNS tumors based on molecular characteristics of these tumors. The subtypes include Embryonal tumor with multilayered rosettes (ETMR), medulloblastoma, medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma and atypical teratoid/rhabdoid tumor (ATRT) which are discussed in detail in Chaps. 8 and 9. Glioneuronal and neuronal tumors of the CNS commonly affect the temporal lobe in early ages, mainly presenting with seizures. Although benign in many cases, anaplasia may transform them to malignant ones requiring chemoradiotherapy for their treatment. Chapter 10 of this book well-described these tumors. Pituitary gland tumors and craniopharyngiomas both affect sellar and parasellar regions and are often benign in nature. Although they may affect both pediatrics and adults, the common manifestations could be different among the age groups.

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These two entities are discussed in detail in Chaps. 11 and 12, respectively. Nerve-sheet tumors mainly refer to schwannomas, neurofibromas and perineuriomas, in addition to malignant peripheral nerve sheath tumors (MPNST) which all together comprise a wide spectrum of CNS tumors, and could be benign or malignant. They can occur as part of a syndrome, in critical areas and be associated with mortality and morbidity. The schwannomas and other nerve-sheet tumors are comprehensively described in Chaps. 13 and 14. Hemangioblastomas and the tumors that are originated from vessels could be part of a genetic syndrome. Although rare and slow-growing, the treatment of these tumors could be sometimes challenging due to their tendency for bleeding. The hemangioblastomas and some other vascular-originating CNS tumors are described in Chap. 15. Germ-line tumors comprise a large entity of tumors affecting different organs, not only the CNS. Similar to germ cell tumors of other parts of the body, germ cell tumors of CNS could be different in their location, pathology and tumor marker (AFP and bHCG). These tumors mostly affect pediatric and adolescent patients and are major topics of Chap. 16. As brain and spinal cord are surrounded by the skull and spine, these bony structures could be the origin to some of CNS tumors, whether invading the CNS tissue or not. Similar to many other tumors, they can have benign or malignant nature, and when affecting the neural tissue, they will cause neurologic deficits. Benign and malignant tumors of brain and spine originating from bone and cartilage are extensively discussed in Chaps. 17 and 18, respectively. The orbital cavity could be not only invaded by intracranial tumors, but also the origin of some of these tumors. The CNS tumors which are either originated from orbital cavity or invade it are discussed in Chap. 19. Lymphomas comprise a large entity of tumors affecting different parts of the body including the CNS. Primary CNS lymphomas more dominantly affect elderly patients, and their molecular characteristics, therapeutic options as well as prognosis are explained in Chap. 20. Similar to many other organs of the body, brain and spine could be affected by metastatic cancerous cells with origins in different other organs. The metastases of CNS could have different pathologies based on their original cancer site, and their therapeutic approaches are sometimes different from primary lesions with so many factors to be considered before approaching them. The metastatic brain and spinal cord lesions are discussed in Chap. 21. The spinal cord tumors, whether benign or malignant, are associated with neurological deficits and morbidities affecting the lives of affected individuals. Different aspects of benign and malignant spinal cord tumors are discussed in detail in Chaps. 22 and 23. Although we aimed to discuss most of the prevalent tumors of brain and spine, there are some less frequent pathologies which are worthy to be discussed, as well as some syndromes and diseases that are accompanied by brain tumors as one of their diagnostic components. Chapters 24 and 25 discussed less prevalent tumors of brain and spine, as well as the syndromes associated with these types of tumors. In addition to physical signs and symptoms of brain tumors, they are accompanied with psychologic and psychiatric manifestations, based on their location and influence on the functional brain tissue. This important topic as well as therapeutic options to prevent cognitive impairments is explained in Chap. 26.

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And, the last but not the least, several surgical approaches and strategies have already been introduced and used for surgical removal of CNS tumors, which is beyond the purpose of this 2-volume book. But, Chap. 27 of this book has discussed the strategies for brain tumor surgery in brief. This two-volume book was prepared by contribution of 139 scientists, neurosurgeons and clinicians, whose contribution made this project possible. I am very grateful for their time, kind cooperation and the great effort they made for preparing and revising the chapters. I am also thankful to Springer to giving us the chance of publishing this book. I hope this book will be a comprehensive, easy to use and explicit reference for neurosurgeons, scientists, researchers and students who would be interested in better understanding of the brain and spinal cord tumors. Hope this work be welcomed by them and be practically helpful in taking a forward step in better understanding of these tumors. Tehran, Iran Tehran, Iran

Nima Rezaei, M.D., Ph.D. Sara Hanaei, M.D., M.Ph.

Acknowledgments We would like to kindly thank the reviewers and editorial assistances of the book, Dr. Shaghayegh Sadeghmousavi and Dr. Esmaeil Mohammadi, whose genuine contribution made it possible to complete the book.

Contents

1

Malignant Glioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Linda M. Wang, Zachary K. Englander, Michael L. Miller, and Jeffrey N. Bruce

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Benign Glioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peter B. Wu, Anna C. Filley, Michael L. Miller, and Jeffrey N. Bruce

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Meningioma and Other Meningeal Tumors . . . . . . . . . . . . . . . Michele Bailo, Filippo Gagliardi, Nicola Boari, Alfio Spina, Martina Piloni, Antonella Castellano, and Pietro Mortini

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Ependymomas in Children and Adults . . . . . . . . . . . . . . . . . . Marios Lampros, Nikolaos Vlachos, and George A. Alexiou

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Medulloblastomas in Pediatric and Adults . . . . . . . . . . . . . . . 117 Sergey Gorelyshev, Olga Medvedeva, Nadezhda Mazerkina, Marina Ryzhova, Olga Krotkova, and Andrey Golanov

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Benign and Malignant Tumors of the Pineal Region . . . . . . . 153 Pavan S. Upadhyayula, Justin A. Neira, Michael L. Miller, and Jeffrey N. Bruce

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Tumors of Choroid Plexus and Other Ventricular Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Pietro Spennato, Lucia De Martino, Carmela Russo, Maria Elena Errico, Alessia Imperato, Federica Mazio, Giovanni Miccoli, Lucia Quaglietta, Massimo Abate, Eugenio Covelli, Vittoria Donofrio, and Giuseppe Cinalli

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Embryonal Tumors of the Central Nervous System with Multilayered Rosettes and Atypical Teratoid/ Rhabdoid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Margarita Kamenova, Radka Kaneva, Kamelia Genova, and Nikolay Gabrovsky

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Glioneuronal and Neuronal Tumors of the Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 Matteo Martinoni, Viscardo Paolo Fabbri, Emanuele La Corte, Mino Zucchelli, Francesco Toni, Sofia Asioli, and Caterina Giannini xvii

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10 Benign and Malignant Tumors of the Pituitary Gland . . . . . . 281 Luigi Albano, Marco Losa, Lina Raffaella Barzaghi, and Pietro Mortini 11 Craniopharyngioma in Pediatrics and Adults . . . . . . . . . . . . . 299 Martina Piloni, Filippo Gagliardi, Michele Bailo, Marco Losa, Nicola Boari, Alfio Spina, and Pietro Mortini 12 Schwannomas of Brain and Spinal Cord . . . . . . . . . . . . . . . . . 331 Venelin Gerganov, Mihail Petrov, and Teodora Sakelarova 13 Other Nerve Sheath Tumors of Brain and Spinal Cord . . . . . 363 Mihail Petrov, Teodora Sakelarova, and Venelin Gerganov 14 Hemangioblastomas and Other Vascular Originating Tumors of Brain or Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . 377 Ignazio G. Vetrano, Andrea Gioppo, Giuseppe Faragò, Valentina Pinzi, Bianca Pollo, Morgan Broggi, Marco Schiariti, Paolo Ferroli, and Francesco Acerbi 15 Brain and Spinal Cord Tumors of Embryonic Origin . . . . . . 405 Marios Lampros and George A. Alexiou 16 Brain and Spinal Tumors Originating from the Germ Line Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 Tai-Tong Wong, Min-Lan Tsai, Hsi Chang, Kevin Li-Chun Hsieh, Donald Ming-Tak Ho, Shih-Chieh Lin, Hsiu-Ju Yen, Yi-Wei Chen, Hsin-Lun Lee, and Tsui-Fen Yang 17 Benign Brain and Spinal Tumors Originating from Bone or Cartilage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 Abhishek Gami, Andrew Schilling, Jeff Ehresman, and Daniel M. Sciubba 18 Malignant Brain and Spinal Tumors Originating from Bone or Cartilage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 Zachary C. Gersey, Georgios A. Zenonos, and Paul A. Gardner 19 Brain Tumors Affecting the Orbit Globe and Orbit Tumors Affecting the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Alfio Spina, Nicola Boari, Francesco Calvanese, Filippo Gagliardi, Michele Bailo, Martina Piloni, and Pietro Mortini 20 Lymphomas of Central Nervous System . . . . . . . . . . . . . . . . . 527 Kiyotaka Yokogami, Minako Azuma, Hideo Takeshima, and Toshinori Hirai 21 Metastatic Lesions of the Brain and Spine . . . . . . . . . . . . . . . 545 Timothy H. Ung, Antonio Meola, and Steven D. Chang 22 Malignant Spinal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 Mohammad Hassan A. Noureldine, Nir Shimony, and George I. Jallo

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23 Benign Spinal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 Mohammad Hassan A. Noureldine, Nir Shimony, and George I. Jallo 24 Other Less Prevalent Tumors of the Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607 Jody Filippo Capitanio and Pietro Mortini 25 Brain and/or Spinal Cord Tumors Accompanied with Other Diseases or Syndromes . . . . . . . . . . . . . . . . . . . . . . 645 Jody Filippo Capitanio and Pietro Mortini 26 Psychological and Psychiatric Aspects of Brain and Spinal Cord Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673 Ahmad Pour-Rashidi, Mohamad Namvar, Arad Iranmehr, Allegra Carpaneto, Sara Hanaei, and Nima Rezaei 27 A Brief Explanation on Surgical Approaches for Treatment of Different Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 Morgan Broggi, Costanza M. Zattra, Francesco Restelli, Francesco Acerbi, Mirella Seveso, Grazia Devigili, Marco Schiariti, Ignazio G. Vetrano, Paolo Ferroli, and Giovanni Broggi Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717

Editors and Contributors

About the Editors Prof. Nima Rezaei, M.D., Ph.D. gained his medical degree (M.D.) from Tehran University of Medical Sciences and subsequently obtained an M.Sc. in Molecular and Genetic Medicine and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also spent a short-term fellowship of Pediatric Clinical Immunology and Bone Marrow Transplantation in the Newcastle General Hospital. Professor Rezaei is now the full professor of Immunology, the vice dean of Research and Technologies, School of Medicine, Tehran University of Medical Sciences, and the co-founder and the head of the Research Center for Immunodeficiencies. He is also the founding president of Universal Scientific Education and Research Network (USERN). Professor Rezaei has already been the director of more than 100 research projects and has designed and participated in several international collaborative projects. Professor Rezaei is the editor, the editorial assistant or the editorial board member of more than 40 international journals. He has edited more than 50 international books, has presented more than 500 lectures/posters in congresses/meetings and has published more than 1,100 scientific papers in the international journals.

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Dr. Sara Hanaei, MD, MPH started medicine at TUMS in 2010 and started a master of public health (M.Ph.) in 2014. She graduated with M.D.-M.Ph. in 2018. She also received TUMS Research Diploma (TUMS-RD) in a 2-year study period from 2013 to 2015. She was a research assistant at Research Center for Immunodeficiencies (RCID) from 2018 to 2021 and further continued neurosurgery as a clinical specialty at TUMS in 2021. She has experience in teaching research skills to students. Medical research was one of her greatest interests since the beginning of her academic education, especially in the fields of Neurosurgery and Immunology; therefore, she started research in those fields. Over the past decade, she contributed to different research projects, books and other research activities including instructing research workshops in statistics, systematic reviews and meta-analysis. She got involved in executive tasks and developed some executive skills through membership in the Universal Scientific Education and Research Network (USERN), where she experienced organizing scientific events, congresses, festivals, scoring, rankings, etc.

Contributors Massimo Abate Department of Pediatric Oncology, Santobono-Pausilipon Pediatric Hospital, Naples, Italy Francesco Acerbi Neurovascular Surgery Unit and Experimental Microsurgical Laboratory, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Luigi Albano Department of Neurosurgery and Gamma Knife Radiosurgery, I.R.C.C.S. Ospedale San Raffaele, Vita-Salute University, Milan, Italy George A. Alexiou Department of Neurosurgery, School of Medicine, University of Ioannina, Ioannina, Greece Sofia Asioli Surgical Pathology Section, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM) – Alma Mater Studiorum – University of Bologna, Bologna, Italy Minako Azuma Departments of Radiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

Editors and Contributors

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Michele Bailo Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Lina Raffaella Barzaghi Department of Neurosurgery and Gamma Knife Radiosurgery, I.R.C.C.S. Ospedale San Raffaele, Vita-Salute University, Milan, Italy Nicola Boari Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Giovanni Broggi Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Scientific Director, Fondazione I.E.N. Milano, Italy Morgan Broggi Neurovascular Surgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Jeffrey N. Bruce Department of Neurosurgery, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurological Surgery, Columbia University, New York, USA Francesco Calvanese Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Jody Filippo Capitanio Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy Allegra Carpaneto Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy Antonella Castellano Department of Neurosurgery and Gamma Knife Radiosurgery, I.R.C.C.S. Ospedale San Raffaele, Vita-Salute University, Milano, Italy Hsi Chang Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan Steven D. Chang Center for Academic Medicine, Department of Neurosurgery, MC: 5327, Stanford University School of Medicine, Palo Alto, CA, USA Yi-Wei Chen Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan Giuseppe Cinalli Department of Pediatric Neurosurgery, SantobonoPausilipon Children’s Hospital, Naples, Italy Eugenio Covelli Department of Neuroradiology, Santobono-Pausilipon Pediatric Hospital, Naples, Italy

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Lucia De Martino Department of Pediatric Oncology, SantobonoPausilipon Pediatric Hospital, Naples, Italy Grazia Devigili Neurological Unit 1, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy Vittoria Donofrio Department of Pathology, Santobono-Pausilipon Pediatric Hospital, Naples, Italy Jeff Ehresman Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA Zachary K. Englander Columbia University Irving Medical Center, New York, NY, USA Maria Elena Errico Department of Pathology, Santobono-Pausilipon Pediatric Hospital, Naples, Italy Viscardo Paolo Fabbri Surgical Pathology Section, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Giuseppe Faragò Interventional Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Paolo Ferroli Neurovascular Surgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Anna C. Filley Department of Neurosurgery, Columbia University Medical Center, New York, USA Nikolay Gabrovsky Department of Neurosurgery, University Hospital “Pirogov”, Sofia, Bulgaria Filippo Gagliardi Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Abhishek Gami Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA Paul A. Gardner UPMC Center for Cranial Base Surgery, Pittsburgh, PA, USA Kamelia Genova Department of Image Diagnostic, University Hospital “Pirogov”, Sofia, Bulgaria Venelin Gerganov International Neuroscience Institute, Hannover, Germany; University Multiprofile Hospital for Active Treatment With Emergency Medicine N. I. Pirogov, Sofia, Bulgaria Zachary C. Gersey Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Editors and Contributors

Editors and Contributors

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Caterina Giannini Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Division of Anatomic Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA Andrea Gioppo Interventional Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Andrey Golanov Department of Radiosurgery, N.N. Burdenko National Medical Research Centre of Neurosurgery, Moscow, Russia Sergey Gorelyshev Pediatric Neurosurgical Department, N.N. Burdenko National Medical Research Centre of Neurosurgery, Moscow, Russia Sara Hanaei Department of Neurosurgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences (TUMS), Tehran, Iran; Universal Scientific Education and Research Network (USERN), Tehran, Iran Toshinori Hirai Departments of Radiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan Donald Ming-Tak Ho Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Pathology and Laboratory Medicine, Cheng Hsin General Hospital, Taipei, Taiwan Kevin Li-Chun Hsieh Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; Department of Medical Imaging, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan Alessia Imperato Department of Pediatric Neurosurgery, SantobonoPausilipon Children’s Hospital, Naples, Italy Arad Iranmehr Department of Neurosurgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences (TUMS), Tehran, Iran George I. Jallo Institute for Brain Protections Sciences, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA Margarita Kamenova Department of Pathology, University Hospital “Pirogov”, Sofia, Bulgaria Radka Kaneva Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University, Sofia, Bulgaria Olga Krotkova N.N. Burdenko National Medical Research Centre of Neurosurgery, Moscow, Russia Emanuele La Corte Division of Neurosurgery, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy

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Marios Lampros Department of Neurosurgery, University of Ioannina, School of Medicine, Ioannina, Greece; Department of Neurosurgery, University Hospital of Ioannina, Ioannina, Greece Hsin-Lun Lee Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan; Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan Shih-Chieh Lin Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan Marco Losa Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Matteo Martinoni Division of Neurosurgery, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Nadezhda Mazerkina Pediatric Neurosurgical Department, N.N. Burdenko National Medical Research Centre of Neurosurgery, Moscow, Russia Federica Mazio Department of Neuroradiology, Santobono-Pausilipon Pediatric Hospital, Naples, Italy Olga Medvedeva Pediatric Neurosurgical Department, N.N. Burdenko National Medical Research Centre of Neurosurgery, Moscow, Russia Antonio Meola Center for Academic Medicine, Department of Neurosurgery, MC: 5327, Stanford University School of Medicine, Palo Alto, CA, USA Giovanni Miccoli Department of Pediatric Neurosurgery, SantobonoPausilipon Children’s Hospital, Naples, Italy Michael L. Miller Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA; Columbia University Irving Medical Center, New York, NY, USA Pietro Mortini Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Mohamad Namvar Department of Neurosurgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences (TUMS), Tehran, Iran Justin A. Neira Department of Neurological Surgery, Columbia University, New York, USA

Editors and Contributors

Editors and Contributors

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Mohammad Hassan A. Noureldine Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Johns Hopkins University School of Medicine, Institute for Brain Protection Sciences, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA Mihail Petrov University Multiprofile Hospital for Active Treatment With Emergency Medicine N. I. Pirogov, Sofia, Bulgaria Martina Piloni Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Valentina Pinzi Radiotherapy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Bianca Pollo Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Ahmad Pour-Rashidi Department of Neurosurgery, Sina Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran Lucia Quaglietta Department of Pediatric Oncology, Santobono-Pausilipon Pediatric Hospital, Naples, Italy Francesco Restelli Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy Nima Rezaei Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran Carmela Russo Department of Neuroradiology, Santobono-Pausilipon Pediatric Hospital, Naples, Italy Marina Ryzhova Department of Neuropathology, N.N. Burdenko National Medical Research Centre of Neurosurgery, Moscow, Russia Teodora Sakelarova University Hospital St. Anna, Sofia, Bulgaria Marco Schiariti Neurovascular Surgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Andrew Schilling Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA Daniel M. Sciubba Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA Mirella Seveso Neuroanesthesia and Neurointensive Care Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy Nir Shimony Johns Hopkins University School of Medicine, Institute for Brain Protection Sciences, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA;

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Geisinger Medical Center, Institute of Neuroscience, Geisinger Commonwealth School of Medicine, Danville, PA, USA; Department of Surgery, St Jude Children’s Research Hospital, Memphis, USA Pietro Spennato Department of Pediatric Neurosurgery, SantobonoPausilipon Children’s Hospital, Naples, Italy Alfio Spina Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy Hideo Takeshima Departments of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan Francesco Toni Division of Neurosurgery, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Programma di neuroradiologia con tecniche ad elevata complessità, IRCCS Istituto delle Scienze Neurologiche di Bologna ETC, Bologna, Italy Min-Lan Tsai Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan Timothy H. Ung Center for Academic Medicine, Department of Neurosurgery, MC: 5327, Stanford University School of Medicine, Palo Alto, CA, USA Pavan S. Upadhyayula Department of Neurological Surgery, Columbia University, New York, USA Ignazio G. Vetrano Neurovascular Surgery Unit, Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Nikolaos Vlachos Department of Neurosurgery, University of Ioannina, School of Medicine, Ioannina, Greece Linda M. Wang Columbia University Irving Medical Center, New York, NY, USA Tai-Tong Wong Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan; Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan Peter B. Wu Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, USA

Editors and Contributors

Editors and Contributors

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Tsui-Fen Yang Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Physical Therapy and Assistive Technology, National Yang-Ming University, Taipei, Taiwan, ROC Hsiu-Ju Yen Division of Pediatric Hematology and Oncology, Department of Pediatrics, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan Kiyotaka Yokogami Departments of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan Costanza M. Zattra Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy Georgios A. Zenonos Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Mino Zucchelli Pediatric Neurosurgery, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy

1

Malignant Glioma Linda M. Wang, Zachary K. Englander, Michael L. Miller, and Jeffrey N. Bruce

Abstract

This chapter provides a comprehensive overview of malignant gliomas, the most common primary brain tumor in adults. These tumors are varied in their cellular origin, genetic profile, and morphology under the microscope, but together they share some of the most dismal prognoses of all neoplasms in the body. Although there is currently no cure for malignant glioma, persistent efforts to improve outcomes in patients with these tumors have led to modest increases in survival, and researchers worldwide continue to strive toward a deeper understanding of the factors that influence glioma development and response to treatment. In addition to well-established epidemiology, clinical manifestations, and common histopathologic and radiologic features of malignant gliomas, this

L. M. Wang . Z. K. Englander . M. L. Miller Columbia University Irving Medical Center, New York, NY 10032, USA e-mail: [email protected] Z. K. Englander e-mail: [email protected] M. L. Miller e-mail: [email protected] J. N. Bruce (&) Department of Neurosurgery, Columbia University Irving Medical Center, New York, NY 10032, USA e-mail: [email protected]

section considers recent advances in molecular biology that have led to a more nuanced understanding of the genetic changes that characterize the different types of malignant glioma, as well as their implications for treatment. Beyond the traditional classification of malignant gliomas based on histopathological features, this chapter incorporates the World Health Organization’s 2016 criteria for the classification of brain tumors, with special focus on disease-defining genetic alterations and newly established subcategories of malignant glioma that were previously unidentifiable based on microscopic examination alone. Traditional therapeutic modalities that form the cornerstone of treatment for malignant glioma, such as aggressive surgical resection followed by adjuvant chemotherapy and radiation therapy, and the studies that support their efficacy are reviewed in detail. This provides a foundation for additional discussion of novel therapeutic methods such as immunotherapy and convection-enhanced delivery, as well as new techniques for enhancing extent of resection such as fluorescence-guided surgery. Keywords

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Malignant glioma Glioblastoma Anaplastic astrocytoma Anaplastic oligodendroglioma Diffuse midline glioma Molecular biology Genetics High-grade glioma Surgical

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© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_1

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resection Chemotherapy Radiation therapy Immunotherapy Fluorescence-guided surgery Convection-enhanced delivery

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Background and Epidemiology

Gliomas are tumors of the central nervous system derived from glial cells, which are the non-neural support cells of the brain. These tumors are the most common primary brain tumor in adults, making up 60% of all primary brain tumors with an average incidence of 6 per 100,000 per year (DeAngelis and Wen 2013; Hankey and Wardlaw 2002). On average, gliomas occur more commonly in men, with a male-to-female incidence ratio of 2:1, although this number varies depending on the specific type of glioma (Hankey and Wardlaw 2002). These tumors are also more commonly diagnosed in individuals of European ancestry (Ostrom et al. 2018). As there are different kinds of glial cells, there are also different kinds of gliomas, each one originating from a different precursor cell type (although the exact cell of origin in many of these tumors remains an active area of research) and named for the predominant morphology seen on histology. Astrocytomas arise from the astrocytic lineage, which gives rise to astrocytes, the most abundant glial cells in the central nervous system. These so-called star-shaped cells actually have a variety of morphologic appearances and perform a diverse array of critical functions throughout the central nervous system, ranging from structural support and organization of the brain parenchyma to regulation of the brain microenvironment through ion homeostasis, neurotransmitter clearance, and synaptic maintenance (Khakh and Sofroniew 2015). Oligodendrogliomas are derived from the oligodendroglial lineage, which produces oligodendrocytes. These cells are responsible for the myelination of neuronal axons within the central nervous system. Ependymomas arise from ependymal cells and their precursors and will be covered in greater detail in another chapter.

Still other gliomas may have mixed features; for example, some gliomas have both astroglial and oligodendroglial characteristics on microscopy. Other tumors may exhibit mixed neuronal and glial features, such as gangliogliomas. Finally, an extremely rare “form” of glioma is gliomatosis cerebri, which actually represents a general growth pattern that can manifest with all types of diffuse gliomas (although it is most commonly seen in anaplastic astrocytomas), where there is extensive spread throughout the central nervous system (Louis et al. 2016). Like tumors elsewhere in the body, gliomas can range from benign to malignant. However, whereas in other parts of the body, “malignant” usually refers to the invasiveness of a tumor and its propensity to metastasize; in the context of the central nervous system, this term refers instead to the overall aggressiveness of a tumor, since most intrinsic brain tumors do not metastasize (Kaye 2005). The terms benign and malignant can be more specifically correlated with tumor grade. Throughout the years, multiple grading schemes have been used for the classification of brain tumors, but the World Health Organization (WHO) Classification of Tumors of the CNS remains the most widely accepted one. Under this system, brain tumors are graded from I to IV based on the absence or presence of certain histologic features. The histologic grade of a lesion is meant to convey information about its likely biological behavior and can be of clinical significance, in some cases informing management options or contributing to discussions of prognosis, although many other factors beyond histology are also involved in determining prognosis (Louis et al. 2016). Lower-grade lesions (grade I–II) generally fall under the categorization benign, while higher-grade lesions (grade III–IV) are classified as malignant. Within gliomas, approximately 80% are highgrade and 20% are low-grade (Hankey and Wardlaw 2002). Malignant, high-grade tumors include anaplastic astrocytoma (grade III astrocytoma), glioblastoma (grade IV astrocytoma), anaplastic oligodendroglioma (grade III

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Malignant Glioma

oligodendroglioma), and diffuse midline glioma (grade IV lesion with predominantly astrocytic features). In contrast to low-grade gliomas, highgrade gliomas have a markedly more aggressive clinical course and worse prognosis.

1.1.1 Astrocytoma Malignant astrocytomas most commonly affect patients between the ages of 40–60 years (Mandigo and Bruce 2012). Anaplastic astrocytomas account for 15–20% of high-grade astrocytomas. These tumors usually present during the 4th and 5th decades of life and are most commonly found in the cerebrum, especially the frontal lobe (DeAngelis and Wen 2013; Louis et al. 2016). In some cases, anaplastic astrocytomas can be the result of a lower-grade lesion that has progressed, but most often there is no evidence of an earlier low-grade tumor. However, anaplastic astrocytomas do generally progress to glioblastoma over the course of several years. Glioblastoma is the most common and malignant adult cerebral tumor and accounts for about half of all gliomas (Kaye 2005). More than 10,000 cases are diagnosed every year in the United States alone (DeAngelis and Wen 2013). The mean age at incidence is 56 years, and there is a known male predominance with a male-to-female ratio of 1.6:1, although this number is an average and varies across the different molecular subtypes of glioblastoma (Hankey and Wardlaw 2002; Yang et al. 2019). Half of all cases involve more than one lobe of the brain, and rarely, these tumors can be multicentric (Hankey and Wardlaw 2002).

1.1.2 Oligodendroglioma Oligodendrogliomas make up 5–10% of all gliomas and occur predominantly in adults, with a peak incidence between 20 and 40 years of age (Olson et al. 2000; Kaye 2005; Hankey and Wardlaw 2002). Oligodendrogliomas are almost always located supratentorially, with most occurring in the hemispheres and about half in the frontal lobe (Kaye 2005).

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As with astrocytomas, oligodendrogliomas can be low-grade or high-grade. High-grade lesions are characterized by a number of histologic features including increased mitotic activity and hypercellularity. One-third of all oligodendroglial tumors and 0.5% of all primary brain tumors are grade III anaplastic oligodendrogliomas (Ostrom et al. 2014). The annual incidence rate for anaplastic oligodendrogliomas is 0.11 cases per 100,000 people (Louis et al. 2016). Like grade II well-differentiated oligodendrogliomas, anaplastic oligodendrogliomas are more commonly found in the frontal lobe. There is a slight male predominance, with a male-to-female incidence ratio of 1.2:1 (Ostrom et al. 2014). Anaplastic oligodendrogliomas typically present in patients aged 40–50 years, with a median patient age at diagnosis of 49 years (DeAngelis and Wen 2013; Ostrom et al. 2014). They may develop independently or by malignant transformation of a grade II oligodendroglioma, in which case the timeframe for progression is estimated to be around six years (Lebrun et al. 2004). Although not all anaplastic oligodendrogliomas arise from grade II lesions, virtually all grade II oligodendrogliomas will eventually progress to a higher grade (Wesseling et al. 2015).

1.1.3 Diffuse Midline Glioma Diffuse midline gliomas are grade IV lesions with predominantly astrocytic differentiation on histology that are more often seen in children but can also occur in adults. The median patient age at diagnosis is 5–11 years, and there does not seem to be a difference in incidence by gender. As suggested by their name, these tumors are most commonly located in the brainstem, thalamus, and spinal cord (Louis et al. 2016). Pontine variants of diffuse midline glioma were previously referred to as diffuse intrinsic pontine glioma (DIPG) but were recently reclassified in the WHO’s 2016 classification of brain tumors based on shared underlying genetic alterations between these tumors and other diffuse gliomas affecting midline structures. These genetic

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changes, in particular those affecting histone H3, will be discussed in greater detail in the next section.

1.2

within and across tumor types has also provided an additional dimension by which to further analyze and classify malignant gliomas, contributing significantly to both diagnosis and management.

Genetics, Immunology, and Molecular Biology 1.2.1 Anaplastic Astrocytoma

The vast majority of malignant gliomas arise sporadically, but about 5% are associated with genetic syndromes, such as Gardner syndrome and Turcot syndrome, or a family history of malignant brain tumors, which confers additional risk (Mandigo and Bruce 2012). However, even in sporadic cases, the pathogenesis of brain tumors is rooted in the acquisition of multiple genetic mutations over the course of an individual’s lifetime that ultimately lead to uncontrolled cell growth and proliferation. Some genetic syndromes have helped increase our understanding of the molecular pathogenesis of brain tumors and other malignancies by highlighting the association between mutations in certain genes and the development of cancer. For example, p53 is a well-known tumor suppressor gene that plays an important role in maintaining the integrity of the genome, and germline mutations in this gene lead to LiFraumeni syndrome, which is associated with gliomas as well as many other malignancies (Kaye 2005). Recent advances in molecular biology have allowed for a more in-depth examination of malignant gliomas on a molecular scale. Much has been discovered about the biological underpinnings of these tumors, although much remains unknown. Innovations in genetic sequencing have allowed researchers to build genetic profiles of brain tumors that have contributed to an increased understanding of their pathogenesis. Certain tumor types may also be characterized by specific genetic mutations that confer valuable prognostic information. In some cases, tumors may be defined by the absence or presence of specific genetic changes. Table 1.1 summarizes the most commonly identified genetic alterations in each type of malignant glioma. Our increased ability to assess patterns of protein expression

Recent molecular analyses have revealed two major subtypes of anaplastic astrocytoma based on isocitrate dehydrogenase (IDH) mutation status. IDH-mutant anaplastic astrocytomas are more common, with IDH-wildtype tumors accounting for only about 20% of all anaplastic astrocytomas (Louis et al. 2016). Mutations in IDH are thought to play a role in gliomagenesis by leading to metabolic abnormalities such as the overproduction of 2-hydroxyglutarate (2-HG), which impairs histone demethylation. Subsequent histone hypermethylation results in changes in chromatin remodeling and gene expression, ultimately leading to defective cellular differentiation (Wesseling et al. 2015; Lu et al. 2012). In addition to mutations in either IDH1 or IDH2, anaplastic astrocytomas also tend to have alterations in TP53 and ATRX. On immunohistochemistry, anaplastic astrocytomas often stain positive for glial fibrillary acidic protein (GFAP) and exhibit strong, diffuse nuclear expression of p53. Most tumors stain positive for R132Hmutant IDH1, and nuclear ATRX is often absent (Louis et al. 2016).

1.2.2 Glioblastoma Glioblastomas have long been known to fall into two broad clinical categories: primary glioblastomas, which appear to arise de novo and behave more aggressively, and secondary glioblastomas, which tend to arise from the progression of lower-grade gliomas and are characterized by a younger age at diagnosis and a more favorable prognosis. In recent years, as with anaplastic astrocytomas, genetic and molecular analyses have led to the discovery that primary and secondary glioblastomas can in fact also be

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Malignant Glioma

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Table 1.1 Common genetic alterations by tumor type Tumor type

Gene/chromosome

Alteration

Prevalence

Anaplastic astrocytoma

IDH1/2

Mutation

80

Chromosome 10

Complete loss

50–70

PTEN

Mutation/deletion

40

TP53 ATRX Glioblastoma, IDH-wildtype

Glioblastoma, IDH-mutant

EGFR

Amplification

30–60

TP53

Mutation

25–30

PI3K

Mutation

25

TERT promoter

Mutation

80

CDKN2A

Homozygous deletion

35–50

PDGFRA

Amplification

15

NF1

Mutation

20

MGMT promoter

Methylation

IDH1

Point mutation at R132

IDH2

Point mutation at R172

TP53

Mutation

ATRX Anaplastic oligodendroglioma

Diffuse midline glioma

60–70 60

MGMT promoter

Methylation

IDH1/2

Mutation

Chromosome 1p/19q

Codeletion

Chromosome 9p

Loss of heterozygosity

TERT promoter

Mutation

95

MGMT promoter

Methylation

90

CIC

Mutation

60

CDKN2A

Deletion

PIK3CA

Mutation

10–20

H3F3A, HIST1H3B, HIS1H3C

H3K27M mutation

100

TP53

Mutation

50

PDGFRA

Amplification

30

CDK4/6

Amplification

CCN1-3

Amplification

ACVR1

Mutation

20

PPM1D

Mutation

15

MYC

Amplification

ATRX

Mutation

15

Source WHO 2016 Classification of Tumors of the Central Nervous System (Brat et al. 2015; Brennan et al. 2013; Buczkowicz et al. 2014; Möllemann et al. 2005; Ohgaki et al. 2004; Ohgaki and Kleihues 2007, 2013; Parsons et al. 2008; Suzuki et al. 2015; Taylor et al. 2014; Watanabe et al. 1996; Weller et al. 2015; Wu et al. 2014; Yan et al. 2009; Reifenberger et al. 1996; Kannan et al. 2012; Jiao et al. 2012; Hartmann et al. 2009)

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classified by IDH mutation status. Primary glioblastomas are also referred to as IDHwildtype glioblastomas, and secondary glioblastomas are IDH-mutant. Both types of glioblastomas are virtually indistinguishable on histology, but their differing molecular profiles and clinical courses suggest that these tumors may represent two distinct disease entities with different cells of origin and modes of pathogenesis. Primary or IDH-wildtype glioblastomas are far more common than their IDH-mutant counterparts and account for about 90% of glioblastomas. They also primarily affect older adults, with a mean age at diagnosis of 62 years and a peak incidence in patients aged 55–85 years, whereas IDH-mutant glioblastomas occur more commonly in younger patients, with a median age at diagnosis of 45 years (Ohgaki and Kleihues 2005). Primary glioblastomas are more commonly diagnosed in male patients, with an average male-to-female incidence ratio of about 1.35:1 (as high as 1.6:1 in the United States), while secondary glioblastomas seem to occur more frequently in female patients, with one analysis finding a male-to-female incidence ratio of 0.65:1 (Ohgaki and Kleihues 2005; Ostrom et al. 2014). In terms of location, primary glioblastomas generally occur throughout the cerebral hemispheres; one study of 987 tumors noted involvement of the temporal lobe in 31% of cases, the parietal lobe in 24%, the frontal lobe in 23%, and the occipital lobe in 16% (Louis et al. 2016). Interestingly, secondary glioblastomas seem to demonstrate a predilection for the frontal lobe, which may reflect their origination from a precursor lesion, as some IDH-mutant lower-grade tumors tend to be found in this area as well (Lai et al. 2011). Perhaps, the most important distinction between IDH-wildtype and IDH-mutant glioblastomas is their marked difference in clinical course and prognosis. Primary IDH-wildtype glioblastomas tend to behave more aggressively and have a shorter duration of symptoms due to their rapid growth, while secondary IDH-mutant glioblastomas progress more slowly and produce a longer clinical history (Ohgaki and Kleihues

L. M. Wang et al.

2007; Nobusawa et al. 2009). In terms of outcome, while both types of glioblastomas are WHO grade IV and associated with limited survival, IDH-mutant secondary glioblastomas are known to have a significantly better prognosis, with one study demonstrating an overall survival time twice as long as that of IDH-wildtype primary glioblastomas (Yan et al. 2009). Aside from IDH mutation status, primary and secondary glioblastomas also differ in their molecular landscape in other ways. Complete loss of chromosome 10, which contains the tumor suppressor gene PTEN, is a common feature of IDH-wildtype glioblastomas (Ichimura et al. 1998). Overall, mutations in PTEN are seen in 15–40% of glioblastomas, almost always primary (Tohma et al. 1998). EGFR amplification is seen in 30–60% of cases and is often associated with overexpression (Fig. 1.1) (Brennan et al. 2013; Ekstrand et al. 1992; Ohgaki et al. 2004; Wong et al. 1987). TP53 mutations are found in about 25% of tumors, but this mutation is far more common in secondary glioblastomas (Ohgaki et al. 2004). Overexpression of MDM2 occurs in over 50% of IDH-wildtype glioblastomas (Biernat et al. 1997). TERT promoter mutations are also typical of primary glioblastomas, and in one study, over 80% of tumors were found to be positive for this alteration (Killela et al. 2013). This gene encodes telomerase reverse transcriptase, a catalytic subunit of telomerase that plays an important role in telomere maintenance and normal cell senescence (Wesseling et al. 2015). Mutations in genes related to chromatin remodeling and epigenetic regulation may be seen as well; for example, EZH2, which plays a role in histone methylation and maintaining a repressive state of chromatin, is overexpressed in IDH-wildtype glioblastomas and thought to potentially contribute to the silencing of important tumor suppressor genes (Louis et al. 2016; de Vries et al. 2015). Other mutations include homozygous deletion of CDKN2A (found in 35–50% of cases), PDGFRA amplification (15%), and mutations in PI3K genes (25%) and the NF1 gene (20%) (McLendon et al. 2008; Parsons et al. 2008; Brennan et al. 2013).

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Malignant Glioma

Fig. 1.1 Chromogenic in situ hybridization demonstrating overexpression of EGFR in glioblastoma (200x)

The most notable genetic alteration in secondary glioblastomas is, of course, a mutation in IDH1 or IDH2. The majority of mutations are in IDH1, and all described IDH1 mutations occur at codon 132, with the overwhelming majority being R132H (although R132C, R132G, R132S, and R132L are also seen in rare cases) (Balss et al. 2008; Watanabe et al. 2009; Yan et al. 2009). A much smaller minority of IDH mutations are in IDH2; these are all located in residue R172, which is the IDH2 analog of IDH1 residue R132 (Yan et al. 2009). It is thought that the presence of an IDH1 mutation is associated with a hypermethylation phenotype, leading to alterations in gene expression that favor oncogenesis (Noushmehr et al. 2010; Turcan et al. 2012; Flavahan et al. 2016). Other typical genetic changes in IDH-mutant secondary glioblastomas include TP53 and ATRX mutations, as well as loss of chromosomal arm 10q (Ohgaki and Kleihues 2013). TP53 mutations are much more common in secondary than primary glioblastomas, with one study demonstrating an incidence of 67% versus 11%, respectively (Watanabe et al. 1996). ATRX mutations are seen in about 60% of cases (Jiao et al. 2012). TERT promoter mutations and EGFR amplification, which are frequently seen in primary glioblastomas, are a relatively uncommon feature of secondary glioblastomas. In fact, there is some evidence that EGFR and TP53 mutations may occur mutually exclusively of each other, further supporting the theory that primary and secondary

7

glioblastomas actually represent two separate disease entities with distinct evolutionary pathways (Watanabe et al. 1996). O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation occurs in both primary and secondary glioblastomas (although research has suggested that it may be more common in IDH-mutant tumors), and studies have shown that about 40–50% of tumors are affected (Brennan et al. 2013; Hegi et al. 2005; Yang et al. 2015; Eoli et al. 2007). This genetic alteration is of particular clinical value as its presence is associated with a more favorable prognosis and an increased response to certain therapies, which will be discussed in greater detail in the section on therapeutic approaches (Hegi et al. 2005).

1.2.3 Anaplastic Oligodendroglioma The hallmark genetic profile associated with all oligodendrogliomas, including anaplastic oligodendrogliomas, is IDH mutation in combination with whole-arm deletion of chromosomes 1p and 19q, usually due to an unbalanced translocation between chromosomes 1 and 19 (Griffin et al. 2006). Oligodendrogliomas were previously diagnosed based on histologic features alone, but with advances in molecular analysis and increasing evidence that IDH mutation and chromosome 1p/19q codeletion are associated with changes in prognosis and treatment response, this genetic profile has in recent years come to be entity-defining. This is reflected in the most recent iteration of the WHO’s classification manual, which stipulates that demonstration of IDH mutation with 1p/19q codeletion is necessary for the classification of oligodendroglioma. Anaplastic oligodendrogliomas are further distinguished from well-differentiated grade II oligodendrogliomas by the presence of certain high-grade features on microscopy, which will be discussed in the section on histopathology and morphology. This updated classification model that is supplemented with genetic information can help distinguish less-obvious anaplastic

8

oligodendrogliomas, for example those with a significant astrocytic component, from other tumors with similar-appearing high-grade histologic features, such as glioblastoma. However, one point that should be clarified is the fact that some adult brain tumors may be considered anaplastic oligodendrogliomas due to their histologic appearance, but testing for IDH mutation or 1p/19q codeletion may be negative or inconclusive. These tumors will be referred to as IDH mutation- or 1p/19q codeletion-negative anaplastic oligodendrogliomas in discussions of prognosis and response to treatment, but it should be noted that by the WHO’s updated classification system, these are technically not a tumor class. In this current age of evolving tumor classification models increasingly based on not only morphology but also molecular profile, the issue of what to call these lesions remains unresolved. Anaplastic oligodendrogliomas, like low-grade oligodendrogliomas, are further characterized genetically by TERT promoter mutations, which are present in over 95% of cases (Louis et al. 2016). MGMT promoter methylation is also present in over 90% of tumors, and 60% of cases have inactivating mutations in CIC, thought to be a tumor suppressor gene. Other genetic alterations seen particularly in anaplastic oligodendrogliomas include 9p loss of heterozygosity, CDKN2A deletion, PIK3CA mutations, and polysomies (Louis et al. 2016; Wesseling et al. 2015). Currently, there is still no specific immunohistochemical marker that distinguishes oligodendrogliomas from other types of tumors. However, some common features of both anaplastic and well-differentiated oligodendrogliomas are immunopositivity for R132Hmutant IDH1, which is the most prevalent IDH mutation. Positive staining for MAP2, S100 protein, and LEU7 is also characteristic, although these markers are often positive in other gliomas as well (Louis et al. 2016). OLIG1, OLIG2, and SOX10 are transcription factors associated with the oligodendrocyte lineage that are frequently expressed by oligodendrogliomas, but again, these markers are not specific to these tumors (Louis et al. 2016).

L. M. Wang et al.

1.2.4 Diffuse Midline Glioma Diffuse midline gliomas are genetically characterized by an H3K27M mutation, representing the replacement of a lysine residue with methionine at position 27 in histone H3 (Louis et al. 2016; Himes et al. 2019). This mutation has been found to occur in either histone variant H3.3 (specifically gene H3F3A) or H3.1 (genes HIST1H3B or HIST1H3C), but the former is more commonly seen (Louis et al. 2016). The H3K27M substitution is thought to decrease methylation at this position, leading to downstream epigenetic changes and alterations in gene expression. This mutation is such a key feature of diffuse midline gliomas that its presence is one of the defining characteristics of this newly recognized category of lesions in the 2016 version of the WHO’s classification scheme (Louis et al. 2016; Himes et al. 2019). There is some variability in genetic alterations across the different types of diffuse midline glioma depending on tumor location, but other common genetic alterations include TP53 mutations (reported in 50% of tumors), PDGFRA amplifications (30%), CDK4/6 or CCND1-3 amplifications (20%), ACVR1 mutations (20%), PPM1D mutations (15%), MYC/PVT1 amplifications (15%), and ATRX mutations (15%) (Louis et al. 2016). Single copy gains of chromosomes 1q and 2 may also be seen (Louis et al. 2016). Almost all diffuse midline glioma tumor cells express NCAM1, S100, and OLIG2 (Louis et al. 2016). Immunostaining for MAP2 is also commonly positive. Some tumors demonstrate nuclear expression of p53, which may reflect the presence of a mutation in TP53. In cases with an ATRX mutation, nuclear ATRX expression may be lost (Louis et al. 2016).

1.3

Histopathology and Morphology

Malignant gliomas are distinguished from benign tumors by their advanced histologic grade, which is determined by the presence or absence of

1

Malignant Glioma

certain cellular and tissue features on microscopic examination. This higher grade is also a reflection of their more aggressive clinical course and poorer prognosis compared to benign lesions. By the WHO’s classification scheme of CNS tumors, which is the most widely used system, grade I lesions typically have low proliferative potential and have the potential for cure after surgical resection. Grade II tumors are often infiltrative and tend to recur, although they still have relatively low proliferative activity. Grade II tumors may progress to higher-grade lesions over time and show cytologic atypia on histology, which is characterized by abnormal nuclear shape, size, or pigmentation (Fig. 1.2) (Louis et al. 2016). High-grade lesions are WHO grade III-IV. Grade III gliomas are distinguished from lowergrade lesions by the presence of anaplasia (which refers to a loss of cellular differentiation and regression to a more primitive phenotype), nuclear atypia, and marked mitotic activity (Fig. 1.3). Patients with grade III lesions often receive radiotherapy or chemotherapy as part of treatment (Louis et al. 2016). In addition to the features above, grade IV lesions are further characterized by areas of necrosis and vascular changes, especially microvascular proliferation (Fig. 1.4), which can be seen under the microscope as abnormal layering of the endothelium or blood vessels with a

Fig. 1.2 Cellular pleomorphism in anaplastic astrocytoma (hematoxylin and eosin, 200x)

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Fig. 1.3 Mitotic figures in anaplastic astrocytoma (hematoxylin and eosin, 200x)

glomeruloid appearance (Louis et al. 2016). Glioblastoma in particular is notable for demonstrating pseudopalisading necrosis (Fig. 1.5), a hallmark feature in which tumor cells accumulate around the edges of irregular regions of necrosis (Wippold et al. 2006). Grade IV tumors are most often rapidly progressive and associated with a fatal outcome. A defining characteristic of high-grade gliomas is their diffusely invasive nature, with microscopic extension of tumor cells beyond what may appear to be the macroscopic border of the tumor (Kaye 2005). This pattern of growth has significant clinical consequences, which will be discussed further in the section on therapeutic approaches.

Fig. 1.4 Microvascular proliferation in glioblastoma (hematoxylin and eosin, 100x)

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a

L. M. Wang et al.

b

Fig. 1.5 Palisading necrosis in glioblastoma. a Lowpower view of palisading necrosis characteristic of glioblastoma (hematoxylin and eosin, 40x). Note the

pattern of areas of dense cellularity surrounding pink regions representing necrosis. b Higher magnification view of palisading necrosis (hematoxylin and eosin, 100x)

1.3.1 Glioblastoma

1.3.2 Anaplastic Oligodendroglioma

One distinguishing feature of glioblastoma that deserves mention is its heterogeneous appearance under the microscope, both within the same tumor and between different lesions. Some tumors are pleomorphic while others may be more monomorphic; some have readily identifiable astrocytic features while others are so poorly differentiated that it can be hard to tell what the cell of origin is. Certain tumors may be characterized by the presence of small cells, primitive neuronal cells, gemistocytes (swollen reactive astrocytes with abundant glassy, pink cytoplasm that pushes the nucleus toward the cell periphery), multinucleated giant cells, granular cells, or lipidized cells with foamy cytoplasm (Louis et al. 2016). Secondary structures such as perineuronal satellitosis or subpial and subependymal aggregation are also often seen. In general, however, all tumors demonstrate the high-grade features of hypercellularity and marked anaplasia, and necrosis and/or microvascular proliferation must be present. IDHmutant glioblastomas are virtually identical to IDH-wildtype lesions on histology, with the exception that palisading necrosis appears to be a less prevalent feature (Nobusawa et al. 2009).

High-grade oligodendrogliomas may be further distinguished from astrocytic tumors on histology by the presence of cells with small round nuclei surrounded by a halo of unstained cytoplasm, well-demarcated cell borders, and few cellular processes, leading to the characteristic “fried egg” appearance (Fig. 1.6) (Hankey and Wardlaw 2002). These tumors also tend to contain delicate, branching capillary networks, producing the classic “chicken wire” pattern (DeAngelis and Wen 2013; Louis et al. 2016). Like low-grade oligodendrogliomas, anaplastic oligodendrogliomas often contain calcium deposits on histology (Fig. 1.7). As with other malignant gliomas, anaplastic oligodendrogliomas may also be characterized by the presence of secondary structures such as perineuronal satellitosis, in which tumor cells aggregate around neurons (often seen in regions of cortical infiltration), as well as subpial and perivascular aggregates, where tumor cells cluster below the pial surface and around cortical small vessels, respectively (Louis et al. 2016; Wesseling et al. 2015).

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Malignant Glioma

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1.3.3 Diffuse Midline Glioma

Fig. 1.6 “Fried egg” cells characteristic of oligodendroglioma (hematoxylin and eosin, 100x)

Diffuse midline gliomas are diffusely infiltrative on microscopy, as their name suggests. These tumors infiltrate both gray and white matter structures. Tumor cells are usually small and monomorphic but can also be large and pleomorphic (Fig. 1.8). These lesions usually appear astrocytic but can present with an oligodendroglial pattern. Generally, they have features consistent with WHO grade IV. A small minority of pontine variants, formerly referred to as DIPG, may demonstrate histology corresponding to a lower grade, but as long as the genetic profile of the tumor is consistent with that of a diffuse midline glioma, this does not alter prognosis (Louis et al. 2016).

1.4

Fig. 1.7 Regions of calcification in oligodendroglioma (hematoxylin and eosin, 200x)

a

Imaging and Radiologic Features

Neuroimaging plays a critical role in diagnosing and coming up with a management plan for all gliomas. Both computed tomography (CT) and magnetic resonance imaging (MRI) are acceptable imaging modalities that can help make a diagnosis, although MRI is the preferred test because it is more sensitive and can provide an

b

Fig. 1.8 Diffuse midline glioma: a hematoxylin and eosin-stained midline biopsy (100x); b immunohistochemistry demonstrating marked nuclear staining of H3K27M mutant protein (100x)

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advantage when dealing with smaller or lowergrade tumors that do not show up as clearly on CT scan. The higher resolution of MRI also allows for better visualization of lesion details and the surrounding anatomy, which can be particularly useful when dealing with lesions in certain locations and is critical for operative planning (Kaye 2005). CT is a suitable alternative for patients with contraindications to MRI such as a cardiac pacemaker (DeAngelis and Wen 2013). Other imaging modalities exist that supplement the information provided by traditional MRI and CT. Diffusion-weighted MRI (DWI), which maps the restricted movement of water molecules and is most commonly used in the setting of acute stroke, serves as an additional tool that may support both the diagnosis of malignant glioma and the evaluation of treatment response (Baehring et al. 2007). Diffusion tensor imaging (DTI) is an analytical technique developed from DWI that has been investigated for its potential to differentiate between high-grade gliomas and metastatic lesions and model white matter tracts, which may contribute to more nuanced operative planning (Wang et al. 2009a, b; Soares et al. 2013; Salama et al. 2018). Magnetic resonance spectroscopy (MRS) is another imaging modality that has proven useful for the evaluation of malignant gliomas, especially for determining true disease progression versus post-treatment pseudoprogression. This method measures the concentrations of various metabolites in tissue and makes use of the fact that brain tumors often demonstrate a metabolic profile that differs from that of normal brain tissue, with the relative amplification of certain signals (e.g., choline, thought to reflect increased membrane turnover) (Horská and Barker 2010). Still other imaging techniques such as positron emission tomography (PET) and magnetic resonance perfusion imaging have been explored in malignant glioma for their potential to guide initial treatment planning and help distinguish between disease recurrence and pseudoprogression or treatment-induced necrosis (Moreau et al. 2019; Verma et al. 2013).

L. M. Wang et al.

Compared to low-grade gliomas, high-grade gliomas are often large with pronounced contrast-enhancement, which represents increased blood–brain barrier breakdown and vascular permeability (Kaye 2005). Enhancement may be patchy and inconsistent, and on CT scan can be punctuated by a central region of lower density, which most often represents a necrotic core. Unlike low-grade gliomas, malignant gliomas are also often surrounded by significant cerebral edema, which can be seen as hyperintensity surrounding the tumor on T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences (Fig. 1.9a) (Kaye 2005).

1.4.1 Astrocytoma On MRI, high-grade astrocytomas usually have low signal intensity on T1-weighted images and high intensity on T2-weighted images (Kaye 2005). Anaplastic astrocytomas may present with variable contrast-enhancement. Glioblastoma often appears as an irregularly shaped, ringenhancing mass with a necrotic core and perilesional edema (Fig. 1.9b) (Louis et al. 2016). Compared to IDH-wildtype glioblastoma, IDHmutant glioblastoma may demonstrate less contrast-enhancement or edema and more cystic components. Significant areas of central necrosis are typically absent, and tumors may be a larger size at diagnosis due to their slower growth rate (Lai et al. 2011; Eoli et al. 2007).

1.4.2 Oligodendroglioma Anaplastic oligodendrogliomas frequently exhibit intratumoral microcalcifications and cysts (Fig. 1.10). Intratumoral hemorrhages and areas of necrosis may also be seen, altogether contributing to a varied appearance on imaging (Louis et al. 2016). Contrast-enhancement is often present and can vary from patchy to uniform but does not need to be present for the diagnosis (Louis et al. 2016). Overall, anaplastic oligodendrogliomas tend to exhibit contrast-

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Malignant Glioma

a

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b

Fig. 1.9 MRI of glioblastoma. a T1 post-contrast MRI demonstrating ring-enhancement. b T2/FLAIR MRI exhibiting significant peritumoral edema

enhancement on MRI more frequently than their lower-grade counterparts (70% of grade III oligodendrogliomas versus 20% of grade II oligodendrogliomas, according to one study of 75 patients) (Khalid et al. 2012).

1.4.3 Diffuse Midline Glioma Diffuse midline gliomas are hypointense on T1weighted MRI and hyperintense on T2-weighted imaging (Fig. 1.11). As with other high-grade gliomas, contrast-enhancement, necrosis, and/or hemorrhage may be present (Louis et al. 2016).

1.5

Clinical Manifestations

Due to their more aggressive nature, malignant gliomas typically present with shorter disease course, with symptoms lasting from weeks to months rather than the years that can be characteristic of low-grade tumors (Kaye 2005). Symptoms can be due to direct destruction of the brain parenchyma by the tumor; they can also be due to tumor-associated edema and mass effect, leading to hydrocephalus (Mandigo and Bruce 2012).

1.5.1 Increased Intracranial Pressure Patients with malignant gliomas often present with signs and symptoms of increased intracranial pressure. Intracranial pressure is determined by the contents of the skull, which consists of three compartments: brain, blood, and cerebrospinal fluid. An increase in any one of the compartments necessitates compensation by the others; however, the skull is fixed and can only compensate to a certain extent before intracranial pressure starts to rise. Thus, increased intracranial pressure in patients with brain tumors can be caused by the mass of the tumor itself, surrounding edema, or hydrocephalus due to disruption of cerebrospinal fluid flow from compression or blockage of the ventricular system (Kaye 2005). Specific symptoms depend on how rapidly the elevated intracranial pressure develops. Headache is a common manifestation of increased intracranial pressure and a presenting symptom in one-third of patients with brain tumors (Mandigo and Bruce 2012). The pain originates from pressure on the vasculature, dura, and some cranial nerves (Mandigo and Bruce 2012). Brain tumor-associated headaches

b

c

Fig. 1.10 MRI of anaplastic oligodendroglioma. a Pre-contrast T1 MRI. Note focus of brightness/hyperintensity within tumor mass representing hemorrhage; b post-contrast T1 MRI. Note patchy contrast-enhancement and intratumoral cysts; c lesion appears bright on T2 FLAIR MRI. Note tumor location in the frontal lobe, frequently seen with oligodendrogliomas

a

14 L. M. Wang et al.

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personality changes, and mood swings. Motor weakness may result if any part of the pyramidal tracts is affected and is often progressive in nature. For example, diffuse midline gliomas involving the thalamus commonly present with hemiparesis (Kramm et al. 2011). Temporal lobe involvement can lead to impairments in both receptive and expressive language processing. Involvement of the visual pathways (spanning the temporal, parietal, or occipital lobes) can produce visual field defects. Diffuse midline glioma patients with tumors affecting the pons in particular may present with signs of brainstem dysfunction or the classic triad of multiple cranial neuropathies, long tract signs such as hyperreflexia or clonus, and ataxia (Warren 2012). Fig. 1.11 T2 FLAIR MRI of diffuse midline glioma. Note midline location of tumor within the brainstem

1.5.3 Seizures may be positional and worse when lying down or in the morning upon awakening. They may also be worsened by bending down or coughing, which can further raise intracranial pressure. They may localize to the side of the lesion but can be bitemporal. Headaches resulting from increased intracranial pressure are often associated with nausea and/or vomiting, and patients may report that vomiting temporarily relieves the pain. More urgent signs of raised intracranial pressure are altered mental status or loss of consciousness. Patients can rapidly decompensate when intracranial pressure is severely elevated— just a small increase further may be enough to push someone from alert to unconscious. The feared complication of raised intracranial pressure is herniation, which may lead to coma and death (Kaye 2005).

1.5.2 Focal Neurologic Deficits Patients with brain tumors may present with focal neurologic deficits, with specific signs depending on the location of the tumor. Frontal lobe lesions may produce cognitive or behavioral symptoms such as disordered executive function,

Epileptic seizures are often seen with tumors involving the cortex that are located in the anterior lobes of the brain, which include astrocytomas and oligodendrogliomas. Seizures are the most common presenting symptom in patients with cerebral astrocytomas, affecting 50– 75% of all patients (Kaye 2005). As many as half of patients with glioblastoma are diagnosed after experiencing a seizure (Vecht et al. 2014). About two-thirds of patients with oligodendrogliomas also present with seizures, and up to 90% of these patients will experience a seizure at some point in their disease course (Louis et al. 2016; Kerkhof et al. 2015; Mirsattari et al. 2011). Although seizures are a more frequent presenting symptom in low-grade tumors, possibly due to their slower rate of growth, they are still a common clinical feature of high-grade tumors (Kerkhof et al. 2015; Hamasaki et al. 2013). Brain tumor-associated seizures may appear focal or generalized, but virtually all are focal in onset, which is a reflection of the location of the tumor within the brain (DeAngelis and Wen 2013; Ertürk Çetin et al. 2017). Generalized seizures represent focal seizures that have undergone secondary generalization, which can be challenging to identify clinically (Maschio

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2012). Seizure semiology varies with tumor location. New onset of seizures in adulthood is suspicious for a brain tumor and should be promptly followed up with imaging.

1.6

Therapeutic Approaches

1.6.1 Surgical Intervention Surgical resection is an essential component of management for almost all newly diagnosed malignant gliomas. Surgery can provide tissue for a definitive diagnosis, reduce tumor bulk and therefore symptoms due to tumor mass effect, and prepare patients for adjuvant treatments if necessary (Kaye 2005). However, surgery is not a cure for disease: when it comes to high-grade gliomas, even in cases of complete resection of macroscopic tumor, microscopic tumor cells still remain and infiltrate extensively into the surrounding brain, sometimes extending as far as 2 cm beyond the tumor’s perceived edge (Hankey and Wardlaw 2002). In other words, complete resection is impossible for malignant gliomas due to their intrinsic nature. Additional limitations to surgical resection include involvement of eloquent cortex (areas governing language, motor, or sensory ability) or brainstem structures, where surgical intervention would result in significant disability (Kaye 2005). Diffuse midline gliomas are frequently inoperable for this reason. Nevertheless, all other patients with malignant glioma should undergo maximal surgical resection whenever possible (Wen and Kesari 2008). Studies have shown that greater extent of surgical resection is tied to longer patient survival in glioblastoma, with one analysis finding that patients who underwent resection of at least 98% of tumor volume had a median survival 4 months longer than that of patients who had lesser extent of resection (Lacroix et al. 2001; Keles et al. 1999; Kuhnt et al. 2011). In cases where surgery is altogether impossible, stereotactic biopsy is an alternative option for making a definitive diagnosis (Fig. 1.12).

Many techniques have been developed over the years to increase the accuracy and safety of neurosurgery for the resection of brain tumors. Malignant gliomas present a particular challenge due to their aforementioned ill-defined borders and infiltrative pattern of growth. Present day neurosurgery is largely guided by frameless stereotactic navigation, using sophisticated computer systems that register an individual patient’s anatomic landmarks intraoperatively with those same landmarks in a three-dimensional model reconstructed from high-resolution cross-sectional imaging studies (Orringer et al. 2012). A camera or detector is then paired with a probe, which can be used to track the location of these landmarks—and the location of neurologic structures of interest relative to those landmarks—intraoperatively. However, as commonplace as frameless stereotaxy has become in neurosurgery, this approach is not without its weaknesses, arguably the most significant one being lack of true real-time intraoperative guidance. While the reconstructed models employed in this technique are of excellent resolution, they are static representations of a patient’s neuroanatomy up to the moment of surgery, and as a result have maximal accuracy prior to the initiation of resection. As surgery progresses, resulting brain shift leads to diminished accuracy of neuronavigation. Intraoperative MRI, CT, and ultrasound are becoming increasingly popular and provide an advantage over frameless stereotactic navigation in this regard (Orringer et al. 2012). Fluorescent agents which preferentially localize to areas of malignant tissue have also been investigated as a means of improving safety and efficacy in tumor resection. This strategy will be discussed further in the section on new therapeutic modalities. Finally, in a subset of patients whose tumors are located in areas of eloquent cortex, awake craniotomy with language or sensorimotor mapping can be a useful adjunct to other navigational strategies for maximizing extent of resection while preserving neurologic function (Hervey-Jumper et al. 2015).

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Malignant Glioma

17 Clinical symptoms concerning for intracranial neoplasm (new onset seizure, focal neurological deficit, signs of elevated ICP)

Imaging (MRI brain with and without contrast)

Diffuse tumor with high-grade features (heterogeneous contrastenhancement, edema, necrosis)

No

Yes

Medically treatable or radiosensitive tumor (e.g. prolactinoma, certain metastases)

Yes

Medical management or radiation therapy

Location amenable to resection

No

No

Yes

Biopsy

Maximal safe resection

Histopathology, genetic/molecular studies

Histopathology, genetic/molecular studies

Chemotherapy, radiation therapy, novel therapeutic approaches via enrollment in clinical trials

Chemotherapy, radiation therapy, novel therapeutic approaches via enrollment in clinical trials

Large or symptomatic tumor

No

Yes

Monitoring vs. surgical resection

Surgical resection

+/- Radiation therapy Recurrence/disease progression Follow up +/- regular imaging

Fig. 1.12 Basic algorithm for the diagnosis and management of benign and malignant gliomas

1.6.2 Chemotherapy and Radiotherapy Radiation therapy is a critical part of treatment for malignant gliomas and serves as an important and effective adjunct to surgery (Wen and Kesari 2008). Two large, randomized trials conducted by the Brain Tumor Study Group demonstrated the efficacy of radiotherapy in prolonging

survival for post-surgical patients with malignant glioma and are part of the reason radiotherapy is widely used in the management of these tumors today (Fine et al. 1993; Walker et al. 1978, 1980). The goal of radiotherapy is to deliver a concentrated dose of radiation to the tumor while simultaneously minimizing the amount of radiation delivered to adjacent areas of relatively normal brain (Kaye 2005). For glioblastoma, the

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addition of radiotherapy to surgery can prolong survival by up to 9 months (Mandigo and Bruce 2012; Wen and Kesari 2008). For diffuse midline gliomas, in which surgical resection is nearly always impossible, radiotherapy serves as the mainstay of treatment (Himes et al. 2019). For many years, the role of chemotherapy in the management of malignant gliomas was not well-established, with multiple studies demonstrating inconsistent results (Fine et al. 1993). However, a large meta-analysis of over 3000 patients published in 1993 was one of the first studies to suggest that adjuvant chemotherapy prolongs survival in patients with high-grade gliomas, and since then, additional clinical trials have been conducted that show clear evidence of a survival benefit (Fine et al. 1993; Stupp et al. 2005). In recent years, adjuvant chemotherapy has become an increasingly important tool in the management of malignant glioma. Temozolomide is currently the initial chemotherapy agent of choice for patients with malignant gliomas, due to its similar efficacy but more favorable toxicity profile in comparison to nitrosoureas, which were the previous first-line agent (Kreisl 2009). In a study of 573 patients with newly diagnosed glioblastoma who were assigned to receive radiotherapy alone or radiotherapy plus concomitant and adjuvant temozolomide, median survival was 14.6 months in the group treated with both radiotherapy and chemotherapy versus 12.1 months in the group that received radiotherapy alone. In addition, the two-year survival rate was 26.5% in patients treated with both adjuvant therapies versus 10.4% in those who received only radiotherapy (Stupp et al. 2005). Other options for chemotherapy include local delivery of carmustine via wafers implanted into the tumor bed post-resection. In this method, the chemotherapeutic agent is released gradually into the surrounding tissue over the course of several weeks. One study of 240 patients with newly diagnosed malignant glioma found that this approach led to an increase in median survival from 11.6 to 13.9 months (Wen and Kesari 2008; Westphal et al. 2003).

L. M. Wang et al.

Certain genetic alterations may be associated with an increased or decreased response to chemotherapy. One important example is MGMT promoter methylation, which is present in about half of glioblastomas (Yang et al. 2015). MGMT encodes a DNA repair enzyme that removes alkyl and methyl groups from DNA, producing relative resistance to alkylating and methylating chemotherapy agents such as temozolomide (Wesseling et al. 2015). Hypermethylation of the MGMT promoter leads to silencing of the gene and low levels of expression, resulting in increased sensitivity to temozolomide and a better prognosis (DeAngelis and Wen 2013; Wen and Kesari 2008). One study found that in patients treated with both temozolomide and radiotherapy, those with MGMT promoter methylation had a median overall survival of 21.7 months versus 12.7 months for those without MGMT promoter methylation (Hegi et al. 2005). Another genetic change with important implications for treatment response is 1p/19q codeletion, a hallmark of both low- and highgrade oligodendrogliomas. These tumors have long been known for their remarkable sensitivity to procarbazine, lomustine, and vincristine chemotherapy (PCV), with about two-thirds of anaplastic oligodendrogliomas demonstrating a durable response to treatment with this regimen (Cairncross et al. 1994, 1998). More recent research has suggested that this chemosensitivity appears to be specifically correlated with the presence of 1p/19q codeletion (Bent et al. 2013). One study found that in patients with 1p/19qcodeleted oligodendrogliomas, the addition of PCV to radiotherapy doubled median survival from 7.3 to 14.7 years. In that same study, patients with 1p/19q-codeleted tumors were found to have longer survival than those without codeletion when treated with radiotherapy and PCV (14.7 years versus 2.6 years, respectively) (Cairncross et al. 2013).

1.6.2.1 Adjuvant Treatment Options Based on Tumor Type Current standard therapy for malignant gliomas generally consists of a combination of surgical

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Table 1.2 Treatment options for malignant glioma Tumor type

Surgical resection

Adjuvant therapy

Anaplastic astrocytoma

Yes

Radiotherapy + concomitant and adjuvant temozolomide Or Radiotherapy + adjuvant temozolomide alone

Glioblastoma

Yes

Radiotherapy + concomitant and adjuvant temozolomide or carmustine wafers

Anaplastic oligodendroglioma

Yes

Radiotherapy alone Or Temozolomide or PCV ± radiotherapy afterward Or Radiotherapy + concomitant and adjuvant temozolomide Or Radiotherapy + adjuvant temozolomide alone

Diffuse midline glioma

No

External beam radiation therapy

Source Wen and Kesari (2008), Kerkhof et al. (2015)

resection followed by radiotherapy and chemotherapy (Wen and Kesari 2008). As mentioned previously, surgery is a crucial part of the treatment paradigm for almost all malignant gliomas; however, adjuvants to surgery may vary depending on the type of lesion. Table 1.2 shows the treatment options for different types of malignant glioma. For glioblastoma, standard of care treatment is maximal safe surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide or carmustine wafers (Wen and Kesari 2008). Radiotherapy is dosed at 60 grays (Gy) given in 30 fractions over 6 weeks. Concomitant temozolomide is given over 42 days with radiotherapy. Starting 4 weeks after radiotherapy, adjuvant chemotherapy is then administered on days 1–5 of each 28-day cycle for 6 cycles (Wen and Kesari 2008; Stupp et al. 2005; Thakkar et al. 2014). After surgical resection, patients with anaplastic astrocytoma may receive radiotherapy with both concurrent and adjuvant temozolomide or radiotherapy with adjuvant temozolomide alone (DeAngelis and Wen 2013; Wen and Kesari 2008). Anaplastic oligodendrogliomas may be managed after surgery with the following options: radiotherapy alone, temozolomide or PCV with or without radiotherapy afterward, radiotherapy with concomitant and adjuvant

temozolomide, or radiotherapy plus adjuvant temozolomide alone (Wen and Kesari 2008). Diffuse midline gliomas differ from other malignant gliomas due to their sensitive location, which almost always precludes surgical resection. In these patients, radiotherapy forms the backbone of their management strategy, and standard treatment consists of external beam radiation therapy delivered over 6 weeks to a total dose of about 60 Gy (Himes et al. 2019; Grimm and Chamberlain 2013). While temozolomide plays a significant role in the management of other types of malignant gliomas, studies of its use in diffuse midline gliomas have produced disappointing results, with no significant improvement in outcome (Sharp et al. 2010; Grimm and Chamberlain 2013; Chassot et al. 2012).

1.6.3 New Therapeutic Modalities The management of malignant gliomas remains an extremely active area of research. Although advances in radiotherapy and chemotherapy over the past several decades have produced substantial improvements in outcome, there is still much work to be done. Recent research has focused on ways of improving upon already existing therapies, such as surgical adjuncts or

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more effective routes of drug administration, as well as novel modes of therapy altogether. In light of newly emerging molecular and genetic information, targeted therapies that make use of these findings are assuming an exciting new role. Fluorescent agents are becoming an increasingly common visual adjunct to glioma neurosurgery. Surgical resection is the foundation of management of most malignant gliomas, and greater extent of resection is known to be associated with better outcomes (Sanai et al. 2011). However, these tumors are diffusely infiltrating with poorly defined borders, and intraoperative identification of the brain tumor interface can be challenging. Moreover, while maximal surgical resection is always the goal, preservation of healthy brain and avoidance of excess neurological deficit is also a priority (Lakomkin and Hadjipanayis 2018). The intraoperative use of fluorescent agents to help delineate the boundary between tumor and normal brain in real time is one technique that aims to address this issue. Widely used agents include fluorescein sodium and 5-aminolevulinic acid (5-ALA). Fluorescein sodium fluoresces in the yellow-green part of the spectrum and, when administered intravenously, localizes to areas of blood–brain barrier breakdown. Interestingly, studies have suggested that it may provide additional visualization of tumor beyond what is revealed on gadoliniumenhanced MRI (Neira et al. 2016). 5-ALA is a hemoglobin precursor protein that is preferentially taken up by glioma cells and metabolized into fluorescent porphyrins which appear blue under red light (Stummer et al. 2006). A randomized controlled trial showed that patients who underwent surgical resection with 5-ALA had a greater likelihood of complete resection and longer progression-free survival when compared to patients who underwent resection under white light (Stummer et al. 2006). New routes of administration for chemotherapeutic drugs and other therapeutic agents represent an area of growing interest as limitations in drug delivery due to the impenetrability of the blood–brain barrier continue to pose an obstacle to maximally effective treatment. Convectionenhanced delivery (CED) is one such method, in

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which a drug is directly delivered to a target area of the brain via infusion catheter, bypassing the blood–brain barrier. This mode of delivery allows for the administration of higher concentrations of a drug than would otherwise be possible due to fear of systemic toxicity (Zhou et al. 2017). CED relies on bulk flow rather than diffusion and generates a pressure gradient that results in greater tissue penetration with a larger volume of distribution (Himes et al. 2019; Mehta et al. 2017). At the same time, a steep fall in concentration outside of the targeted area limits toxicity to the surrounding brain, a property that is especially useful in treating tumors located in sensitive areas like the brainstem (Zhou et al. 2017). Focused ultrasound is another alternative route of drug administration that has gained attention in recent years. In this minimally invasive method, low-intensity ultrasound waves are used to induce transient disruption of the blood–brain barrier, represented on MRI by increased contrast-enhancement post-procedure (Mainprize et al. 2019). Aside from their value in maximizing the effectiveness of existing chemotherapeutic agents, these alternate modes of delivery will likely also play an important role in the determining the effectiveness of newer treatments that target tumor cells on a molecular level, which will be discussed next. As more is uncovered about the molecular and genetic changes underlying malignant gliomas and their pathogenesis, there has been increasing excitement surrounding therapies that directly target the alterations and pathways thought to be critical to tumor progression. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has been investigated in the treatment of glioblastoma, which is known for its highly vascular nature. In recurrent tumors, bevacizumab has been found to result in longer progression-free survival along with decreased peritumoral edema and glucocorticoid requirement (Vredenburgh et al. 2007). Numerous trials have explored the effectiveness of targeted therapy against a variety of other molecules thought to facilitate tumor growth and survival such as EGFR, PDGF, mTOR, PI3K, PKC, c-Met, histone deacetylase enzymes, TGF-

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b, integrins, and tubulin, just to name a few (Sim et al. 2018). In diffuse midline gliomas, the H3K27M mutation may point to potential targets for therapy, as the ubiquitous expression of this alteration seems to suggest it plays an important role in tumor formation (Himes et al. 2019; Morales La Madrid et al. 2015). Sharing some overlap with targeted therapies, immunotherapy is also a growing field of interest in the treatment of malignant gliomas. This novel therapy seeks to harness the power of the immune system in destroying tumor cells. Vaccine-based therapies like rindopepimut, which consists of a peptide encoded by an EFGR variant commonly found in glioblastoma that is then conjugated to a carrier protein for enhanced immunogenicity, are used to stimulate an immune response against tumor cells carrying the associated mutation (Sim et al. 2018). Other potential targets for anti-tumor vaccines include IDH1 mutations, which are prevalent in many high-grade gliomas. Immune checkpoint inhibitors such as nivolumab or pembrolizumab are of great interest due to their positive results in the treatment of certain brain metastases, although their efficacy in primary brain tumors remains to be seen (Sim et al. 2018). Antibody–drug conjugates may offer an additional option for precise delivery of therapeutic agents, with the antibody component recognizing and binding to a characteristic mutant protein expressed by tumor cells, thus resulting in direct delivery of the accompanying drug (Sim et al. 2018). Despite all of these exciting new developments, many studies of targeted therapy and immunotherapy have thus far shown limited efficacy in the management of malignant glioma. This is thought to be related to multiple factors, one of which is inadequate drug delivery due to the blood–brain barrier. An additional obstacle faced by targeted therapies is the genetic heterogeneity of malignant gliomas; oftentimes different cells within the same tumor are characterized by different genetic alterations, and only those with the relevant target can be expected to respond to treatment (Sim et al. 2018; de Groot 2015). Nevertheless, as evidenced by the ongoing work surrounding CED

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and focused ultrasound, significant efforts are being undertaken to address these limitations and translate these innovative new treatment strategies into better outcomes for patients.

1.6.4 Symptomatic Management Along with direct treatment of the underlying tumor, management of tumor-associated symptoms is a critical component of caring for patients with malignant glioma. Glucocorticoids are used to treat tumor-associated edema and may be given to symptomatic patients with evidence of increased intracranial pressure or neurologic dysfunction (de Groot 2015). Dexamethasone is commonly used due to its low mineralocorticoid activity (DeAngelis and Wen 2013). Because long-term use of steroids is associated with multiple adverse effects including weight gain, osteoporosis, hyperglycemia, myopathy, lymphopenia, and behavioral changes, treatment is usually only temporary. As patients improve clinically and/or prepare to undergo definitive treatment, the dose should be tapered accordingly (Wen et al. 2006). Patients with malignant glioma who present with seizures should be treated with antiepileptic drugs. Agents that do not induce hepatic cytochrome P450 enzymes (levetiracetam, lamotrigine, lacosamide, valproic acid) are preferred to agents such as phenytoin or carbemazpine, which can interact with or alter the metabolism of chemotherapeutic agents, certain targeted therapies, and dexamethasone (Wen et al. 2006; de Groot 2015). The general consensus is that antiepileptic drugs are not necessary as prophylaxis in patients who have never experienced a seizure, although they may be administered prior to surgery to reduce the risk of post-operative seizures (Wen and Kesari 2008; de Groot 2015; Pruitt 2015). Venous thromboembolic disease occurs in about 20–30% of patients with malignant glioma (Wen and Kesari 2008). Prophylaxis with enoxaparin may help reduce the risk of venous thromboembolism in the perioperative setting (Agnelli et al. 1998). Patients with proven

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venous thromboembolism should be treated with therapeutic anticoagulation (Wen and Kesari 2008; de Groot 2015). An inferior vena cava filter may be placed if anticoagulation therapy is contraindicated, for example due to recent craniotomy or intracerebral hemorrhage, but otherwise the risk of intratumoral hemorrhage from anticoagulation in these patients is low relative to the complication rate associated with inferior vena cava filters (Ruff and Posner 1983; Levin et al. 1993; Wen et al. 2006; Wen and Kesari 2008).

1.7

Follow-Up and Prognosis

There is no cure for malignant glioma. Median survival for glioblastoma after maximal treatment is 12–18 months, and 5-year survival is less than 5% (Hou et al. 2006). Patients with anaplastic astrocytoma have a median survival of about three years (DeAngelis 2001). Even after surgery and adjuvant therapy, tumors often recur, and all grade III anaplastic astrocytomas eventually progress to grade IV glioblastoma. The most common location for recurrence is locally in the tumor bed, representing growth of infiltrating malignant cells inevitably left behind during surgical resection (Kaye 2005). Treatment options for recurrent disease are limited and can vary widely among different patients. Although some patients may benefit from repeat surgical resection, reirradiation, chemotherapy, and/or newer targeted agents such as bevacizumab for recurrent glioblastoma, there is no standard accepted treatment for recurrent disease (Hou et al. 2006; DeAngelis 2001; Gallego 2015). While low-grade oligodendrogliomas may grow slowly over many years and have a median survival of 10–15 years, virtually all will progress to a higher-grade lesion over time (Wesseling et al. 2015; Olson et al. 2000). Grade III anaplastic oligodendrogliomas have a worse prognosis and behave more similarly to highgrade astrocytomas, with a median survival of 3– 6 years, although their prognosis ultimately remains slightly more favorable than that of anaplastic astrocytomas (DeAngelis and Wen

2013; Mandigo and Bruce 2012). Diffuse midline gliomas have a median survival of about 1 year and a 2-year survival rate of less than 10% (Louis et al. 2016; Himes et al. 2019). Despite these general patterns, as with any malignancy, outcomes can vary among different patients. Favorable prognostic factors for all types of gliomas are younger age at diagnosis, high functional status (as measured by the Karnofsky Performance Status Scale), greater extent of resection, and lower histologic grade at diagnosis. In patients with glioblastoma, greater extent of necrosis is associated with worse outcome, while MGMT promoter methylation is associated with better prognosis due to increased sensitivity to alkylating and methylating chemotherapy agents. IDH mutation status is an important prognostic indicator in both glioblastoma and anaplastic astrocytoma. One study found that in patients with glioblastoma who received surgery and radiotherapy, mean overall survival was 27.1 months versus 11.3 months for IDH-mutant tumors compared to IDH-wildtype tumors, respectively (Nobusawa et al. 2009). For anaplastic astrocytomas, IDH1- or IDH2-mutant status is also associated with a more favorable outcome; IDH-wildtype anaplastic astrocytomas more closely resemble IDH-wildtype glioblastomas in terms of outcome and may even fare worse than IDH-mutant glioblastoma (Hartmann et al. 2010). Similarly, for anaplastic oligodendrogliomas, IDH mutation and 1p/19q codeletion status have a significant impact on prognosis. Studies have demonstrated longer median survival in patients with 1p/19q-codeleted anaplastic oligodendrogliomas compared to patients with codeletionnegative tumors (8.5 versus 3.7 years, respectively) (Lassman et al. 2011). It is known that codeletion is associated with a more favorable response to certain chemotherapy regimens such as PCV, which may contribute to this improvement in survival (Cairncross et al. 1994). However, one study also found a survival difference between patients with and without 1p/19q codeletion when treated with radiotherapy alone, suggesting the possibility that codeletion

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is associated with a more favorable prognosis independent of response to PCV chemotherapy (Cairncross et al. 2013).

1.8

Conclusion

Malignant glioma remains a formidable disease, but with advances in treatment strategies brought about by decades of research, affected patients are living longer than ever before. The role of palliative care is also growing, with the goal of minimizing suffering and maximizing quality of life; in patients with other incurable cancers, studies have found that early introduction of palliative care may even prolong survival (Pruitt 2015; Temel et al. 2010). Worldwide, researchers are continuing their efforts to disentangle the molecular and genetic drivers of malignant glioma and translate these findings into meaningful clinical benefit for patients, with the hope that each new study brings us one step closer to finding a cure for this devastating disease.

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Ann Neurol 13(3):334–336. https://doi.org/10.1002/ ana.410130320 Salama GR, Heier LA, Patel P, Ramakrishna R, Magge R, Tsiouris AJ (2018) Diffusion weighted/tensor imaging, functional MRI and perfusion weighted imaging in glioblastoma—foundations and future. Front Neurol 8(660). https://doi.org/10.3389/fneur.2017.00660 Sanai N, Polley M-Y, McDermott MW, Parsa AT, Berger MS (2011) An extent of resection threshold for newly diagnosed glioblastomas. 115(1):3.https:// doi.org/10.3171/2011.2.Jns10998 Sharp JR, Bouffet E, Stempak D, Gammon J, Stephens D, Johnston DL, Eisenstat D, Hukin J, Samson Y, Bartels U, Tabori U, Huang A, Baruchel S (2010) A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma. Eur J Cancer 46(18):3271–3279. https://doi.org/10.1016/j.ejca. 2010.06.115 Sim H-W, Morgan ER, Mason WP (2018) Contemporary management of high-grade gliomas. CNS Oncol 7 (1):51–65. https://doi.org/10.2217/cns-2017-0026 Soares J, Marques P, Alves V, Sousa N (2013) A hitchhiker’s guide to diffusion tensor imaging. Front Neurosci 7(31). https://doi.org/10.3389/fnins.2013. 00031 Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen H-J (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401. https:// doi.org/10.1016/S1470-2045(06)70665-9 Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10):987–996. https://doi.org/10.1056/NEJMoa 043330 Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y, Shiraishi Y, Shimamura T, Niida A, Motomura K, Ohka F, Yamamoto T, Tanahashi K, Ranjit M, Wakabayashi T, Yoshizato T, Kataoka K, Yoshida K, Nagata Y, Sato-Otsubo A, Tanaka H, Sanada M, Kondo Y, Nakamura H, Mizoguchi M, Abe T, Muragaki Y, Watanabe R, Ito I, Miyano S, Natsume A, Ogawa S (2015) Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 47(5):458–468. https://doi.org/10.1038/ng.3273 Taylor KR, Mackay A, Truffaux N, Butterfield Y, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46 (5):457–461. https://doi.org/10.1038/ng.2925

29 Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ (2010) Early palliative care for patients with metastatic nonsmall-cell lung cancer. N Engl J Med 363(8):733–742. https://doi.org/10.1056/NEJMoa1000678 Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL (2014) Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev 23 (10):1985–1996. https://doi.org/10.1158/1055-9965. EPI-14-0275 Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H (1998) PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol 57(7):684–689. https://doi. org/10.1097/00005072-199807000-00005 Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483(7390):479–483. https://doi. org/10.1038/nature10866 Vecht CJ, Kerkhof M, Duran-Pena A (2014) Seizure prognosis in brain tumors: new insights and evidencebased management. Oncologist 19(7):751–759. https://doi.org/10.1634/theoncologist.2014-0060 Verma N, Cowperthwaite MC, Burnett MG, Markey MK (2013) Differentiating tumor recurrence from treatment necrosis: a review of neuro-oncologic imaging strategies. Neuro Oncol 15(5):515–534. https://doi. org/10.1093/neuonc/nos307 Vredenburgh JJ, Desjardins A, Herndon JE, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259. https://doi.org/10.1158/10780432.Ccr-06-2309 Walker MD, Alexander E, Hunt WE, MacCarty CS, Mahaley MS, Mealey J, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA (1978) Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. 49(3):333. https:// doi.org/10.3171/jns.1978.49.3.0333 Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Owens G, Ransohoff J 2nd, Robertson JT, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA (1980) Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303(23):1323–1329. https://doi.org/10.1056/ nejm198012043032303 Wang S, Kim S, Chawla S, Wolf RL, Zhang W-G, O’Rourke DM, Judy KD, Melhem ER, Poptani H

30 (2009a) Differentiation between glioblastomas and solitary brain metastases using diffusion tensor imaging. Neuroimage 44(3):653–660. https://doi.org/10. 1016/j.neuroimage.2008.09.027 Wang W, Steward CE, Desmond PM (2009b) Diffusion tensor imaging in glioblastoma multiforme and brain metastases: the role of p, q, L, and fractional anisotropy. AJNR Am J Neuroradiol 30(1):203–208. https://doi.org/10.3174/ajnr.A1303 Warren KE (2012) Diffuse intrinsic pontine glioma: poised for progress. Front Oncol 2:205–205. https:// doi.org/10.3389/fonc.2012.00205 Watanabe K, Tachibana O, Sato K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6(3):217–223. https://doi.org/10.1111/j. 1750-3639.1996.tb00848.x Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174(4):1149–1153. https://doi.org/10.2353/ajpath. 2009.080958 Weller M, Weber RG, Willscher E, Riehmer V, Hentschel B, Kreuz M, Felsberg J, Beyer U, LöfflerWirth H, Kaulich K, Steinbach JP, Hartmann C, Gramatzki D, Schramm J, Westphal M, Schackert G, Simon M, Martens T, Boström J, Hagel C, Sabel M, Krex D, Tonn JC, Wick W, Noell S, Schlegel U, Radlwimmer B, Pietsch T, Loeffler M, von Deimling A, Binder H, Reifenberger G (2015) Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol 129(5):679–693. https://doi.org/10.1007/s00401-015-1409-0 Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507. https://doi.org/10. 1056/NEJMra0708126 Wen PY, Schiff D, Kesari S, Drappatz J, Gigas DC, Doherty L (2006) Medical management of patients with brain tumors. J Neurooncol 80(3):313–332. https://doi.org/10.1007/s11060-006-9193-2 Wesseling P, van den Bent M, Perry A (2015) Oligodendroglioma: pathology, molecular mechanisms and markers. Acta Neuropathol 129(6):809–827. https:// doi.org/10.1007/s00401-015-1424-1 Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jääskeläinen J, Ram Z (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 5(2):79–88. https://doi.org/10.1093/neuonc/5.2.79

L. M. Wang et al. Wippold FJ 2nd, Lammle M, Anatelli F, Lennerz J, Perry A (2006) Neuropathology for the neuroradiologist: palisades and pseudopalisades. AJNR Am J Neuroradiol 27(10):2037–2041 Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84 (19):6899–6903. https://doi.org/10.1073/pnas.84.19. 6899 Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, Zhu X, Qu C, Chen X, Zhang J, Easton J, Edmonson M, Ma X, Lu C, Nagahawatte P, Hedlund E, Rusch M, Pounds S, Lin T, Onar-Thomas A, Huether R, Kriwacki R, Parker M, Gupta P, Becksfort J, Wei L, Mulder HL, Boggs K, Vadodaria B, Yergeau D, Russell JC, Ochoa K, Fulton RS, Fulton LL, Jones C, Boop FA, Broniscer A, Wetmore C, Gajjar A, Ding L, Mardis ER, Wilson RK, Taylor MR, Downing JR, Ellison DW, Zhang J, Baker SJ (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46(5):444–450. https://doi.org/10. 1038/ng.2938 Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773. https://doi. org/10.1056/NEJMoa0808710 Yang P, Zhang W, Wang Y, Peng X, Chen B, Qiu X, Li G, Li S, Wu C, Yao K, Li W, Yan W, Li J, You Y, Chen CC, Jiang T (2015) IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget 6(38):40896–40906. https://doi.org/10.18632/oncotarget.5683 Yang W, Warrington NM, Taylor SJ, Whitmire P, Carrasco E, Singleton KW, Wu N, Lathia JD, Berens ME, Kim AH, Barnholtz-Sloan JS, Swanson KR, Luo J, Rubin JB (2019) Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data. Sci Transl Med 11(473): eaao5253. https://doi.org/10.1126/scitranslmed. aao5253 Zhou Z, Singh R, Souweidane MM (2017) Convectionenhanced delivery for diffuse intrinsic pontine glioma treatment. Curr Neuropharmacol 15(1):116–128. https://doi.org/10.2174/1570159x1466616061409 3615

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Benign Glioma Peter B. Wu, Anna C. Filley, Michael L. Miller, and Jeffrey N. Bruce

Abstract

Benign glioma broadly refers to a heterogeneous group of slow-growing glial tumors with low proliferative rates and a more indolent clinical course. These tumors may also be described as “low-grade” glioma (LGG) and are classified as WHO grade I or II lesions according to the Classification of Tumors of the Central Nervous System (CNS) (Louis et al. in Acta Neuropathol 114:97–109, 2007). Advances in molecular genetics have improved understanding of glioma tumorigenesis, leading to the identification of common mutation profiles with significant treatment and prognostic implications. The most recent WHO 2016

P. B. Wu Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, USA e-mail: [email protected] A. C. Filley . J. N. Bruce (&) Department of Neurosurgery, Columbia University Medical Center, New York, USA e-mail: [email protected] A. C. Filley e-mail: [email protected] M. L. Miller Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA e-mail: [email protected]

classification system has introduced several notable changes in the way that gliomas are diagnosed, with a new emphasis on molecular features as key factors in differentiation (Wesseling and Capper in Neuropathol Appl Neurobiol 44:139–150, 2018). Benign gliomas have a predilection for younger patients and are among the most frequently diagnosed tumors in children and young adults (Ostrom et al. in Neuro Oncol 22:iv1–iv96, 2020). These tumors can be separated into two clinically distinct subgroups. The first group is of focal, well-circumscribed lesions that notably are not associated with an increased risk of malignant transformation. Primarily diagnosed in pediatric patients, these WHO grade I tumors may be cured with surgical resection alone (Sturm et al. in J Clin Oncol 35:2370–2377, 2017). Recurrence rates are low, and the prognosis for these patients is excellent (Ostrom et al. in Neuro Oncol 22: iv1–iv96, 2020). Diffuse gliomas are WHO grade II lesions with a more infiltrative pattern of growth and high propensity for recurrence. These tumors are primarily diagnosed in young adult patients, and classically present with seizures (Pallud et al. Brain 137:449– 462, 2014). The term “benign” is a misnomer in many cases, as the natural history of these tumors is with malignant transformation and recurrence as grade III or grade IV tumors (Jooma et al. in J Neurosurg 14:356–363, 2019). For all LGG, surgery with maximal

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_2

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safe resection is the treatment of choice for both primary and recurrent tumors. The goal of surgery should be for gross total resection (GTR), as complete tumor removal is associated with higher rates of tumor control and seizure freedom. Chemotherapy and radiation therapy (RT), while not typically a component of first-line treatment in most cases, may be employed as adjunctive therapy in high-risk or recurrent tumors and in some select cases. The prognosis of benign gliomas varies widely; non-infiltrative tumor subtypes generally have an excellent prognosis, while diffusely infiltrative tumors, although slow-growing, are eventually fatal (Sturm et al. in J Clin Oncol 35:2370–2377, 2017). This chapter reviews the shared and unique individual features of the benign glioma including diffuse glioma, pilocytic astrocytoma and pilomyxoid astrocytoma (PMA), subependymal giant cell astrocytoma (SEGA), pleomorphic xanthoastrocytoma (PXA), subependymoma (SE), angiocentric glioma (AG), and chordoid glioma (CG). Also discussed is ganglioglioma (GG), a mixed neuronal-glial tumor that represents a notable diagnosis in the differential for other LGG (Wesseling and Capper 2018). Ependymomas of the brain and spinal cord, including major histologic subtypes, are discussed in other chapters. Keywords

.

.

Pilocytic astrocytoma Diffuse astrocytoma Diffuse oligodendroglioma Angiocentric glioma Chordoid glioma Subependymal giant cell astrocytoma Pleomorphic Xanthoastrocytoma Subependymoma Pilomyxoid astrocytoma Low-grade glioma

.

.

2.1

. .

.

.

.

Background and Epidemiology

Benign gliomas are primary CNS tumors derived from neoplastic glial cells, including astrocytic, oligodendroglial, and ependymal cell lineages. They may be described as either focal, circumscribed, or diffusely infiltrating lesions and are classified as WHO grade I or II based on their

growth pattern and overall clinical course. In contrast to high-grade glial neoplasms, low-grade gliomas are more common in pediatric and young adult populations. They account for 45.5% of tumors in children and young adults ages 0–19, including 51.6% of brain tumors in children under age 15, and 25.6% of those in adolescent and young adults aged 15–39 (Ostrom et al. 2020). A notable exception to this is subependymomas, which are slow-growing WHO grade I tumors that are seen in an older patient population than typical for LGG; most occur in middle-aged adults, with 80% of tumors diagnosed in patients over 40 (Nguyen et al. 2017). Also seen in slightly older patients are chordoid glioma and angiocentric glioma. These are both extremely rare tumors whose study has been limited to case reports and small case series, though are notable differential diagnoses to consider for benign glioma. Among benign glioma, the most common diagnosis is pilocytic astrocytoma, which accounts for 17.7% of brain tumor diagnoses in children under 15 and 8.3% in adolescents aged 15–19. The median age at diagnosis of these focal, well-circumscribed WHO grade I tumors is 12 years (Ostrom et al. 2020). Most LGG are sporadic lesions, however on occasion, maybe the manifestation of an underlying tumor predisposition syndrome such as neurofibromatosis type 1 (NF1) or tuberous sclerosis (TSC). The latter is strongly associated with SEGA; these lesions are commonly found during childhood with median age at diagnosis of 8 years (Jansen et al. 2019). An important demographic to be aware of is young adult patients presenting with seizures. New-onset seizures are the most common presenting symptom of diffuse low-grade gliomas. These WHO grade II lesions were previously sub-classified according to histologic features as either oligodendroglioma or astrocytoma; however, more recent classification schemes rely more heavily on molecular markers for diagnosis. These are relatively common tumors, representing approximately 15% of gliomas, and have highest incidence in the age group of 35– 44 years (Jooma et al. 2019). The median age of

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diagnosis is 44 years for oligodendroglioma and 46 years for diffuse astrocytoma (Ostrom et al. 2020). Also closely linked to drug-resistant epilepsy is ganglioglioma (GG), a low-grade glioneuronal tumor. GG is relatively common, accounting for up to 6.5% of all intracranial tumors, and is strongly associated with clinical seizures (Siddique et al. 2002). A less frequently diagnosed cause of brain tumor-associated epilepsy is pilomyxoid xanthoastrocytoma (PXA). These WHO grade II neoplasms account for less than 1% of all brain tumors, (Shaikh et al. 2019) and have a median age at diagnosis of 21.5 years (Ida et al. 2015).

2.1.1 Pilocytic Astrocytoma (PA) Pilocytic astrocytoma is the most frequently diagnosed primary brain tumor in children and young adults. PA accounts for 17.7% of childhood (age 0–14) and 8.3% of young adult (age 15–19) primary brain tumors, with an overall incidence of 14.9% of primary brain tumors in these age groups; the average annual ageadjusted incidence rate is 0.92 per 100,000 and decreases with age (Ostrom et al. 2020). Tumorigenesis is thought to stem from alterations affecting the MAPK pathway. The most common such mutation is the KIAA1549-BRAF fusion protein, though BRAF V600E, KRAS, and NF1 mutations may be seen as well (Collins et al. 2015). The most common location for pilocytic astrocytomas is the cerebellum, followed by supratentorial locations, optic pathway, and brainstem. The posterior fossa is particularly common for pediatric tumors, accounting for * 2/3 of all PAs (Burkhard et al. 2003; Cyrine et al. 2013). Cerebellar tumors tend to have a shorter pre-operative duration of symptoms when compared with supratentorial lesions (median 3.3 months vs. 18.3 months), which is true of most lesions in this location (Burkhard et al. 2003). Supratentorial PAs are almost exclusively seen in adult patients, where they occur at equal frequency to infratentorial tumors (Lee et al. 2018; Ohgaki and Kleihues 2005).

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Optic pathway tumors tend to be associated with an underlying diagnosis of NF1 (Lewis et al. 1984).

2.1.2 Pilomyxoid Astrocytoma (PMA) Pilomyxoid astrocytoma (PMA) is a relatively new diagnosis that refers to a unique group of tumors, previously considered to be a variant of PA, exhibiting a distinctive set of histologic, radiographic, and clinical features (Louis et al. 2007). Classical features of PA and PMA are summarized in Table 2.1. Initially described as WHO grade II tumors (Louis et al. 2007), more recent classification does not recommend a definitive WHO grade for all lesions, as they are known to harbor characteristics of both WHO grade I and WHO grade II tumors (Wesseling and Capper 2018). The true incidence of these tumors is relatively unknown given that they are generally grouped with PA in historical published reports.

2.1.3 Subependymal Giant Cell Astrocytoma (SEGA) Subependymal giant cell astrocytomas (SEGA) are low-grade intraventricular tumors that are classically found in patients with tuberous sclerosis (TSC). Tuberous sclerosis is an autosomal dominant genetic disease caused by a mutation in one of two tumor suppressor genes, TSC1 or TSC2 (Nguyen et al. 2018). The protein products of these genes, hamartin and tuberin, respectively, form a dimer that inhibits mTOR signaling (Jozwiak et al. 2015). In the absence of these inhibitors, cell-cycle progression is allowed to proceed unimpeded, leading to overgrowth and tumor formation (Jozwiak et al. 2015). Patients with TSC are predisposed to developing a variety of tumors throughout the body. In the brain, this manifests with subependymal nodules or “tubers,” SEGAs, and other cortical dysplasia. Patients often present at a young age with developmental delay and medication-refractory epilepsy (Ebrahimi-Fakhari and Franz 2020).

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Table 2.1 Classical features of PMA and PA Feature

PMA

PA

Monophasic Prominent Absent Rare Frequent

Biphasic Infrequent/occasional Present Present Rare

Histology (Komotar et al. 2004a) Architecture Myxoid background Rosenthal fibers Eosinophilic granular bodies Angiocentric growth

NF1

Associated diagnoses Genetic mutations (Hawkins et al. 2011)

KIAA1549-BRAF fusion protein

BRAF V600E point mutation

Composition Enhancement Infiltrative margins

Predominantly solid Homogeneous Absent

Substantial cystic component Heterogeneous Absent

Tumor location (Komotar et al. 2004b)

Supratentorial Midline (hypothalamus, thalamus)

Posterior fossa Supratentorial

Average age at diagnosis (Komotar et al. 2004a)

18 months

58 months

PFS (age-matched) OS (age-matched)

26 (25) 63 (60)

147 (163) 213 (233)

CSF dissemination

Occasional [14%] (Komotar et al. 2004a)

Extremely rare (Wallner et al. 1988)

Local recurrence (Komotar et al. 2004a) (%)

76

50

Radiographic appearance (Komotar et al. 2004b)

Prognosis (months) (Komotar et al. 2004a)

Given this propensity for intracranial lesions, the NIH Consensus Conference guidelines for screening recommend that children with TSC have a brain MRI as routine surveillance screening every 1–3 years (Hyman and Whittemore 2000).

2.1.4 Subependymoma (SE) Subependymoma (SE) are WHO grade I tumors of ependymal cell origin. They classically arise from the ventricular lining, growing into the ventricular system. They are most commonly found within the lateral or 4th ventricles (Bi et al. 2015; Jain et al. 2012; Vitanovics et al. 2014), but may develop as intramedullary spinal tumors (Bi et al. 2015; Jain et al. 2012; Ragel et al. 2006) or in an intraparenchymal location (Bi et al. 2015; Hou et al. 2013; Ragel et al. 2006). SE is

more common in males and typically is diagnosed either in middle-aged individuals around the 5th decade of life (Nguyen et al. 2017; Rushing et al. 2007; Vitanovics et al. 2014) or less commonly, in the pediatric population (Bi et al. 2015; Hou et al. 2013). SE are relatively rare, accounting for < 0.1% of intracranial neoplasms (Bi et al. 2015). Matumura et al. reported a frequency of 0.4% of asymptomatic SE on 1000 serial routine autopsies, and of 0.7% in 1000 serial surgical specimens (Matsumura et al. 1989). Overall, SE has estimated incidence of 0.055 per 100,000 person-years (Nguyen et al. 2017), although the true incidence may be higher given that many tumors are asymptomatic and discovered on autopsy or routine imaging obtained for other reasons (Jain et al. 2012; Varma et al. 2018). Symptomatic patients tend to present with deficits caused by mass effect or obstructive hydrocephalus (Varma et al. 2018).

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2.1.5 Angiocentric Glioma Angiocentric glioma is an uncommon benign tumor with a unique perivascular growth pattern and strong association with medically refractory epilepsy (Louis et al. 2007). They arise superficially within the cortex and subcortical white matter, most commonly in the frontal and temporal lobes (Cheng et al. 2015; Lellouch-Tubiana et al. 2005; Lian et al. 2020; Wang et al. 2005). These are extremely rare tumors, and most of the available literature on the topic exists in the form of case reports (Alexandru et al. 2013; Chen et al. 2014; Cheng et al. 2015; Fulton et al. 2009; Gonzalez-Quarante et al. 2017; Koral et al. 2012; Kuncman et al. 2018; Lellouch-Tubiana et al. 2005; Lian et al. 2020; Lu et al. 2013; Marburger and Prayson 2011; Miyata et al. 2012; Mott et al. 2010; Preusser et al. 2007; Shakur et al. 2009; Sugita et al. 2008; Takada et al. 2011; Weaver et al. 2017). Most have been diagnosed during the first few decades of life in patients primarily presenting with seizures (Chen et al. 2014; Cheng et al. 2015; Fulton et al. 2009; GonzalezQuarante et al. 2017; Koral et al. 2012; LellouchTubiana et al. 2005; Lian et al. 2020; Marburger and Prayson 2011; Miyata et al. 2012; Preusser et al. 2007; Shakur et al. 2009; Sugita et al. 2008; Takada et al. 2011).

2.1.6 Ganglioglioma Ganglioglioma (GG) is mixed glioneuronal neoplasms that is commonly associated with intractable epilepsy. GG accounts for between 0.3% and 6.5% of all brain tumors according to several case series (Siddique et al. 2002). GG is more commonly diagnosed in children and young adults, with a slight male predominance (Prasad et al. 2016). They are frequently associated with other structural abnormalities or focal cortical dysplasia (Blumcke et al. 2014; Kakkar et al. 2017). These tumors fall into the category of “long-term epilepsy-associated tumors (LEATs),” which tend to involve the temporal lobes and present at a young age with medicallyrefractory seizures (Blumcke et al. 2014; Luyken

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et al. 2004). Seizures are the most common presenting symptom of GG, present in approximately 75% of patients (Southwell et al. 2012) and gangliogliomas account for 14% of all epilepsy surgeries overall (Wolf and Wiestler 1993). Lesional resection in these cases is primarily indicated from the standpoint of seizure control. Important in the treatment of these patients is an accurate identification of the epileptogenic tissue, which may or may not correspond to radiographically visible lesion (Blumcke et al. 2014). Even in the absence of residual or recurrent tumor, patients may require multiple surgeries to adequately control their seizures.

2.1.7 Chordoid Glioma (CG) Chordoid glioma (CG) is a rare low-grade glial tumor that arises from the anterior part of the third ventricle. With less than 100 reported cases in the literature, much of what is known is from individual reports and small case series. Chordoid glioma receives its name from a histologic appearance similar to chordoma, yet IHC findings are consistent with glial neoplasm. The exact origins of CG are unknown, but lesions are postulated to arise from tanycytes, specialized glial cells, in the anterior third ventricle near the lamina terminalis (Brat 2006). Genomic profiling has identified a recurrent missense mutation in the PRKCA gene in nearly all tumors, suggesting its implication in tumorigenesis (Goode et al. 2018; Yao et al. 2020).

2.1.8 Pleomorphic Xanthoastrocytoma (PXA) Pleomorphic xanthoastrocytoma (PXA) are relatively rare primary glial neoplasms, classically found in the temporal lobes of young adult patients presenting with seizures (Gallo et al. 2013; Giannini et al. 1999; Korshunov and Golanov 2001; Perkins et al. 2012). Inherent in their name, PXA demonstrate a characteristic cellular and nuclear pleomorphism on histologic sections that differentiates them from other

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“benign” glioma. PXA are relatively uncommon tumors, representing < 1% of all astrocytomas (Shaikh et al. 2019). They are primarily diagnosed in the second decade of life with a median age at diagnosis of 21.5 years (Ida et al. 2015), at relatively equal frequency in male and female patients (Perkins et al. 2012). Differentiating them from other benign gliomas is an almost exclusive supratentorial location, with a predilection for the temporal lobes (Gallo et al. 2013; Giannini et al. 1999; Korshunov and Golanov 2001; Perkins et al. 2012). Patients may present with a variety of symptoms based on tumor location, with the most common symptom being seizures (Gallo et al. 2013; Giannini et al. 1999; Korshunov and Golanov 2001; Perkins et al. 2012). Recurrence is not uncommon, and * 15–20% of lesions ultimately undergo anaplastic transformation and recur as more diffusely infiltrative, aggressive tumors (Giannini et al. 1999; Korshunov and Golanov 2001).

2.1.9 Diffuse Low-Grade Glioma Diffuse low-grade gliomas are among the most common primary CNS tumors. Historically, they have been classified as either astrocytomas or oligodendrogliomas based on histologic architecture. An astrocytoma type is more common than oligodendroglioma histology; these entities account for 1.8% and 0.9% of all CNS tumors, respectively. Diffuse gliomas are diagnosed at similar rates in men and women and occur more often in adults than in children. The incidence of oligodendroglioma peaks in the 35–44-year-old age group, whereas the incidence of astrocytoma continues to increase with age (Ostrom et al. 2020). Particularly common in patients with diffuse low-grade gliomas are seizures, present in 70– 90% of patients at the time of diagnosis (Chang et al. 2008; Pallud et al. 2014; Santos-Pinheiro et al. 2019; You et al. 2012). In almost half of cases, seizures are refractory to medical management (Chang et al. 2008; Pallud et al. 2014). This is more common with cortical-based lesions and oligodendroglioma histology (Chang et al. 2008).

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2.2

Genetics, Immunology, Molecular Biology

Low-grade gliomas arise in the setting of a variety of genetic changes. Understanding the genetic underpinnings of these tumors is of great importance and has significant implications for diagnosis, prognostication, and management of low-grade gliomas within existing treatment paradigms. Moving forward, advances allowing improved characterization of tumor mutation profiles or their unique immunologic microenvironment have potential to revolutionize the treatment of benign glioma through the identification of new therapeutic targets. Among the most frequent genetic aberrations are those affecting the mitogen-activating protein kinase (MAPK) pathway, including mutations in the BRAF and NF1 genes. BRAF oncogene mutations lead to constitutive MEK/MAPK/ ERK/p16 activity and promote mTOR pathway signaling as well. The mTOR pathway is involved in cell survival, metabolism, growth, and protein synthesis; activation of the pathway seen in solid tumors causes increased cellular proliferation (Tian et al. 2019). Activating mutations of the BRAF oncogene are present in most low-grade glioma, but largely absent from higher-grade lesions (Behling and Schittenhelm 2019). Two mutations in particular have been widely characterized with respect to their role in benign glioma. The first is a tandem duplication at 7q34 resulting in the formation of a constitutively active kinase domain, termed the KIAA1549-BRAF fusion protein. This is seen in * 2/3 of pilocytic astrocytomas (Jones et al. 2008), particularly cerebellar tumors, 90% of which harbor this genetic change (Collins et al. 2015). The second mutation is the BRAF V600E mutation, which is caused by a glutamic acid (E) substitution for valine (V) at position 600 in the BRAF protein. This is commonly observed in supratentorial pilocytic astrocytoma, PXA, and gangliogliomas (Collins et al. 2015). Notably, the BRAF V600E-mutated tumors are associated with improved overall survival (Vuong et al. 2018). There are several ongoing clinical trials

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evaluating the efficacy of BRAF inhibitors like dabrafenib and vemurafenib in the treatment of a subgroup of LGG patients harboring these mutations (Chen et al. 2017). Supporting the underlying importance of the MAPK pathway in tumorigenesis of low-grade glioma is the increased frequency of LGG in patients with neurofibromatosis type 1 (NF1). This genetic tumor predisposition syndrome is caused by a mutation in the NF1 protein neurofibromin, which also has a role in the MAPK pathway (Collins et al. 2015). Tuberous sclerosis (TSC) is another tumor syndrome associated with benign glioma, in this case SEGAs (Wesseling and Capper 2018). TSC is caused by inactivating mutations in either TSC1 (encoding tuberin) or TSC2 (encoding hamartin). When functional, the protein products of these genes form a dimer that inhibits mTOR signaling (Jozwiak et al. 2015). Knowledge of molecular genetics has led to the widespread use of everolimus, an mTOR inhibitor, which has been shown to reduce tumor volume and improve seizure control in patients with SEGA (Franz et al. 2018). The p53 gene, located on chromosome 17 at 17p13.1, is a core cell-cycle regulator that acts at the G1/S checkpoint and can initiate apoptosis under certain conditions. Loss of p53 is an early genetic change observed in many malignancies, and its somatic mutation is responsible for tumor predisposition in cancer syndromes like LiFraumeni. P53 mutations are more common in malignant glioma (63.8%) than benign glioma (41.6%) (Jin et al. 2016) and have been implicated in the progression of low-grade to highgrade tumors (Ishii et al. 1999). The most common genetic mutation in PXA is in the BRAF gene, specifically the BRAF V600E mutation, which is observed in at least 2/3 of tumors. Present in both grade II and grade III lesions, the BRAF V600E mutation is thought to represent an early event in tumorigenesis (Ida et al. 2015; Koelsche et al. 2014; Schindler et al. 2011). BRAF-mutated tumors are associated with CD34 expression (75% of BRAF-mutated vs. 23% of BRAF-wt) and with development of a dense reticulin network. The presence of the

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BRAF V600E mutation has also been strongly associated with location; temporal lobe tumors have been found to nearly all (96%) exhibit BRAF V600E mutations as compared to 53% of PXA in other locations (Koelsche et al. 2014). Based on BRAF mutation status, PXA may be separated into two clinically distinct subgroups with different natural history and response to potential therapies. Notably, BRAF-mutated tumors tend to have a better prognosis, with longer overall survival seen in these patients as compared to those with BRAF-wt lesions (Ida et al. 2015). Another common mutation in PXA, observed in about half of tumors, is a homozygous deletion of 9p21.3, a locus which includes the CDKN2A tumor suppressor gene (Schindler et al. 2011; Weber et al. 2007). Low-grade gliomas harboring both BRAF and CDKN2A have a notably more aggressive and treatmentresistant phenotype across multiple tumor types (Phillips et al. 2019). The frequency of BRAF mutations has prompted the evaluation of BRAF/ kinase inhibitors in the treatment of PXA. Vemurafenib, a BRAF inhibitor, has been evaluated as a potential salvage therapy in relapsed tumors harboring the V600E mutation, with activity in a subset of patients in small cohorts, although future large-scale trials will be required to establish efficacy (Chamberlain 2013). For diffuse glioma, there is recent interest in characterizing the role of somatic mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes, which encode an enzyme in the tricarboxylic acid cycle, in glioma tumorigenesis and progression. Mutations of IDH1, classically at the R132 residue, have been identified in more than 70% of WHO grade II and III diffuse astrocytomas and oligodendrogliomas, and are notably absent from other subtypes of LGG (Yan et al. 2009). Study of IDH mutation status has also led to the identification of a genetically distinct subgroup of secondary glioblastomas (GBMs) that develop from IDH-mt LGG (Yan et al. 2009). For all diffuse glioma, IDH mutation status has important implications for prognostication and survival; overall, IDH-mutated (IDHmt) tumors tend to have better overall outcomes than their IDH-wild type (IDH-wt) counterparts

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(Cancer Genome Atlas Research et al. 2015; Chen et al. 2017; Choi et al. 2020). With the introduction of the 2016 WHO classification of CNS tumors, diffuse low-grade glioma can now be classified into three genetically distinct groups with significant implications for treatment and prognostication. The first group are IDH-mutated tumors that harbor a codeletion of the short arm of chromosome 1 (1p) and long arm of chromosome 19 (19q), the molecular signature of oligodendroglioma; further distinguishing them from other LGG are frequent CIC, FUBP1, NOTCH1, and TERT promoter mutations (Cancer Genome Atlas Research et al. 2015). These tumors are uniquely chemosensitive, and multiple studies have established a significant survival benefit conferred with the addition of PCV chemotherapy that is not seen in the other glioma subtypes (Chen et al. 2017). Among diffuse glioma, these tumors have the best overall prognosis. The second group contains IDH-mt tumors that lack the 1p/19q codeletion, thereby conferring a diagnosis of astrocytoma. These tumors exhibit loss of function of the p53 cell-cycle regulator and inactivation of ATRX, another tumor suppressor gene involved in chromatin remodeling. They notably do not exhibit the same degree of sensitivity to chemotherapy and radiation treatments and carry an intermediate prognosis (Cancer Genome Atlas Research et al. 2015). The final group is comprised of IDH-wt tumors that also lack the 1p/19q codeletion. This subgroup of diffuse astrocytomas do not demonstrate ATRX or TP53 mutations and instead are associated with aberrations in the PTEN, CDKN2A, or EGFR pathways (Cancer Genome Atlas Research et al. 2015; Yan et al. 2009). Of all diffuse LGG, IDHwt tumors have the worst overall prognosis (Chen et al. 2017).

2.3

Histopathology and Morphology

Gliomas arise from a neoplastic proliferation of glial cell types including astrocytoma, oligodendroglioma, and ependymoma; there are also

mixed subtypes that contain several histologically distinct components. Reflecting an astrocytic origin, benign gliomas are usually positive for GFAP on immunohistochemistry (IHC) (Popova et al. 2014). Inherent in their classification as WHO grade I or II lesions, benign gliomas lack histologic features of malignancy. The presence of anaplastic features or an elevated mitotic index is seen with grade III tumors, and the presence of prominent necrosis or microvascular proliferation tends to be indicative of a grade IV tumor (Louis 2016). The primary difference between grade I and grade II gliomas is their well-circumscribed versus infiltrative growth, respectively. Macroscopically, focal gliomas contain variable proportions of cystic and solid components and are radiographically and histologically well demarcated from surrounding brain tissue. Diffusely infiltrative lesions show grossly and microscopically infiltrative margins (Louis 2016).

2.3.1 Pilocytic Astrocytoma (PA) On macroscopic analysis, tumors grossly appear as a soft gray masses often with a cystic component (Collins et al. 2015). They are well circumscribed and tend to displace, rather than invade the surrounding parenchyma. Lesions are comprised of cytologically benign tumor cells and are notably hypocellular with very rare (if any) mitotic figures. The term “pilocytic” is derived from the presence of dense, elongated hair-like projections on neoplastic cells. Other notable histologic features include eosinophilic granular bodies and Rosenthal fibers, common in low-grade astrocytomas (Bornhorst et al. 2016). Tumor cells are strongly GFAP immunoreactive. Lesions demonstrate an immune microenvironment comprised principally of microglia (Klein and Roggendorf 2001), with decreased perivascular and intratumoral invasion of CD8 and CD56 positive immune cells when compared with higher-grade tumors like glioblastoma (Yang et al. 2011). Representative histological features of PA are shown in Figs. 2.1, 2.2 and 2.3.

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Fig. 2.1 Typical radiographic appearance of a, b focal, circumscribed glioma and c–d diffusely infiltrating glioma. a, b Slices from a 9-year-old boy with NF and pilocytic astrocytoma. a T1-weighted contrast-enhanced axial image demonstrates a large cystic structure with peripheral enhancing nodule within the left frontal lobe. b The T2FLAIR sequence illustrates the predominantly cystic

structure with peripheral solid component. c, d Slices from a 49-year-old woman with grade II astrocytoma. c Axial T1weighted contrast-enhanced image shows a T1 hypointense lesion within the left insular region. A lack of enhancement is typical for low-grade diffuse gliomas. d Lesion borders are often best appreciated with T2-FLAIR sequence. This is a classic appearance for diffusely infiltrating glioma

Fig. 2.2 Pilocytic astrocytoma: radiographic features. a T1-weighted contrast-enhanced axial image from a 31-year-old woman with cerebellar pilocytic astrocytoma demonstrates a large, well-circumscribed cystic structure in the right lateral cerebellum. There is mass effect on the 4th ventricle. This appearance with a peripheral contrast-enhancing nodule is classic for pilocytic astrocytoma. b T1-weighted contrast-

enhanced sagittal image from a 7-year-old girl with optic pilocytic astrocytoma. A contrast-enhancing heterogeneous mass is noted in the optic region. c, d T1-weighted contrast-enhanced axial (c) and sagittal (d) images of dorsally exophytic pontomedullary pilocytic astrocytoma in a 36-year-old woman. A well-circumscribed, enhancing lesion is seen at the pontomedullary junction

2.3.2 Pilomyxoid Astrocytoma (PMA)

classical features of PA (Komotar et al. 2004b). Similar to PA, PMA are associated with BRAF alterations, though more often with the KIAA1549-BRAF fusion protein rather than the V600E mutation (Hawkins et al. 2011). They are also associated with overexpression of several developmental genes: H19, DACT2, COL1A1, COL2A1, and IGF2BP3 (Kleinschmidt-DeMasters et al. 2015). A representative histopathologic section from a PMA is shown in Figs. 2.4, 2.5 and 2.6.

Histologically, PMA are comprised of monomorphic bipolar tumor cells loosely arranged within a prominent myxoid background. Their monophasic architecture differs from the biphasic pattern seen in PA. Occasionally, tumor cells can be seen clustering around vessels, a feature largely absent in PA (Louis et al. 2007). PMA also lack eosinophilic granular bodies and Rosenthal fibers,

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Fig. 2.3 Histopathological Features of Pilocytic Astrocytoma. a–d Neoplastic cells display long hair-like processes that form a dense network most recognizable on cytologic preparations (a). Numerous Rosenthal fibers can be seen (b) and the cells aggregate to form a “pennies

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on a plate” pattern (c). The neoplastic cells express high levels of GFAP, confirming their astrocytic histogenesis, which can be illustrated with an immunohistochemical preparation (d). (a–c hematoxylin and eosin; d GFAP IHC; scale bars = 50 um)

2.3.3 Subependymal Giant Cell Astrocytoma (SEGA)

Fig. 2.4 Histopathological Features of Pilomyxoid Astrocytoma. The neoplastic astrocytes are embedded within a dense myxoid background. Notably absent are eosinophilic granular bodies and rosenthal fibers, which are more often seen in pilocytic astrocytoma. (Scale bar = 50 um)

On microscopic exam, SEGA are comprised of multiple cell types including bundles of fibrillated spindle cells, large ganglion-like cells, and swollen gemistocytic astrocytes with eosinophilic cytoplasm, usually with prominent T-cell inflammatory infiltrates (Sharma et al. 2004). Immunohistochemical staining is positive for GFAP and S100, particularly in the spindle cell component, reflective of an astrocytic origin. Neuronal markers may also be present; NSE, NF, and synaptophysin-positive staining may be observed in ganglion-like cells (Sharma et al. 2004; Tahiri Elousrouti et al. 2016). Considered WHO grade I lesions, SEGAs are histologically

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Fig. 2.5 Pilomyxoid Astrocytoma. Slices from 14-yearold girl with an optic nerve tumor with pilomyxoid astrocytoma. a Axial T1-weighted pre-contrast and b post-contrast images show a slightly T1-hypointense, contrast-enhancing lesion. c Sagittal post-contrast T1

image shows a homogeneous lesion in the optic region. This tumor is in the classical midline location of PMA. d T2-weighted image shows a homogeneously hyperintense lesion with some surrounding edema

Fig. 2.6 SEGA. Sections from a 7-year-old girl with tuberous sclerosis and subependymal giant cell astrocytoma. a Axial T1-weighted contrast-enhanced images show a well-circumscribed, contrast-enhancing masses in the subependymal space of the right lateral ventricle. This patient has bilateral SEGA, which is often seen in

tuberous sclerosis. b These lesions are hyperintense on T2-weighted sequences. Also, notable are several other T1-hypointense, T2-hyperintense, non-enhancing lesions throughout the hemispheric subcortical spaces, consistent with tubers, also common in patients with TSC

benign and do not undergo malignant transformation (Moavero et al. 2011). The histopathological features of SEGA are shown in Figs. 2.7, 2.8 and 2.9.

2.3.4 Subependymoma (SE) SE are grossly white, rubbery, hypovascular lesions that are well demarcated from surrounding

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Fig. 2.7 Histopathological features of subependymal giant cell astrocytoma. a These tumor cells are large and polygonal, and their abundant pink cytoplasm is reminiscent of gemistocytic astrocytes while their nuclear

features, such as vesicular chromatin with prominent nuclei, are reminiscent of neurocytic differentiation. b An immunoperoxidase preparation for TTF1 shows diffuse staining in the neoplastic nuclei. (Scale bar = 50 um)

Fig. 2.8 Subependymoma. Sections from a 57-year-old man with Subependymoma. Contrast-enhanced T1weighted axial (a), sagittal (b), and coronal (c) slices

show a heterogeneously enhancing mass within the fourth ventricle, a common location for these tumors

tissue. Microscopically, they are comprised of hypocellular clusters of cytologically bland tumor cells within a dense fibrillary glial background (Ragel et al. 2006). An appreciable portion of SE demonstrates a mixed histology, containing distinct regions of ependymoma or astrocytoma pathology (Bi et al. 2015; Rushing et al. 2007). Lesions are histologically benign and designated as WHO grade I tumors. Mitoses are generally absent as are features such as nuclear pleomorphism, necrosis, or infiltration (Ragel et al. 2006). They are generally positive for GFAP on IHC, with variable staining for synaptophysin,

vimentin, S100, olig2, NHERF1, and CD44 (Bi et al. 2015; D'Amico et al. 2017).

2.3.5 Angiocentric Glioma Angiocentric gliomas are WHO grade I tumors with an excellent prognosis. Surgical resection is often curative, with complete seizure freedom in nearly all patients treated with GTR. Angiocentric gliomas receive their name from a uniquely perivascular ultrastructure characterized by accumulation of neoplastic cells with

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Fig. 2.9 Ganglioglioma. Slices from a 20-year-old woman with ganglioglioma. a Axial T1-weighted contrast-enhanced image reveals a contrast-enhancing

nodule with several associated cysts. T2-FLAIR sequences, b show minimal peritumoral edema

circumferential, radial, or longitudinal alignment around both large and small vessels (LellouchTubiana et al. 2005; Shakur et al. 2009; Wang et al. 2005). Neoplastic cells also classically aggregate in the subpial spaces and can be seen diffusely infiltrating cortical tissue (Marburger and Prayson 2011; Shakur et al. 2009; Wang et al. 2005). Notably absent from all tumors are histologic features common to other low-grade gliomas including Rosenthal fibers and eosinophilic granular bodies (Mott et al. 2010; Wang et al. 2005). Neoplastic cells are monomorphic, uniform bipolar slender cells with elongated nuclei that are positive for GFAP, vimentin, and S100 protein, as well as for EMA in a dot-like pattern (Cheng et al. 2015; Lellouch-Tubiana et al. 2005; Marburger and Prayson 2011; Mott et al. 2010; Wang et al. 2005). On a molecular level, tumorigenesis is linked to MYB-QKI rearrangement through established mechanisms including disruption of the QKI tumor suppressor, activation of the MYB oncogene, or aberrant expression of an MYB-QKI fusion oncogene (Bandopadhayay et al. 2016; Lian et al. 2020).

2.3.6 Ganglioglioma Tumors are defined histologically by the presence of two main components, dysmorphic ganglion cells and neoplastic glial cells. Tumors exhibit mild nuclear pleomorphism and frequently contain eosinophilic granular bodies or Rosenthal fibers and extensive microscopic calcifications (Kakkar et al. 2017; Pekmezci et al. 2018). On IHC, they are positive for GFAP within the glial component and chromogranin, synaptophysin, and NeuN in the neuronal component (Kakkar et al. 2017). GG is associated with genetic mutations that lead to constitutive activation of the MAPK signaling pathway (Pekmezci et al. 2018). In particular, GG is linked with the BRAF V600E mutation (Kakkar et al. 2017; Qi et al. 2018). The vast majority of lesions are designated as WHO grade I, although a grade III anaplastic variant also exists (Kakkar et al. 2017). Anaplastic gangliogliomas represent 1–5% of all gangliogliomas and are associated with poor tumor control and shorter overall survival; recurrent tumors are often treated with

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Fig. 2.10 Histopathological Features of Ganglioglioma. a, b These glioneuronal tumors are characterized by both atypical glial cells as well as dysplasticappearing gangliocytic cells (a), the latter of which display centrally placed and prominent nucleoli (b). c, d Based on immunohistochemical preparations, the dysplastic neurons may express chromogranin (c), while

GFAP expression highlights the fibrillary glial component. e Expression of CD34 highlights bushy-type astrocytic processes as well as a subset of the dysplastic neurons. f These tumors typically harbor BRAF V600E mutation which can be detected by immunohistochemistry using a mutant-specific antibody. (Scale bar = 50 um)

repeat resection in combination with adjuvant therapy, though ultimately tend to be fatal (Lucas et al. 2015). Typical histopathological features of GG are shown in Figs. 2.10 and 2.11.

reactivity to S100 protein or synaptophysin (Yao et al. 2020). The differential diagnosis for CG includes suprasellar lesions and those classically arising in the anterior third ventricle. Avid staining for GFAP differentiates CG from chordomas and other third ventricular masses that are not glial in origin, such as meningiomas. Positive CD34 also helps to distinguish CG from chordoid meningioma, pilocytic astrocytoma, and ependymomas (Morais et al. 2015). Chordoid gliomas tend to have a fairly classic radiographic appearance as well. They appear as wellcircumscribed ovoid lesions within the anterior third ventricle, with variable suprasellar extension. On MRI, CG is homogeneously enhancing, isointense on T1, and slightly hyperintense on T2-weighted sequences. They are hyperdense on

2.3.7 Chordoid Glioma (CG) CG has a fairly uniform histologic appearance. Tumors are comprised of clusters of eosinophilic epithelioid cells embedded in a vacuolated, mucinous matrix with prominent lymphoplasmacytic infiltrates. CG lacks features such as frequent mitoses, necrosis, or microvascular proliferation. On immunohistochemistry, tumors are diffusely positive for GFAP, vimentin, EMA, CD34, and cytokeratin without significant

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Fig. 2.11 Pleomorphic Xanthoastrocytoma. Slices from a 27-year-old man with pleomorphic Xanthoastrocytoma. a Axial T1-weighted contrast-enhanced images show a heterogeneously contrast-enhancing lesion with cystic components in the anterior left temporal lobe. PXA is

classically a cortical-based lesion. The T2-FLAIR b signal is also heterogeneous, with both hyperintense and isointense regions, c the lesion does not diffusion restrict, typical for low-grade astrocytomas, though DWI + areas may be seen in anaplastic tumors

CT and usually solid but may have a mixed solid-cystic composition, at times with calcifications (Morais et al. 2015).

dense reticulin network (Giannini et al. 1999; Schindler et al. 2011). Increased mitotic activity and foci of necrosis are present in a small proportion of lesions, usually recurrent tumors (Giannini et al. 1999) or those undergoing anaplastic transformation (Korshunov and Golanov 2001). Grade III anaplastic tumors exhibit more malignant features such as an elevated mitotic index (greater than 5 mitoses per 10 highpower field), epithelial metaplasia, and foci of necrosis (Korshunov and Golanov 2001; Louis 2016; Marucci and Morandi 2011). These lesions notably retain a typical PXA architecture, which differentiates them from other high-grade astrocytomas such as GBM, which exhibits a characteristic pseudopalisading appearance with microvascular proliferation (Korshunov and Golanov 2001). Figure 2.12 shows the histopathological findings typical of PXA.

2.3.8 Pleomorphic Xanthoastrocytoma (PXA) On gross inspection, tumors contain variable proportions of solid and cystic components, with approximately half of lesions being predominantly cystic (Giannini et al. 1999). PXA are moderately cellular tumors that, true to their name, exhibit characteristic cellular and nuclear pleomorphism. They are comprised of a variety of bizarre pleomorphic cells including spindleshaped tumor cells with elongated nuclei, large round multinucleated giant cells, and enlarged xanthomatous cells containing prominent cytoplasmic lipid droplets, with scattered foci of lymphocytic infiltration (Giannini et al. 1999; Korshunov and Golanov 2001). Tumor cells have eosinophilic cytoplasm with variable amounts of hyaline and lipid droplets and are variably positive for GFAP on immunohistochemistry (Giannini et al. 1999; Korshunov and Golanov 2001). Other features such as eosinophilic granular bodies and Rosenthal fibers may be seen as well (Giannini et al. 1999; Schindler et al. 2011). Lesions characteristically have a

2.3.9 Diffuse Low-Grade Glioma On gross inspection, diffuse gliomas appear as soft, gray masses; the presence of calcification may confer a gritty texture. Microscopically, lesions have infiltrating margins, which is a defining feature of diffuse low-grade glioma (Louis 2016). Designated as WHO grade II, these tumors are well differentiated and lack histologic

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Fig. 2.12 Histopathological Features of Pleomorphic Xanthoastrocytoma. The neoplastic astrocytes of PXA can display bizarre nuclear pleomorphism that can be mistaken for overt malignancy; however, mitotic activity in these tumors is typically low (a). A subset of cells displays vacuolated cytoplasm with a foamy,

xanthomatous appearance (a, inset). While staining for GFAP shows diffuse positivity (b) consistent with an astrocytic origin, the tumor cells can also express neuronal markers (not shown) suggestive of neurocytic/mixed glioneuronal differentiation. (Scale bar = 50 um)

features such as high mitotic activity or cellular anaplasia (WHO grade III) and microvascular proliferation or necrosis (WHO grade IV) (Louis et al. 2020). Although characterization based on histologic features has been supplanted by the use of a molecular classification scheme, histology may still be of use in making the broader diagnosis of diffuse low-grade glioma. Oligodendrogliomas classically are comprised of uniform, rounded nuclear with perinuclear halo giving a “fried-egg” appearance on processed sections; these are highly vascular tumors that exhibit a characteristic “chicken-wire” vascular appearance. These features are notably absent in astrocytoma, which are comprised of neoplastic cells with irregular nuclei and prominent fibrillary processes (Sepulveda-Sanchez et al. 2018). The typical histopathological features of diffuse oligodendroglioma are shown in Fig. 2.15, and those of diffuse astrocytoma are shown in Fig. 2.16.

imaging (MRI) is the ultimate imaging modality of choice for characterization of glioma, both benign and malignant, and can be used to differentiate between the two. Benign glioma can be broadly sorted into one of two categories based on imaging appearance. Focal gliomas are welldemarcated, often cystic lesions that have clear radiographic borders and tend to displace, rather than invade, surrounding parenchyma. The classical example is pilocytic astrocytoma. The second category includes white matter lesions with a more infiltrative growth pattern, namely diffuse astrocytomas and oligodendrogliomas. Characteristic radiographic features of these lesions on MRI are illustrated in Fig. 2.1. Focal gliomas grossly appear as welldemarcated cystic lesions, often with a nodular enhancing component. On CT, lesions are generally hypodense. On MRI, they tend to be hypointense on T1 and hyperintense on T2weighted images. Contrast enhancement may be present, particularly of the nodular component of the tumor (Lee et al. 1989). In contrast, diffusely infiltrating gliomas have poorly defined borders. The size and anatomical boundaries of diffuse low-grade gliomas are typically best estimated by the extent of T2/FLAIR hyperintense signal. MRI typically shows that these intra-axial lesions are centered

2.4

Imaging and Radiologic Features

In most cases, the first screening image obtained is a non-contrast computed tomography (CT) scan. However, magnetic resonance

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on white matter tracts, differentiating them from other primary cortical-based brain tumors (DNET, metastases). Classically, lesions appear hypointense to isointense on MR T1-weighted images, appear hyperintense on T2-weighted images, and generally do not significantly enhance with administration of gadolinium-based contrast. They are typically iso to hypodense and may have prominent calcifications on CT (Castillo et al. 1992). Metabolically active regions are typically confined to FLAIR-positive areas, but notably can extend outside these margins (Pirzkall et al. 2002). Although not routinely ordered, taskbased blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) studies can be performed to assess tumor proximity to eloquent areas of cortical function, such as the motor and language areas. Additionally, resting-state BOLD fMRI signal correlates with tumor burden in benign and malignant glioma (Bowden et al. 2018). This can aid in surgical planning by correlating anatomical and structural relationships with underlying function, helping to define surgical goals and boundaries. For T2/FLAIR hyperintense lesions, the apparent diffusion coefficient (ADC) can be used to differentiate benign gliomas that exhibit T2 hyperintensity from highgrade gliomas, which typically have lower ADC values suggesting higher tumor density with diffusion restriction (Wang et al. 2020). Assessment of cerebral blood volume (CBV) is another parameter that can be directly correlated with malignancy and can reliably predict tumor grade. This can also be used to monitor response to treatment, differentiating treatment effects from recurrent tumor or malignant transformation (Caseiras et al. 2010). Advanced imaging can also be of diagnostic use in benign glioma. On MR spectroscopy, both groups of benign gliomas generally exhibit decreased N-acetyl aspartate (NAA) and creatine (Cr), and elevated choline (Cho). An elevated ratio of Cho to NAA and Cr reflects a more rapid cell turnover and increases with higher tumor grades (Porto et al. 2011).

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2.4.1 Pilocytic Astrocytoma (PA) Radiographically, the classic appearance of pilocytic astrocytoma is a well-circumscribed cystic lesion with an enhancing mural nodule arising within the lateral cerebellum. The cystic fluid tends to be iso to hypodense on CT, iso to hypointense on T1 and hyperintense on T2weighted images and does not enhance with administration of contrast. Examples of the radiographic features of PA are shown in Fig. 2.2. Lesions demonstrate increased diffusion (ADC bright and DWI dark) (Bornhorst et al. 2016). These features distinguish them from higher-grade tumors that tend to be hypercellular and diffusion restricting, such as high-grade astrocytomas and medulloblastomas (Wang et al. 2018b). Optic pathway gliomas appear as enhancing fusiform lesions growing along and enlarging the optic nerve or chiasm (Collins et al. 2015). Less commonly, PA arise as brainstem lesions with dorsally exophytic growth into the fourth ventricle; this contrasts against high-grade brainstem gliomas that exhibit a diffusely infiltrative, expansile growth pattern, primarily affecting the pons (Collins et al. 2015).

2.4.2 Pilomyxoid Astrocytoma (PMA) Radiographically, PMA are well-circumscribed lesions that tend to be isointense on T1-weighted sequences and homogeneously enhance with contrast administration. Similar to PA, they have well-defined margins that lack parenchymal infiltration and rarely are associated with any peritumoral edema. In contrast to PA, the majority of PMA are solid (84.6%) with a minority containing a minimal cystic component (Komotar et al. 2004b). Also contrasting with the primarily posterior fossa location of PA, PMA tend to arise from midline structures and are more commonly seen in the hypothalamic/chiasmatic region (76.9%) (Komotar et al. 2004b). Common radiographic features of PMA are shown in Fig. 2.5.

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2.4.3 Subependymal Giant Cell Astrocytoma (SEGA) SEGA are large (> 10 mm), well-circumscribed, intraventricular lesions that classically arise at the caudothalamic groove (Chan et al. 2020). Radiographically, they are isodense on CT, hypo to isointense on T1, hyperintense on T2weighted sequences, and avidly contrast enhancing. Due to their location near the Foramen of Monro, SEGA may block the flow of CSF, leading to the development of obstructive hydrocephalus (Adriaensen et al. 2009; Sharma et al. 2004). Typical radiographic features of SEGA are shown in Fig. 2.6.

2.4.4 Subependymoma (SE) Radiographically, SE are well-defined, lobulated, or nodular tumors that demonstrate frequent cystic degeneration (Bi et al. 2015). There is radiographic evidence of hydrocephalus in at least half of patients (Jain et al. 2012; Nguyen et al. 2017). On CT, lesions are isodense to hypodense and do not contain prominent calcifications (Hou et al. 2013; Ragel et al. 2006). On MRI, lesions are hypointense to isointense on T1 and hyperintense on T2-sequences. Differentiating them from other ventricular lesions, particularly ependymomas, SE exhibit little to no enhancement with administration of contrast. Peritumoral edema is infrequent (Hou et al. 2013; Ragel et al. 2006). Representative radiographic images of SE are shown in Fig. 2.8.

2.4.5 Angiocentric Glioma Angiocentric gliomas are radiographically wellcircumscribed lesions that are hypodense on CT. The majority (> 90%) are predominantly solid, although a small proportion contain a prominent cystic component (Cheng et al. 2015). On MRI, lesions are T2-hyperintense and generally do not enhance with administration of contrast; some series describe a rim of cortical hyperintensity on T1-weighted images, though this is not present in

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all tumors (Cheng et al. 2015; Koral et al. 2012; Lellouch-Tubiana et al. 2005; Takada et al. 2011).

2.4.6 Ganglioglioma GG is generally well-defined lesions that is hypodense on CT scans and often demonstrates prominent calcifications (Compton et al. 2012). On MR, lesions tend to be isointense on T1 and hyperintense on T2-weighted sequences, with variable enhancement, usually of a peripheral nodule (Compton et al. 2012). Radiographic features of GG are shown in Fig. 2.9.

2.4.7 Pleomorphic Xanthoastrocytoma (PXA) Radiographically, PXA are well-defined masses that tend to be located superficially within the cerebral hemispheres, often with reactive leptomeningeal involvement (Korshunov and Golanov 2001). Lesions contain solid and cystic components. On CT, the solid component is of variable density and may contain foci of calcification; the cystic component tends to be homogeneously isodense. MR images demonstrate T1isointense and T2-hyperintense solid components that heterogeneously enhance with administration of contrast. A thin peripheral rim of enhancement is often present around the cystic component. There may be associated vasogenic edema or localized enhancement of the leptomeninges (Shaikh et al. 2019). PXA are hypovascular tumors, with decreased perfusion on SPECT imaging and minimal tumor-associated vasculature on angiography (Shaikh et al. 2019). The common radiographic features of PXA are shown in Fig. 2.11. The most recent WHO classification system allows categorization of PXA into grade II or grade III lesions, with the majority being WHO grade II (Gallo et al. 2013; Perkins et al. 2012). A small proportion of more histologically malignant appearing lesions receive a WHO grade III anaplastic (aPXA) designation (Gallo et al. 2013; Perkins et al. 2012). Anaplastic lesions may appear radiographically

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similar to other high-grade astrocytomas. These lesions tend to be larger, with more prominent contrast enhancement and peritumoral edema, and may demonstrate diffusion restriction (She et al. 2018).

2.4.8 Diffuse Low-Grade Glioma Classically, oligodendrogliomas are cortically based tumors. In contrast, astrocytomas tend to arise deep within the white matter, though with tumor growth may involve superficial structures as well (Sepulveda-Sanchez et al. 2018). Radiographically, diffuse LGG is hypodense to isodense on CT, although they may show hyper-density in some areas as a result of calcification, a feature particularly common in oligodendrogliomas (Sepulveda-Sanchez et al. 2018). On MRI, lesions are generally homogeneously hypointense on T1 and hyperintense on T2/FLAIR sequences. In contrast to focal gliomas, the borders of these tumors are less well defined and tumor margins are often defined by the extent of T2/FLAIR signal. Although classically non-enhancing, * 40% of tumors exhibit some degree of contrast enhancement (44%), though to a lesser degree than what is seen with grade III (84%) or IV lesions; a lack of contrast enhancement in diffuse glioma has been suggested as a positive predictor for PFS (Zhou et al. 2017). Perfusion imaging demonstrates lower relative cerebral blood volume (rCBV), indicative of lower tumor microvascularity seen with less aggressive tumors. In contrast to highergrade glioma, diffuse astrocytomas are typically non-enhancing and show less diffusion restriction due to their low cellularity (Sepulveda-Sanchez et al. 2018). Representative radiographic images for diffuse oligodendroglioma and diffuse astrocytoma are shown in Figs. 2.13 and 2.14, respectively (Figs. 2.15 and 2.16).

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for other reasons (Potts et al. 2012). Seizures are the most common presenting symptom for lowgrade glioma and are reported in as many of 90% of cases (Pallud et al. 2014). Commonly associated tumors are diffuse glioma, ganglioglioma, angiocentric glioma, as well as dysembryoplastic neuroepithelial tumors (DNET) (Erturk Cetin et al. 2017; Qi et al. 2018; Slegers and Blumcke 2020). These lesions have a predilection for the temporal lobes and are often associated with focal cortical dysplasia (Qi et al. 2018). Tumor-related seizures tend to be refractory to pharmacologic intervention, and an appreciable portion of these patients already have medication-refractory seizures at the time of surgery. Symptomatic lesions also tend to present with deficits related to tumor location or with signs or symptoms of elevated intracranial pressure (headache, nausea/vomiting, altered mental status) secondary to tumor enlargement or obstruction of CSF pathways. Patients with supratentorial tumors may present with motor weakness, abnormal sensation, personality changes or executive dysfunction. Optic pathway lesions present with visual field deficits or loss of visual acuity. Tumors involving the hypothalamus or other midline structures may present with endocrine abnormalities including diabetes insipidus or syndrome of inappropriate antidiuretic hormone (SIADH), precocious puberty or menstrual irregularities, or electrolyte imbalances. Cranial nerve palsies may be seen with skull base or infratentorial tumors. Posterior fossa lesions classically cause cerebellar dysfunction, and patients experience ataxia and issues with balance or gait. (Perkins and Liu 2016). Progressive lesion enlargement may also lead to 4th ventricular effacement and presentation with acute obstructive hydrocephalus (O'Brien et al. 2001).

2.5.1 Pilomyxoid Astrocytoma (PMA)

2.5

Clinical Manifestations

Benign gliomas are slow-growing lesions that tend to present insidiously and are often discovered as incidental findings on imaging obtained

Patients with PMA most commonly present with symptoms such as generalized weakness, feeding difficulties or failure to thrive, developmental delay, altered mental status, or signs and symptoms of elevated ICP (Komotar et al. 2004a).

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a

b

c

d

e

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Fig. 2.13 WHO grade II diffuse oligodendroglioma. Slices from a 27-year-old man with a diffuse oligodendroglioma. a Non-contrast head CT shows a large, hypodense lesion in the left frontal insular region with focal calcification. T1-weighted pre-contrast (b) and post-contrast (c) axial slices show a hypointense

lesion. d T2-FLAIR axial slice showing a hyperintensity extending into left insula, basal ganglia, and anterior temporal pole. This is a typical location and appearance of diffuse low-grade glioma. e A focus of calcification is again noted. f DWI slice shows minimal restriction

Fig. 2.14 WHO grade II diffuse astrocytoma. Slices from a 49-year-old woman with diffuse astrocytoma. Axial T1-weighted pre-contrast (a) and post-contrast (b) show a T1-hypointense, non-enhancing lesion in the left insular region. The lesion is hyperintense on T2 (c), as is typically seen in diffuse low-grade gliomas. This lesion does not diffusion restrict on DWI (d). The patient’s

tumor eventually recurred (e). The recurrent tumor was found to be heterogeneously contrast-enhancing with a cystic component on T1-weighted images. These features are consistent with progression of this low-grade glioma into a high-grade glioma. At the subsequent resection, the lesion was determined to be grade III on histologic analysis

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Fig. 2.15 Histopathological features of oligodendroglioma. a, b Hypercellular brain tissue involved by neoplastic oligodendrocytes diffusely infiltrating cortex (a). At high power, the nuclei are relatively round and monotonous, and the typical perinuclear halos which produce a fried-egg appearance can be recognized. These tumor cells highly express Olig-2, a nuclear transcription factor, which confirms their glial histogenesis. c, d Similar to their astrocytic counterparts, these tumors typically harbor a IDH1 or IDH2 mutation, and the IDH1 R132H

mutant-specific antibody can be used for immunohistochemical detection of this oncoprotein. e Compared to diffuse astrocytic neoplasm, however, oligodendrogliomas retain their expression of ATRX which can be assessed by immunohistochemistry (Scale bar = 50 um). f These tumors can also upregulate PDGFR-A which can be detected by an immunohistochemical stain that shows strong membranous staining with a relative paucity of cytoplasmic processes that would be more prominent in astrocytic tumors. (Scale bar = 50 um)

2.5.2 Subependymal Giant Cell Astrocytoma (SEGA)

2.5.3 Chordoid Glioma (CG)

SEGA is usually diagnosed in children or young adults, with mean age at diagnosis of 8 years. Symptomatic lesions may present with behavioral or cognitive changes, visual deficits, seizures, and signs or symptoms of elevated intracranial pressure (Jansen et al. 2019). However, more often, patients are asymptomatic at the time of diagnosis and lesions are detected radiographically on routine surveillance scans (Jansen et al. 2019; Jozwiak et al. 2015).

CG is classically diagnosed in middle age, affecting women twice as often as men (Morais et al. 2015). Patients may present with symptoms of elevated ICP (headache, nausea, vomiting, altered mental status) from the development of obstructive hydrocephalus, visual deficits from optic pathway compression, endocrine abnormalities from hypothalamic compression (amenorrhea, diabetes insipidus, hypothyroidism), memory deficits (forniceal involvement), and other cognitive or behavioral changes (Zhang

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Fig. 2.16 Histopathological features of diffuse astrocytoma. a, b Hypercellular brain tissue involved by neoplastic astrocytes diffusely infiltrating cortex (a). At high power, the large and angulated nuclear contours of the neoplastic astrocytes can be better assessed (b). c These tumors typically harbor an IDH1 or IDH2

mutation, and the most common mutant can be detected by immunohistochemistry using an IDH1 R132H mutantspecific antibody. d Compared to oligodendrogliomas, diffuse IDH-mutant astrocytomas typically lack ATRX expression which can be assessed by immunohistochemistry as well. (Scale bar = 50 um)

et al. 2020). Symptom duration tends to be subacute to chronic, with mean time from symptom onset to surgical intervention * 22 months (Ampie et al. 2015; Vanhauwaert et al. 2008).

can guide subsequent therapy. In most cases, surgical resection is performed with the goal of complete lesion removal. For focal glioma, a gross total resection (GTR) has potential to be curative; even for diffuse glioma, numerous studies have established clear benefits to lesion resection. Ultimately, the surgeon must weigh the risks of surgical morbidity against the severity of the patient’s current symptoms and long-term risk of progression, morbidity, and mortality. Risk of recurrence or malignant transformation should individually inform treatment paradigms and frequency of follow-up. No clear data exists on how often a benign glioma should be imaged in patients managed with active surveillance only. In the pediatric population, there is data supporting imaging

2.6

Therapeutic Approaches

With evolving understanding of the natural history, progression, and transformation of benign glioma, the approach to management of these lesions is becoming less generic and increasingly personalized and subtype-specific. However, common across all subtypes is the crucial role of surgical intervention in the diagnostic and treatment paradigm. At the minimum, surgery provides a tissue sample for histologic diagnosis that

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surveillance at 0, 3, 6, 12, 24, 36, 60, and 72 months post-operatively (Zaazoue et al. 2020).

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absence of functional TSC1 or TSC2 tumor suppressors, radiation therapy increases risk for secondary malignant glial neoplasms (Matsumura et al. 1998).

2.6.1 Observation 2.6.2 Surgical Intervention Given the slow growth and benign clinical course of grade I tumors, these lesions may be managed non-operatively. In some cases, the surgeon may feel confident in selecting this approach based on the lesion’s appearance on imaging studies alone (Nguyen et al. 2017). However, if the underlying diagnosis is unclear, a biopsy is usually performed given the crucial role of histology in prognostication and predicting the risk of malignant transformation. Even without biopsyconfirmed diagnosis, lesions that may be considered for observation include asymptomatic, small lesions that have been stable on repeat imaging studies, particularly those in deep or eloquent locations that are relatively inaccessible due to an unacceptably high risk of surgical morbidity. These lesions may be managed expectantly with radiographic surveillance. Interval growth or change in lesion characteristics such as emergence of new focus of enhancement in presumed low-grade lesions may prompt a change in management strategy and force the surgeon’s hand toward operative intervention, as these features may indicate malignant transformation. In SEGA, conservative management with radiographic surveillance may be appropriate for asymptomatic patients without any signs or symptoms of elevated ICP. For these patients, interval MRI scans should be performed every 3– 6 months (Goh et al. 2004). For symptomatic tumors or those with radiographic evidence of growth or hydrocephalus, the two main treatment options are either operative, either with surgical resection or CSF diversion, and pharmacologic, with mechanistic target of rapamycin (mTOR inhibitors) (Ebrahimi-Fakhari and Franz 2020). Radiation is not typically employed in routine treatment of these lesions (Nguyen et al. 2018). In fact, concerns have been raised that in the

2.6.2.1 Biopsy Operative biopsy provides tumor tissue to confirm the diagnosis of low-grade glioma and rule out underlying high-grade malignancy, infection, gliosis, or other dysplasia. The gold standard for histologic diagnosis is with operative specimen obtained via open surgical resection. Current recommendations are to consider the use of preoperative imaging including advanced imaging techniques (perfusion, spectroscopy, metabolic studies) to target areas of highest interest for biopsy (Ragel et al. 2015). Sampling of the bulk tumor mass, particularly of any enhancing areas (as these may represent foci of malignant transformation), is considered highest yield. Stereotactic biopsy alone may be performed to obtain histologic diagnosis to guide adjuvant treatment for patients in whom surgical resection is not possible or deemed too risky, for example, in cases of deep-seated lesions or those within eloquent cortex, or for patients who are very medically sick (Ragel et al. 2015). The introduction of image-guided localization has made targeted lesional biopsies extremely safe and effective; however, one notable risk of stereotactic biopsy is inadequate tumor sampling yielding an inconclusive diagnosis. This may be particularly important in heterogeneous gliomas or diffuse lesions (Jackson et al. 2001). In one series, 29% of patients had a different tissue diagnosis at resection when compared with biopsy (Woodworth et al. 2005). Review of techniques reveals similar diagnostic yield and procedural morbidity / mortality for frameless and frame-based procedures (Ragel et al. 2015). Risks associated with biopsy are minimal and typically restricted to bleeding (4.8%); permanent neurological deficit is rare (1.5%) (Kongkham et al. 2008).

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2.6.2.2 Surgical Resection Surgical resection is the primary definitive treatment for low-grade glioma, both for primary lesions and in cases of recurrence (Bowers et al. 2001; Uppstrom et al. 2016). The goals of surgery may include establishing a histologic diagnosis, alleviating symptomatic compression of neural structures, or removing lesions that may have inherent potential for malignant transformation. In cases of elevated ICP, lesion removal or tumor debulking may relieve compression and restore normal CSF flow; this is particularly important for intraventricular tumors or those causing obstructive hydrocephalus (Hou et al. 2013). Open surgical resection also provides access to a larger bulk of tumor tissue, decreasing the likelihood of sampling error and leading to a more accurate histopathologic diagnosis and tumor phenotyping. Evidence favors early timing for surgical resection over biopsy or expectant management (Jakola et al. 2012). For all types of benign glioma, extent of resection correlates with outcome and a gross total resection (GTR) should be performed when possible (Choi et al. 2020). For localized grade I tumors, complete resection may be curative (Ogiwara et al. 2012). Superior outcomes are seen in patients who undergo a gross total resection (GTR) as compared to subtotal resection (STR) or biopsy alone; extent of resection is strongly associated with low rates of recurrence and high rates of symptomatic improvement and seizure control (Aghi et al. 2015; Chang et al. 2008; Wang et al. 2018a; Xia et al. 2018). Specifically, resection of more than 80% of the FLAIR-positive tumor mass is associated with seizure freedom in low-grade glioma (Xu et al. 2018). Some studies have also suggested that an extent of resection higher than 90% may confer an added survival benefit, supporting the recommendation for a “supra-total” resection that includes all FLAIR abnormality in low-grade gliomas (Smith et al. 2008). Surgical resection should attempt maximal tumor removal, however keeping in mind the potential risk of incurred deficits, which complicate anywhere from 2.9 to 20.8% of procedures (Jackson et al. 2016).

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Surgical Resection for Pilocytic Astrocytoma PAs are WHO grade I tumors and have a relatively benign clinical course. They are slowgrowing tumors that do not metastasize and notably do not carry the risk of transformation to higher-grade lesions seen with many other lowgrade gliomas. Standard treatment for PA is with surgical resection, particularly of the enhancing mural nodule. Extent of resection is particularly important with these tumors, as a gross total resection is often curative and subtotal resection is the most significant predictor of recurrence (Ogiwara et al. 2012). Surgical Resection for Pilomyxoid Astrocytoma (PMA) PMA is treated in a similar manner to other primary astrocytic tumors, with maximal safe surgical resection, particularly for enlarging or symptomatic lesions (Komotar et al. 2004a). However, as is the case of most tumors involving optic/hypothalamic structures, the morbidity associated with surgery in this region often precludes a GTR. In particular, there is concern for damage to the pituitary gland, optic apparatus, hypothalamus, and carotid arteries (Komotar et al. 2004a). As such, patients commonly undergo subtotal resection and receive some form of adjuvant treatment, chemotherapy or radiation (Komotar et al. 2004a; Shoji et al. 2020). Case reports have also suggested that these tumors can respond to vemurafenib, likely due to their association with BRAF alterations (Skrypek et al. 2014). Surgical Resection for Subependymal Giant Cell Astrocytoma (SEGA) Surgery is indicated in the setting of acutely symptomatic lesions and may also be considered for asymptomatic patients with documented interval tumor growth or the development of ventriculomegaly (Jansen et al. 2019; Jozwiak et al. 2013). Post-operative complications include hydrocephalus requiring CSF diversion, hemorrhage, infection, and persistent neurologic deficits may occur and must be considered when weighing risks and benefits of management strategies. Greater surgical morbidity and higher

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rates of complication have been associated with larger lesions (> 2 cm), bilateral tumors, in children younger than 3 years of age (Kotulska et al. 2014). Surgical Resection for Subependymoma (SE) Traditionally, SEs are either managed with observation and radiographic surveillance, or with surgical resection (Nguyen et al. 2017; Ragel et al. 2006). Conservative management is appropriate for asymptomatic lesions with a reassuring radiographic appearance that is classical for SE (Nguyen et al. 2017). Surgery may be performed to establish definitive histologic diagnosis, alleviate symptomatic compression of neural structures, or restore CSF flow (Nguyen et al. 2017; Ragel et al. 2006). The major cause of morbidity in patients with SE is hydrocephalus, which is the primary indication for surgical intervention in many cases (Hou et al. 2013). Given a greater potential to lead to obstructive hydrocephalus with tumor growth, surgery may also be recommended for 4th ventricular lesions even if asymptomatic (Jain et al. 2012). In patients with hydrocephalus, temporary CSF diversion with intra-operative ventricular catheter may be employed; however, the majority of patients do not require permanent CSF diversion, indicating that tumor resection is sufficient to restore CSF flow (Jain et al. 2012). SE has a relatively indolent course. Resection tends to be curative, and even in cases of STR, long-term survival without symptomatic tumor recurrence can be expected (Bi et al. 2015; Jain et al. 2012; Ragel et al. 2006; Varma et al. 2018; Vitanovics et al. 2014). Recurrence is extremely rare and has been associated with subtotal tumor resection (Rushing et al. 2007). Some studies have shown improved outcomes with GTR; however, even in cases of subtotal resection, outcomes are excellent (Nguyen et al. 2017; Ragel et al. 2006). As a result, surgical resection is typically performed without any adjuvant therapy and conservative management is generally employed even after STR in follow-up (Jain et al. 2012). Rarely, radiation is employed postoperatively in cases of STR or mixed tumor histology; however, it has not been shown to be

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associated with effect on outcomes (Bi et al. 2015; Nguyen et al. 2017). Surgical Resection for Angiocentric Glioma Angiocentric gliomas are treated with surgical resection with the primary goal of achieving seizure control. Post-operative seizure freedom is achieved in over 90% of patients undergoing GTR (Alexandru et al. 2013; Cheng et al. 2015; Fulton et al. 2009; Koral et al. 2012; Marburger and Prayson 2011; Preusser et al. 2007). Early studies noted an association between angiocentric glioma and the presence of adjacent cortical abnormalities on MR imaging (Lellouch-Tubiana et al. 2005). Intra-operative electrocorticography has provided valuable information regarding seizure localization, often revealing epileptogenic foci extending beyond lesional tissue into neighboring cortical areas of dysplasia (Chen et al. 2014; Marburger and Prayson 2011; Takada et al. 2011). Extended cortical resections may be performed in these cases, with successful control of seizures (Takada et al. 2011). Seizure control after STR is less common, with roughly half of patients experiencing seizure recurrence (Cheng et al. 2015; Gonzalez-Quarante et al. 2017; Koral et al. 2012; Shakur et al. 2009). The addition of radiotherapy has been reported in several cases after biopsy of lesions that were not amenable to resection (e.g., due to proximity to motor areas) with improved seizure control (Cheng et al. 2015; Mott et al. 2010; Shakur et al. 2009). Recurrence is extremely rare and associated with tumors with malignant histologic features; adjuvant radiation and chemotherapy have been employed in these cases, though ultimately these lesions have a poor prognosis (Kuncman et al. 2018; Lu et al. 2013; Wang et al. 2005). Surgical Resection for Ganglioglioma GG should be treated surgically whenever possible, and in cases of epilepsy, resection may be performed under electrocorticography-guidance (Kakkar et al. 2017). Seizure control may be achieved with surgical resection, particularly with GTR (Compton et al. 2012; Lundar et al. 2018; Prasad et al. 2016). Given high rates of local tumor control with complete resection

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alone, adjuvant therapy is typically not employed after GTR. Chemotherapy is not generally used for ganglioglioma, but can be considered as salvage therapy on an individual basis (Compton et al. 2012; Lucas et al. 2015). Surgical Resection for Chordoid Glioma (CG) Although designated as a low-grade tumor (WHO grade II), outcomes for these patients have been extremely poor due to high rates of treatment-related morbidity and mortality (Ampie et al. 2015). Subtotally resected tumors frequently recur and may be fatal (Brat et al. 1998; Destefani et al. 2015; Erwood et al. 2017; Jung and Jung 2006). However, complete tumor removal in many cases is not possible due to their anatomic location. Masses are often tightly adherent to the hypothalamus, and their close proximity to critical neural structures increases the risk of post-operative complications (Destefani et al. 2015; Pomper et al. 2001; Raizer et al. 2003; Vanhauwaert et al. 2008). Mortality in the immediate post-operative period has historically been extremely high and is attributed to a variety of non-neurologic complications including pulmonary embolism, pneumonia, sepsis, meningitis, and cardiac arrest (Ampie et al. 2015). The most common non-fatal postoperative complications are endocrinopathies related to hypothalamic dysfunction (Raizer et al. 2003; Vanhauwaert et al. 2008; Yao et al. 2020; Zhang et al. 2020). Other notable sequelae related to surgery include hydrocephalus requiring permanent CSF diversion (Carrasco et al. 2008; Erwood et al. 2017; Jung and Jung 2006; Zhang et al. 2020), seizures, persistent short-term memory deficits (Desouza et al. 2010; Reifenberger et al. 1999; Suetens et al. 2019), infections (pneumonia, sepsis) (Bongetta et al. 2015; Destefani et al. 2015), and a relatively high proportion of thromboembolic events (Ampie et al. 2015; Bongetta et al. 2015; Brat et al. 1998; Cenacchi et al. 2001; Reifenberger et al. 1999; Yao et al. 2020; Zhang et al. 2020). Despite high rates of post-operative complications, surgical resection with complete tumor removal remains the optimal management strategy. Recent studies have shown excellent rates of

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long-term tumor control and freedom from recurrence in patients receiving GTR (Ampie et al. 2015; Raizer et al. 2003; Zhang et al. 2020). Given the significant risks associated with surgery in this area, however, some have advocated for a less invasive approach to treatment when achievement of GTR is not thought to be possible. Partial resection or biopsy followed by stereotactic radiosurgery has been shown to be safe and effective (Chen et al. 2020; Kobayashi et al. 2013; Nakajima et al. 2003; Yang et al. 2017), and gamma knife radiosurgery represents a reasonable treatment modality as an adjunctive therapy after subtotal resection or in otherwise inoperable lesions (Chen et al. 2020). Surgical Resection for Pleomorphic Xanthoastrocytoma (PXA) Standard treatment for PXA is with maximal safe resection (Giannini et al. 1999; Perkins et al. 2012). There is limited data to support the adjuvant use of chemotherapy and radiation (Gallo et al. 2013; Perkins et al. 2012). These modalities are employed on a case-by-case basis, usually after subtotal resection and in higher grade or recurrent tumors as salvage therapy (Giannini et al. 1999; Perkins et al. 2012). Surgical Resection for Diffuse Low-Grade Glioma Recommended treatment for diffuse low-grade glioma is with surgical resection; primary goals of surgery are both to address the underlying lesion and to control seizures. Overall, an aggressive approach to surgical resection is associated with improved survival and recommended for LGG when possible (Smith et al. 2008; Tom et al. 2019). However, even after complete removal, diffuse gliomas have > 50% risk of tumor recurrence after 5 years. In one study of 111 patients who underwent GTR for diffuse WHO grade II astrocytoma or oligodendroglioma, post-operative MRI was used to quantify and correlate radiographic residual disease with risk of recurrence. For MR residual of < 1 cm, 1–2 cm, and > 2 cm, overall recurrence rates were 26%, 68%, and 89%, respectively. Recurrence was also greater for patients

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with astrocytoma histology than oligodendroglioma (54% vs. 32%); when stratified by radiographic residual of < 1 cm, 1–2 cm, and > 2 cm, recurrence rates were 28% versus 23%, 88% versus 43%, and 100% versus 75% for astrocytoma and oligodendroglioma, respectively. Ultimately, this study identified tumor size, histology, and extent of resection as significantly predictive of recurrence. In patients who had all 3 positive factors (< 4 cm pre-op diameter, < 1 cm residual, oligodendroglioma pathology), the 3- and 5-year PFS were 100% and 70%, respectively (Shaw et al. 2008). Recurrent lesions commonly demonstrate evidence of malignant transformation to grade III or IV tumors (Wahl et al. 2017).

2.6.3 Chemotherapy and Radiotherapy 2.6.3.1 Radiation Given the excellent outcomes seen with surgery alone, adjuvant therapy is not commonly employed in the routine treatment of focal glioma, particularly after GTR. The addition of radiotherapy (RT) is recommended in the treatment of certain subgroups of patients that have a higher risk of recurrence or malignant transformation (Ryken et al. 2015). For example, adjuvant RT may be used to improve tumor control after STR, which is one of the most important risk factors for recurrence. This may be particularly important for midline lesions that are less likely to be completely resected, such as pilomyxoid astrocytoma (Komotar et al. 2004a) or chordoid glioma (Ampie et al. 2015). Similarly, for diffusely infiltrative LGG, post-operative radiotherapy has been shown to prolong PFS (van den Bent et al. 2005). The typical dose for these patients is 45–54 Gy in 30 fractions, at 1.8 Gy per fraction. The target area is typically comprised of the resection cavity, surrounding areas of pre-operative FLAIR signal, and an additional 1–2 cm margin (Buckner et al. 2017). Iatrogenic complications from radiation include radionecrosis, neuroendocrine dysfunction, delayed cognitive impairment, and new radiation-

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induced secondary malignancy (Williams et al. 2018). Given the propensity for diffuse low-grade glioma to recur, chemoradiotherapy is frequently utilized as a component of treatment. Lesions are typically treated with 45–54 Gy at 1.8–2 Gy per fraction to the resection cavity and any regions of residual T2/FLAIR hyperintense signal with an additional 1–2 cm margin (Tom et al. 2019). With respect to timing of therapy, immediate post-operative radiation has been shown to prolong progression-free survival (5.3 years vs. 3.4 years for control) in patients with low-grade diffuse gliomas or subtotally resected pilocytic astrocytomas. However, overall survival outcomes were not statistically different from patients in whom RT was deferred until the time of progression (van den Bent et al. 2005). Escalation to higher dose (54–65 Gy) treatment paradigms has not been shown to have a meaningful effect on tumor progression or overall survival outcomes at time point up to 15 years (Breen et al. 2020; Prabhu et al. 2021; Shaw et al. 2002), and some studies have suggested that patients receiving higher dose therapy experience decreased quality of life, with self-reported lower level of functioning and greater presence of treatment-related symptoms (Kiebert et al. 1998). Radiographic abnormalities including parenchymal atrophy and the presence of white matter lesions have been found in patients with LGG who have undergone prior radiation therapy (Postma et al. 2002; Swennen et al. 2004). These findings tend to be more severe and frequent in patients receiving whole brain radiotherapy, particularly in those over the age of 40 (Swennen et al. 2004). Overall recommendations are for lower dose therapy (Ryken et al. 2015).

2.6.3.2 Chemotherapy Chemotherapy may be also employed as an adjunct treatment in high-risk lesions. PCV, a regimen of procarbazine + CCNU + vincristine, has the most clinical support for efficacy in the treatment of LGG. Phase 3 trial data has shown significant survival benefit among high-risk patients with grade II glioma treated with radiation plus PCV chemotherapy, as compared to

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radiation alone. In the landmark clinical trial, RTOG 9802, patients with WHO grade II diffuse glioma at high risk for progression, including those aged > 40 and/or those with STR, were randomized to receive post-operative RT with or without PCV chemotherapy (Buckner et al. 2016; Shaw et al. 2012). Patients receiving radiation alone had a median overall survival of 7.8 years compared to 13.3 years in patients receiving radiation with PCV (van den Bent 2014). Improved outcomes were of greatest significance in patients with oligodendroglioma, as well as all patients with IDH1-R132H-mutated tumors (Bell et al. 2020; Buckner et al. 2016). PCV chemotherapy has been shown to confer significant survival benefit to patients with 1p/19q co-deleted tumors with anaplastic features as well (Cairncross et al. 2014; van den Bent et al. 2013). In these patients, RT + chemotherapy was shown to provide better disease control than either RT or chemo alone, with PCV shown to be more effective than TMZ (Lassman et al. 2011). Although a clear survival benefit has been shown in anaplastic grade III tumors, this has not been proven in grade II tumors. The use of PCV as an adjuvant therapy, however, has been limited by its side effect profile; patients commonly require dose reductions with subsequent cycles or discontinue therapy entirely. In RTOG 9802, the median number of completed cycles was 3 for procarbazine, 4 for CCNU, and 4 for vincristine (Buckner et al. 2016). Patients most commonly report constitutional symptoms of fatigue, anorexia, nausea, and vomiting, which are most commonly grade 1 or 2 adverse events. Hematologic toxicity, including anemia, thrombocytopenia, and neutropenia is not uncommon and may be severe. PCV also carries the risk of secondary malignancy (myelodysplasia or leukemia) (Jutras et al. 2018). The alkylating agent temozolomide is used in standard treatment for high-grade glioma and is also commonly employed in the treatment of high-risk low-grade diffuse lesions. Preliminary data from a phase III clinical trials has suggested that temozolomide combined with radiation

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improves overall survival compared to radiation alone in diffuse astrocytoma (5-year OS: 55.9% vs. 44.1%, respectively) (van den Bent et al. 2017). Chemotherapy for Pilocytic Astrocytoma Chemotherapy and radiation are only very rarely employed for PA given the high success rate of surgery and concerns regarding potential toxicity in the pediatric population. In one large review of treatment for 3865 patients with WHO grade I PA, 294 (7.6%) received chemo, 233 (6%) received radiation, and 42 (1.1%) received both (Parsons et al. 2021). The use of adjuvant therapy was associated with a decreased overall survival and most commonly employed after STR; cerebellar tumors were less likely to be treated with adjuvant therapy. Younger patients were more likely to receive chemotherapy, with RT typically reserved for older patients. Recurrent lesions tend also to be grade I tumors and are similarly treated with re-operation, usually without other additional adjunct therapy (Burkhard et al. 2003). Chemotherapy for Subependymal Giant Cell Astrocytoma (SEGA) Pharmacologic treatment with everolimus, an mTOR inhibitor, has been shown to be safe and effective in the treatment of SEGA in patients with TSC (Franz et al. 2013; Krueger et al. 2010), including in pediatric patients under 2 years of age (Saffari et al. 2019). In addition to reducing tumor volume, everolimus has been shown to produce a robust reduction in seizure frequency (Franz et al. 2018). As it has diseasemodifying effects on other manifestations of TSC, it may be particularly advantageous for patients with multi-organ involvement (Jansen et al. 2019; Saffari et al. 2019). In addition to using as an adjunctive therapy, mTOR inhibitors may also be used as primary treatment for patients with large, bilateral, or recurrent tumors that are not amenable to resection. Clinical trials, such as the EXIST-1 trial, have shown that Everolimus is an effective monotherapy for SEGA and support its use as maintenance therapy in patients with TSC, particularly those who

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are not surgical candidates (Franz et al. 2014; Trelinska et al. 2017). Chemotherapy for Diffuse Low-Grade Glioma There is level 1 evidence to support the use of adjuvant chemotherapy in the treatment of patients with high-risk low-grade glioma following resection and RT. In patients with highrisk low-grade glioma, the combination of radiotherapy with chemotherapy has been shown to prolong overall survival and progression-free survival when compared with radiation alone (Buckner et al. 2016; Fisher et al. 2020; Shaw et al. 2012; van den Bent 2014). Treatment with PCV alone following subtotal resection has been shown to produce meaningful tumor regression in a subset of patients (Buckner et al. 2003). With respect to chemotherapeutic agent, many favor the use of PCV for IDH-mutated tumors, particularly those harboring 1p/19q codeletion (McDuff et al. 2020). In the landmark clinical trial, RTOG 9802, patients with WHO grade II diffuse glioma at high risk for progression, including those aged > 40 and/or those with STR, were randomized to receive post-operative RT with or without PCV chemotherapy (Buckner et al. 2016; Shaw et al. 2012). Long-term followup of patients from this study demonstrated a clear survival benefit to 6 cycles of PCV chemotherapy. PCV chemotherapy in addition to RT prolonged median overall survival to 13.3 years versus 7.8 years in patients receiving RT alone. The rate of PFS and OS at 10 years were 51 and 60% in the group receiving RT + PCV chemo, as compared to 21 and 40% in patients receiving RT alone (Buckner et al. 2016). When these patients were analyzed according to the 2016 WHO molecular subgroup classification, the results showed a striking divergence in terms of overall survival, with median survival times on subgroup analysis of 1.9 years (IDH-wt), 6.9 years (IDH-mut/non-codeleted), and 13.9 years (IDH-mut/co-deleted). There appeared to be a significant benefit of PCV chemotherapy in patients with IDH-mutated tumors, particularly those with 1p/19q codeletion; median survival times were: 1.9 versus 2.1 years (IDH-wt), 4.3 versus 11.4 years (IDH-

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mut/non-co-deleted), and 13.9 years versus not yet reached (IDH-mut/co-deleted) for RT alone versus RT + PCV (Bell et al. 2020). The addition of PCV chemotherapy to RT has not been shown to adversely affect cognitive outcome, as measured by the mini-mental status examination (MMSE) (Prabhu et al. 2014). However, the addition of chemotherapy dramatically increases the risk of treatment-related side effects and toxicity, particularly myelosuppression (Buckner et al. 2003; Jutras et al. 2018; Keogh et al. 2021; Shaw et al. 2012). In initial reports of RTOG 9802, the incidences of grade 3 and 4 hematologic toxicities were 51 and 15% in the group receiving RT + PCV chemotherapy, compared to 8 and 3% with RT alone (Shaw et al. 2012). The significant side effect profile of PCV chemotherapy has led many to utilize TMZ as the adjuvant chemotherapeutic agent for patients with high-risk or progressive LGG, despite positive results for PCV in clinical trials. Adjuvant TMZ in patients with diffuse grade II glioma after STR with mean follow-up of 7.5 years demonstrated overall 6% response rate with median PFS of 4.2 years and OS 9.7 years. Patients with 1p/19q codeletion notably demonstrated a 0% risk of progression during treatment, introducing adjuvant TMZ as a feasible option to delay RT in these patients (Wahl et al. 2017). RTOG 0424 is a phase II, single-arm study of RT + concurrent and adjuvant TMZ in 136 patients with grade II glioma with high-risk features. 3-year OS was 73.5%, which exceeds reported historical control of 54% treated with RT alone. Five- and ten-year OS were 60.9% and 34.6%, respectively, and 5- and 10-year PFS were 46.9% and 25.5%. Median survival time was 8.2 years (Fisher et al. 2020).

2.6.4 New Therapeutic Modalities Targeted molecular therapies are being investigated in specific subgroups of higher-risk patients. For example, selumetinib, a MEK1/2 inhibitor, has shown efficacy in phase II clinical trials against recurrent pilocytic astrocytoma in pediatric patients with either NF1 mutation or

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BRAF-mutated tumors (Fangusaro et al. 2019; Gajjar et al. 1997). GG is associated with BRAF activation and has shown response to BRAF inhibitors in small case reports (Chamberlain 2016). Adjuvant RT has not been shown to improve outcomes in cases of STR and may be associated with a worse prognosis (Lin et al. 2021; Yust-Katz et al. 2014). Additionally, some interest has been generated in the use of mTOR inhibitors for pediatric low-grade glioma (Rodriguez et al. 2014). In vitro studies have shown that specific cell lines are susceptible to killing via targeting of the mTOR pathway with inhibitors (Rodriguez et al. 2014). It is not entirely clear what the mechanism of action for these agents would be, although some studies have shown an increased level of PI3K-mTOR activation on IHC (Rodriguez et al. 2014). Early trials have also suggested that agents erlotinib and EGFR inhibitor may be safe in pediatric low-grade glioma; however, it remains unclear how effective this drug actually is (Yalon et al. 2012). Bevacizumab has also been identified as a potential agent for salvage therapy in pediatric low-grade gliomas. While there is some evidence that pediatric low-grade glioma responds to Bevacizumab, it appears that disease progression occurs relatively rapidly after drug cessation (Hwang et al. 2013).

2.7

given the slow proliferative rate of these lesions. In contrast, grade II tumors are characterized by a relatively slow course but in many cases ultimately are fatal. These lesions have a more infiltrative growth pattern and, despite a low proliferative capacity, have a greater tendency to recur. These diffuse glioma also are notably characterized by ultimate malignant transformation to higher-grade anaplastic or glioblastoma histology (Jooma et al. 2019). The most significant factor in prognostication is differentiating between localized (pilocytic) gliomas and diffusely infiltrating subtypes. Fiveyear OS rates are estimated to be 94% for pilocytic astrocytoma, 83% for grade II oligodendrogliomas, and 53% for diffuse grade II astrocytomas (Ostrom et al. 2020).

2.7.1 Pilocytic Astrocytoma (PA) The overall prognosis for patients with PA is excellent, with 10-year overall survival rates ranging from 80 to 100% (Austin and Alvord 1988; Fernandez et al. 2003; Forsyth et al. 1993; Park et al. 2019). Even in the case of subtotal resection, outcomes remain good with overall survival of 83% at 10 years and 70% at 20 years post-operatively; PFS at these time points was 74% and 41%, respectively (Wallner et al. 1988).

Follow-Up and Prognosis 2.7.2 Pilomyxoid Astrocytoma (PMA)

Gliomas are classified according to histologic features and clinical malignant potential according to the Classification of Tumors of the Central Nervous System (CNS). “Low-grade” gliomas are WHO grade I or II tumors. Grade I lesions are defined as those with low proliferative rates and potential for a surgical cure. Among grade I lesions are the localized, non-infiltrative gliomas, pilocytic astrocytoma, ganglioglioma, subependymoma, subependymal giant cell astrocytoma, and angiocentric glioma. These lesions have an overall excellent prognosis and are often cured after gross total resection (Ogiwara et al. 2012). Clinical outcomes are still good for patients who undergo subtotal resection

Clinically, PMA tend to behave more aggressively than PA and a higher propensity for recurrence. The overall prognosis for patients with PMA is worse than that for those with PA, reinforcing the importance of distinguishing between the two diagnoses. In one study comparing demographics and clinical outcomes of 63 patients with hypothalamic-region astrocytomas including 21 patients with PMA and 42 patients with PA, patients with PMA tended to be younger (average age at diagnosis of 18 months for PMA versus 58 months for PA), more likely to develop recurrent or disseminated disease, and had worse overall survival than patients with PA.

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Even when accounting for the extent of resection (typically lower with midline tumors as compared to hemispheric or posterior fossa lesions), patients with PMA still had higher rates of local recurrence (76% for PMA versus 50% for PA) with shorter PFS (25 months vs. 163 months). Mortality rates were 33% versus 17% with overall survival in age-matched groups of 60 months versus 233 months for PMA and PA, respectively (Komotar et al. 2004a).

2.7.3 Subependymal Giant Cell Astrocytoma (SEGA) Definitive management with gross total resection tends to be curative; however, if unable to achieve complete resection, recurrence rates are high (Kotulska et al. 2014). Overall, SEGA has an excellent 9-year survival rate of 88%. Patients who were under the age of 18 at time of diagnosis have longer survival than those over 18 (5year OS: 96.8% vs. 82.7%, respectively). Those who undergo surgical resection have better survival than patients managed with observation (5year OS: 96.2% vs. 86.7%) (Nguyen et al. 2018). Some studies have also found better long-term outcomes in patients who undergo surgical resection at a younger age (Goh et al. 2004).

2.7.4 Subependymoma (SE) Overall outcomes are excellent, with 10-year OS rates as high as 93% with associated PFS of 86% (Bi et al. 2015). Proposed positive prognostic indicators include younger age, female sex, a location within the ventricular system or near the brainstem, and treatment with surgery (Nguyen et al. 2017).

2.7.5 Ganglioglioma GG has an overall excellent prognosis, with long-term overall survival rates exceeding 80% after GTR (Compton et al. 2012; Lundar et al. 2018; Yust-Katz et al. 2014). Extent of resection

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is strongly associated with tumor recurrence (Compton et al. 2012; Pekmezci et al. 2018; Rades et al. 2010). In one large study of outcomes after GG resection, median time to progression was 16.7 years and 1.8 years for GTR and STR, respectively (Compton et al. 2012). Prolonged PFS has been associated with a temporal tumor location, initial presentation with long-standing seizures, lower histologic grade, and achievement of GTR (El Khashab et al. 2009; Lin et al. 2021; Luyken et al. 2004). Patients with frontal or higher-grade lesions as well as those who have undergone STR should undergo close radiographic surveillance due to an increased risk of recurrence (Luyken et al. 2004).

2.7.6 Pleomorphic Xanthoastrocytoma (PXA) Overall, the prognosis for PXA is relatively good, with 5- and 10-year overall survival rates exceeding 75% and 65%, respectively (Gallo et al. 2013; Giannini et al. 1999; Perkins et al. 2012). Recurrence after resection is not uncommon, estimated to occur in 10–35% of cases; however, lesions are typically slow growing and have a relatively benign clinical course (Korshunov and Golanov 2001). Subtotal resection is associated with a shorter time to tumor recurrence, with one study finding 5-year PFS rates of 45.5% in STR compared to 84.9% in GTR (Marucci and Morandi 2011).

2.7.7 Diffuse Low-Grade Glioma Diffuse low-grade glioma has the worst prognosis of the benign gliomas due to the high risk of recurrence and subsequent malignant transformation. For patients with LGG, extent of resection is a major predictor of tumor recurrence (Breen et al. 2020; Shaw et al. 2008). Extent of resection has also been correlated with improved seizure control in patients with glioma-associated epilepsy (Chang et al. 2008; Englot et al. 2012; Pallud et al. 2014; Xu et al. 2018; You et al.

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2012). Patients with uncontrolled seizures tended to have insular tumors or tumors in close proximity to functional areas (Pallud et al. 2014). Preoperative functional MRI (fMRI) may be used for tumors in proximity to eloquent areas to identify regions that are pertinent to speech or motor functions (Hall et al. 2005). Intra-operative functional cortical and subcortical mapping has been used to identify epileptogenic foci and avoid functional locations to guide safe lesion resection in patients with gliomas. More recently, intra-operative electrocorticography (ECoG) data has identified abnormalities in peri-lesional tissue that may ultimately be used to identify infiltrating margins in LGG (Ghinda et al. 2020). In cases of STR, the addition of radiation therapy may help seizure control (Sepulveda-Sanchez et al. 2018). Notably, post-operative return of seizures and increased seizure frequency have been correlated with early tumor recurrence (Chang et al. 2008; Santos-Pinheiro et al. 2019). Overall, patients who presented with epileptic seizures tend to have a longer PFS for malignant transformation and prolonged overall survival (Pallud et al. 2014). Overall survival at 1, 5, and 10 years for astrocytoma and oligodendroglioma are 76.3% and 94.9%, 53% and 83.4%, and 43.1% and 69.6%, respectively. These rates are highest for pediatric patients and tend to decrease with age (Ostrom et al. 2020). The prognosis tends to be better for patients with oligodendroglioma 1p/19q co-deleted subtype (Daniels et al. 2011; Shaw et al. 2002) and worst in IDH-wild type tumors (Baumert et al. 2016). Known predictors of worse survival in these patients include age > 40 years, larger initial tumor diameter, incomplete tumor resection, and presence of preoperative neurologic deficit or poor functional capacity (Breen et al. 2020; Daniels et al. 2011; Sepulveda-Sanchez et al. 2018; Shaw et al. 2008). Patients with a high risk of progression may be better candidates for immediate postoperative adjuvant therapy. Standard of care combination RT + chemo w PCV in all patients requires adjuvant treatment. For IDH-mutant gliomas without 1p/19q codeletion who cannot tolerate PCV, adjuvant TMZ is also a reasonable

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option (McDuff et al. 2020; Tom et al. 2019). Patients with low-risk features may initially be observed post-operatively given overall good prognosis, to avoid treatment-related side effects (Sepulveda-Sanchez et al. 2018). Follow-up for these patients should include routine radiographic surveillance with T2/FLAIR weighted sequences. It is recommended that patients undergo imaging after the completion of therapy, followed by every 3–4 months for the subsequent year, then every 6 months for 2 years, and annually thereafter (Sepulveda-Sanchez et al. 2018). Of diffuse glioma, a better prognosis has been seen with IDH-mutated tumors and, in particular, those that harbor 1p/19q codeletion, which is associated with an oligodendroglioma histologic subtype. Patient presentation also may influence prognosis. Patients presenting with epilepsy tend to have a better prognosis than those without seizures (Capelle et al. 2013; Liang et al. 2020). Older patients and those with lower pre-operative function, as measured by Karnofsky performance score (KPS) < 85, tend to have a worse overall prognosis as well (Capelle et al. 2013; Liang et al. 2020). Aside from tumor histology, the next most significant prognostic variable is the extent of resection, which has implications both for overall survival and seizure freedom. For diffuse glioma, incompletely resected tumors have a high risk of recurrence. In one report, patients with diffuse low-grade glioma were nearly 4 times more likely to be alive at 5 years after GTR compared with STR (Xia et al. 2018). For patients with tumor-related seizures, surgical resection of the epileptogenic focus has been shown to be an effective means of controlling symptoms. Early surgery and extent of resection have been shown to be crucial in achieving seizure freedom; 90% of diffuse lowgrade glioma patients are Engel class III or better 12 months following resection (Chang et al. 2008; Erturk Cetin et al. 2017). In one comprehensive review of post-operative seizure control in 1181 patients with epilepsy after resection of LGG (diffuse astrocytoma), ganglioglioma, or DNET, 79% of patients were seizure-free after GTR compared with 43% after STR; addition of

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Fig. 2.17 Diagnostic-therapeutic algorithm in low-grade glioma

selective tailored resection including the hippocampus increased seizure freedom rates to 87% (Englot et al. 2012).

2.8

Conclusion

In conclusion, benign glioma is a term that encompasses multiple distinct histopathological diseases. The most significant unifying features are their slow proliferative rate and relatively indolent course. These tumors tend to occur in younger patients and are often associated with seizures. Although radiation and chemotherapy can be used to manage these tumors, their efficacy is overall not well established in most histopathological subtypes and they are generally reserved for inoperable or recurrent disease. These tumors can usually be managed surgically via resection, with some tumors even being curable through surgery; maximal safe resection should always be the goal to obtain the best outcome for patients. The diagnostic-therapeutic algorithm for low-grade glioma is summarized in Fig. 2.17.

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69 literature. J Neurooncol 63:39–47. https://doi.org/10. 1023/a:1023752717042 Reifenberger G et al (1999) Chordoid glioma of the third ventricle: immunohistochemical and molecular genetic characterization of a novel tumor entity. Brain Pathol 9:617–626. https://doi.org/10.1111/j.17503639.1999.tb00543.x Rodriguez FJ et al (2014) mTOR: anew therapeutic target for pediatric low-grade glioma? CNS Oncol 3(2):89–91 Rushing EJ et al (2007) Subependymoma revisited: clinicopathological evaluation of 83 cases. J Neurooncol 85:297–305. https://doi.org/10.1007/s11060-0079411-6 Ryken TC, Parney I, Buatti J, Kalkanis SN, Olson JJ (2015) The role of radiotherapy in the management of patients with diffuse low grade glioma: a systematic review and evidence-based clinical practice guideline. J Neurooncol 125:551–583. https://doi.org/10.1007/ s11060-015-1948-1 Saffari A et al (2019) Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age—a multicenter retrospective study. Orphanet J Rare Dis 14:96. https://doi. org/10.1186/s13023-019-1077-6 Santos-Pinheiro F et al (2019) Seizure burden pre- and postresection of low-grade gliomas as a predictor of tumor progression in low-grade gliomas. Neurooncol Pract 6:209–217. https://doi.org/10.1093/nop/npy022 Schindler G et al (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405. https:// doi.org/10.1007/s00401-011-0802-6 Sepulveda-Sanchez JM et al (2018) SEOM clinical guideline of diagnosis and management of low-grade glioma (2017). Clin Transl Oncol 20:3–15. https://doi. org/10.1007/s12094-017-1790-3 Shaikh N et al (2019) Pleomorphic xanthoastrocytoma: a brief review. CNS Oncol 8:CNS39. https://doi.org/10. 2217/cns-2019-0009 Shakur SF, McGirt MJ, Johnson MW, Burger PC, Ahn E, Carson BS, Jallo GI (2009) Angiocentric glioma: a case series. J Neurosurg Pediatr 3:197–202. https:// doi.org/10.3171/2008.11.PEDS0858 Sharma MC, Ralte AM, Gaekwad S, Santosh V, Shankar SK, Sarkar C (2004) Subependymal giant cell astrocytoma—a clinicopathological study of 23 cases with special emphasis on histogenesis. Pathol Oncol Res 10:219–224. https://doi.org/10.1007/ BF03033764 Shaw E et al (2002) Prospective randomized trial of lowversus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol 20:2267–2276. https:// doi.org/10.1200/JCO.2002.09.126 Shaw EG et al (2008) Recurrence following neurosurgeon-determined gross-total resection of adult

70 supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg 109:835–841. https:// doi.org/10.3171/JNS/2008/109/11/0835 Shaw EG et al (2012) Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol 30:3065–3070. https://doi.org/10.1200/JCO.2011.35.8598 She D, Liu J, Xing Z, Zhang Y, Cao D, Zhang Z (2018) MR imaging features of anaplastic pleomorphic xanthoastrocytoma mimicking high-grade astrocytoma AJNR. Am J Neuroradiol 39:1446–1452. https://doi. org/10.3174/ajnr.A5701 Shoji T et al (2020) Frequent clinical and radiological progression of optic pathway/hypothalamic pilocytic astrocytoma in adolescents and young adults. Neurol Med Chir 60:277–285. https://doi.org/10.2176/nmc. oa.2019-0208 Siddique K, Zagardo M, Gujrati M, Olivero W (2002) Ganglioglioma presenting as a meningioma: case report and review of the literature. Neurosurgery 50:1133–1135; discussion 1135–1136. https://doi.org/ 10.1097/00006123-200205000-00034 Skrypek M, Foreman N, Guillaume D, Moertel C (2014) Pilomyxoid astrocytoma treated successfully with vemurafenib. Pediatr Blood Cancer 61:2099–2100. https://doi.org/10.1002/pbc.25084 Slegers RJ, Blumcke I (2020) Low-grade developmental and epilepsy associated brain tumors: a critical update 2020. Acta Neuropathol Commun 8:27. https://doi. org/10.1186/s40478-020-00904-x Smith JS et al (2008) Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol 26:1338–1345. https://doi.org/10.1200/ JCO.2007.13.9337 Southwell DG, Garcia PA, Berger MS, Barbaro NM, Chang EF (2012) Long-term seizure control outcomes after resection of gangliogliomas Neurosurgery 70:1406–1413; discussion 1413–1404. https://doi. org/10.1227/NEU.0b013e3182500a4c Sturm D, Pfister SM, Jones DTW (2017) Pediatric gliomas: current concepts on diagnosis biology, and clinical management. J Clin Oncol 35:2370–2377. https://doi.org/10.1200/JCO.2017.73.0242 Suetens K, Swinnen J, Stessens L, Van Cauter S, Gelin G (2019) Chordoid glioma as a differential diagnosis of anterior third ventricle tumours: a rare case report and five-year follow-up case. Rep Radiol 2019:3584837. https://doi.org/10.1155/2019/3584837 Sugita Y, Ono T, Ohshima K, Niino D, Ito M, Toda K, Baba H (2008) Brain surface spindle cell glioma in a patient with medically intractable partial epilepsy: a variant of monomorphous angiocentric glioma? Neuropathology 28:516–520. https://doi.org/10.1111/j. 1440-1789.2007.00849.x Swennen MH, Bromberg JE, Witkamp TD, Terhaard CH, Postma TJ, Taphoorn MJ (2004) Delayed radiation toxicity after focal or whole brain radiotherapy for low-grade glioma. J Neurooncol 66:333–339. https:// doi.org/10.1023/b:neon.0000014518.16481.7e

P. B. Wu et al. Tahiri Elousrouti L et al (2016) Subependymal giant cell astrocytoma (SEGA): a case report and review of the literature. J Med Case Rep 10:35. https://doi.org/10. 1186/s13256-016-0818-6 Takada S, Iwasaki M, Suzuki H, Nakasato N, Kumabe T, Tominaga T (2011) Angiocentric glioma and surrounding cortical dysplasia manifesting as intractable frontal lobe epilepsy—case report. Neurol Med Chir 51:522–526. https://doi.org/10.2176/nmc.51.522 Tian T, Li X, Zhang J (2019) mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int J Mol Sci 20. https://doi.org/10.3390/ijms20030755 Tom MC, Cahill DP, Buckner JC, Dietrich J, Parsons MW, Yu JS (2019) Management for different glioma subtypes: are all low-grade gliomas created equal? Am Soc Clin Oncol Educ Book 39:133–145. https://doi.org/10.1200/EDBK_238353 Trelinska J et al (2017) Maintenance therapy with everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis (the EMINENTS study). Pediatr Blood Cancer 64. https://doi.org/10. 1002/pbc.26347 Uppstrom TJ, Singh R, Hadjigeorgiou GF, Magge R, Ramakrishna R (2016) Repeat surgery for recurrent low-grade gliomas should be standard of care. Clin Neurol Neurosurg 151:18–23. https://doi.org/10.1016/ j.clineuro.2016.09.013 van den Bent MJ (2014) Practice changing mature results of RTOG study 9802: another positive PCV trial makes adjuvant chemotherapy part of standard of care in low-grade glioma. Neuro Oncol 16:1570–1574. https://doi.org/10.1093/neuonc/nou297 van den Bent MJ et al (2005) Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366:985–990. https:// doi.org/10.1016/S0140-6736(05)67070-5 van den Bent MJ et al (2017) Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390:1645–1653. https://doi.org/10.1016/S0140-6736 (17)31442-3 van den Bent MJ et al (2013) 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 31:344–350. https://doi.org/10.1200/ JCO.2012.43.2229 Vanhauwaert DJ, Clement F, Van Dorpe J, Deruytter MJ (2008) Chordoid glioma of the third ventricle. Acta Neurochir 150:1183–1191. https://doi.org/10.1007/ s00701-008-0014-6 Varma A, Giraldi D, Mills S, Brodbelt AR, Jenkinson MD (2018) Surgical management and long-term outcome of intracranial subependymoma. Acta Neurochir 160:1793– 1799. https://doi.org/10.1007/s00701-018-3570-4 Vitanovics D, Afra D, Nagy G, Hanzely Z, Turanyi E, Banczerowski P (2014) Symptomatic subependymomas

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of the ventricles. Review of twenty consecutive cases. Ideggyogy Sz 67:415–419 Vuong HG, Altibi AMA, Duong UNP, Ngo HTT, Pham TQ, Fung KM, Hassell L (2018) BRAF mutation is associated with an improved survival in glioma—a systematic review and meta-analysis. Mol Neurobiol 55:3718–3724. https://doi.org/10.1007/ s12035-017-0599-y Wahl M et al (2017) Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide. Neuro Oncol 19:242–251. https://doi.org/10.1093/neuonc/now176 Wallner KE, Gonzales MF, Edwards MS, Wara WM, Sheline GE (1988) Treatment results of juvenile pilocytic astrocytoma. J Neurosurg 69:171–176. https://doi.org/10.3171/jns.1988.69.2.0171 Wang DD, Deng H, Hervey-Jumper SL, Molinaro AA, Chang EF, Berger MS (2018a) Seizure outcome after surgical resection of insular glioma. Neurosurgery 83:709–718. https://doi.org/10.1093/neuros/nyx486 Wang M et al (2005) Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol 64:875–881. https://doi. org/10.1097/01.jnen.0000182981.02355.10 Wang QP, Lei DQ, Yuan Y, Xiong NX (2020) Accuracy of ADC derived from DWI for differentiating highgrade from low-grade gliomas: Systematic review and meta-analysis. Medicine 99:e19254. https://doi.org/10. 1097/MD.0000000000019254 Wang W, Cheng J, Zhang Y, Wang C (2018b) Use of apparent diffusion coefficient histogram in differentiating between medulloblastoma and pilocytic astrocytoma in children. Med Sci Monit 24:6107–6112. https://doi.org/10.12659/MSM.909136 Weaver KJ, Crawford LM, Bennett JA, Rivera-Zengotita ML, Pincus DW (2017) Brainstem angiocentric glioma: report of 2 cases. J Neurosurg Pediatr 20:347–351. https://doi.org/10.3171/2017.5.PEDS16402 Weber RG et al (2007) Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytomas. Oncogene 26:1088–1097. https:// doi.org/10.1038/sj.onc.1209851 Wesseling P, Capper D (2018) WHO 2016 classification of gliomas. Neuropathol Appl Neurobiol 44:139–150. https://doi.org/10.1111/nan.12432 Williams NL et al (2018) Late effects after radiotherapy for childhood low-grade glioma. Am J Clin Oncol 41:307–312. https://doi.org/10.1097/COC.0000000 000000267 Wolf HK, Wiestler OD (1993) Surgical pathology of chronic epileptic seizure disorders. Brain Pathol 3:371–380. https://doi.org/10.1111/j.1750-3639.1993. tb00765.x Woodworth G, McGirt MJ, Samdani A, Garonzik I, Olivi A, Weingart JD (2005) Accuracy of frameless and

71 frame-based image-guided stereotactic brain biopsy in the diagnosis of glioma: comparison of biopsy and open resection specimen. Neurol Res 27:358–362. https://doi.org/10.1179/016164105X40057 Xia L, Fang C, Chen G, Sun C (2018) Relationship between the extent of resection and the survival of patients with low-grade gliomas: a systematic review and meta-analysis. BMC Cancer 18:48. https://doi.org/ 10.1186/s12885-017-3909-x Xu DS, Awad AW, Mehalechko C, Wilson JR, Ashby LS, Coons SW, Sanai N (2018) An extent of resection threshold for seizure freedom in patients with low-grade gliomas. J Neurosurg 128:1084–1090. https://doi.org/10.3171/2016.12.JNS161682 Yalon M et al (2012) A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric lowgrade glioma Pediatric Blood. Cancer 60(1):71–76 Yan H et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. https://doi.org/10.1056/ NEJMoa0808710 Yang D et al (2017) Chordoid glioma: a neoplasm found in the anterior part of the third ventricle. J Craniofac Surg. https://doi.org/10.1097/SCS.0000000000002514 Yang I, Han SJ, Sughrue ME, Tihan T, Parsa AT (2011) Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology. J Neurosurg 115:505–511. https://doi.org/10.3171/ 2011.4.JNS101172 Yao K et al (2020) PRKCA D463H mutation in chordoid glioma of the third ventricle: a cohort of 16 cases, including two cases harboring BRAFV600E mutation. J Neuropathol Exp Neurol 79:1183–1192. https://doi. org/10.1093/jnen/nlaa107 You G et al (2012) Clinical and molecular genetic factors affecting postoperative seizure control of 183 Chinese adult patients with low-grade gliomas. Eur J Neurol 19:298–306. https://doi.org/10.1111/j.1468-1331.2011. 03509.x Yust-Katz S et al (2014) Clinical and prognostic features of adult patients with gangliogliomas. Neuro Oncol 16:409–413. https://doi.org/10.1093/neuonc/not169 Zaazoue MA, Manley PE, Mehdar MA, Ullrich NJ, Dasenbrock HH, Chordas CA, Goumnerova LC (2020) Optimizing postoperative surveillance of pediatric low-grade glioma using tumor behavior patterns. Neurosurgery 86:288–297. https://doi.org/10.1093/ neuros/nyz072 Zhang GB, Huang HW, Li HY, Zhang XK, Wang YG, Lin S (2020) Intracranial chordoid glioma: a clinical, radiological and pathological study of 14 cases. J Clin Neurosci 80:267–273. https://doi.org/10.1016/j.jocn. 2020.09.019 Zhou H et al (2017) MRI features predict survival and molecular markers in diffuse lower-grade gliomas. Neuro Oncol 19:862–870. https://doi.org/10.1093/ neuonc/now256

3

Meningioma and Other Meningeal Tumors Michele Bailo, Filippo Gagliardi, Nicola Boari, Alfio Spina, Martina Piloni, Antonella Castellano, and Pietro Mortini

Abstract

Meningiomas develop from meningothelial cells and approximately account for more than 30 percent of central nervous system (CNS) tumors. They can occur anywhere in the dura, most often intracranially and at dural reflection sites. Half of the cases are usually at parasagittal/falcine and convexity locations; other common sites are sphenoid ridge, suprasellar, posterior fossa, and olfactory groove. The female-to-male ratio is approximately 2 or 3–1, and the median age at diagnosis is 65 years. Meningiomas are generally extremely slow-growing tumors; many are asymptomatic or paucisymptomatic at diagnosis and are discovered incidentally. Clinical manifestations, when present, are influenced by the tumor site and by the time course over which it develops. Meningiomas are divided into three grades. Grade I represents the vast majority of cases; they are considered typical or benign, although their CNS location can still lead to severe morbidity or mortality, resulting in a reported ten-year

M. Bailo (&) . F. Gagliardi . N. Boari . A. Spina . M. Piloni . A. Castellano . P. Mortini Department of Neurosurgery and Gamma Knife Radiosurgery, I.R.C.C.S. Ospedale San Raffaele, Vita-Salute University, Via Olgettina 60, 20132 Milano, Italy e-mail: [email protected]

net survival of over 80%. Atypical (WHO grade II) meningiomas are considered “intermediate grade” malignancies and represent 5–7% of cases. They show a tendency for recurrence and malignant degeneration with a relevant increase in tumor cell migration and surrounding tissue infiltration; ten-year net survival is reported over 60%. The anaplastic subtype (WHO III) represents only 1–3% of cases, and it is characterized by a poor prognosis (ten-year net survival of 15%). The treatment of choice for these tumors stands on complete microsurgical resection in case the subsequent morbidities are assumed minimal. On the other hand, and in case the tumor is located in critical regions such as the skull base, or the patient may have accompanied comorbidities, or it is aimed to avoid intensive treatment, some other approaches, including stereotactic radiosurgery and radiotherapy, were recommended as safe and effective choices to be considered as a primary treatment option or complementary to surgery. Adjuvant radiosurgery/radiotherapy should be considered in the case of atypical and anaplastic histology, especially when a residual tumor is identifiable in postoperative imaging. A “watchful waiting” strategy appears reasonable for extremely old individuals and those with substantial comorbidities or lowperformance status, while there is a reduced threshold for therapeutic intervention for relatively healthy younger individuals due to the

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_3

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expectation that tumor progression will inevitably necessitate proactive treatment. To treat and manage meningioma efficiently, the assessments of both neurosurgeons and radiation oncologists are essential. The possibility of other rarer tumors, including hemangiopericytomas, solitary fibrous tumors, lymphomas, metastases, melanocytic tumors, and fibrous histiocytoma, must be considered when a meningeal lesion is diagnosed, especially because the ideal diagnostic and therapeutic approaches might differ significantly in every tumor type. Keywords

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Dural lesion Meningioma Hemangiopericytoma Solitary fibrous tumor Dural lymphoma Dural metastasis Dural melanocytic tumor Fibrous histiocytoma Management Surgery Radiosurgery Radiotherapy

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Background and Epidemiology

29% in the middle third, and 22% along in the posterior third (Park et al. 2009). Multiple meningiomas or meningiomatosis are encountered in 2.5% of cases (Park et al. 2009). The reported intracranial incidence is 8.3/100,000 in the USA. The occurrence rate varies among races: blacks have a 1.2-fold greater incidence than Caucasians (Ostrom et al. 2017). Their incidence increases progressively with age, with a median age at diagnosis of 65 years. They are rare in the pediatric population (Liu et al. 2008), except in those with hereditary syndromes including neurofibromatosis type 2 (NF2) or a history of radiation therapy (Banerjee et al. 2009; Marosi et al. 2008; Park 2020). Meningiomas are more frequent in women: the female-to-male ratio is approximately 2 or 3–1 (Brodbelt et al. 2019; Claus et al. 2005; Marosi et al. 2008; Ostrom et al. 2017; Umansky et al. 2008). The female predominance is highest among middle-aged adults (35– 54 years), while it is less pronounced (or absent) in those with atypical or anaplastic meningiomas, children, and those affected by radiation-induced meningiomas (Park 2020).

3.1.1 Epidemiology Meningiomas are tumors that develop from meningothelial cells and account for roughly 30– 37% of all new diagnoses of central nervous system (CNS) tumors (Brodbelt et al. 2019; Mohammadi et al. 2021; Pereira et al. 2019; Whittle et al. 2004). Despite the benign nature of most meningiomas, their serious morbidity or mortality is related to the respective CNS location. Approximately 90% of them occur intracranially, while 10% in the spinal meninges (Ostrom et al. 2017). The most frequent intracranial locations include parasagittal/falcine 25%, convexity 19%, sphenoid ridge 17%, suprasellar 9%, posterior fossa 8%, olfactory groove 8%, middle fossa/Meckel’s cave 4%, tentorial 3%, peritorcular 3%, lateral ventricle 1–2%, foramen magnum 1–2%, and orbit/optic nerve sheath 1–z2% (Christensen et al. 2003; Park et al. 2009). Among the parasagittal meningiomas, 49% are located in the anterior third of the falx,

3.1.2 Risk Factors Numerous factors have been investigated for their possible association with the development of meningiomas, one of these hazards is exposure to ionizing radiation, which is identified as the most relevant acquired risk factor (Braganza et al. 2012; Park 2020; Umansky et al. 2008). Epidemiologic studies with long-term follow-up have reported that the incidence of radiationinduced meningioma is increased even after several decades following the exposure to radiation and the risk may be highest among patients who were treated at a younger age. Radiationinduced meningiomas have a higher incidence of multiplicity and atypia than sporadic ones (Bowers et al. 2017; Friedman et al. 2010; Kok et al. 2019; Park 2020). A genetic predisposition to meningioma is best characterized in patients with NF2. Still, patients with multiple endocrine neoplasia type 1

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Fig. 3.1 a Preoperative post-gadolinium MRI of a 48years-old female patient operated for a large olfactory groove meningioma, suffering from anosmia, behavior disorders, and progressive bilateral impairment of visual acuity. The patient was discharged 7 days after the procedure without any additional neurological deficit.

The final histology was WHO grade I Meningothelial meningioma. b Postoperative MRI (8-year follow-up) confirming a gross total resection of the tumor with no sign of recurrence. Visual acuity and behavior disorders recovered completely, while only slight healing of olfactory sensation was observed at follow-up

(MEN1) also show an augmented risk of meningioma, although at lower rates than NF2 (Park 2020). Hormonal factors may play a role in meningioma development, as suggested by multiple studies (Wiemels et al. 2010). The meningioma incidence is higher in post-pubertal women than men, and the female-to-male ratio is highest during the peak reproductive years, while it decreases in older individuals. Progesterone and androgen receptors are expressed by tumoral cells in approximately 2/3 of the patients, while estrogen receptors have been identified in about 10% (Park 2020). A meta-analysis of 6 prospective case–control studies including more

than 1600 meningiomas found that ever-use of hormone therapy was correlated with a small but significant increase in the risk of meningioma (relative risk [RR] 1.35, 95% CI 1.2–1.5) (Benson et al. 2015; Muskens et al. 2019; Park 2020).

3.2

Genetics, Immunology, and Molecular Biology

A strong association between the risk of recurrence in meningiomas and the tumor molecular profile has been reported in previous studies (Bi et al. 2016). Genomic instability is one of the main factors that lead to the differences between

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Fig. 3.2 a Preoperative MRI of a 79-years-old female patient who underwent surgical removal of an extra-axial lesion involving the clival and foramen magnum dura, significantly compressing and dislocating the medulla. The patient was suffering from progressive right hemiparesis. b Postoperative MRI showing a gross total resection. The final histology was WHO grade I

Meningothelial meningioma. In the early postoperative period, the patient presented dysphagia. After a rehabilitation period of 4 weeks, the patient recovered from dysphagia and had a progressive improvement of the right hemiparesis, with full recovery of autonomy in the activity of daily living despite the persistence of a subtle deficit in the fine motility of the right hand

grade I and grade II–III meningiomas (Pereira et al. 2019). It has been found that the alteration in karyotypes such as deletion of 1p, 6q, 9p, 10, 14q, 18q, and gaining an additional chromosome including 1q, 9q, 12q, 15q, 17q, and 20q are higher in WHO grade II and grade III meningiomas compared to benign ones (Mawrin and Perry 2010; Venur et al. 2018). The bi-allelic mutation or loss of the NF2 tumor suppressor gene on chromosome 22 is found in about 50–60% of sporadic meningiomas (Clark et al. 2013; Pereira et al. 2019; Venur et al. 2018). NF2 encodes the protein “Merlin” (Schwannomin). Merlin downregulates

mammalian target of rapamycin (mTOR) signaling complex 1 and upregulates mTOR signaling complex 2, which leads to cell motility and growth (James et al. 2009, 2012; Venur et al. 2018). Merlin also regulates numerous other pathways that contribute to meningioma pathogenesis, such as the Notch and Hippo pathways (Curto and McClatchey 2008; Venur et al. 2018). Recent research employing next-generation sequencing methodologies has detected new driver mutations in meningiomas, including AKT1, SMO, TRAF7, KLF4, PIK3CA, NOTCH2, CHEK2, SMARCE1, SMARCB1, and POLR2A, particularly in the remaining half of NF2 wild-

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Fig. 3.3 a Preoperative MRI of a 54-years-old female patient with a right petroclival meningioma. The patient was suffering from progressive hearing impairment in the right ear. The patient experienced a transient partial VI cranial nerve paresis (causing diplopia on right lateral gaze), mild dysphagia, and House-Brackmann grade II facial nerve deficit postoperatively. The final histology

was WHO grade I Meningothelial meningioma. Symptoms recovered in the first four months after surgery. b A Gamma Knife radiosurgery treatment was performed on the residual tumor infiltrating the petrous bone and posterior cavernous sinus 6 months after the operation. c Follow-up MRI acquired 3 years after radiosurgery showing radiological control of the residual tumor

type meningiomas (Clark et al. 2013; Pereira et al. 2019). Many genetic mutations are correlated with specific tumor phenotypes. Alterations in TERT, BAP1, and DMD correlate with worse clinical outcomes (Venur et al. 2018). Anterior skull base meningiomas are enriched with SMO, AKT, and PIK3CA alterations (Venur et al. 2018). BAP1 mutations are frequent in progressive rhabdoid lesions, while KLF4 mutations are specific for the secretory histological variant (Venur et al. 2018). Extensive sequencing of whole-exome and whole-genome has provided a large amount of information concerning the mutational landscape in meningioma (Clark et al. 2013; Pereira et al. 2019). Four different subgroups have been proposed, defined by their mutations in NF2, the hedgehog pathway, TRAF7, or POLR2A. However, classification based on mutational analysis alone is insufficient to meet the clinical criteria to

identify and choose patients who possibly can benefit from adjuvant treatment (Clark et al. 2013; Pereira et al. 2019). Exome, transcriptome, methylome, and future techniques for epigenetic features in meningiomas may be combined to provide a more thorough understanding of mechanisms underlying tumor growth and, therefore, a more tailored clinical approach in these patients (Pereira et al. 2019). However, the mainstay in the definition of tumor prognosis is detecting the WHO histological grading and genomic biomarkers, which are becoming progressively more helpful in identifying individuals with worse prognosis. For instance, copy number modifications have been related to an increased risk of recurrence (Aizer et al. 2016; Domingues et al. 2014; Venur et al. 2018). Additionally, there is growing evidence that DNA methylation profiling entails prognostic significance in meningiomas (Olar et al. 2017; Sahm et al. 2017; Venur et al. 2018).

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Fig. 3.4 a Preoperative MRI of a 69-years-old male patient diagnosed with a parasagittal extra-axial expansive lesion infiltrating the superior sagittal sinus after a tonicclonic seizure. A subtotal resection was achieved; the histopathological diagnosis was atypical (WHO grade II) meningioma. He was discharged 5 days postoperatively

3.3

Histopathology and Morphology

Meningiomas are categorized into three grades based on the WHO classification in 2016 (Louis et al. 2016). Grade I tumors are considered typical or benign and represent 88–94% of all meningiomas. They are stratified into nine histological subtypes: meningothelial, transitional, fibrous, psammomatous, angiomatous, secretory, lympho-plasmacyte-rich, microcystic, and metaplastic (Hale et al. 2018). The treatment strategy remains identical for all of these different subtypes. Atypical (WHO grade II) meningiomas are considered “intermediate grade” malignancies and represent 4.7–7.2% of cases (Kshettry et al. 2015). They show a tendency for recurrence and malignant degeneration with a relevant increase in tumor cell migration and surrounding tissue

with no additional neurologic deficits. b A Gamma Knife radiosurgery treatment was performed 3 months after the operation on the residual tumor infiltrating the superior sagittal sinus. c Follow-up MRI acquired 5 years after radiosurgery showing radiological control of the residual tumor

infiltration (Sicking et al. 2018). They include atypical, clear cell, and chordoid meningiomas. Grade II meningioma is diagnosed via several histological properties including an increased mitotic activity which is defined by 4 or higher mitoses per 10 high-powered fields, brain invasion, or detection of three or more than three features that are high cellularity, prominent nucleoli, presence of a high nuclear-tocytoplasmic ratio in small cells, uninterrupted pattern-less or sheet-like growth, or foci of spontaneous or geographic necrosis (Park 2020). The anaplastic subtype (WHO III) represents only 1–3% of all meningiomas, and it is characterized by a poor prognosis (Pereira et al. 2019). Anaplastic, rhabdoid, and papillary meningiomas are included in this subtype. While the malignant features of meningiomas may be common in sarcoma, carcinoma, or melanoma, some malignancy indices, such as over 20 mitoses per 10 high-powered fields, highly define anaplastic meningiomas. Features supporting the

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diagnosis of anaplastic meningioma include the loss of typical growth patterns, infiltration of the adjacent brain tissue, abundant mitoses with atypical forms, and multifocal microscopic foci of necrosis (Park 2020). Although WHO grade III meningiomas are considered malignant, distant metastases are rare, and the primary issue is a local recurrence, which requires additional treatment beyond surgery and can ultimately cause death (Hanft et al. 2010; Park 2020). The WHO grading correlates with the outcome, thus having a paramount impact on treatment strategy. Individuals harboring WHO grade II or III meningiomas are considerably more likely to have an invasive disease, a local recurrence following the primary treatment, and, ultimately, a shorter overall survival (OS) than patients affected by benign meningiomas (Park 2020).

3.4

Imaging and Radiologic Features

Meningiomas can develop anywhere from the dura, most often intracranially and at dural reflection sites including the falx cerebri, tentorium cerebelli, and venous sinuses (Park 2020; Whittle et al. 2004). Less common locations are the choroid plexus and the optic nerve sheath, and about 10% are located in the spinal column. Also, extradural locations have been reported for meningiomas (Mattox et al. 2011; Park 2020). A typical meningioma appears on magnetic resonance imaging (MRI) as an extra-axial, dural-based mass that is iso- or hypointense to the gray matter on T1-weighted images and isoor hyperintense on T2-weighted images (Park 2020). After gadolinium injection, there is usually a noticeable, uniform contrast enhancement. The typical “tail” sign of a meningioma is a marginal dural thickening that tapers peripherally (Park 2020). On computed tomography (CT), the typical meningioma is a well-defined extra-axial mass displacing the brain. They are adjacent to dural layers, smooth in contour, and sometimes calcified or multilobulated. Isodensity with the

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surrounding brain could make the diagnosis arduous on a non-contrasted acquisition, but intravenous contrast administration leads to a uniformly bright enhancement. Secondary involvement of adjacent bone (erosion, reactive sclerosis, invasion) is unusual with convexity meningiomas but present in as much as one-half of skull base lesions (e.g., spheno-orbital en plaque meningiomas) (Park 2020). Differentiating an atypical or anaplastic meningioma from a grade I meningioma solely based on radiological imaging is hard. MRI characteristics that may indicate the presence of a higher-grade tumor rather, than a benign one, include the following (Hanft et al. 2010; Hsu et al. 2010; Hwang et al. 2016; Nagar et al. 2008; Park 2020; Zhang et al. 2008): intratumoral cystic modification, peritumoral brain edema, hyperostosis of the adjacent skull and/or bone invasion/destruction, tumor extension through the skull base, elevated cerebral blood volume (rCBV), low apparent diffusion coefficient (ADC) values. Nevertheless, none of the aforementioned radiological characteristics are sufficiently specific to be clinically reliable (Park 2020). 18-F Fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning has pointed out an association between a more intense uptake and higher-grade histology in some, but not all, studies and is of limited diagnostic value (Rogers et al. 2010). Innovative PET tracers, including specific somatostatin receptor ligands, appear more promising but are not yet widely accessible for clinical use (Galldiks et al. 2017; Nowosielski et al. 2017; Park 2020). Prior to the diffusion of MR and computed tomography (CT) scans, angiography was utilized to suggest meningioma diagnosis by exhibiting arterial supply from meningeal vessels and a characteristic delayed vascular blush. The use of angiography is currently limited to tumor embolization before surgical resection in selected cases such as giant convexity meningiomas or petroclival meningiomas, in which the presumed feeding arteries are not readily accessible to the surgeon (Park 2020). While meningioma is the most frequent cause of a discrete, dural-based enhancing mass, many

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other lesions can involve the peri-dural space, resulting in an MRI/CT appearance that may mimic a meningioma. These include metastatic carcinoma, lymphoma, plasmacytoma, solitary fibrous tumor, melanocytic neoplasms, gliosarcoma, inflammatory lesions such as sarcoidosis and granulomatosis, and infections such as tuberculosis (Johnson et al. 2002; Nowosielski et al. 2017; Park 2020). A definitive diagnosis of meningioma and classification as WHO grades I, II, and III requires histologic confirmation. Nonetheless, imaging studies often provide a provisional diagnosis and might be sufficient for empiric treatment when obtaining tissue for histopathological confirmation entails an unacceptable risk of causing morbidity (Park 2020).

3.5

Clinical Manifestations

Clinical manifestations are influenced by tumor site and by the time course over which it develops. Meningiomas are generally extremely slowgrowing; many are asymptomatic or paucisymptomatic and are found incidentally in a neuroimaging study performed for other reasons or at autopsy (Islim et al. 2019; Park 2020). In a systematic review and meta-analysis on incidental findings of brain MRI in about 20,000 children and adults, meningioma was detected in 0.29% of cases. Accordingly, meningioma has been considered the most common incidental intracranial tumor (Morris et al. 2009). The prevalence of incidental diagnosis is higher in older ages. After evaluation of brain MRI of older adult volunteers with a mean age of 65– 70 years, it was reported that meningioma was detected in approximately 2.5% of participants (Bos et al. 2016; Cerhan et al. 2019), with convexity (62%) and falx cerebri (15%) being the most common locations (Bos et al. 2016). Headache is a frequent symptom (Brodbelt et al. 2019). Seizures are identified preoperatively in nearly 30% of patients harboring an intracranial meningioma (Englot et al. 2016). The chance of seizure is higher when dealing with non-skull base locations (e.g., convexity and

parasagittal/falcine tumors) and the presence of peritumoral edema (Park 2020). Specific tumor locations are related to characteristic focal deficits. Examples of these lesions are acuity and visual field impairment when concerning the optic pathways, hearing impairment with cerebellopontine angle meningiomas, mental status changes with large frontally located meningiomas, loss of smell with olfactory groove meningioma, extremity weakness (foramen magnum, parasagittal, spinal meningiomas), obstructive hydrocephalus (especially with posterior fossa tumor).

3.6

Therapeutic Approaches

The management of patients affected by meningiomas demands a balance between the definitive treatment of the tumor and avoidance of treatment-related neurologic morbidity. Patientspecific variables such as age, comorbidity, presence or absence of symptoms, location of the tumor and its distance to crucial neurovascular structures, and tumor grades are all vital elements while deciding the optimal treatment (Bailo et al. 2019; Euskirchen and Peyre 2018; Park and Shih 2020). Regarding advancements in neuroimaging and increased frequency of clinical and radiological checkups, the discovery of incidental, asymptomatic meningioma is growingly common. Initial treatment methods include observation with regular imaging follow-up (FU), microsurgery, and stereotactic radiosurgery (SRS), considering the condition of each patient (Kim et al. 2018).

3.6.1 Observation A “watchful waiting” strategy appears reasonable for extremely old individuals and those with substantial comorbidities or low-performance status. In this situation, after an initial observation with clinical and contrast-enhanced MRI for six months, if patients are still asymptomatic and no proof of tumor growth is recognized, clinical

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and radiological monitoring can be continued yearly for 3–5 years, then every 2–3 years for as long as they continue being putative candidates for treatment. Nevertheless, proactive treatment is advised if the tumor grows considerably or becomes symptomatic at FU (Bailo et al. 2019; Goldbrunner et al. 2016; Islim et al. 2019; Park and Shih 2020). There is a reduced threshold for therapeutic intervention for relatively healthy younger individuals due to the expectation that tumor progression will inevitably necessitate treatment (Bailo et al. 2019; Park and Shih 2020).

3.6.2 Surgical Intervention 3.6.2.1 Intracranial Meningiomas General principles of meningioma surgery rely on the early interruption of their blood supply, internal decompression using an ultrasonic aspirator or cautery loops, delicate dissection of the tumor capsule from the surrounding nervous structures, and removal of attached bone and dura when it is possible (Lee and Sade 2009). Asymptomatic meningiomas which are large, growing, infiltrating, or associated with surrounding edema, as well as symptomatic tumors, should undergo maximal safe resection when feasible (Bailo et al. 2019; Goldbrunner et al. 2016; Park and Shih 2020). Radical tumor excision (along with its dural attachment) is desirable when meningiomas are in accessible locations since it can be curative (Bailo et al. 2019). Gross total resection (GTR), when achievable, is correlated with significantly higher local tumor control and progression-free survival (PFS) compared with partial resection, independent of tumor grade and other prognostic factors (Bailo et al. 2019; Goldbrunner et al. 2016; Kotecha et al. 2011; Marciscano et al. 2016; Nanda et al. 2017; Park and Shih 2020). GTR should include removal of the tumor dural attachment and any abnormal bone. Simpson grading system has been adopted to classify the degree of resection in convexity meningiomas (Simpson 1957):

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. Grade 1, complete removal, including the dural attachment and any abnormal bone . Grade 2, complete removal, with cauterization of the dural attachment . Grade 3, complete removal, without resection or coagulation of the dural attachment . Grade 4, subtotal removal . Grade 5, biopsy only. Studies demonstrating an OS and PFS advantage from complete resection of benign meningiomas generally antedate the routine use of postoperative MRI and the adjuvant adoption of SRS/RT with state-of-the-art conformal techniques on the residual disease. The utilization of present-day adjuvant SRS/RT techniques to treat residual tumors appears to be more efficient and has minimized treatment-related complications compared to more aggressive surgery (Park and Shih 2020). In contemporary practice, the aim of surgery is to obtain as extensive removal as possible while minimizing neurologic morbidity (a.k.a. “maximal safe resection”). The amount of resection differs according to tumor location, proof of invasion on imaging, and patient preoperative clinical status (e.g., presence of comorbidities and neurologic deficits) (Bailo et al. 2019; Park and Shih 2020). Complete removal is generally attempted for tumors belonging to the convexity, anterior third of the sagittal sinus, olfactory groove, and some posterior fossa and tentorial tumors (Figs 3.1 and 3.2). Partial resection might be more suitable for less accessible tumors, such as those implicating the cranial base and the posterior sagittal sinus region. The reported incidence of postoperative neurologic morbidity related explicitly to surgery varies from 2 to 30%, depending upon the extent of resection and tumor location. Cortical brain injury may take place when arachnoid and pia firmly adhere to the tumor capsule and when disruption of pial vasculature, with subsequent cortical microinfarction, occurs. Skull base surgery entails a major threat of cranial nerve impairment, and intraoperative cranial nerve monitoring needs to be used when operating

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close to these structures (Bailo et al. 2019; Park and Shih 2020). The reported overall surgical mortality varies broadly, reflecting disparities in patient selection criteria along with differences in surgical care. Factors associated with augmented mortality include poor preoperative clinical condition, advanced age, tumor-related brain compression, incomplete tumor resection, and intracranial hematoma requiring surgical evacuation (Bailo et al. 2019; Park and Shih 2020). The historic series indicated that the mortality was greater in elderly patients. More recent series, adopting present-day neurosurgical techniques, have demonstrated that surgery is possible even in carefully selected senior adults (Amano et al. 2018; Bailo et al. 2019; Park and Shih 2020). Along with surgical-related neurologic deficits, common medical complications include seizures, deep venous thrombosis (DVT) and pulmonary embolism, pneumonia, arrhythmias, and myocardial infarction (Bailo et al. 2019; Park and Shih 2020). Prophylactic antiepileptic therapy is usually not indicated before treatment in individuals without a history of seizures (Bailo et al. 2019; Drappatz and Avila 2019; Park and Shih 2020). Corticosteroids can be administered preoperatively to reduce brain edema in symptomatic patients, but they should be rapidly tapered postoperatively (Bailo et al. 2019; Park and Shih 2020). Symptomatic and asymptomatic postoperative venous thromboembolism have been reported with a rate of 4% and 26%, respectively (Carrabba et al. 2018). In patients undergoing surgical treatment, it is advised to use pneumatic compression stockings combined with postoperative low molecular weight (LMW) heparin or unfractionated heparin beginning 12 to 24 h after surgery and continuing until ambulation is resumed (Bailo et al. 2019; Park and Shih 2020). Management of peritumoral edema mainly relies on the use of glucocorticoids such as dexamethasone and also anti-angiogenic medications such as bevacizumab can be considered in exceptional circumstances when long-term negative effects or insufficient efficacy is being faced (Euskirchen and Peyre 2018).

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3.6.2.2 Spinal Meningiomas Surgical resection to remove the tumor and decompress the spinal cord represents the primary therapy (Euskirchen and Peyre 2018; Goldbrunner et al. 2016). The degree of removal should be adjusted to the tumor location: for easily accessible, laterally or dorsally located meningiomas where dural repair is feasible, Simpson grade I resection should be pursued, but only if it can be obtained without compromising neurological function and if a safe and uncomplicated dural repair is possible (Goldbrunner et al. 2016). In anteriorly located tumors, when neurological preservation is at risk or in the case of calcified dural attachment, coagulation of the involved dura, rather than resection, should be attempted due to an augmented risk of morbidity (Euskirchen and Peyre 2018; Kim et al. 2016). Adjuvant therapy should be considered in intracranial meningiomas (Euskirchen and Peyre 2018). Spinal meningiomas have been reported to have a 1.3–14.7% recurrence rate after microsurgery (Goldbrunner et al. 2016; Kim et al. 2016). Partial resection is universally considered a risk factor for recurrence, but whether Simpson grade I resection achieves better long-term outcomes than Simpson grade II is not clear (Goldbrunner et al. 2016; Kim et al. 2016). For rare cases in which surgical resections cannot be performed for any reason, or decompression of the spinal cord does not seem necessary, hypofractionated SRS or RT can be considered as an alternative (Goldbrunner et al. 2016). Adjuvant therapy is performed according to WHO grading and resection status for cranial meningiomas. 3.6.2.3 Advancements in Surgical Techniques Several neurosurgery advancements, including the use of the microscope and endoscope, enhanced preoperative radiological imaging, intraoperative neuro-navigation, and neurophysiological monitoring, have extended the neurosurgeon's capacity to remove tumors previously considered only partially removable or unresectable while lessening morbidity (Park and Shih 2020; Sicking et al. 2018). Minimally

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invasive keyhole techniques, which utilize a smaller craniotomy than traditional trans-cranial approaches, are also increasingly described. Still, with any of these evolving techniques, the aim of maximal safe removal should be preserved, particularly in the case of higher-grade meningiomas (Bi and Dunn 2017). Advanced preoperative and postoperative radiological techniques are progressively employed for tumor delineation, identifying residual tumor mass, and determining brain or bone invasion, and their use is encouraged (Euskirchen and Peyre 2018; Galldiks et al. 2017). For instance, 68 Ga-DOTATATE showed a better signal-to-background ratio for tumor delineation in regions with low MRI contrast such as the para-falcine region, skull base, orbit, or sinus and bone infiltration was identified as well (Euskirchen and Peyre 2018; Kunz et al. 2017). Adjuncts as 5-aminolevulinic acid (5ALA) fluorescence have been studied for their role in augmenting tumor satellite cells identification in the adjacent brain, dura, and bone in case of invasive meningiomas, with initial promise (Bi and Dunn 2017). It is unavoidable that surgery and biology will become further interlaced. An exciting prospect is the preoperative identification of targetable mutations with neoadjuvant drug therapy to reduce tumor size and make subsequent surgery safer (Bi and Dunn 2017; Pour-Rashidi et al. 2021). Two recently published, large longitudinal observational studies compared 817 and 1469 patients, respectively, who were operated on for their intracranial meningioma during the last three decades (Meling et al. 2019; Sicking et al. 2018). The series from Meling et al. documented a relevant reduction, in the last analyzed decade, of patients presenting at the time of surgery with low-performance status, augmented intracranial pressure, and/or neurologic deficits (Meling et al. 2019). Sicking et al. reported increased preoperative MRI availability and a diminished rate of angiography and tumor embolization (Sicking et al. 2018). Both studies

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(Meling et al. 2019; Sicking et al. 2018) found a trend toward operating on older patients; this is likely due to multiple factors, including increased use of neuroimaging in later decades, increased life expectancy, and the fact that elderly patients are now considered surgical candidates. The proportion of higher-grade meningiomas over the years had diverging results in the two series (Meling et al. 2019). The increased use of intraoperative neuromonitoring and neuro-navigation was reported (Sicking et al. 2018). Interestingly, the Simpson grade I achievement rate raised from 33 to 46% following the year 2000 (Meling et al. 2019) in one series, while it decreased from 42 to 24% in the other one (Sicking et al. 2018). Multiple variables might play a role; an earlier diagnosis leads to smaller tumor size at surgery, while the advancement of neuroimaging and intraoperative techniques such as the use of neuro-navigation has been reported to increase the rate of Simpson grade I achievement over time (Bir et al. 2016). Growing attention has focused on the importance of preserving the quality of life in patients. Accordingly, a trend toward combined approaches has been generated (e.g., STR followed by adjuvant SRS/RT on the residual tumor). Retreatment-free survival was increased over time only in the Meling et al. series (Meling et al. 2019). Despite the increasing age, the rate of perioperative mortality and worsened neurologic outcome were significantly decreased in the later decades (Meling et al. 2019; Sicking et al. 2018). On the contrary, no substantial differences were identified concerning postoperative hematoma and infections (Meling et al. 2019; Sicking et al. 2018). The median duration of hospitalization diminished progressively (Sicking et al. 2018): this can be partly explained by fewer emergencytype and more planned admissions with the organization of preoperative diagnostics, improved medical treatment, and, not to be overlooked, financial pressure on neurosurgical departments.

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3.6.3 Radiation Therapy 3.6.3.1 Radiation Therapy as Primary Treatment SRS/RT alone can effectively treat meningiomas that are not amenable to even an STR because of their vicinity to critical neurologic structures, offering excellent tumor control and avoiding surgical-related risks (Bailo et al. 2019; Korah et al. 2010). The approach is most commonly adopted for skull base and optic nerve sheath meningiomas. Tumor size is a crucial variable that cannot be miscalculated when considering SRS/RT alone. Larger lesions with remarkable mass effect are related to an augmented risk of reactive edema following SRS/RT, which can generate seizures and neurologic deficits that differ based on tumor location. STR before SRS/ RT is often considered to reduce the risk of radiation-related complications (Park and Shih 2020). SRS, especially when operated with Gamma Knife, has a shallow risk of long-term cognitive deterioration and secondary brain radio-induced tumors, particularly compared to conventional RT (Goldbrunner et al. 2016; Lindquist and Paddick 2007; Marta et al. 2015). Besides, the enhanced dose response of SRS makes it more advantageous for meningioma (a/b ratio near to normal brain). Certainly, new radiobiological mechanisms such as profound vascular damage, antigen expression, and enhanced immune response, which come in addition to the traditional DNA damage, are involved in SRS dose delivery regimens (Fuks and Kolesnick 2005; Garcia-Barros et al. 2003; Kirkpatrick et al. 2009; Prabhu et al. 2018; Santacroce et al. 2013; Song et al. 2015; Sperduto et al. 2015). A series of 35 retrospective studies showed a 5-year PFS of 86–100% after primary SRS (Rogers et al. 2015). SRS is an effective and safe alternative to microsurgery, particularly in elderly individuals or those who do not choose surgery, especially when there is a small/middle size tumor in functionally high-risk or deep locations. If the whole tumor can’t be approached with a single or hypo-fractionated SRS regimen, RT of 50–54 Gy delivered in doses of 1.8–2.0 Gy per

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fraction can be chosen. In multiple studies, the efficacy rate of RT has been reported 75–92%. The integration of STR with RT is associated with OS and PFS rates similar to those recorded after GTR (Goldbrunner et al. 2016). Some authors advocate proactive SRS as a practical option for asymptomatic patients with no significant comorbidity limiting life expectancy (Flannery and Poots 2019; Kim et al. 2018). Maximal safe resection still represents the primary choice to be looked at for a tumor going through symptomatic progression (Goldbrunner et al. 2016); however, SRS might, once more, be regarded as an effective and safe alternative for asymptomatic small- to moderate-sized tumors showing enlargement on serial imaging, especially in case of critical location, comorbidities or patients desiring to avoid surgery (Apra et al. 2018a, b; Flannery and Poots 2019; Goldbrunner et al. 2016; Rogers et al. 2015; Shaikh et al. 2018). Aside from the invasiveness and potential risk of severe morbidity, it is essential to contemplate the impact that microsurgery has on patients’ private and working life, both in the short term (e.g., hospitalization and time required to recover) and long term, as indicated in recent research reporting a 40% rate of cognitive or psychological issues (e.g., anxiety or depressive symptoms) following surgery (van der Vossen et al. 2014).

3.6.3.2 Radiation Therapy as Adjuvant/Salvage Treatment The utilization of a planned combination of treatments, consisting of subtotal/partial resection followed by SRS or RT, allows definite tumor treatment while decreasing surgery-related risks, particularly in cases where the tumors are located in critical areas such as the cavernous sinus (Bailo et al. 2019; Goldbrunner et al. 2016) (Figs 3.3 and 3.4). SRS is the adjuvant treatment of choice when GTR cannot be achieved in benign meningiomas (Euskirchen and Peyre 2018). The dose can be administered in a single session (typical prescription dose ranges from 12 to 16 Gy) or

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through hypo-fractionated (2–5 sessions) schemes (Bailo et al. 2019; Flannery and Poots 2019; Santacroce et al. 2012) according to tumor size, the proximity to organ at risks (e.g., optic pathways or brainstem) and the applied technique. When RT is preferred for the treatment of postoperative residual tumor (for instance, in case of irregular margins, complex target definition, large residual tumor, or closeness to the organs at risk), a dose of 50–54 Gy in 1.8–2 Gy daily fractions is usually suggested (Rogers et al. 2015). In atypical or malignant meningiomas, RT with higher doses ( ≥ 54 Gy) is the adjuvant treatment of choice (Euskirchen and Peyre 2018). Observational studies pointed out that RT delivered soon after incomplete resection of WHO grade II-III tumors considerably enhances PFS compared with partial resection alone (Bailo et al. 2019; Euskirchen and Peyre 2018). When managing anaplastic meningiomas, adjuvant RT is recommended, no matter the degree of resection (Goldbrunner et al. 2016). For individuals who have undergone partial removal or biopsy of an atypical meningioma, adjuvant RT rather than watchful waiting is recommended postoperatively (Goldbrunner et al. 2016). In patients with radiological progression, RT should be administered, if not already performed, following initial surgery, with or without a second surgical attempt (Goldbrunner et al. 2016). In gross-totally resected tumors, consideration should be given to whether the potential advantages of RT outweigh the danger of side effects and delayed toxicity (Goldbrunner et al. 2016; Kaur et al. 2014). Overall, pharmacological treatment should be contemplated after further progression of WHO grade II meningiomas (Goldbrunner et al. 2016). Adjuvant SRS/RT for partially resected, WHO grade I, meningiomas has been shown to ameliorate local control, but its proper timing and indication are still disputed; thus, it is more selectively used after partial resection of benign meningiomas as compared to more malignant tumors. Retrospective data support the role of SRS/RT in incompletely resected tumors located in poorly

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accessible areas such as the posterior sagittal sinus or the skull base (Park and Shih 2020).

3.6.4 Chemotherapy and New Therapeutic Modalities Numerous systemic drugs have been explored in meningioma but have exhibited, to date, limited benefit in clinical trials (Venur et al. 2018). Chemotherapies (ChT) such as temozolomide, irinotecan, and a combination of cyclophosphamide, vincristine, and doxorubicin have been mostly unproductive (Wen et al. 2010). Due to the expression of somatostatin receptors in nearly 90% of meningiomas, somatostatin analogs have been tested in many small studies, although most trials have not shown significant PFS enhancement (Simo et al. 2014; Venur et al. 2018). Studies with other agents such as mifepristone, imatinib, interferon-a, and hydroxyurea have failed to show consistent advantage (Chamberlain and Glantz 2008a; Grunberg et al. 2006; Ji et al. 2015; Venur et al. 2018; Wen et al. 2009). Meningiomas are well-vascularized tumors; nevertheless, attempts to target vascular endothelial proliferation receptors with bevacizumab (which inhibits vascular endothelial growth factor A) and sunitinib (multiple receptor tyrosine kinases inhibitor) have yielded only modest results (Furtner et al. 2016; Kaley et al. 2015). Research assessing the combination of everolimus (mTOR inhibitor) and bevacizumab in 17 meningioma patients experiencing tumor progression after microsurgery and RT demonstrated a median PFS of 22 months, with 88% of the patients having a stable disease as the best response (Shih et al. 2016; Venur et al. 2018). A phase 2 study examined the combination of everolimus and octreotide, a somatostatin analog, in 20 patients with progressive intracranial meningioma showing preliminary evidence of this combination's activity within six months PFS of 58.5% (Graillon et al. 2017; Venur et al. 2018). A novel dual mTORC1 and mTORC2 inhibitor, AZD2014, hampered the proliferation of meningioma cell lines, and these findings have

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led to two early phase clinical trials (NCT03071874 and NCT02831257) (Beauchamp et al. 2015). Other molecules, such as CDK4/6 inhibitors, PD-1 inhibitors, and FAK inhibitors, are currently under investigation (Venur et al. 2018). SMO and AKT1 inhibitors are under evaluation in an ongoing Alliancesponsored cooperative group phase II trial in the USA (Venur et al. 2018).

3.7

Prognosis and Follow-Up

Intraoperative estimation of the amount of resection should be confirmed by a postoperative MRI obtained within 48 h from surgery, or after three months, in order to avoid surgery-related artifacts (Bailo et al. 2019; Goldbrunner et al. 2016). GTR (Simpson Grades 1–3) remains the principal goal of surgery for meningioma and is obtained in nearly one-half to two-thirds of cases in surgical series, including all intracranial locations and in more than 95% when considering convexity meningiomas only (Mirimanoff et al. 1985; Morokoff et al. 2008; Pollock et al. 2000; Rogers et al. 2015). For WHO grade I meningiomas, GTR is considered a definitive treatment. However, with extended FU, recurrences in this setting are not uncommon (Rogers et al. 2015). In 5 distinct series, local recurrence rates after GTR were 7– 23% at five years, 20–39% at ten years, and 24– 60% at 15 years (Mirimanoff et al. 1985; Rogers et al. 2015). The higher rates documented in the most recent studies probably reflect the contemporary use of a serial assessment with contrastenhanced MRI (Rogers et al. 2015). Due to their superficial localization and easier control of the feeding vascularization, the vast majority of benign convexity meningiomas can be totally removed with an exceptional prognosis after microsurgery alone (Park and Shih 2020). After Simpson grade I or grade II resection range, recurrence rates are reported as 3–10% (Hasseleid et al. 2012; Nanda et al. 2016; Oya et al. 2012; Park and Shih 2020; Voss et al. 2017). Simpson grades III and IV resections are

associated with unquestionably higher recurrence rates (10–25% and 33–50%, respectively) (Hasseleid et al. 2012; Nanda et al. 2016; Oya et al. 2012; Park and Shih 2020; Voss et al. 2017). The prognosis of benign meningiomas is mostly favorable, with an overall recurrence rate of 20% at 20 years. However, anaplastic lesions (WHO grade III) have a poor prognosis with a median OS of only 1.5 years (Bailo et al. 2019; Euskirchen and Peyre 2018). Five- and ten-year net survival for cranial meningiomas were 90% and 81%, respectively, for WHO grade I, 80% and 63% for grade II, and 30% and 15% for WHO grade III tumors (Brodbelt et al. 2019).

3.8

Other Meningeal Tumors

3.8.1 Hemangiopericytoma/Solitary Fibrous Tumor Although somewhat variable in histology and certainly in prognosis, solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are considered variants of a single pathological entity (extra-pleural solitary fibrous tumor/hemangiopericytoma) characterized by the presence of a NAB2-STAT6 fusion protein (Schweizer et al. 2013). However, in neuropathological practice, the two phenotypes are still distinguished when they arise in the dura (Chheda and Wen 2020; Louis et al. 2016). They are both rare dural-based lesions accounting for < 1% of all primary CNS tumors (Louis et al. 2016). They usually occur at adult age (mean age at diagnosis: 40–50 years) (Guthrie et al. 1989; Hall et al. 2012; Sung et al. 2018). Males are slightly more affected than females. The distribution within the CNS is similar to meningiomas: 70% are located in the supratentorial space, 15% in the posterior fossa, and 15% in the spine. Extracranial metastases may occur, most frequently in the bones, lungs, and liver (Chheda and Wen 2020; Ratneswaren et al. 2018). CT often shows a hyperdense extra-axial mass with focal hypodense areas. Erosion of the bone

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can be spotted, but there is usually no sign of hyperostosis. MRI signal is isointense in T1- and T2-weighted sequences, with the presence of flow voids; there is a heterogeneous enhancement after contrast administration. The “dural tail” sign is identifiably in approximately 50% of the cases, and peritumoral edema is often present. Additionally, a “corkscrew” vascular configuration might be present (Chheda and Wen 2020). CNS SFT/HPCs accompanied by a classic solitary fibrous tumor phenotype are consistent with WHO grade I (Louis et al. 2016). When the size of SFT/HPC grade I tumors slowly increases and consequently compression of adjacent structures occurs or the intracranial pressure increases, symptoms can be seen (Chheda and Wen 2020). In the histopathological evaluation, the SFT phenotype is characterized by a short fascicular pattern or pattern-less architecture, with hypercellular and hypocellular sites along with thick collagen bands. Thin-walled branching vessels may be spotted. Typically, mitotic activity is minimal ( ≤ 3 mitoses per 10 high-power fields [HPF]). SFTs have a typical immunohistochemical profile of vimentin, Bcl-2, and CD34 positivity, differentiating these tumor entities from other pathologies containing fibrous elements (such as fibrous meningioma) (Louis et al. 2016). Confirmation of NAB2-STAT6 fusion or identification of STAT6 expression in the nucleus with immunohistochemistry is advocated for diagnosis. They entail a generally good prognosis after surgical resection alone, although STR may be accompanied by local recurrence (Metellus et al. 2007). Recurrent lesions may be approached with re-intervention, RT, or SRS, but they are related to decreased survival (Cai and Kahn 2004; Chheda and Wen 2020; Nakahara et al. 2006; Pakasa et al. 2005). CNS SFT/HPCs with a hemangiopericytoma phenotype are regarded as malignant lesions (Louis et al. 2016). According to mitotic count, they are further classified as grade II or grade III (< 5 vs. ≥ 5 mitoses per 10 HPF). The common symptoms are headache, focal neurologic deficits, or seizures due to the mass effect or edema in adjacent brain parenchyma.

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Because of the rapid growth, the onset of symptoms is usually less than one year (Chheda and Wen 2020). The histopathological properties of HPC phenotype are an increase in cellularity and closely opposed ovoid cells with little intervening stroma. Higher mitoses and necrosis are detected in the field of the lesion. Cells are poorly labeled with CD34. Confirmation of NAB2-STAT6 fusion or detection of STAT6 nuclear expression with immunohistochemistry assists in the diagnosis and distinguishing these tumors from other entities such as dural-based Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), mesenchymal chondrosarcoma, and synovial sarcoma (Chheda and Wen 2020; Louis et al. 2016). SFT/HPC with a hemangiopericytoma phenotype is invasive, and postoperative RT helps in most cases. Even after GTR, they often relapse within CNS or even outside of it (e.g., bone, lung, liver). After RT, it has been reported higher local control, PFS, and OS rates (Chheda and Wen 2020; Kano et al. 2008; Rutkowski et al. 2012; Schiariti et al. 2011; Soyuer et al. 2004). In selected cases of recurrent disease after RT, ChT may be valuable (Chamberlain and Glantz 2008b). Innovative therapies, including antiangiogenic medications, are being investigated for extracranial SFT/HPC (Ebata et al. 2018; Park and Araujo 2009) and might also have a role in intracranial disease. One report described a significant clinical and radiological response to pazopanib (a receptor tyrosinase kinase inhibitor that hampers angiogenesis, in two patients with recurrent meningeal SFT/HPC (Apra et al. 2018a, b; Chheda and Wen 2020). Grades II and III SFT/HPC have a worse prognosis compared to meningiomas. After the assessment of 199 patients with CNS HPC, 5and 10-year OS rates were 80% and 54%, respectively (Hall et al. 2012). While, extracranial HPC cases have been reported to have worse outcomes, with a 5- and 10-year OS of 58 and 44% (Chheda and Wen 2020). In a series of 39 cases, over 24 years, recurrence rates at 1, 5, and 15 years were reported as

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4%, 46%, and 92%, respectively (Schiariti et al. 2011). Extracranial metastases occurred in 26%, at an average of 10 years after primary surgery. The mean OS for the group was 18 years, and 13 patients died due to tumor-related causes at FU. Those undergoing GTR and receiving adjuvant RT appear to harbor an improved recurrence-free survival (Chheda and Wen 2020).

3.8.2 Melanocytic Tumors Melanocyte proliferation can result in either localized or diffuse, benign or malignant conditions (Painter et al. 2000). Somatic mutations in the GNAQ or GNA11 genes, usually implying codon 209 in either case, are commonly identified in melanocytomas and less frequently in primary meningeal melanomas (Chheda and Wen 2020; Kusters-Vandevelde et al. 2010; Louis et al. 2016). Meningeal melanocytomas are typically located in the cervical or thoracic spinal cord, and they are well-differentiated low-grade lesions arising from leptomeningeal melanocytes. They may be dural-based or associated with nerve roots or spinal foramina. Meningeal melanocytomas are macroscopically and histologically similar to meningiomas, although ultrastructurally different. Supratentorial and posterior fossa tumors arising from the leptomeninges are less frequent (Rousseau et al. 2005). They are well-defined, solid, and attached to the meninges, while not involving the cortex. These lesions should be considered in the differential diagnosis of lesions in the posterior fossa, Meckel's cave, or spinal canal. They have a higher prevalence in the fourth and fifth decades. Neuroimaging alone is not able to definitively differentiate a meningeal melanocytoma from a meningioma, although tumors rich in melanin might appear hyperintense on T1-weighted MRI. Albeit meningeal melanocytomas were historically regarded as benign, there is a significant reduction in survival in individuals undergoing an STR, possibly due to a malignant degeneration

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into melanoma (O'Brien et al. 2006). The 5-year survival rate may be as low as 42% in those who underwent STR without adjuvant RT (Chheda and Wen 2020; O’Brien et al. 2006). Primary malignant melanomas of the CNS typically affect young adults in their fourth decade of life, but there is a secondary peak in incidence in the first decade. These melanomas are dural-based, poorly circumscribed, diffuse, and usually invade cerebral and spinal cord parenchyma. Given the rarity of meningeal melanoma compared with metastatic cutaneous melanoma, a systemic evaluation with PET/CT is suggested whenever a meningeal melanoma is identified (Chheda and Wen 2020). Symptoms of primary malignant melanoma are often related to increased intracranial pressure. Other symptoms may include seizures, cranial nerve palsies, or focal motor or sensory abnormalities. On MRI, CNS melanomas are hyperintense and hypointense on T1 and T2, respectively, and after gadolinium administration, their enhancement occurs. Occasionally, hemorrhagic components can be detected on imaging. In a subarachnoid disease, through cerebrospinal fluid (CSF) cytology, the diagnosis can be obtained (Chheda and Wen 2020). Primary CNS melanomas are aggressive tumors. Management is surgical intervention whenever possible, followed by adjuvant RT; unfortunately, these tumors are relatively radioresistant. Overall, they entail a poor prognosis, with an OS shorter than a year in most cases (Brat et al. 1999; Chheda and Wen 2020; Freudenstein et al. 2004). To target these tumors and treat them properly, molecular testing for mutations in BRAF is helpful; however, such modifications are not frequent in primary meningeal melanomas (Louis et al. 2016). Immunotherapy in advanced cutaneous melanoma can be efficient although the rate of advantage of using this treatment is different in every patient. However, the efficacy and safety of these therapies in meningeal melanoma have not yet been confirmed (Chheda and Wen 2020).

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3.8.3 Sarcomas A variety of sarcomas subtypes can affect the CNS; some arise directly in the meninges from mesenchymal cells, while others present with direct extension from the skull base, sinuses, cranial vault, or even extracranial soft tissue. On MRI, they appear hypointense on T1 and hyperintense on T2. Other radiological characteristics are connected to specific tumor differentiation. Sarcomas may be differentiated along several lines, including fibrosarcoma, rhabdomyosarcoma, osteosarcoma, chondromas, chondrosarcomas, leiomyosarcomas, liposarcoma, or angiosarcomas. Therapeutic approaches are GTR, whenever possible, accompanied by RT and CT. Even with aggressive treatment, the survival in 5-year is reported to be poor (Berger and Prados 2005; Uluc et al. 2004). Due to the rare occurrence of these tumors in the CNS, the evaluation and management should be considered in a multidisciplinary setting (Chheda and Wen 2020).

3.8.4 Lymphomas Dural lymphomas present as contrast-enhancing lesions with an extension that might resemble a nodular meningioma with a dural tail, an en plaque meningioma, dural hypertrophy, or even a subdural hematoma. An expansion deep into the arachnoid spaces and sulci is especially suspicious. Primary dural lymphomas are uncommon, and they should not be mistaken for primary CNS lymphoma. They are primarily of the mucosa-associated lymphoid tissue (MALT) type (Goetz et al. 2002; Rottnek et al. 2004), although other types and even Hodgkin's disease have been reported (Johnson et al. 2000). They entail a better prognosis than primary central nervous system lymphoma (PCNSL) and show a good response to cranial RT (Beriwal et al. 2003). Many of the reported dural lymphomas were initially misdiagnosed based on their neuroimaging appearance, and therefore, some underwent resection. Cranial RT is recommended even after resection,

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but certainly after biopsy (Westphal et al. 2010).

3.8.5 Fibrous Histiocytoma Fibrous histiocytomas are composed of atypical fibroblasts and histiocytes and may be either malignant or benign (Berger and Prados 2005; Pimentel et al. 2002). When they present in the CNS, they may be dural-based or grow inside the brain parenchyma (Chheda and Wen 2020). They may present with headache, seizures, cranial neuropathy, or hemiparesis. Primary intracranial malignant fibrous histiocytomas may appear as large masses on CT images. In case the mass is accompanied by cystic components, it may demonstrate previous hemorrhage or liquefied necrosis. MRI shows a heterogeneous extraaxial mass with thick, irregular enhancement. Areas of liquefied necrosis may cause an intense T2 signal while T2 hypointensity represents the tumor matrix (Chheda and Wen 2020; Ogino et al. 1996). Benign fibrous histiocytomas can be managed with surgery alone. Treatment of malignant subtypes is still unsatisfactory, despite the addition of RT and ChT to the surgery. In a review of the literature, including 18 cases of malignant fibrous histiocytoma, the one- and two-year OS were 46% and 23%, respectively (Chheda and Wen 2020).

3.8.6 Metastases Metastatic spreading to the brain is observed with growing frequency. Still, in comparison with the parenchymal or leptomeningeal variants, purely dural involvement is uncommon and is identified most often in the context of suspected meningioma (Laidlaw et al. 2004; Tagle et al. 2002). While in intraparenchymal disease a metastasis is more easily suspected due to the neuroimaging features and the knowledge of the primary tumor, the diagnosis of a dural metastasis is much more difficult (Tagle et al. 2002). When purely dural and mimicking the typical

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features of a meningioma, the differential diagnosis is nearly impossible without a tissue sample and histopathological analysis because the imaging techniques may not provide enough evidence for differentiation. The tumors may be dural with a flat spread, nodular, or show a combination of subdural, dural, and skull extension. Depending on the context of the patient's overall status, there may be an indication for surgical removal, especially when a definite diagnosis cannot be made without histology and there is no primary tumor. As the spectrum of histological origins is very heterogeneous, there are no published studies about the role of RT or ChT as there are for leptomeningeal metastatic diseases. The management following histological verification of a dural metastasis will rely on the established treatment paradigms for the primary tumor and must be determined by an interdisciplinary tumor board (Kremer et al. 2004; Westphal et al. 2010). A large series of combined surgical and autoptic cases revealed a surprisingly broad spectrum of primary tumors involved, including the expected high number of breast cancer cases, and even a higher number of underlying prostate cancer cases, which can manifest in a variety of ways, as well as primaries like the larynx, stomach, and gall bladder which rarely metastasize to the brain (Kleinschmidt-DeMasters 2001; Westphal et al. 2010).

3.9

Conclusion

Meningiomas develop in meningothelial cells and account for roughly one-third of central nervous system (CNS) tumors. Most meningiomas are benign although their CNS location can still cause severe morbidity or mortality; accordingly, a proper treatment strategy is required. Complete microsurgical resection is the standard treatment if it can be achieved with minimal or no morbidity. However, stereotactic radiosurgery and radiotherapy have been reported as appropriate treatment options, which could be considered either as primary approaches or as complementary to surgery, especially in cases

with cranial base meningiomas or accompanied comorbidity or wishing to avoid invasive treatments. Adjuvant radiosurgery/radiotherapy should be considered in the case of atypical and anaplastic histology, especially when a residual tumor is identifiable in postoperative imaging. A “watchful waiting” strategy appears reasonable for extremely old individuals and those with substantial comorbidities or lowperformance status, while there is a reduced threshold for therapeutic intervention for relatively healthy younger individuals due to the expectation that tumor progression will inevitably necessitate proactive treatment. Meningioma management is a field of complementary disciplines and both neurosurgeons and radiation oncologists should coordinate to achieve the optimal approach to treat these patients. The possibility of other rarer tumors (hemangiopericytomas/solitary fibrous tumors, lymphomas, metastases, melanocytic tumors, and fibrous histiocytoma) must be considered when encountering a meningeal lesion since the ideal diagnostic and therapeutic approach might differ consistently in that occurrence.

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97 Fink K, Deangelis LM, Mehta M, Di Tomaso E, Drappatz J, Kesari S, Ligon KL, Aldape K, Jain RK, Stiles CD, Egorin MJ, Prados MD (2009) Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01– 08). Neuro Oncol 11(6):853–860. https://doi.org/10. 1215/15228517-2009-010 Westphal M, Lamszus K, Tonn JC (2010) Meningiomas and meningeal tumors. In: Tonn J-C, Westphal M, Rutka JT (eds) Oncology of CNS tumors. Springer Berlin Heidelberg, pp 95–118. https://doi.org/10.1007/ 978-3-642-02874-8_4 Whittle IR, Smith C, Navoo P, Collie D (2004) Meningiomas. Lancet 363(9420):1535–1543. https://doi.org/ 10.1016/S0140-6736(04)16153-9 Wiemels J, Wrensch M, Claus EB (2010) Epidemiology and etiology of meningioma. J Neurooncol 99(3):307– 314. https://doi.org/10.1007/s11060-010-0386-3 Zhang H, Rodiger LA, Shen T, Miao J, Oudkerk M (2008) Perfusion MR imaging for differentiation of benign and malignant meningiomas. Neuroradiology 50(6):525–530. https://doi.org/10.1007/s00234-0080373-y

4

Ependymomas in Children and Adults Marios Lampros, Nikolaos Vlachos, and George A. Alexiou

Abstract

Ependymomas account for approximately 5% of all CNS tumors in adults and around 10% in the pediatric population. Contrary to traditional theories supporting that ependymomas arise from ependymal cells, recent studies propose radial glial cells as the cells of origin. In adults, half of the ependymomas arise in the spinal cord, whereas in the pediatric population, almost 90% of ependymomas are located intracranially. Most of the ependymomas are usually low-grade tumors except anaplastic variants and some cases of RELA-fusionpositive ependymomas, a molecular variant consisting the most recent addition to the 2016 World Health Organization (WHO) classification. Of note, the recently described molecular classification of ependymomas into nine distinct subgroups appears to be of greater clinical utility and prognostic value compared to the traditional histopathological classification, and parts of it are expected to be adopted by the WHO in the near future. Clinical manifestations depend on the location of the tumor with infratentorial ependymomas presenting with acute hydrocephalus. Gross total resection

M. Lampros . N. Vlachos . G. A. Alexiou (&) Department of Neurosurgery, University of Ioannina, School of Medicine, 45500 Ioannina, Greece e-mail: [email protected]

should be the goal of treatment. The prognostic factors of patients with ependymomas include age, grade, and location of the tumor, with children with intracranial, anaplastic ependymomas having the worst prognosis. In general, the 5-year overall survival of patients with ependymomas is around 60–70%. Keywords

Ependymoma Prognosis

4.1

. Intracranial . Spinal .

Background and Epidemiology

Ependymomas constitute neuroepithelial tumors that can arise throughout the central nervous system (CNS). They account for approximately 5% of all CNS tumors in adults, amounting to around 10% in the pediatric population, with a slight male predominance (Delgado-López et al. 2019; Wild et al. 2018). Although they were thought to originate from ependymal cells lining the walls of the cerebral ventricles and the spinal canal, recently it has been suggested that these neoplasms derive from radial glial stem cells along the CNS (Taylor et al. 2005). In adults, ependymomas most frequently arise in the spinal cord (*45%), whereas the infratentorial (*35%) and supratentorial (*20%) compartments are less frequently affected. On the

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_4

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contrary, in pediatric population, the vast majority of ependymomas (*90%) are located intracranially; of these, almost two-third are in the posterior fossa and one-third supratentorial while the spinal cord represents a rather uncommon site (Hübner et al. 2018). Extremely rarely, ependymomas may be found in extraCNS locations with sacrococcygeal region being the most common (Alexiou et al. 2012). Correlation between familial cancer syndromes and ependymomas is well known; particularly, neurofibromatosis type 2 (NF2) has been associated with an increased incidence of spinal ependymomas (Yao et al. 2011).

4.1.1 Epidemiology Across All Age Groups Ependymomas have an annual incidence of 0.2– 0.4 per 100,000 with male-to-female ratio that varies from 1.2 to 1.8:1. Caucasians appear to be more frequently affected compared to other race groups. These tumors appear to have two distributional peaks: 0–4 and 55–59 years of age. Approximately 50% of ependymomas are located in the spinal cord, followed by posterior fossa, supratentorial compartment, and other CNS sites. With regard to the histological type, Grade II ependymomas are the most frequently observed followed by myxopapillary ependymomas, subependymomas, and anaplastic ependymomas (Villano et al. 2013).

4.1.2 Epidemiology of Ependymomas in Adults The majority of ependymomas in adults (50– 60%) arise in the spinal cord with the brain being less frequently affected. Older adults tend to develop ependymomas intraventricular and in the posterior fossa. With advancing age, the incidence of subependymomas appears to increase, whereas the incidence of myxopapillary ependymomas tends to decrease (McGuire et al. 2009b).

M. Lampros et al.

4.1.3 Epidemiology of Ependymomas in Children and Adolescents Ependymomas represent the third most common pediatric CNS tumor behind astrocytomas and medulloblastomas. They also comprise approximately 10% of all pediatric intracranial tumors and around 25% of all pediatric spinal tumors (Alexiou et al. 2011b). The most common site is the infratentorial compartment, while only 20% of these tumors originate from the spinal cord. Particularly, children appear to develop ependymomas in specific anatomical regions at different ages: the mean age is around 12 years old for spinal ependymomas, around 8 years for supratentorial, and approximately 5 years for infratentorial ependymomas. Anaplastic ependymomas are almost 6 times more frequent in children and adolescents compared to adults (Vitanza and Partap 2016).

4.2

Genetics, Immunology, and Molecular Biology

Ependymomas are tumors with a highly heterogeneous clinical behavior and prognosis, even between tumors with similar histological features. The latter implies that the tumorigenesis of these neoplasms is probably guided by distinct genetic and epigenetic alterations. Recently, numerous studies have attempted to elucidate the genetic landscape of ependymomas. In a large study, Patjer et al. proposed a new molecular classification of ependymomas, categorizing them into nine distinct subgroups. This classification is extensively discussed in Sect. 4.3.2 (Pajtler et al. 2015). The tumorigenesis of ependymomas is a profoundly complicated process regulated by multiple signaling pathways, including pathways involved in the development of the CNS such as Notch, Wnt, and Sonic hedgehog (SHH) pathways. The latter is consistent with the theory supporting the radial glial cells as the cells of origin of ependymomas (Taylor et al. 2005). In an exhaustive literature

4

Ependymomas in Children and Adults

review, Seo et al. described three different pathogenetic mechanisms to explain the malignant transformation of radial glial cells (RGCs) into malignant ependymal cells. The first pathway involved the increased expression of the Empty Spiracles Homeobox 2 (EMX2) that leads to an increased symmetrical division of RGC into two stem cells. In contrast, asymmetrical division leads to the formation of one stem cell and one non-stem cell. In the last process, the PAX6 gene is involved. The loss of balance between the activity of EMX2 and PAX6 genes, with hyperexpression of EMX2, leads to an unopposed symmetrical division that emerges as potential cancer stem cells. The second pathway involves the deletion of a-E-cadherin and hyperactivation of the SHH pathway. This process results in the deregulation of apoptotic mechanisms and finally in the formation of malignant ependymal cells. The third mechanism involves the deregulation of the Notch and EPHB-Ephrin pathways via upregulation of the Jagged canonical notch ligand 1–2 and Notch receptors. The activation of Notch has been found to be related with the pathogenesis of ST-EPN-RELA ependymomas, and specifically, the ST-EPN-RELA seems to promote the activation of the Notch pathway (Seo et al. 2021). Additionally, Gilbertson et al. found that activation of the Notch signaling pathway in pediatric patients with ependymomas is related to overexpression of the ERBB2 receptors (ERBB2-HER 2/4) (Gilbertson et al. 2002). Other common possible pathogenetic mechanisms of ependymomas include the hyperexpression of the homeobox (HOX) family that is related to the pathogenesis of myxopapillary ependymomas and spinal ependymomas and deletion of the RAC family small GTPase 2 (RAC2), C22orf2/Chibby family member 1 (CBY1) genes that are located on chromosome 22. Karakoula et al., by performing real-time polymerase chain reaction (PCR) in pediatric patients with ependymomas, found that gene losses on the chromosome 22 were detected in 81% of the patients, and the RAC2 and C22orf2 genes, both involved in cell growth, were more frequently affected. Additionally, they found that gains into the 1q chromosome were detected in

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61% of the cases, while gain of translocated promoted region (TPR), an oncogenic activator of protooncogenes, located on 1q25 is being detected in around 40% of the cases (Karakoula et al. 2008). The role of some common oncogenes such as TP53 and CDK2NA seems to be limited in the tumorigenesis of ependymomas (Gupta et al. 2016). The exact correlation of the known familial cancer syndromes with the tumorigenesis of ependymomas is currently unclear. Nevertheless, an increased incidence of spinal ependymomas in patients with NF2 has been observed. Additionally, loss of the 22q chromosome, in which the NF2 gene is located or sporadic mutations in the NF2, has been found in patients with spinal ependymomas. However, this gene is rarely found mutated in intracranial ependymomas. An increased frequency of ependymomas has also been reported in patients with genetic alterations (Li-Fraumeni syndrome or sporadic mutations) in the tumor suppressor TP53 gene. However, it should be noted that these familiar cases represent only a minority of patients with ependymomas, and even in this case, these genes are not considered to be the main driver genes in the tumorigenesis of ependymomas (Pajtler et al. 2015; Yao et al. 2011). The genome of the simian virus 40 (SV40) is found in most patients with ependymomas. This virus was found to contaminate poliovirus vaccine pools utilized for the production of the Salk vaccine between 1955 and 1963. Later, this virus was found to have oncogenic properties in animal models, and there was an initial concern for an increased risk of cancer development in the vaccinated individuals. Nevertheless, in the following years, large epidemiological studies discredit this virus as a cause of cancer development in humans (Gupta et al. 2016; Shah 2004). Several cytogenetic abnormalities, mainly chromosomal deletions and gains, have been reported in patients with ependymomas. Concerning intracranial ependymomas, gain of 1q chromosome and loss of 6q (6q21, 6q23, 6q24– 26) are among the most frequent reported cytogenetic abnormalities, with the loss of 1q being related with the anaplastic variant, and are

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considered a poor outcome predictor. In spinal ependymomas, characteristic cytogenetic abnormalities include the loss of 22q (associated with NF2) and gains in the chromosome 7q. The gains in chromosome 7 and 9q24.3-qter are more common in the pediatric age group and can be found in up to 60% of children with ependymomas. Other common chromosomal gains in patients with ependymomas are detected in 1q, 9q, 7q, 7q34, 1p34, 2p24, and 6p21, while other frequently reported chromosomal losses are detected in 11q, 22q, 1p36, 5q31, 16q24, 9p24.31, and 9p23 (Yang et al. 2012; Yao et al. 2011). Epigenetic factors may also contribute to the pathogenesis of ependymomas as well. Particularly, hypermethylation in the promoters (within dinucleotide CpG islands) of tumor suppressor genes has been described in patients with ependymomas. Waha et al. studied the methylation status of the hypermethylated in cancer-1 (HIC-1) gene and found that this gene was hypermethylated in 83% of patients with ependymomas. Additionally, they found that this gene was downregulated in 81% of the patients with ependymomas (Waha et al. 2004). Similarly, inactivation of the tumor suppressor Ras association domain family 1 isoform A (RASSF1A) gene has also been found to be hypermethylated in most patients with ependymomas (Donninger et al. 2007; Yao et al. 2011). Despite that, the epigenetic of ependymomas is not sufficiently studied, and future larger studies should be performed to determine the exact role of epigenetics in the tumorigenesis of ependymomas. The role of immunochemistry in the diagnosis of ependymomas is probably limited due to the heterogeneity in the expression of immunochemistry markers among the different ependymoma variants (Gupta et al. 2016). Vege et al. studied the expression of several glial and epithelial markers in 52 ependymomas. They found that almost all tumors were immunoreactive for glial fibrillary acidic protein (GFAP), S100, and keratin AE1/AE3. The expression of GFAP was prominent in glial appearing ependymomas with perivascular pseudorosettes,

M. Lampros et al.

while diffuse staining for S-100 was observed in ependymomas with epithelial features (Vege et al. 2000). It should be noted that the expression of GFAP is negatively correlated with the level of malignancy, with lower grade ependymomas having greater expression. Epithelial membrane antigen (EMA) is another marker that is positive in around 70% of ependymomas with epithelial features. The expression of EMA is probably more prominent in Grade II and Grade III ependymomas (Suri et al. 2004). Two patterns of EMA staining are generally observed, the intracytoplasmic dot-like pattern and the ring-like pattern, with the dot-like pattern being more common in anaplastic ependymomas. Additionally, vimentin is another marker that is typically positive in ependymomas, while the expression of different cytokeratin types varies (5–40%). Finally, the expression of CD-99 may be a useful marker to differentiate ependymal from nonependymal tumor (Mahfouz et al. 2008). The expression of Ki-67 (MIB-1) index has been correlated with the ependymoma grade, with higher grades having increased mean Ki-67 index. As a general, the mean Ki-67 index is around 0–2% for Grade I ependymomas, 1–4% for Grade II ependymomas, and over 10% for Grade III ependymomas (Mahfouz et al. 2008). In addition, Preusser et al. found that the Ki-67 index is an independent prognostic factor for patients with ependymomas (Preusser et al. 2008). Similar to the Ki-67 index, the expression of p53 is associated with the tumor grade and can be utilized in the staging of ependymomas as it is considered a poor outcome predictor (Mahfouz et al. 2008).

4.3

Histopathology and Morphology

4.3.1 WHO Classification The 2016 World Health Organization (WHO) classification of CNS tumors incorporated—for the first time ever—the molecular features of the tumors to the classical histological classification resulting in the deletion of a variant

4

Ependymomas in Children and Adults

of Grade II ependymoma, the cellular ependymoma, and the addition of one distinct subtype: “Ependymoma, RELA-fusion positive” (Neumann et al. 2020). The WHO classification divides ependymomas into: . Grade I: Myxopapillary ependymoma and subependymoma; . Grade II: Ependymoma (papillary, clear cell, tanycytic); . Grade II/III: Ependymoma, RELA-fusion positive; . Grade III: Anaplastic ependymoma. Myxopapillary ependymomas (Grade I) predominantly originate from the region of cauda equina, conus medullaris, or filum terminale. These tumors mainly affect young adults with an average age at diagnosis of approximately 35 years, but occasionally can be found in the pediatric population in whom they tend to arise in the soft tissue of the sacrococcygeal region and usually have a more indolent clinical course compared to those in the spinal cord. Macroscopically, they appear as encapsulated, intradural masses. Microscopically, they consist of papillary structures made up of ependymal cells, accumulation of mucoid material around these cells, and hyaline degeneration of the blood vessels. Subependymomas (Grade I) typically develop in the fourth (50–60%) and the lateral ventricles (30–40%) but occasionally can be found in the spinal cord, particularly in the cervical spine. They affect almost exclusively adult patients with a high male predominance. Macroscopically, they constitute well-demarcated, noninfiltrating lesions which are easily distinguished from the normal parenchyma. Microscopic examination can reveal clusters of isomorphic cells within a dense fibrillary stroma. Pseudorosettes and cysts can also be seen. Increased mitotic activity, vascular endothelial proliferation, and necrosis are rare, but their appearance in the tumor specimen should not increase the grade of the tumor (Hübner et al. 2018). The distinction between Grade II and Grade III ependymomas is of dubious prognostic value. Grade II ependymomas, also referred as

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“classical” ependymomas, represent welldemarcated masses with little to no infiltration. Histological features of these tumors include perivascular pseudorosettes as well as pathognomonic true ependymal rosettes. Occasionally, they may also exhibit moderate cellularity with less than 800 cells per high-power field, nuclear atypia as well as foci of calcification. Grade II ependymomas consist of three subtypes: papillary, clear cell, and tanycytic ependymomas. Papillary ependymomas contain papillary structures which surround vascular cores. Lack of cytokeratin and ultrastructural characteristics can facilitate their differential diagnosis from choroid plexus papillomas. Clear cell ependymomas may contain cystic elements and oligodendrogliomalike cells with rounded nuclei. This subtype appears to have the highest Ki-67 and p53 expression of all Grade II ependymomas. Tanycytic ependymomas are composed of elongated cells and eosinophilic fibrillar processes (Alexiou et al. 2011c, 2013a). The absence of Rosenthal fibers and their positive staining for glial fibrillary acidic protein (GFAP) could assist in distinguishing them from fibrillary astrocytoma and schwannoma, respectively (Neumann et al. 2020). Anaplastic ependymomas (Grade III) may exhibit true ependymal rosettes as well as features of malignancy including increased mitotic activity, microvascular proliferation, and pseudopalisading necrosis (Vitanza and Partap 2016). Ependymomas, RELA-fusion positive (Grade II/III) is a molecular rather than pathological variant of ependymomas and the newest addition to the WHO classification of CNS tumors. These tumors represent a distinct subset of Grade II and Grade III supratentorial ependymomas in children and young adults. From a molecular perspective, they harbor a fusion between “C11orf95” gene and the “nuclear factor kappa B effector RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A)”. The latter fusion represents a large chromosomal rearrangement on chromosome arm 11 defined as “chromothripsis”. Expression of the L1 Cell Adhesion Molecule (L1CAM) can distinguish this variant from other ependymomas (Gerstner and Pajtler 2018).

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4.3.2 Molecular Classification The distinction between Grade II and Grade III ependymomas, even when the histological examination is performed by experienced neuropathologists, is often challenging and of limited prognostic significance (Ellison et al. 2011; Tihan et al. 2008). In 2015, Pajtler et al. was the first to propose a new molecular classification of ependymomas (Table 4.1). Based on DNA methylation profiling in 500 tumor specimens, the authors identified nine distinct subgroups of ependymomas, three in each of the three compartments of the CNS: spinal cord, posterior fossa, and supratentorial compartment (Pajtler et al. 2015). Regarding the spinal cord, the three variants included spinal subependymoma (SP-SE), histologically diagnosed as Grade I subependymoma; spinal myxopapillary ependymoma (SPMPE), previously diagnosed as Grade I myxopapillary ependymoma; and spinal classic ependymoma (SP-EPN), previously identified as Grade II/III ependymoma. Similarly, the

infratentorial compartment included infratentorial subependymoma (PF-SE), Grade I tumor according to the WHO classification; infratentorial ependymoma type A (PF-EPN-A), WHO Grade II/III; and infratentorial ependymoma type B (PF-EPN-B), also WHO Grade II/III. Supratentorially, the three molecular subtypes included supratentorial subependymoma (ST-SE), identified as the WHO Grade I; supratentorial ependymoma RELA positive (ST-EPN-RELA), an entity that was incorporated in the most recent WHO classification (WHO Grade II/III); and supratentorial ependymoma YAP1 positive (ST-EPNYAP1), identified as Grade II/III by the WHO (Delgado-López et al. 2019; Pajtler et al. 2015). Similar to RELA-positive ependymomas, YAP1-positive ependymomas feature genetic fusion involving the HIPPO signaling regulator YAP1 compared to NF-kB effector in RELApositive ependymomas (Hübner et al. 2018). Each of the nine subgroups represented a unique entity with different features concerning its location, patients’ age, chromosomal aberrations,

Table 4.1 Molecular subgroups of ependymoma Molecular variant

Location

Gender

Age

WHO grade

Prognosis

SP-SE

Spinal cord

(Cervical)

M=F

Adults only

Grade I

Good

SP-MPE

Spinal cord

(Conus, filum, cauda equina)

M=F

Young adults and adults

Grade I

Good

SP-EPN

Spinal cord

(All levels)

M>F

Adolescents and young adults

Grade II/III

Good

PF-SE

Infratentorial

(Posterior fossa)

M>F

Adults only

Grade I

Good

PF-EPN-A

Infratentorial

(Posterior fossa)

M>F

Infants/children

Grade II/III

Poor

PF-EPN-B

Infratentorial

(Posterior fossa)

M 3 years at the time of diagnosis with GTR or tumor residuals < 1.5 cm2 and without macroscopic signs of metastasis (M0) and with non-anaplastic and non-large-cell medulloblastomas. The high-risk group includes children under 3 years of age or the size of the residual tumor > 1.5 cm2 or the presence of metastases (M2–3) (in some protocols the presence of tumor cells in CSF (M1) is considered). The low-risk group includes patients with the molecular genetic group WNT (b-catenin+) or desmoplastic form of the tumor. GTR should be considered if intraoperative and postoperative MRI data do not reveal the residuals. Subtotal removal is considered when data according to intraoperative findings and MRI on one of the scans indicate that the maximum area of the residual tumor is less than 1.5 cm2. This criterion is an empirical value confirmed in numerous statistical studies. All other cases are evaluated as partial. The residuals > 1.5 cm2 significantly worsen the prognosis (Fig. 5.28), but surgeons should understand that the survival rate of patients does not change with any residual size less than 1.5 cm2. Thus, the desire for total removal of the

tumor when it infiltrates the floor of the IV ventricle does not lead to an improvement in the oncological prognosis, but causes numerous neurological complications. For the accurate estimation of the size of the residual tumor, it is necessary to perform MRI with contrast in T1 mode in the interval of 24– 48 h after surgery. This technique is generally recognized and is included in all international clinical protocols. The presence of metastases in the brain and/or spinal cord at the time of surgery (stage M2–3) also significantly worsens the prognosis (Fig. 5.29). At the time of surgery, almost half of the patients have metastases. In order to obtain the most accurate results, MRI of the spinal cord is ideally performed before surgery or in the first 48 h after surgery (or later than 14 days after surgery). This excludes over-diagnosis of metastasis, which is due to the blood in CSF (Bartlett et al. 2013; Gerber et al. 2014). The prognostic role of tumor cells in the cerebrospinal fluid (M1) remains controversial (Zeltzer et al. 1999). Despite the generally accepted opinion about the necessity to include these patients in a high-risk group, there are a number of authoritative researchers who disagree with it. It should also be remembered that in order to obtain reliable data, it is necessary to examine the CSF for cells in the interval of 14– 28 days, since earlier analysis can lead to false positive results. Currently, stratification of patients into risk groups is performed before the treatment, and in the standard group of patients, radiation therapy is performed at a reduced dose (24 Gy). The high-risk group (including stage M1) includes 40–50% of patients. Histological features of the tumor play an extremely important role in the prognosis. The best survival rate was observed in patients with desmoplastic form of the tumor (5-year RFS = 82–100%), worse outcome was for patients with the classical form (70–80%), and the lowest survival rate was observed in patients with large-cell/anaplastic medulloblastomas (40– 62%) (Massimino et al. 2013a, 2013b; McManamy et al. 2003, 2007). This criterion is used in

5

Medulloblastomas in Pediatric and Adults

a number of modern stratification protocols, for example, patients with large-cell medulloblastomas and anaplasia are excluded from the standard-risk group due to poor prognosis (Fig. 5.30). However, the most promising in the further development of neuro-oncology is investigations of molecular and biological features of tumors (Fig. 5.31). The best prognosis was found in the WNT group (5-RFS = 100%). This group includes mostly older children. Tumors are represented by the classic variant and rarely metastasize. In the most up-to-date studies (PNET 5 MB), these patients were referred to a low-risk group with a reduced doses therapy protocol, which should significantly decrease the rate of endocrine and neuropsychological disorders. The survival rate in the SSH group was 75% (5y-RFS). Most of these tumors are represented by desmoplastic and classical types, and many patients do not have metastases at the time of diagnosis. In the future, this group is also a candidate for reducing the intensity of adjuvant therapy (Rutkowski et al. 2005, 2010), as well as for using targeted therapy with various SHH signaling pathway inhibitors [for example, LDE225/Erismodegib (Buonamici et al. 2010; Heller et al. 2012), GDC-0449/Vismodegib (LoRusso et al. 2011)]. The worst survival rates were in group 3 (“C”) (5y-RFS = 44%). It includes mostly young children, most of them boys. Medulloblastomas are mainly represented by large-cell and classical forms. In the future, these patients may also become candidates for the targeted therapy due to activation of the MYC and TGF-b signaling pathways. In group 4 (“D”), survival rates were intermediate (5y-RFS = 80%). No specific features of the distribution of patients by age, gender, and degree of metastasis were obtained. Identification of gene expression and methylation profiles in the future will allow dividing this group into subgroups (Taylor et al. 2012). According to the results of research at the end of 2019, there are already 12 molecular genetic

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groups, each of which has its own clinical features (Table 5.1).

5.7.2 Long-Term Follow-Up Unfortunately, even modern protocols of combined treatment did not allow avoiding numerous complications and improving the quality of life.

5.7.2.1 Endocrine Disorders High frequency of hormonal disorders (52– 100%) (Fossati et al. 2009; Frange et al. 2009; Laughton et al. 2008; Uday et al. 2015) as well as the possibility of their correction by modern drug therapy makes their diagnosis especially important. Neither tumor nor surgery leads to endocrine disorders, however, such complications could be caused by subsequent radiation and chemotherapy (Table 5.7). The most sensitive to the damaging effects of cranial radiation is related to the growth hormone function, which is followed by thyroidstimulating and gonadotropic, while ACTH deficiency develops the last (Lam et al. 1991; Sklar 1999). The degree of hypopituitarism depends on several factors: the radiation dose, the time after radiation therapy, and the patient’s age at the time of therapy. Irradiation at a dose of 18–24 Gy causes neurosecretory dysfunction of GH, while more than 30 Gy causes isolated GH deficiency, and radiation at a dose of more than 40–50 Gy results in multiple hormone insufficiency of the anterior pituitary (Lam et al. 1991; Littley et al. 1989). However, diabetes insipidus due to radiation therapy usually does not develop. Children are more sensitive to radiation therapy than adults (Sklar and Constine 1995). The hypothalamus is more radiosensitive than the pituitary gland; at doses of less than 50 Gy damage develops in hypothalamus (most often isolated GH deficiency), higher doses lead to direct damage to the anterior pituitary and rapid development of panhypopituitarism. Despite the fact that in a year after surgery, growth hormone deficiency occurs in half of the children, during this period children still do not

144 Table 5.7 Endocrine disorders 1 year and 5 years after surgery (personal data)

S. Gorelyshev et al. Endocrine disorders

1 year after surgery

5 years after surgery

GH deficiency (%)

58

98

SDS of growth

−0.06

−1.4

SDS of the upper body segment

−0.65

−2.58

Growth rate

2.54 cm/year

2.84 cm/year

Hypothyroidism

37

86

Hypocorticoidism (%)

5

20

Hypogonadism

21

59

show delay in growth from their peers, but the early signs of disproportional development of the body with retardation of the upper body segment due to spinal irradiation may present. During follow-up period, the incidence of GH deficiency increases up to 90%, the growth lag from peers increases, and the growth retardation of the upper body segment from the lower one becomes especially pronounced. Proton radiation therapy compared to conventional photon therapy, when used for CSI treatment, significantly improves dose-sparing to the vertebral bodies and improve final height outcome. Other non-hormonal factors that affect growth include intensive chemotherapy (especially in maintenance mode) and nutritional disorders during treatment. Chemotherapy can disrupt the synthesis of IRF-1 in the liver and directly affect bone growth. Early or precocious puberty after cranial irradiation can worsen final height outcome, particularly because GH deficiency is almost always present and leads to attenuation of the pubertal growth spurt. Treatment involves GH substitution therapy. In the future, protocols with a reduced dose of spinal radiation will significantly improve patient’s growth. Immediately after the end of radiation and chemotherapy (1 year after surgery), there is a significant decrease in body weight, which is followed by an increase within 5 years, and finally the body weight normalizes. The decrease in body weight can be explained by a decrease in appetite, as well as nausea and vomiting during chemotherapy. In rare cases, some patients may become overweight or develop obesity. Hypothyroidism develops in the vast majority of patients in the long-term follow-up period. In

one year after surgery, hypothyroidism is detected in 1/3 of patients. A number of patients develop isolated central hypothyroidism as a result of cranial radiation, and more often primary or mixed (primary and secondary) hypothyroidism develops as a result of spinal radiation and possibly chemotherapy. The frequency of primary hypothyroidism after treatment of medulloblastoma may vary from 28 to 83% (Chin and Maruyama 1984; Livesey et al. 1990; Paulino 2002). Reducing the dose of CSI, as well as the hypofractionation mode compared to the routine mode, can reduce the risk of developing thyroid pathology (Chin and Maruyama 1984; Ricardi et al. 2001). CSI may also predispose to the development of thyroid nodules and thyroid cancer. T4 replacement therapy should be started in case of hypothyroidism, as it can also decrease the risk of thyroid cancer in MB survivors. Hypocortisolism (central adrenal insufficiency) is not a common complication of combination therapy, especially at the beginning of the follow-up period. Signs of hypocortisolism appear mainly in 2–3 years of follow-up, and later they are observed in about 20% of patients. Despite this, hypocortisolism is one of the most dangerous complications of cranial irradiation. Mineralocorticoid function is usually not affected, but serum sodium may be slightly reduced due to the indirect effect of cortisol on the renal clearance of free water. Symptoms of ACTH deficiency include delayed adrenarche, weakness, fatigue, slow recovery from infections, poor appetite and weight loss, nausea, vomiting, and a tendency to hypotension or hypoglycemia. It should be

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remembered that during intercurrent diseases, an adrenal crisis may develop. Hypogonadism is one of the most common complications of combination therapy for medulloblastomas. In one year after surgery, hypogonadism is detected in 21% of patients (mainly in girls), and later increases to 30–60%. Cranial irradiation can lead to central hypogonadism, spinal radiation and chemotherapy cause direct damage to the gonads, which depends on sex. In girls, oocytes are necessary for the production of sex hormones, so both fertility and the production of sex steroids suffer during treatment. Patients who received treatment at a younger age are less sensitive to radiation therapy due to the sufficient number of follicles. However, even with preserved sexual function, patients who received radiation and chemotherapy have a high risk of infertility and early menopause. In boys, Sertoli cells are more sensitive to the effects of radiation and alkylating drugs than Leydig cells, so in some cases an isolated violation of spermatogenesis develops. The most gonadotoxic drugs are platinum and cyclophosphamide. It should be remembered that the task of fertility preservation should be discussed before the start of adjuvant therapy. In order to reduce the risk of ovarian damage, a number of countries use oophoropexy before radiation, and great importance is given to planning spinal radiation. Freezing of sperm and oocytes is widely used in patients in puberty and post-puberty age; freezing the tissue of pre-pubertal gonads is being investigated. In general, to improve endocrine functions, it is important to identify standard and low-risk groups to use reduced doses of CSI.

5.7.2.2 Cognitive Impairment Cognitive impairment is a key point in assessing the quality of life of patients with medulloblastomas and directly affects the development of new treatment protocols. The causes of cognitive defects are damage to the cerebellum, craniospinal radiation, hydrocephalus, sensory, and motor disorders. Recently, it has become clear that just as the cerebellum regulates the speed, strength, rhythm, and accuracy of movement, it regulates the

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speed, consistency, and coherence of thinking as well (Schmahmann 2004). Diffusion tensor imaging (DTI-based tractography) MRI data demonstrated the presence of connections between the dentate nucleus, the main source of ascending signals from the cerebellum, and the contralateral zones of the prefrontal and parietal cortex of the large hemispheres (Ramnani 2006). In addition, it was shown that cognitive functions are most closely related to the lateral hemispheres of the cerebellum (Kh et al. 2014) and the inferior vermis (Sang et al. 2012). Almost all children after combination therapy develop neuropsychological disorders of varying severity: praxis disorders (90%), visual gnosis disorders (60%), impaired constructive activity (58%), speech disorders (50%), memory loss (50%), thinking disorders (46%), decreased attention (45%), and decreased activity (30%). The younger the child at the start of combined treatment, the greater the subsequent decline in cognitive functions (Fig. 5.36). To our data, the critical age is 6 years. Children who start radiation therapy after the age of 6 had minor cognitive defects that practically do not prevent them from mastering the secondary school program or from fully communicating with their peers. If the radiotherapy starts at the age of less than 6 years, children develop disabling cognitive defects in combination with sharply limited socialization opportunities. Attention, speech, and thinking are particularly affected. Considering that IQ in such children decreases by 3–4 points per year, research all over the world is aimed at the reduction of craniospinal radiation doses (Jain et al. 2008; Mulhern et al. 1998).

5.7.2.3 Ototoxicity Ototoxicity and pathology of the middle ear is detected in 20–90% of cases after combined treatment, bilateral in the absolute majority: II– III degrees of severity. The main factor is the use of cisplatin drugs, which causes damage to internal and external hair cells, atrophy of the vascular strip, as well as degeneration of the spiral ganglion and cochlear nerve (Hoistad et al. 1998).

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Fig. 5.36 Influence of the child’s age at the start of treatment on the severity of cognitive disorders. Correlation analysis shows that the younger the child at the start of combined treatment, the more impaired cognitive functions. (personal data)

Radiation therapy primarily causes mucosal inflammation, and hypertrophy of the arteriole’s intima, which lead to temporary conductive hearing loss, and in long-term lead to irreversible sensorineural hearing loss (Herrmann et al. 2006; Hoistad et al. 1998; Hua et al. 2008; Johannesen et al. 2002; Sklar and Constine 1995).

5.8

Conclusion

In conclusion, it should be noted that despite the fact that medulloblastomas are one of the most malignant human tumors, it is here that a great breakthrough has been achieved in our understanding of oncogenesis and the development of real methods of treatment. Currently, 80% of patients can already be cured, however, the quality of life of patients in the long-term period, consisting of many components, including endocrinological, cognitive, neurological, and otoneurologic aspects, remains quite low. Thus, the main task of international research is to optimize existing protocols and develop fundamentally new ones based on molecular genetic research in order to improve the quality of life.

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Medulloblastomas in Pediatric and Adults

Ryzhova M, Shishkina L, Zheludkova O, Golanov A, Gorelyshev S, Pitskhelauri D, Bekiashev A, Kobiakov G, Absaliamova O, Sycheva R, Korshunov A (2014) [Comparative characteristics of genetic aberrations in glioblastomas in children and adults]. Zhurnal voprosy neĭrokhirurgii imeni N. N. Burdenko 78:3– 11; discussion 11 Sang L, Qin W, Liu Y, Han W, Zhang Y, Jiang T, Yu C (2012) Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures. Neuroimage 61:1213–1225 Schmahmann JD (2004) Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci 16:367–378 Sharma DS, Gupta T, Jalali R, Master Z, Phurailatpam RD, Sarin R (2009) High-precision radiotherapy for craniospinal irradiation: evaluation of threedimensional conformal radiotherapy, intensitymodulated radiation therapy and helical TomoTherapy. Br J Radiol 82:1000–1009 Sklar CA (1999) Overview of the effects of cancer therapies: the nature, scale and breadth of the problem. Acta Paediatr Suppl 88:1–4 Sklar CA, Constine LS (1995) Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31:1113–1121 Standefer M, Bay JW, Trusso R (1984) The sitting position in neurosurgery: a retrospective analysis of 488 cases. Neurosurgery 14:649–658 Tarbell NJ, Loeffler JS, Silver B, Lynch E, Lavally BL, Kupsky WJ, Scott RM, Sallan SE (1991) The change in patterns of relapse in medulloblastoma. Cancer 68:1600–1604 Tarbell NJ, Friedman H, Polkinghorn WR, Yock T, Zhou T, Chen Z, Burger P, Barnes P, Kun L (2013) High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiationtherapy (POG 9031). J Clin Oncol 31 (23):2936–2941. https://doi.org/10.1200/JCO.2012. 43.9984. Epub 2013 Jul 15. PMID: 23857975 Tarbell N, Friedman H, Kepner J, Barnes P, Burger P, Kun L (2000) Outcome for children with high stage medulloblastoma: results of the pediatric oncology group 9031. Int J Radiat Oncol Biol Phys 48:179–179 Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, Lucraft H, Gilbertson R, Tait DM, Walker DA, Pizer BL, Imeson J, Lashford LS (2003) Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The international society of paediatric oncology/United Kingdom Children’s cancer study group pnet-3 study. J Clin Oncol 21:1581–1591 Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, Ironside J, Pizer BL, Lashford LS (2005) Outcome for patients with metastatic (M2–3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 41:727–734

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Benign and Malignant Tumors of the Pineal Region Pavan S. Upadhyayula, Justin A. Neira, Michael L. Miller, and Jeffrey N. Bruce

Abstract

Pineal region tumors fall into five broad categories: benign pineal region tumors, glial tumors, papillary tumors, pineal parenchymal tumors, and germ cell tumors. Genetic and transcriptional studies have identified key chromosomal alterations in germinomas (RUNDC3A, ASAH1, LPL) and in pineocytomas/pineoblastomas (DROSHA/DICER1, RB1). Pineal region tumors generally present with symptoms of hydrocephalus including nausea, vomiting, papilledema, and the classical Parinaud’s triad of upgaze paralysis, convergence-retraction nystagmus, and lightnear pupillary dissociation. Workup requires neuroimaging and tissue diagnosis via biopsy. In germinoma cases, diagnosis may be made based on serum or CSF studies for

P. S. Upadhyayula . J. A. Neira . J. N. Bruce (&) Department of Neurological Surgery, Columbia University, New York, USA e-mail: [email protected] P. S. Upadhyayula e-mail: [email protected] J. A. Neira e-mail: [email protected] M. L. Miller Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA e-mail: [email protected]

alpha-fetoprotein or beta-HCG making the preferred treatment radiosurgery, thereby preventing the need for unnecessary surgeries. Treatment generally involves three steps: CSF diversion in cases of hydrocephalus, biopsy through endoscopic or stereotactic methods, and open surgical resection. Multiple surgical approaches are possible for approach to the pineal region. The original approach to the pineal region was the interhemispheric transcallosal first described by Dandy. The most common approach is the supracerebellar infratentorial approach as it utilizes a natural anatomic corridor for access to the pineal region. The paramedian or lateral supracerebellar infratentorial approach is another improvement that uses a similar anatomic corridor but allows for preservation of midline bridging veins; this minimizes the chance for brainstem or cerebellar venous infarction. Determination of the optimal approach relies on tumor characteristics, namely location of deep venous structures to the tumor along with the lateral eccentricity of the tumor. The immediate post-operative period is important as hemorrhage or swelling can cause obstructive hydrocephalus and lead to rapid deterioration. Adjuvant therapy, whether chemotherapy or radiation, is based on tumor pathology. Improvements within pineal surgery will require improved technology for access to the pineal region along with targeted therapies that

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_6

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can effectively treat and prevent recurrence of malignant pineal region tumors. Keywords

.

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Pineal region tumors Biomarkers Histopathology Surgical approaches Pineal gland

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6.1

.

Background and Epidemiology

The pineal gland is a midline extra-axial neuroendocrine structure critical in regulation of the body's circadian rhythm. It sits ventrally to the posterior commissure, and the dorsal aspect abuts the velum interpositum, a membranous structure containing the internal cerebral veins and choroid plexus. The paired internal cerebral veins and the paired basal veins encircle the gland to join the vein of Galen dorsal to the pineal body. The pineal body receives its major blood supply from the medial posterior choroidal arteries and smaller tributaries from the quadrigeminal arteries (Erlich and Apuzzo 1985; Duvernoy et al. 2000). A three-dimensional reconstruction of the pineal gland and relevant anatomy can be found in Fig. 6.1. Based on its relationship to the midbrain, third ventricle, and thalamus, these structures are often compromised with high-grade infiltrative lesions originating in the pineal body. The normal pineal gland is lobulated with pinealocytes. Historically, pinealocytes have been classified as “light” or “dark,” differentiating serotonin-containing versus melatonin-containing pinealocytes (Al-Hussain 2006). More recent single-cell sequencing has verified this finding that the pineal gland has two predominant types of pinealocytes defined by differential expression of Acetylserotonin O-methyltransferase (ASMT) (Mays et al. 2018). Aside from pinealocytes, the pineal body contains microglia, astrocytes, and endothelial cells (Mays et al. 2018). Neoplasms of the pineal region are relatively infrequent, comprising about 1.2% of all central nervous system (CNS) tumors (Ostrom et al. 2019). Primary pineal parenchymal tumors and germ cell tumors are the most common tumor

types making up 27% of pineal region tumors each. Gliomas (17%) and papillary tumors (8%) are the next most common entities. Of the pineal parenchymal tumors, grade II and grade II tumors or pineal parenchymal tumors of intermediate differentiation (PPTIDs) are the most common comprising 66% of pineal parenchymal tumors. Pineocytomas are the least common making up only 13% of pineal parenchymal tumors. Pineoblastomas make up one fifth of said tumors (Mottolese et al. 2015).

6.2

Genetics, Immunology, and Molecular Biology

Comprehensive genomic and RNA sequencing of pineal tumors have lagged behind other CNS tumors due to their relative rarity. Even so, a few studies have examined chromosomal abnormalities, gene expression profile, and/or methylation patterns in pineal region tumors. Primary pineal parenchymal tumors (PPTs) and papillary tumors of the pineal region (PTPRs) are the most thoroughly classified clinical entities. The other tumor types are best understood for how pineal region tumors differ from similar tumors in other brain regions. In general, pineal germinomas share characteristics with gonadal and extragonadal germ cell tumors. Only a single study has comprehensively studied gene expression profiles in pineal germinomas. This study of pediatric cases correlated gene expression, methylation patterns, and chromosomal alterations across pediatric pineal germinomas and found alterations in genes related to neuronal processing (RUNDC3A), immune function (CDC24.7), miRNA regulation (TRA2A), cell cycle (ASAH1), and fatty acid metabolism (LPL, NPC2) (Pérez-Ramírez et al. 2017). PTPRs have been shown to overexpress SPDEF, a gene known to be highly expressed within the subcommissural organ. Notably, high expression levels of SPDEF and other subcomissural organ genes have been repeatedly demonstrated by PTPRs but not by ependymal or choroid plexus tumors (Fèvre-Montange et al. 2006a; Heim et al. 2016).

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Fig. 6.1 3D model of relationship between venous structures, ventricular system, and pineal gland. Model created with BodyParts3D, © Database Center for Life Science licensed under CC Display Inheritance 2.1 Japan

A special focus has been put on PPTs, specifically what the genetic or expression profiles related to malignancy are. Benign pineocytomas have expression profiles consistent with normal neural tissue such as high levels of ASMT or genes related to phototransduction (Fèvre-Montange et al. 2006a). Multiple studies have highlighted the importance of RNase related to microRNA processing in determining malignant potential of primary parenchymal pineal tumors. DROSHA and DICER1 mutations, two RNase III enzymes that work in concert to cleave primary microRNA transcripts into mature microRNA (Li and Patel 2016) are characteristic of pineoblastomas (Snuderl et al. 2018; Li et al. 2020a). The final mature microRNA created by DROSHA and DICER1 cleavage work with the RNA-induced silencing complex to specifically and selectively silence transcript expression. Whole exome and whole genome

surveys have shown that in pineoblastoma DROSHA and DICER1 are inactivated due to copy number loss, frameshift mutations, or hotspot missense mutations (Snuderl et al. 2018; Lee et al. 2019b). Findings from the Rare Brain Tumor Consortium have classified pineoblastomas into 5 molecular subgroups based on whole exome, microRNA, and copy number variant sequencing techniques. These five groups are characterized by: . . . . .

Group 1: DROSHA loss Group 2: DICER1 loss Group 3: no consistent loss Group 4: retinoblastoma (RB1) loss Group 5: MYC amplification or gain of function.

Importantly, malignant lower grade PPTs such as PPTIDs do not have DROSHA or

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DICER1 mutations. Instead, insertions within the KBTBD4 gene, a ubiquitin ligase complex initially identified as overexpressed in medulloblastomas, have been identified. Importantly, the pattern of heterozygous variants that cluster at mutational hotspots suggests this mutation is a gain of function mutation (Northcott et al. 2017; Lee et al. 2019b). In the context of pineal region gliomas, no consistent findings have separated pineal region gliomas from gliomas arising elsewhere. There continues to be much focus on the H3K27 trimethylation phenotype and its association with midline gliomas, however.

6.3

Histopathology and Morphology

Neoplastic lesions of the pineal region can be grouped as follows: benign pineal region tumors, glial tumors, papillary tumors, pineal parenchymal tumors, and germ cell tumors. Non-neoplastic lesions can occur, specifically vascular lesions such as cavernous malformations, vein of galen malformations, or arteriovenous malformations (Fukui et al. 1983; Fetell et al. 1991). A summary of relevant characteristics of various pineal region tumors is provided in Table 6.1, and histology is presented in Fig. 6.2.

6.3.1 Benign Pineal Region Tumors Benign pineal region tumors include meningiomas, dermoids, epidermoids, teratomas, pineal cysts, and differentiated ependymomas. Benign pineal cysts may mimic pilocytic astrocytomas but can be differentiated based on their indolent clinical course (Al-Holou et al. 2011). In all such cases, complete surgical resection is curative and in cases of incomplete surgical resection observation is warranted (DeGirolami and Armbrustmacher 1982; Barnett et al. 1995; Clark et al. 2010; Levidou et al. 2010).

6.3.2 Glial Pineal Tumors Glial tumors of the pineal region arise from astrocytes within the pineal gland and can span the gamut from Grade I to Grade IV neoplasms. These lesions tend to be encapsulated and cystic having features similar to pilocytic astrocytomas (DeGirolami and Armbrustmacher 1982; Dashti et al. 2005). Tectal gliomas arising from the roof of the brainstem can involve the pineal gland. Ependymomas, most specifically those originating in the posterior aspect of the third ventricle, can push on or invade the pineal gland (Schwartz et al. 1999). Rarely, glioblastoma of the pineal gland or thalamus can arise (D’Amico et al. 2018; Li et al. 2020b). Endoscopic third ventriculostomy for management of hydrocephalus is an appropriate initial treatment. Deciding between biopsy, resection, and/or radiation is based on the lesion features including invasion and rate of growth. Histology and immunohistochemical findings depend on the type of glial tumor that may arise. Reported cases of pineal gliomas include pilocytic astrocytomas, anaplastic astrocytomas, glioblastomas, ependymomas, and oligodendrogliomas (Hirato and Nakazato 2001).

6.3.3 Papillary Tumors of the Pineal Region Papillary tumors of the pineal region (PTPR) likely arise from specialized subcommissural ependyma (Jouvet et al. 2003; Fèvre Montange et al. 2015). This uncommon tumor entity occurs in younger patients. Most often, it is treated with radical resection and radiotherapy (FèvreMontange et al. 2006b). A retrospective analysis of 71 studies of 177 cases showed that papillary tumors of the pineal region have a 73% 5year overall survival and that adjuvant therapies did not improve survival significantly (Yamaki et al. 2019). Squash prep generally shows papillary structures with potential for perivascular pseudorosettes. Other potential papillary tumors

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Table 6.1 Summary of immunohistopathologic characteristics of pineal region tumors Radiologic features

IHC features

Staining markers

Benign pineal region tumors Pineal cyst

Circumscribed with cystic area of signal similar to CSF

Three-layer cyst of gliotic tissue, pineal parenchymal tissue, and connective tissue. Prominent calcification and lymphocytic infiltration (Boulagnon-Rombi et al. 2017)

+GFAP (inner layer), Synaptophysin/NF (middle layer)

Pineal meningioma

Homogeneously enhancing with dural tail. T1 hypo- to isointense, T2 iso- to hyperintense

Syncytia and whorls of cells with fusiform cells (Zondek et al. 1953)

+EMA, SSTR2A, PR (Zacharia and Bruce 2011)

Most commonly DA, then GBM, then ependymoma, and PA

+GFAP

Papillary architecture, perivascular pseudorosettes. Pale columnar cells (Bruce and Stein 1995)

+CK 18, NSE, EMA, Vimentin, S100, PanCK, Nuclear CRX&FOXJ1 (Jouvet et al. 2003)

Glial pineal region tumors Grade I–IV glial tumors

Depends on tumor grade can range from well-circumscribed (PA) to aggressive and infiltrative

Papillary tumors of pineal region Circumscribed, with solid and cystic areas with T1 hyperintensitiy

Primary parenchymal pineal region tumors Pineocytoma

Circumscribed, 10– 15%) (Fig. 7.3n), while is approximately 1–2%

7.3.4 Differential Diagnosis 7.3.4.1 Choroid Plexus with Villous Hypertrophy CPPs are difficult to distinguish from normal choroid plexus and villous hypertrophy. Very low Ki67 labeling, together with cytomorphologic features (regular, uncrowded cells with cobblestone appearance) should identify nonneoplastic lesions. 7.3.4.2 Ependymoma Papillary ependymoma shares architectural features with CPP, but has perivascular anucleate processes and pseudorosettes; immunohistochemically, it shows characteristic dot-like positivity for EMA. CPC may resemble anaplastic ependymoma; lack of ependymal rosettes and perivascular pseudorosettes, absent microvascular proliferation, and strong CK staining favor the diagnosis of choroid plexus tumor. 7.3.4.3 Germ Cell Tumors Tumors such as embryonal carcinoma and yolk sac tumor mimic the CPC (especially the tumors with hyaline globules), but they are characteristically immunoreactive for placental alkaline phosphatase (PLAP) and SALL4.

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Fig. 7.4 Giant choroid plexus carcinoma in a 1-year-old baby girl. Axial non-enhanced CT images a–c show heterogeneous mass from the lateral ventricle with foci of

hyperattenuation consistent with calcification, as well as foci of hypoattenuation consistent with cystic areas. Hydrocephalus is present

7.3.4.4 AT/TR Atypical teratoid/rhabdoid tumors can be somewhat challenging to distinguish from CPCs poorly differentiated with rhabdoid morphology; however, the loss of nuclear staining with INI1 (BAF-47), typical of AT/TR, reliably differentiates these tumors (Fig. 7.3o).

(Figs. 7.4 and 7.5). CPPs are often welldelineated masses while CPCs many times invade through the ventricular ependyma into the adjacent brain. However, imaging features of all three primary choroid plexus tumors may overlap and so differentiating CPCs from ACPPs and CPP is frequently not possible on the basis of conventional radiological appearances. The presence of necrosis, heterogeneous enhancement, cystic components, and massive edema in the brain parenchyma is more suggestive of CPC; CSF seeding is also more common in carcinomas (Bisdas and D’Arco 2019).

7.3.4.5 Intraventricular Meningioma Whorl formation, vesicular nuclei, and syncytial cytoplasm, together with EMA positivity help to differentiate intraventricular meningioma from CPP. 7.3.4.6 Metastases CPP must be differentiated from papillary or solid metastatic carcinoma; whereas CKs are not helpful in this setting, demonstration of transthyretin, S100, GFAP, and/or synaptophysin positivity can be useful in recognizing choroid plexus tumors. Additional immunohistochemical stains may be needed in some cases, i.e., TTF1+ (lung adenocarcinoma), PAX8, CAIX+ (clear cell renal cell carcinoma), etc.

7.4

Imaging and Radiologic Features

A lobulated intraventricular mass with a frondlike pattern and strong enhancement, resulting in a cauliflower-like appearance, is typical of CPTs

7.4.1 Computed Tomography Findings In the pediatric population clinical symptoms of CPPs, ACPPs and CPCs are often related to increased intracranial pressure. Despite computed tomography (CT) evaluation must be weighed against radioprotection issues in the pediatric age group, in this emergency setting the role of non-enhanced CT (NECT) is essential for a rapid orientation. CT allows for identifying the tumor mass and its possible complications including hydrocephalus and bleedings as to assess whether the patient needs urgent neurosurgery (Fig. 7.4).

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Fig. 7.5 Brain MRI study of the same patient of Fig. 7.3. Axial T1-weighted (a) and T2-weighted images (b) confirm a large heterogeneous mass with cystic and solid components arising from the left lateral ventricle with surrounding vasogenic edema and hydrocephalus. Solid components show hypercellularity on ADC map (c) and avid enhancement on 3D TFE sequence (d) with lack of enhancement centrally, consistent with necrosis (black arrow). BFFE image (e) better depicts tumoral cystic components, with peripheral enhancement on 3D TFE sequence (f). Multiple intratumoral microbleeds are shown on SWI sequence (minimum intensity projection reconstructions, MinIP), as well as hypertrophy of left deep venous system (g, h). An enlarged anterior choroidal artery (white arrow) is appreciated on MRA (3D TOF technique) with maximum intensity projection (MIP) and volume rendering (VR) reconstructions (i–l)

On NECT CPPs, ACPPs and CPCs are usually heterogeneous with foci of calcification reported in about 25% of cases by Kornienko and Pronin (Kornienko and Pronin 2009) and are readily demonstrated on CT scans. CPPs are

typically iso-hyperdenselobulated lesions with regular margins, while CPCs show irregular margins and surrounding edema and are strongly heterogeneous for calcifications, necrosis, and cysts (Barkovich 1992). All of them enhance

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Fig. 7.5 (continued)

intensely after contrast and an enlarged choroidal artery leading into the tumor mass can sometimes be seen in post-contrast images (Gupta 2003).

7.4.2 Magnetic Resonance Imaging Findings MRI is the state-of-the-art imaging technique for the diagnosis and follow-up of CPTs. MRI does not use ionizing radiation and has a significant role in surgical planning. Multiplanar imaging is used to precisely localize and determine the extent of the tumor and easily depicts local parenchymal invasion, which is occasionally present. Moreover, MRI is an effective tool not only to confirm the exact location of CPTs but also to provide better discrimination of parenchyma invasion and tumor vascularity. Diffuse cerebrospinal fluid (CSF) dissemination is uncommon but does occur with

histologically benign CPPs, while ACPPs and mostly CPCs metastasize with greater frequency. Therefore, preoperative imaging of the entire neuroaxis is recommended (Fig. 7.6). A significant issue in pediatric MRI is the capability of pediatric patients to cooperate long and well enough to obtain quality imaging studies. Given that MRI investigation for choroid plexus tumors should include brain and spinal imaging with contrast medium administration, younger or severely ill children typically require sedation. A proposed MRI study protocol is summarized in Table 7.1. Brain MRI should involve the acquisition of 3D T1-weighted whole-brain isotropic sequence, with a high spatial resolution of 1–2 mm or less (Fig. 7.5). Subsequent multiplanar reformats (MPR) enable the accurate identification of subtle structural anomalies. We recommend also an axial T1-weighted spin echo (SE) sequence to

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Fig. 7.6 Spinal MRI. Sagittal (a) and axial (b) contrastenhanced T1-weighted images show linear and micronodular enhancement along pial surface of spinal cord and

cauda equina roots, consisting with metastases of choroid plexus carcinoma (c)

assess tumor features, as well as brain anatomy and degree of myelination. Axial and coronal T2weighted turbo/fast spin echo (TSE/FSE) and fluid-attenuated inversion recovery (FLAIR) sequences are useful for additional evaluation of tumor features and tumoral edema, as well as for any white matter abnormalities. Of note, FLAIR has limited value in children younger than 2 years of age because of their incomplete myelination. Diffusion-weighted imaging (DWI) with ADC maps (apparent diffusion coefficient) is necessary to probe tumor cellularity, which increases with the malignancy grade.

In the evaluation of tumoral hemorrhage, calcifications, and vascular structures, 3D susceptibility-weighted imaging (SWI) and 2D gradient echo imaging (GRE), and magnetic resonance angiography (MRA) are recommended. Particularly, SWI can help distinguish tumoral calcifications from tumoral microhemorrhage. Bolus injection is essential in the assessment of perfusion dynamics in imaging tumors and associated vascular anomalies. Post-contrast brain study should include a 3D T1-weighted sequence and, at least, an axial SE T1 sequence, which

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Table 7.1 Sample brain and spine conventional MRI protocol for children with CPTs Sequence

Slice thickness (mm)

Comment

3D T1 MPRAGEa/SPGR/FFE/TFE

1–1.5

Sagittal, coronal, or axial plane MPR reconstructions

Axial and coronal T2 TSE/FSE

4

Axial FLAIR

4

Brain

>2 years

Axial T1 SE

4

Optional

Axial DWI (b = 0, 1000) with ADC

4

Or axial DTI

SWI1 OR axial T2* GE2

1

3D CISS or 3D BFFE

1–1.5/42

10%). On nonenhanced CT, they usually appear iso/hyperdense compared to gray matter. On MRI they may be associated with peritumoral edema. They are typically hyperintense lesions on T2-weighted (T2-WI) fluid-attenuated inversion recovery (FLAIR) and slightly hypointense on T1weighted images (Tl-WI). Hemorrhage has been reported sporadically and could be easily detected on CT and T2* GRE MRI. After

medium contrast injection, they may have variable enhancement. (Fig. 9.1).

9.4.2 Cerebellar Liponeurocytoma It develops mainly in adult patients consisting in a mixed mesenchymal/neuroectodermal posterior fossa neoplasm. Liponeurocytoma is usually described as a hypodense lesion on CT and primarily hypointense lesion on Tl-WI. On T2-WI and FLAIR, it appears hyperintense in almost 88% of cases (Gembruch et al. 2018). After gadolinium, injection patchy and irregular enhancement is a common finding.

9.4.3 Desmoplastic Infantile Astrocytoma, Desmoplastic Infantile Ganglioglioma These tumors typically present within the first 2 years of life. Hemispheric tumors usually are large cystic lesions with a cortical enhancing

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Fig. 9.9 Diffuse glioneuronal tumor: a, b, d T1/T2-WI CISS sequence axial and IR T1-WI MR showing multiple subpial hyperintense cystic lesions both supratentorial (basal cisterns) and infratentorial cisterns

(interpeduncular, pontine cistern), along the cerebellar folia, as well as in all spinal cord (e, f). c Post contrast T1 WI showing the non-enhancing nature of the leptomeninges and the multiple subpial lesions

nodule. Suprasellar tumors are normally smaller solid tumors hypointense on T2-WI with homogeneous gadolinium enhancement.

similar to diffuse low-grade glial tumors, or GG, and it may be difficult to distinguish one from another. On CT scan, they appear as corticalsubcortical hypodense lesions sometimes with a scalloping of the inner table of the skull. Calcification may be pointed out. On MRI, they manifest as pseudocystic, multinodular cortical masses hypointense on T1WI and hyperintense on T2-WI without significant mass effect and surrounding vasogenic edema (Ozlen et al. 2010). When they involve multiple cortical gyri, they may produce a soap

9.4.4 Dysembryoplastic Neuroepithelial Tumor (DNET) They may appear as well-demarcated, wedgeshaped, multinodular, “bubbly” intracortical tumors. However, sometimes they could be

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Fig. 9.10 Papillary glioneuronal tumor: a Axial T1-WI after gadolinium injection shows an intramedullary thoracic tumor. Sagittal T2 (b) and T1 after gadolinium injection, c show the extension of the intra-axial lesion

from T9 to T11. d Postoperative sagittal T1-WI after gadolinium injection shows the results of laminotomy and tumor removal

bubble appearance at the cortical margin (“megagyrus” appearance). Multi-cystic morphology is more frequent in DNETs than in GGs. Less than one-third of DNETs enhance after contrast medium injection (Hammond et al. 2000) (Fig. 9.2).

9.4.5 Ganglioglioma and Gangliocytoma (GG & GC) Neuroimaging reveals a solid or cystic or solidcystic mass typically located in the periphery of a cerebral hemisphere. Tumor size is variable,

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Fig. 9.11 Papillary glioneuronal tumor is a low-grade neoplasm with papillary architecture [red arrows] composed of flat to cuboidal glial cells [green arrows] lining

hyalinized vessels [blue arrow] and neuronal cells, neurocytes, and rarely ganglion cells in interpapillary spaces. (H&E stain, 20x and 40x)

even if rarely they exceed 3 cm. They usually lack surrounding vasogenic edema and mass effect reflecting their benign behavior. On CT scan calcification could be a common finding especially in solid-appearing lesions (Adachi and Yagishita 2008; Ozlen et al. 2010). Superficial lesions may expand on the cortex and remodel bone. On MRI, they are often hypo/isointense lesions compared to gray matter on short TR images and hyperintense compared to gray matter on long TR images. However, some solid GG may manifest as hyperintense mass on T1-WI plenty of calcifications that can mimic in T2* GRE area of “blooming”. They commonly have some regions of hyperintensity on T2-WI. After medium contrast injection they usually have moderate but heterogeneous enhancement. Sometimes it could be “ring-like”

and sometimes it may be absent (Figs. 9.5 and 9.6).

9.4.6 Diffuse Leptomeningeal Glioneuronal Tumor (DLGNT) It primarily presents in the pediatric population. Classical neuroradiological signs are multiple non-enhancing subpial cystic lesions (T1-WI and FLAIR hypointense, T2-WI hyperintense) typically encountered along the cerebellar folia and spinal cord. They may be seen in the subpial location without any leptomeningeal enhancement. Hydrocephalus could be not rarely associated. Medium contrast enhancement is typical for the anaplastic form (Fig. 9.9).

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Fig. 9.12 Fourth ventricle rosette forming glioneuronal tumor: a CT scan at admission showed a well-defined round hemorrhagic lesion inside the fourth ventricle. MR axial pre- (b) and post-contrast (c) T1-WI revealed a spontaneously hyperintense lesion without strong

enhancement. On axial (d) and sagittal (e) T2-WI the mass appeared heterogeneous and well demarcated, strictly connected to the superior cerebellar peduncle. f Coronal Gradient Echo T2* WI sequences showed a remarkable intralesional hemosiderin deposit

9.4.7 Papillary Glioneuronal Tumor (PGNT)

hemorrhage are not rare (Yadav et al. 2017) (Fig. 9.10).

They usually occur in young adults and mostly involve the cerebral hemispheres and paraventricular white matter. Temporal lobe is the favorite site, and calcifications are frequent. On neuroimaging, they could appear both solid and solid-cystic. On CT scan they are hypo/isodense. On MRI, solid lesions appear hypointense in T1WI, while cystic lesions are hyperintense. On T2WI and FLAIR tumors are hyperintense or heterogeneous. After contrast agent administration, there is a heterogeneous enhancement of the solid portion or of the cyst wall. Signs of

9.4.8 Rosette-Forming Glioneuronal Tumor (RGNT) They are usually located in cerebellum and fourth ventricle; however, other locations, i.e., midline structures, temporal lobe, and spinal cord, have been described. On CT scan, these tumors are mostly hypodense. On MRI, they may appear cystic, solid or mixed cystic-solid. They are mostly hypointense on T1-WI and hyperintense on T2-WI. After the administration of

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Fig. 9.13 Rosette forming glioneuronal tumor: a Histopathologic examination evidenced a lesion with wide hemorrhagic extravasation and hemosiderin deposits (Hematoxylin & Eosin, 40X). b Admixed to these areas a

glioneuronal tumor with neurocytic components forming perivascular rosette and pseudorosette was present (Hematoxylin & Eosin, 200X)

Fig. 9.14 Paraganglioma: a Sagittal T1 WI after gadolinium injection showing a roundish intradural lesion. b Axial T1 WI and c T2 WI evidence the

displacement of the cauda equina bilaterally and no relationship with the neural foramen

contrast medium, they frequently show moderate enhancement. Rarely they may have hemorrhagic presentation (Fig. 9.12).

well circumscribed, intradural extramedullary tumors strongly enhancing after gadolinium injection. Leptomeningeal dissemination at the lumbar level might be observed (Fig. 9.14).

9.4.9 Paraganglioma The majority are found in the jugular glomus and carotid bodies (approximately 90% of them), while other locations could be affected as well including pineal and pituitary glands, cerebellopontine angle, and, rarely, spinal cord. They usually manifest in the fifth or sixth decades. They appear as hypointense or isointense on T1-WI and hyperintense on T2-WI. In the spinal cord, they are

9.4.10 Polymorphous Neuroepithelial Tumor of the Young (PLNTY) Often located in the posterior/posterobasal portion of the temporal lobe, these tumors are considered as cortical-subcortical lesions. Cystic components and calcification are frequently found both on CT scan and MRI (Johnson et al.

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Fig. 9.15 Paraganglioma of the spinal cord a Nesting or trabecular pattern of round to oval cells with abundant granular eosinophilic cytoplasm (H&E stain, 20x). Note

the prominent vascular network (blue arrows). b Cells are diffusely positive for Synaptophysin (IHC, 20x)

2019). Considering that these tumors are welldefined lesions, they present with heterogeneous signal intensities on T1-WI, T2-WI, and FLAIR with hypointensity in the dense calcification region covered by hyperintensity around the calcification. There could be a slight enhancement on T1-WI after gadolinium injection (Fig. 9.16).

tumors usually show both hyper-echoic and hypo/anechoic signal. Presence of intra/ perilesional calcifications in the GNTs is often demonstrated as hyper-echoic lesions with an underlying shadow cone. After ultrasound medium contrast injection (CEUS), most GGs show strong and homogenous enhancement (Fig. 9.5).

9.5 9.4.11 Intraoperative Ultrasound (IUS) Intraoperative ultrasound represents an effective low-cost technique leading the surgeon in the identification of the GNTs during surgery. Solid GNTs typically appear as well-circumscribed hyper-echoic lesions compared to the surrounding gray matter. Cystic or mixed solid cystic

Clinical Manifestations

The most common clinical presentation of GNTs is epilepsy that may manifest as generalized seizures, focal seizures with secondary generalization or, rarely, as status epilepticus. GNTs represent, indeed, the second most common pathology in epilepsy surgery series after hippocampal sclerosis (Blümcke et al. 2016). In general, complex partial seizures with aura are

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Fig. 9.16 Polymorphous low-grade neuroepithelial tumor of the young: Axial T2-WI and coronal FLAIR showing a subcortical left temporobasal hyperintense lesion (asterisk) at the level of the inferior temporal gyrus, below the Labbé vein (arrow). CT displays a slight

hypodensity corresponding to the tumor(asterisk). Cortical subcortical location is well defined inIR T1WI (d). After medium contrast injection the tumor does not enhance (e). Postoperative CT scan confirming tumor removal (f)

more common in temporal GNTs, whereas secondary generalization is more common in epilepsies associated with extratemporal GNTs (Morris et al. 1998). Regarding epileptogenesis in GNTs two main hypotheses have been proposed: the former suggests that epileptogenicity originates from the tumor itself, while the latter argues that it originates from peritumoral tissue (Stone et al. 2018b). The proposed mechanisms are: (a) disrupted glutamate homeostasis, (b) alterations in the blood–brain barrier (BBB), (c) inflammation within the tumor or disrupted glutamate homeostasis, (d) alteration in ion channels, BBB, intercellular connection, in brain network, and (e) inflammation in the peritumoral tissue. Moreover, a mechanism has been described to explain the link between the activity of the BRAF V600E-mutant oncoprotein kinase and seizures. The constitutive BRAF V600E ! MEK ! ERK signaling results in expression of

c-MYC, which eventually stimulates increased expression of REST. Subsequently, this leads to a significant reduction in transcription of mRNAs which are responsible for proper neuronal function, and finally, development of intractable epileptic seizures (Koh et al. 2018). Liponeurocytoma, RFGNT and DLGNT constitute the three entities rarely associated with epilepsy among all GNTs (Yang et al. 2017; Gembruch et al. 2018; Chen et al. 2020). Besides epilepsy, many other clinical manifestations have been described for GNTs. Since they are typically slow-growing, intra-axial near cortical brain tumors, they usually displace neurons and neuronal networks even if in rare cases (varying from 0 to 15% and mostly associated with anaplastic transformation or intralesional hemorrhage), they may infiltrate and damage neuronal structures, giving rise to neurological deficit (i.e., GNTs located in brainstem, cranial

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Fig. 9.17 Polymorphous Low-grade Neuroepithelial Tumor of the Young (PLNTY), shows an oligodendroglioma-like pattern (H&E stain, 20x), exhibiting intratumoral heterogeneity, from oligodendrocyte-like

elements having uniformly small and perfectly rounded nuclei [red arrows] to cells displaying variation in nuclear size [green arrows] (H&E stain, 40x). Neoplastic cells are strongly and diffusely positive for CD34 (IHC, 20x)

nerve, and spinal cord) (Fig. 9.18) (Ozlen et al. 2010). Obstructive hydrocephalus due to intraventricular GNTs localization or dissemination has been noticed (Silveira et al. 2019; Chen et al. 2020). Focal neurological deficits could be present in hemorrhagic GNTs as well as in spinal GNT and in tumors with malignant transformation (Riesberg et al. 2018).

zone removal with favorable outcomes in 80–90% of cases (Aronica et al. 2001; Clusmann et al. 2002; Luyken et al. 2003; Cataltepe et al. 2005; Pelliccia et al. 2017). From an oncological point of view a precise diagnosis and the removal of a lesion that potentially may have malignant transformation is mandatory. New techniques and technologies such as neuronavigation, intraoperative ultrasound, intraoperative MRI, intraoperative electrical monitoring, awake surgery, fluorescence-guided surgery, and virtual reconstruction of white matter pathways with Diffusion Tensor Imaging (DTI) represent new tools of the surgical armamentarium helping to maximize tumor resection while minimizing morbidity. Intraoperative electrocorticography in the identification of the epileptogenic zone (GNTs + perilesional cerebral

9.6

Therapeutic Approaches

The current standard of care for symptomatic GNTs is surgery which positively affects quality of life. Epileptological reasons are that GNTrelated epilepsy is usually resistant to antiepileptic drugs (AEDs), whereas it can be extremely responsive to surgical epileptogenic

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Fig. 9.18 Hemorrhagic ganglioglioma: a Coronal T2WI showing a parietal cortical-subcortical hyperintense tumoral lesion with hypointense intratumoral signs of bleeding. b The same lesion shows mild contrast enhancement on postgadolinium T1-WI. c CT scan confirms intralesional bleeding. d Axial T2-WI shows tumor removal and absence of relapse at 5 years follow-up scan

tissue) seems promising even if burdened by several interpretative caveats that still make it controversial (Bonney et al. 2015; Fallah et al. 2015; Roessler et al 2019).

9.6.1 Surgical Intervention Surgical treatment of GNTs is the main therapeutic approach to target oncologic control and achieve seizure freedom (Morris et al. 1998; Radhakrishnan et al. 2016; Giulioni et al. 2017; Devaux et al. 2017). A careful evaluation should be considered prior to any surgical intervention to decide on the most appropriate surgical approach, namely, to determine whether only a tumor resection is sufficient (lesionectomy) or it is necessary to remove the lesion and the surrounding epileptogenic zone (tailored epilepsy resection) (Luyken et al. 2003; Cataltepe et al. 2005; Giulioni et al. 2009). For mesial temporal

lobe tumors (a common site of GNTs), different approaches have been described including anterior temporal lobectomy, transsylvian, transcortical, sub-temporal approaches, and infratentorial supracerebellar approach (Rhoton 2003; Yaşargil et al. 2010). There are some shared opinions and consensus that lesionectomy alone may provide good seizure outcome in GNTs located in the extratemporal and lateral/posterolateral temporal regions if clinical and neuroradiological findings exclude an epileptogenic temporomesial involvement (Luyken et al. 2003; Cataltepe et al. 2005; Giulioni et al. 2009). Conversely, tumors located in the medial temporal lobe appear more prone to have a wide temporomesial epileptogenicity involving the entorhinal, hippocampal, and parahippocampal cortex; therefore, tailored epilepsy surgery is advised rather than only lesionectomy (Luyken et al. 2003; Giulioni et al. 2006, 2009). A treatment algorithm is proposed (Fig. 9.19).

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Symptoms

GNT w/o contrast ehancement

MRI (Brain +/- Spine) GNT +/- other neuroradiological findings (FCD, HS)

MRI follow up

MRI (Brain +/- Spine)

Neurological deficit

GNT with contrast enhancement Epileptological and neurological work up

Brain localisation

Spinal localisation Possible total resection

Mesial temporal lobe

Not possible total resection

Lateral temporal lobe Extratemporal lobe

Epilepsy oriented approach (tailored surgery)

Biopsy

Lesionectomy

subtotal resection Confirmed GNTs

follow up +/- CMT or target therapy +/- RT

total resection BUT anaplastyc tumor total resection WHO grade I

CMT or target therapy +/- RT limited MRI follow up

Fig. 9.19 Treatment algorithm for GNTs

9.6.2 Chemotherapy and Radiotherapy Although there is a paucity of evidence and no current treatment guidelines, the use of adjuvant therapies such as radiotherapy and/or chemotherapy is mainly reserved in the setting of high-grade tumors, such as anaplastic gangliogliomas (Terrier et al. 2017). Despite the controversies regarding the optimal chemotherapeutic regimen in aggressive GNTs, different regimens have been reported in several published case series including the standard combined chemoradiotherapy according to Stupp protocol, second-line chemotherapy such as PCV (procarbazine, lomustine, vincristine), irinotecan, bevacizumab, and fotemustine (Majores et al. 2008; Terrier et al. 2017; Mallick et al. 2018). In liponeurocytoma postoperative radiotherapy seems to decrease the risk of tumor recurrence both after complete and incomplete surgical resection and should be offered to the patient (Gembruch et al. 2018). Even in the presence of residual tumor, postoperative radiotherapy is not routinely administered in paraganglioma. Clinical and radiological

follow-up should be continued for a long time in order to identify recurrent cases which have been reported even up to 30 years after surgical removal (Tuleasca et al. 2019).

9.6.3 New Therapeutic Modalities Recently, BRAF V600E has been reported as targetable mutation in some tumors including malignant melanoma, hairy cell leukemia, thyroid carcinoma, and in CNS tumors such as pilocytic astrocytoma, ganglioglioma, pleomorphic xanthoastrocytoma and papillary craniopharyngioma (MacConaill et al. 2009; Flaherty et al. 2010; Dias-Santagata et al. 2011; Schindler et al. 2011; La Corte et al. 2018). Moreover, BRAF inhibitors have shown promising clinical results in the treatment of single case reports of pilocytic astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, and craniopharyngioma (Chamberlain 2013; Bautista 2014; Brastianos et al. 2016; Grever 2016; Miller et al. 2016). Specifically, there are few published case reports of BRAF V600E-mutated gangliogliomas treated with a BRAF inhibitor monotherapy (such as

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vemurafenib or dabrafenib) that showed a positive sustained response (Del Bufalo et al. 2014; Kaley et al. 2018). To overcome the common development of resistance to RAF inhibitor monotherapy, there are some reports of combined RAF and MEK inhibitors in GGs (Marks et al. 2018; Touat et al. 2018; Beland et al. 2018). There are two case reports of pediatric desmoplastic infantile astrocytoma (DIA) harboring a BRAF V600E mutation that relapsed after conventional treatment and was successfully treated with BRAF inhibitors monotherapy (vemurafenib) and combined BRAF-MEK inhibitors (dabrafenib and trametinib), respectively, showing a good clinical and radiological response (van Tilburg et al. 2018; Blessing et al. 2018). Future clinical trials are needed to address whether BRAF V600E mutation in CNS neoplasms, such as GG, PXA, and PA will benefit from a BRAF-targeted molecular therapy. KIAA1549-BRAF fusion represents a class II BRAF mutation commonly present in PA and DLGNT (Behling and Schittenhelm 2019; Schreck et al. 2019). The activation of the MAPK downstream pathway is different from BRAF V600E activating mutation mechanism because it acts as a dimerization signal (Yao et al. 2015). Therefore, tumors expressing such BRAF fusions and treated with BRAF inhibitors may have a paradoxical MAPK activation. A preclinical study evaluated the efficacy of second-generation selective RAF inhibitor PLX PB-3, which could address such downstream targets and induce little paradoxical MAPK activation in BRAF fusionexpressing cells (Sievert et al. 2013). There is no currently approved personalized drug treatment targeting FGFR mutation in GNTs, but preclinical studies employed new inhibitor molecules that showed promising results to target FGFR pathway (Peng et al. 2019).

9.7

Follow-Up and Prognosis

Surgical removal of GNTs guarantees the best oncological and epileptological outcome (Aronica et al. 2001; Luyken et al. 2003; Giulioni et al. 2017; Pelliccia et al. 2017; Mallick et al. 2018).

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Almost 80% of patients with GNTs and drugresistant epilepsy achieve seizure freedom after surgery (Giulioni et al. 2017). It has been reported that seizure outcome in drug-responsive epilepsy is better (98% of cases) compared to DRE (88% of cases). On the other hand, after discontinuation of AEDs almost 50% of patients with drug-responsive epilepsy achieve seizure freedom compared to 30% of DRE subjects. Early intervention after seizure onset is associated with a better seizure outcome, and long epilepsy duration is associated with development of neuropsychological deficits above all in younger children (under 4 years old) (Yang et al. 2011; Giulioni et al. 2017). In our experience, extratemporal and temporolateral GNTs could benefit from pure lesionectomy if a wider epileptogenic zone has been excluded with the presurgical workup. On the contrary, epilepsy due to temporomesial GNTs seems to benefit more from the removal of temporo-mesial structures (i.e., anteromesial temporal lobectomy) because of the frequent coexistence of temporomesial GNTs and FCD or HS (that could reach 40% of cases) (Babini et al. 2013; Giulioni et al. 2013; Pelliccia et al. 2017). In these cases, the epileptogenic zone is larger than the tumor, and hippocampal-extrahippocampal circuits are involved. DLGNT represents a challenge due to its wide anatomical distribution that often prevents radical surgical removal. Furthermore, features of anaplasia with increased mitotic and proliferative activity are not so uncommon in DLGNT.

9.8

Conclusion

GNTs are rare and challenging neuropathological entities. Pre-surgical neurological and neuroradiological investigations followed by a proper tailored surgical strategy have led to the best postoperative results. While neuroradiological follow up may be considered for asymptomatic not enhancing GNTs, an early surgical treatment of patients with symptomatic GNTs should be offered in order to improve seizure and cognitive outcome, to decrease psychological and social

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impact of the disease and to avoid rare but possible malignant transformation. A correct diagnosis is crucial to differentiate GNTs to other glial tumors and to correctly address the possible adjuvant therapy. For this reason, biomarkers such as BRAF, 1p19q, IDH1, and CD34 should be systematically used.

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Benign and Malignant Tumors of the Pituitary Gland

10

Luigi Albano, Marco Losa, Lina Raffaella Barzaghi, and Pietro Mortini

Abstract

Pituitary gland tumors represent approximately 10–15% of all brain tumors and the most common neoplasms of the sellar region. Among them, pituitary adenomas are the widespread accounting for more than 80%. Recently, the fourth edition of the World Health Organization (WHO) 2017 classified pituitary tumors focusing on histopathologic and molecular genetics features and introduced new entities like pituitary blastoma. Most of pituitary gland neoplasms occur sporadically, whereas 5% are related to familial syndromes. They present with several clinical manifestations including signs and symptoms related to excessive hormone secretion by the tumor, signs of hormone deficits by the normal pituitary gland and others commonly secondary to mass effects, and compression of nearby structures such as the optic chiasm; headache and visual disturbance are the most frequent mass effect symptoms. Some tumors, however, are detected as an incidental finding on magnetic resonance

L. Albano (&) . M. Losa . L. R. Barzaghi . P. Mortini Department of Neurosurgery and Gamma Knife Radiosurgery, I.R.C.C.S. Ospedale San Raffaele, Vita-Salute University, Via Olgettina 60, 20132 Milan, Italy e-mail: [email protected]

imaging (MRI) or computed tomography (CT) scans performed for some other reasons. A correct evaluation involves the assessment of hypothalamic–pituitary hormonal function and an ophthalmological examination once a pituitary lesion is encountered. Surgery, more specifically transsphenoidal approach, represents the primary treatment chosen for the majority of pituitary tumors (except for prolactinomas where medical treatment is indicated) allowing for pathologic analysis and complete or partial tumor removal. On the contrary, to date, craniotomy is rarely performed. Sometimes, due to the proximity of critical structures and to tumor’s location and characteristics, a successful surgical procedure may often not be achievable due to the high risks related to the procedure itself. Therefore, the treatment of pituitary tumors commonly requires a multimodal approach, including surgery, radiosurgery, radiation therapy, and medical therapy. Aggressive pituitary tumors or carcinomas are associated with poor prognosis due to limited therapeutic options. Furthermore, they tend to recur quickly after initial surgical treatment or present metastasis, may be unresponsive to therapy, and are difficult to manage. In this chapter, we provide an overview of the most common pituitary gland tumors focusing on epidemiology, new pathological features, diagnosis, available treatment, and prognosis.

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_10

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Keywords

Pituitary tumors Transsphenoidal

10.1

. Adenoma . . Radiosurgery

Background and Epidemiology

Tumors of the pituitary gland and sellar region represent approximately 15–20% of all brain tumors. They include neoplasms of different histological natures, both benign and malignant. According to the new 2017 World Health Organization (WHO) classification, tumors originating from the adenohypophysis are pituitary adenomas, pituitary carcinomas, and less frequently pituitary blastomas, whereas the neurohypophysis tumors include granular cell tumors, pituicytomas, and spindle cell oncocytomas (Table 10.1) (Mete and Lopes 2017). Despite the benign histology and the very slow growth rates of the majority of these tumors, over many years, they may cause clinical symptoms due to mass effects (headache, visual failure), impaired normal pituitary function (hypopituitarism), and/or hormone hypersecretion. Pituitary adenomas are benign neoplasms originating in adenohypophyseal cells and they are the most common neoplasms of the sellar region and pituitary gland, accounting for more than 80% of all pituitary tumors. Magnetic resonance imaging (MRI) scans of normal volunteers also show a 10% prevalence of the human population (Hall et al. 1994), but other pathologic entities may have a similar appearance, such as Rathke’s cysts and metastatic tumors (Famini et al. 2011). The incidence rate of pituitary adenomas is approximately 2–3 cases per 100,000 people/year and occurs mainly in people aged 30– 60 years; furthermore, they arise earlier in females (20–45 years) compared to males (35– 60 years) due to the larger frequency of prolactinsecreting adenomas in young females. Pituitary adenomas are classified according to tumor size in microadenomas ( 2 months

3.7

Hyponatremia

4.7

CSF cerebrospinal fluid; DI diabetes insipidus a At least one axis

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are the most common side effects of dopamine agonists (Molitch 2017). Several subgroups of medical therapy with hormonal control rate and the most common adverse effects are summarized in Table 10.3 (Molitch 2017).

Radiation therapy, including both conventional fractionated radiotherapy and modern radiation techniques, plays a crucial role as adjuvant treatment in patients with residual or recurrent pituitary tumors following surgery in general or sometimes as primary therapy for

Table 10.3 Medical therapy for pituitary adenomas treatment Medication

Drug class

Hormonal control (%)

Side effects

Prolactin-secreting tumor Bromocriptine

Dopamine agonist

60–80

Nausea, vomiting, constipation, dizziness, headache, compulsive behavior

Cabergoline

Dopamine agonist

80–90

Nausea, vomiting, constipation, dizziness, headache, compulsive behavior, cardiac valve disorders (high doses > 2 mg/wk)

Growth hormone-secreting tumor Cabergoline

Dopamine agonist

32

Nausea, vomiting, constipation, dizziness, headache, compulsive behavior, cardiac valve disorders (high doses [>2 mg/wk])

Octreotide LAR

Somatostatin analog

20–35

Abdominal cramps, flatulence, diarrhea, gall bladder stones and sludge, alopecia

Lanreotide depot

Somatostatin analog

20–35

Abdominal cramps, flatulence, diarrhea, gall bladder stones and sludge, alopecia

Pasireotide LAR

Somatostatin analog

30–40

Abdominal cramps, flatulence, diarrhea, gall bladder stones and sludge, alopecia, worsening of diabetes

Pegvisomant

Growth hormone receptor blocker

63–90

Hepatotoxicity, nausea, diarrhea

Adrenocorticotropic hormone-secreting tumor Ketoconazole

Enzyme inhibitor

49

Hepatotoxicity, nausea, dizziness, diarrhea, rash, hypogonadism in men

Cabergoline

Dopamine agonist

32

Nausea, vomiting, constipation, dizziness, headache, compulsive behavior

Mifepristone

Cortisol receptor blocker

60–87

Adrenal insufficiency, hypokalemia, menorrhagia, edema

Pasireotide

Somatostatin analog

26

Abdominal cramps, flatulence, diarrhea, gall bladder stones and sludge, alopecia, worsening of diabetes

Etomidate

Enzyme inhibitor

100

Sedation (avoid overdose [>0.1 mg/kg/h], which will cause apnea and somnolence)

Metyrapone

Enzyme inhibitor

50–76

Hirsutism, acne, hypokalemia, hypertension

Thyrotropin-secreting tumor Octreotide LAR

Somatostatin analog

90

Abdominal cramps, flatulence, diarrhea, gall bladder stones and sludge, alopecia

Lanreotide depot

Somatostatin analog

90

Abdominal cramps, flatulence, diarrhea, gall bladder stones and sludge, alopecia

LAR, long-acting release; wk, week

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Benign and Malignant Tumors of the Pituitary Gland

those where surgery is contraindicated (Albano et al. 2020; Minniti et al. 2016). However, the role of radiotherapy is not clearly defined in cases of neurohypophysis tumors due to the rarity of these conditions and the few case series reported in medical literature. To date, adjuvant radiotherapy is indicated only in cases of atypical or clear recurrence of neurohypophysis tumors. Conventional radiation therapy is effective for pituitary tumors at a total dose of 45–60 Gy delivered in 25–33 fractions (1.6–2.0 Gy per day, five days a week for 5–7 weeks). Stereotactic radiosurgery, which refers to the delivery of large doses of radiation to small targets, is usually given in a single fraction or, less frequently, in a reduced number of fractions (from 2 to a maximum of 5) (Albano et al. 2019). The stereotactic techniques mainly used include Gamma Knife radiosurgery or a modified linear accelerator (LINAC)-based radiosurgical system. The advantages of stereotactic radiosurgery are the more precise dose delivery associated with the rapid fallout of radiation resulting in a reduction of normal brain tissue irradiated to high radiation dose, such as the optic pathway and the brain stem. Secreting pituitary adenomas require higher doses (range 18–34 Gy) than nonfunctioning adenomas to achieve hormonal hypersecretion remission or control; however, to reduce tumoral growth in non-functioning pituitary adenomas, 15 Gy is usually sufficient (range 12–16 Gy) (Minniti et al. 2016). When considering pituitary carcinoma, intensity-modulated radiation therapy (IMRT) is the most common radiotherapy modality reported in several case series in the medical literature (total dose: 45–54 Gy) and used as adjuvant treatment following surgery. Conventional radiotherapy is usually used in case of posterior pituitary tumors with successful control of tumor recurrence growth. Chemotherapy may be used in cases of aggressive pituitary adenoma or pituitary carcinoma resistant to standard therapies (SantosPinheiro et al. 2019). Temozolomide is the drug most widely employed. It is considered as the

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standard of care in the management of gliomas, but it has also proven efficient in the treatment of malignant neuroendocrine tumors. It is usually well tolerated; its most common side effects are fatigue and nausea. Temozolomide has been used as monotherapy, concurrently with radiation therapy and immediately following radiotherapy or in combination with other drugs, such as capecitabine, without a clear guideline. Moreover, there are no prospective and comparative studies among those. Losa and colleagues published an Italian survey analyzing 31 patients with aggressive pituitary adenomas or carcinomas undergoing Temozolomide as salvage therapy. They reported a 2-year disease control rate of 59.1% and overall survival rates of 83.9% and 59.6% at 2 and 4 years, respectively (Losa et al. 2016).

10.6.3 New Therapeutic Modalities Novel targeted therapies, such as mammalian target of rapamycin (mTOR) inhibitors and antivascular endothelial growth factor (VEGF) agents, may be warranted for further investigation following a case report of a patient showing disease control for 26 months after administration of the angiogenesis inhibitor bevacizumab and data showing the in vitro effect of Everolimus on cell viability in cell cultures from nonfunctioning pituitary adenomas (Zatelli et al. 2010). The relevant role of EGF and its receptor (EGFR) has also encouraged research focusing on the use of tyrosine kinase inhibitors, especially the EGFR inhibitor, as a targeted medical therapy for ACTH adenomas, demonstrating auspicious in vitro results (Langlois et al. 2018). Notably, some promising surgical techniques such as the implantation of Gliadel (carmustine) wafers in patients affected by aggressive pituitary adenomas have shown disease stabilization and/or even objective responses in many cases (Chatzellis et al. 2015). Because most pituitary tumors are generally slow-growing tumors and often never recur after

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10%, 13%, and 11% in lactotroph, somatotroph, corticotroph, thyrotroph, and gonadotroph/null cell adenomas, respectively (Molitch 2017; Mortini et al. 2018). The control of pituitary adenoma growth after radiotherapy or radiosurgery during long-term follow-up has been reported between 90 and 100% of cases (Albano et al. 2019; Losa et al. 2017). Figure 10.5 shows pre-radiosurgical treatment (a, b) and follow-up (c, d) MR images demonstrating a significant reduction in tumor volume. According to the study of surveillance, epidemiology, and end results, the overall survival rates for pituitary carcinoma are 57.1%, 28.6%, and 28.5% at 1, 2, and 5 years, respectively (Santos-Pinheiro et al. 2019). In the largest case series published in the literature, early use of chemotherapy, in particular temozolomide, combined with standard pituitary carcinoma management (surgical resection and radiotherapy) was well tolerated and associated with improved survival rates compared to the previous literature (Santos-Pinheiro et al. 2019). The prognosis of tumors of the neurohypophysis is variable because of the limited number of cases and short follow-up time. Some data are reported for spindle cell oncocytoma that recurs in approximately 40% of cases after surgery (Sali et al. 2017). Adjuvant radiation therapy for residual or recurrent tumor leads to a 5-

complete resection, new therapeutic approaches need to have virtually no toxicity for them to be used broadly. Mutant GNAS1, USP8, and BRAF may be optimal targets for corticotroph and somatotroph adenomas (Ilie et al. 2019). Future studies will be crucial to find out a clearer molecular classification of each pituitary tumor type and subtype (Faltermeier et al. 2019; Neou et al. 2020).

10.7

Follow-Up and Prognosis

Follow-up of patients affected by pituitary tumors should include clinical, ophthalmological, neuroradiological, and hormonal assessment. This should be done 3–6 months after treatment, at a 6-month interval for the first year, and yearly thereafter for 5 years. After this period, clinical control including neuroimaging and hormonal evaluation should be scheduled at a two-year interval. When considering pituitary adenomas, overall remission rate of surgical treatment (including giant invasive tumors) is ranged from 64.4% to 79.6% according to pituitary adenoma types. As shown in Table 10.4, in selected subgroups, like microadenomas or adenomas without cavernous sinus invasion, surgery is more effective (Mortini et al. 2018). The overall recurrence rate after 5 years from surgery is approximately 15%, 5%,

Table 10.4 Surgical outcomes of patients operated for pituitary adenoma by transsphenoidal microsurgical approach Type of adenoma

Surgical remission % Overall

Microadenomas

Macroadenomas

Cavernous sinus invasive tumors

Non-invasive tumors

Somatotroph adenomas

66

88.7

60.4

14.3

80.2

Corticotroph adenomas

79.6

80.9

74.5

36

81.9

Lactotroph adenomas

64.4

81.2

50

0

74

Thyrotroph adenomas

74.5

92.8

67.6

16.7

92.3

Null cell adenomas

66.9

100

67.1

32.7

82.6

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Fig. 10.5 Pre-Gamma Knife radiosurgical treatment axial (a) and coronal (b) T1-weighted MR images with gadolinium, respectively, showing tumor recurrence (blue line) close to the anterior optic pathway. A prescription dose of 7 Gy per fraction (yellow isodose line) was

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delivered in three consecutive sessions to the margin of adenoma; follow-up axial (c) and coronal (d) T1-weighted MR images with contrast, respectively, obtained 48 months from radiosurgery demonstrating a significant reduction in tumor volume

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year progression-free survival (PFS) of 90% (Sali et al. 2017). A recent case series on Gamma Knife radiosurgery for residual or recurrent spindle cell oncocytoma reports a 4-year PFS of 100% (Akyoldas et al. 2019). To date, however, regular clinical and radiological follow-up is imperative, considering the uncertain behavior of these tumors and the current lack of clinical guidelines.

10.8

Conclusion

Pituitary tumors are frequent intracranial neoplasms, commonly benign in nature. Advances in immunology, molecular biology, and imaging as well as new treatment options improved the understanding of the natural history of these tumors and their management. However, the complexity of their diagnosis and treatment is a strong argument for recommending that a multidisciplinary team composed of physicians with expertise in the field of pituitary disease should direct the care of patients with pituitary gland tumors.

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Giantini Larsen AM et al (2018) Spindle cell oncocytoma of the pituitary gland. J Neurosurg 131:517–525. https://doi.org/10.3171/2018.4.JNS18211 Gillam MP, Molitch ME, Lombardi G, Colao A (2006) Advances in the treatment of prolactinomas. Endocr Rev 27:485–534. https://doi.org/10.1210/er.2005-9998 Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH (1994) Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 120:817–820. https://doi.org/10.7326/0003-4819120-10-199405150-00001 Hardy J, Vezina JL (1976) Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neurol 15:261-273 Ilie MD, Lasolle H, Raverot G (2019) Emerging and novel treatments for pituitary tumors. J Clin Med 8. https://doi.org/10.3390/jcm8081107 Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–617; discussion 617–618. https://doi.org/10.1227/ 00006123-199310000-00008 Langlois F, Chu J, Fleseriu M (2018) Pituitary-directed therapies for cushing's disease. Front Endocrinol (Lausanne) 9:164. https://doi.org/10.3389/fendo.2018.00164 Losa M et al (2016) Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. J Neurooncol 126:519–525. https://doi.org/10.1007/ s11060-015-1991-y Losa M, Spatola G, Albano L, Gandolfi A, Del Vecchio A, Bolognesi A, Mortini P (2017) Frequency, pattern, and outcome of recurrences after gamma knife radiosurgery for pituitary adenomas. Endocrine 56:595– 602. https://doi.org/10.1007/s12020-016-1081-8 Melmed S (2011) Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7:257–266. https://doi.org/10.1038/ nrendo.2011.40 Mete O, Lopes MB (2017) Overview of the 2017 WHO classification of pituitary tumors. Endocr Pathol 28:228– 243. https://doi.org/10.1007/s12022-017-9498-z Minniti G, Clarke E, Scaringi C, Enrici RM (2016) Stereotactic radiotherapy and radiosurgery for nonfunctioning and secreting pituitary adenomas. Rep Pract Oncol Radiother 21:370–378. https://doi.org/10. 1016/j.rpor.2014.09.004 Molitch ME (2017) Diagnosis and treatment of pituitary adenomas: a review. JAMA 317:516–524. https://doi. org/10.1001/jama.2016.19699 Mortini P, Albano L, Barzaghi LR, Spina A, Losa M (2021) The open sella technique for surgical treatment of pituitary macroadenomas: safety and efficacy in a

297 large clinical series. Br J Neurosurg 1–8. https://doi. org/10.1080/02688697.2021.1950629 Mortini P, Barzaghi LR, Albano L, Panni P, Losa M (2018) Microsurgical therapy of pituitary adenomas. Endocrine 59:72–81. https://doi.org/10.1007/s12020017-1458-3 Mortini P, Barzaghi R, Losa M, Boari N, Giovanelli M (2007) Surgical treatment of giant pituitary adenomas: strategies and results in a series of 95 consecutive patients. Neurosurgery 60:993–1002; discussion https://doi.org/10.1227/01.NEU. 1003–1004. 0000255459.14764.BA Neou M et al (2020) Pangenomic classification of pituitary neuroendocrine tumors. Cancer Cell 37 (123–134):e125. https://doi.org/10.1016/j.ccell.2019. 11.002 Raverot G, Jouanneau E, Trouillas J (2014) Management of endocrine disease: clinicopathological classification and molecular markers of pituitary tumours for personalized therapeutic strategies. Eur J Endocrinol 170:R121-132. https://doi.org/10.1530/EJE-13-1031 Robertson JC, Jorcyk CL, Oxford JT (2018) DICER1 syndrome: DICER1 Mutations in Rare Cancers. Cancers (Basel) 10. https://doi.org/10.3390/ cancers10050143 Sali A, Epari S, Tampi C, Goel A (2017) Spindle cell oncocytoma of adenohypophysis: review of literature and report of another recurrent case. Neuropathology 37:535–543. https://doi.org/10.1111/neup.12393 Santos-Pinheiro F et al (2019) Treatment and long-term outcomes in pituitary carcinoma: a cohort study. Eur J Endocrinol 181:397–407. https://doi.org/10.1530/EJE18-0795 Secci F, Merciadri P, Rossi DC, D'Andrea A, Zona G (2012) Pituicytomas: radiological findings, clinical behavior and surgical management. Acta Neurochir (Wien) 154:649–657; discussion 657. https://doi.org/ 10.1007/s00701-011-1235-7 Wilson CB (1984) A decade of pituitary microsurgery. Herbert Olivecrona Lect J Neurosurg 61:814–833. https://doi.org/10.3171/jns.1984.61.5.0814 Zatelli MC et al (2010) Effect of everolimus on cell viability in nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 95:968–976. https://doi.org/10. 1210/jc.2009-1641 Zhang X, Fei Z, Zhang J, Fu L, Zhang Z, Liu W, Chen Y (1999) Management of nonfunctioning pituitary adenomas with suprasellar extensions by transsphenoidal microsurgery. Surg Neurol 52:380–385. https://doi. org/10.1016/s0090-3019(99)00120-2

Craniopharyngioma in Pediatrics and Adults

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Martina Piloni, Filippo Gagliardi, Michele Bailo, Marco Losa, Nicola Boari, Alfio Spina, and Pietro Mortini

Abstract

Craniopharyngiomas are rare malignancies of dysembryogenic origin, involving the sellar and parasellar areas. These low-grade, epithelial tumors account for two main histological patterns (adamantinomatous craniopharyngioma and papillary craniopharyngioma), which differ in epidemiology, pathogenesis, and histomorphological appearance. Adamantinomatous craniopharyngiomas typically show a bimodal age distribution (5– 15 years and 45–60 years), while papillary craniopharyngiomas are limited to adult patients, especially in the fifth and sixth decades of life. Recently, craniopharyngioma histological subtypes have been demonstrated to harbor distinct biomolecular signatures. Somatic mutations in CTNNB1 gene encoding b-catenin have been exclusively detected in adamantinomatous craniopharyngiomas, which predominantly manifest as cystic lesions, while papillary craniopharyngiomas are driven by BRAF V600E mutations in up to 95% of cases and are typically solid masses.

M. Piloni . F. Gagliardi . M. Bailo . M. Losa . N. Boari . A. Spina . P. Mortini (&) Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy e-mail: [email protected]

Despite the benign histological nature (grade I according to the World Health Organization classification), craniopharyngiomas may heavily affect long-term survival and quality of life, due to their growth pattern in a critical region for the presence of eloquent neurovascular structures and possible neurological sequelae following their treatment. Clinical manifestations are mostly related to the involvement of hypothalamic–pituitary axis, optic pathways, ventricular system, and major blood vessels of the circle of Willis. Symptoms and signs referable to intracranial hypertension, visual disturbance, and endocrine deficiencies should promptly raise the clinical suspicion for sellar and suprasellar pathologies, advocating further neuroimaging investigations, especially brain MRI. The optimal therapeutic management of craniopharyngiomas is still a matter of debate. Over the last decades, the surgical strategy for craniopharyngiomas, especially in younger patients, has shifted from the aggressive attempt of radical resection to a more conservative and individualized approach via a planned subtotal resection followed by adjuvant radiotherapy, aimed at preserving functional outcomes and minimizing surgery-related morbidity. Whenever gross total removal is not safely feasible, adjuvant radiotherapy (RT) and stereotactic radiosurgery (SRS) have gained an increasingly important role to manage tumor residual or recurrence. The role of intracavitary

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_11

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therapies, including antineoplastic drugs or sealed radioactive sources, is predominantly limited to monocystic craniopharyngiomas as secondary therapeutic option. Novel findings in genetic profiling of craniopharyngiomas have unfold new scenarios in the development of targeted therapies based on brand-new biomolecular markers, advancing the hypothesis of introducing neoadjuvant chemotherapy regimens in order to reduce tumor burden prior to resection. Indeed, the rarity of these neoplasms requires a multispecialty approach involving an expert team of endocrinologists, neurosurgeons, neuro-ophthalmologists, neuroradiologists, radiotherapists, and neuro-oncologists, in order to pursue a significant impact on postoperative outcomes and long-term prognosis.

bimodal distribution has been observed (Bunin et al. 1998; Nielsen et al. 2011; Zacharia et al. 2012): they may be either diagnosed in pediatric population, with peak incidence at 5–14 years, and in older patients between the fifth and seventh decades of life (Nielsen et al. 2011; Zacharia et al. 2012). Population-based studies reported in literature have not highlighted a clear gender difference (Bunin et al. 1998; Sorva and Heiskanen 1986). An underlying genetic susceptibility to develop craniopharyngiomas throughout life has not been identified (Bunin et al. 1998; Sorva and Heiskanen 1986); nevertheless, a significant number of ectopic craniopharyngiomas have been reported in patients affected by an autosomal dominant form of familial colorectal polyposis, also known as Gardner’s syndrome (Gabel et al. 2017).

Keywords

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Craniopharyngioma Sellar and suprasellar tumors Surgery Radiotherapy Stereotactic radiosurgery

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Background and Epidemiology

Craniopharyngiomas are benign epithelial, extraaxial tumors related to Rathke’s pouch that predominantly involve the sellar and suprasellar regions. They represent approximately 1.2–4.6% of all intracranial tumors, comprising up to 5– 11% of intracerebral neoplasms in childhood (90% (Hill et al. 2019). Available data in the literature report a 10-year RFS rate of 66.9% after GTR, 31.8% after partial tumor resection, and 79.6% after incomplete removal associated to subsequent RT (Attuati and Picozzi 2016; Fahlbusch et al. 1999; Honegger et al. 1999; Iannalfi et al. 2013; Karavitaki et al. 2005; Lin et al. 2008; Mark et al. 1995; Minniti et al. 2009; Mortini et al. 2013a; Muller et al. 2010; Rao et al. 2017; Savateev et al. 2017; Stripp et al. 2004; Zacharia et al. 2012). Of note, GTR was not significantly different from incomplete resection in the matter of tumor recurrence, as demonstrated in a systematic review and meta-analysis with comparative recurrence rates of 17% and 27% for GTR and incomplete resection, respectively (Dandurand et al. 2018). The role of timing in RT delivery is less clear. Although significant differences in terms of 10and 20-year RFS and OS have not been found between immediate and late adjuvant RT (Pemberton et al. 2005), delay of RT at time of tumor progression may lead to an increase in late

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complications, specifically neurocognitive impairment (Iannalfi et al. 2013). Hence, many authors suggest performing RT within 3– 4 weeks after STR, especially when dealing with children (Attuati and Picozzi 2016; Habrand et al. 1999; Lee et al. 2014; Lin et al. 2008; Minniti et al. 2009; Moon et al. 2005; Muller et al. 2010; Regine et al. 1993; Weiss et al. 1989). Conventional RT is delivered through multidirectional X-rays beams classically arranged in two to four fields focused on the target volume. A fractionated total volume dose of 54 Gy has been established worldwide (Muller 2014). Irradiation with a dose less than 54 Gy was associated with higher relapse rate (44%) compared to a minimum dose of 54 Gy (16%) (Regine et al. 1993). Nowadays, availability of modern imaging utilizing CT simulation with MRI fusion and technological implantation in linear accelerators have allowed to yield high rates of tumor local control (Merchant et al. 2006). Threedimensional conformal RT (3DCRT) represents the current standard, allowing a more precise dosimetry and a better protection of risky zones, such as visual pathways. The optimal irradiation procedure (static-shaped beams, dynamic conformal arc beams, multiple circular beams, intensity modulated beams) and fractionation regimen are selected according to multiple radiobiological, physical, and geometric parameters (Muller et al. 2019). Latest studies have demonstrated fractionated stereotactic RT (FSRT) to allow a precise, stereotactically guided coverage of tumor target, and steep fall of the irradiation dose to the surrounding normal tissue (Muller 2014); thus, it has been suggested that FSRT provides an increased tumor control rate (ranging between 62 and 100% at 10 years), with low toxicity (Iannalfi et al. 2013; Marta et al. 2015), and it is less constrained by tumor volume or proximity to critical structures, as opposed to SRS (Iannalfi et al. 2013; Kobayashi et al. 2015; Minniti et al. 2009; Xu et al. 2011). Intensity-modulated radiotherapy (IMRT) improves conformability of dose distribution for

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treatment of complex-shaped lesions, providing a different dose delivery to areas of the tumor or to nearby radiosensitive structures through tailored beams of varying shape and intensity; it has been also noted a greater local control of solid component of the tumor (Greenfield et al. 2015). In a comparative dosimetry study between 3DCRT and IMRT planning for craniopharyngioma treatment in 15 pediatric patients, IMRT demonstrated reduced mean doses to critical organ at risks (cochlea, temporal lobes, and hippocampus) (Beltran et al. 2010). Exposure of patients to ionizing rays increases the risk of short-term and late-onset adverse effects. Short-term adverse effects arise during the treatment course and may include headache, nausea and vomiting, fatigue, and local hair loss. If residual tumor is present, enlargement in cyst volume with significant clinical consequences may occur and require immediate surgical intervention and/or correction of irradiation planning (Muller 2014; Winkfield et al. 2009). Long-term adverse effects are of greatest concern, especially those leading to fatal events. They include radionecrosis (especially for optic pathways), cerebrovascular accident associated with postradiation arteritis, secondary malignancies within the previous irradiation field, hormone deficiencies, and neuropsychological and cognitive impairment (Dolson et al. 2009; Lo et al. 2014; Rodriguez et al. 2007; Winkfield et al. 2011). Treatment-related neurotoxicity associated with the use of RT should be mostly considered in younger children, due to longer lifeexpectancy and greater susceptibility of the developing brain to radiation-induced damages (Attuati and Picozzi 2016).

11.6.2.4 Stereotactic Radiosurgery (SRS) To overcome some of the postoperative complications encountered in GTR and long-term radiation-induced sequelae, SRS has been proposed for the treatment of residual or recurrent craniopharyngiomas (Gopalan et al. 2008; Niranjan et al. 2010; Suh and Gupta 2006), and it

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has been reported as a safe and effective primary treatment modality in selected cases (Saleem et al. 2013). SRS is performed either through a gamma unit device (Gamma Knife) or a linear accelerator mounted on a robotic arm producing highenergy photons (Cyber Knife). The tumor volume is defined in a stereotactic setting to ensure accurate targeting and delivering of high doses, in a single session or in a limited number of fractions. Competent literature reports a broad variation of prescription dose for treatment of craniopharyngiomas, ranging between 8 and 20 Gy (Attuati and Picozzi 2016; Dho et al. 2018; Khamlichi et al. 2013; Kobayashi et al. 1994, 2015; Lee et al. 2014; Losa et al. 2018; Niranjan et al. 2010). Optimal therapeutic dose has yet to be defined, but a prescription dose of 9–12 Gy may be considered as sufficiently effective in tumor growth control as safe in sparing nearby critical radiosensitive structures (Dho et al. 2018). Current recommendations for dose tolerance limits of normal tissues in patients receiving SRS suggest a maximum of 12 Gy as point dose constrain to the optic pathways to prevent radioinduced optic neuropathy (RION) (Pollock et al. 2014). Other cranial nerves coursing in the cavernous sinus are considered less radiosensitive, tolerating up to 15 Gy without significant complications (Attuati and Picozzi 2016). Safe dose thresholds for pituitary stalk and gland are estimated up to 7.3 Gy and 15.7 Gy, respectively (Sicignano et al. 2012). Considering that most of patients undergoing SRS already manifest hypopituitarism at time of treatment (Ulfarsson et al. 2002), optic apparatus frequently represents the main dose-limiting structure. Indeed, multiple radiobiological, physical, and geometric parameters have to be assessed in therapeutic decisions on the use of SRS, such as tumor volume, proximity to organs at risk (OAR), and previous irradiation. Several authors suggest irradiating the entire tumor volume (including both solid and cystic components) to

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achieve a better long-term tumor control (Niranjan et al. 2010). In cases of cystic craniopharyngiomas, an appropriate strategy may contemplate cyst drainage prior to SRS to reduce the target volume and to overcome the close relationship to the optic apparatus (Niranjan et al. 2010). Tumor control rate reported in most single session (Albright et al. 2005; Amendola et al. 2003; Barua et al. 2003; Chiou et al. 2001; Chung et al. 2000; Hasegawa et al. 2010; Jeon et al. 2011; Khamlichi et al. 2013; Kobayashi et al. 2005, 2012, 1994, 2015; Lee et al. 2014; Losa et al. 2018; Mokry 1999; Niranjan et al. 2010; Park et al. 2011; Prasad et al. 1995; Saleem et al. 2013; Ulfarsson et al. 2002; Xu et al. 2011; Yomo et al. 2009; Yu et al. 2000) and hypofractionated SRS series (Iwata et al. 2012; Jee et al. 2014; Lee et al. 2008; Losa et al. 2018; Miyazaki et al. 2009; Pollock et al. 2014) are around 90–100%, 70–80%, and 60–70% for solid, cystic, and mixed craniopharyngiomas, respectively. Average 5-year and 10-year PFS rates were 72% and 60% in single-session series (Albright et al. 2005; Amendola et al. 2003; Barua et al. 2003; Chiou et al. 2001; Chung et al. 2000; Hasegawa et al. 2010; Jeon et al. 2011; Khamlichi et al. 2013; Kobayashi et al. 2005, 2012, 1994, 2015; Lee et al. 2014; Losa et al. 2018; Mokry 1999; Niranjan et al. 2010; Park et al. 2011; Prasad et al. 1995; Saleem et al. 2013; Ulfarsson et al. 2002; Xu et al. 2011; Yomo et al. 2009; Yu et al. 2000), while mean PFS at 3 years and 5 years for hypofractionated SRS were 81% and 67%, respectively (Iwata et al. 2012; Jee et al. 2014; Lee et al. 2008; Losa et al. 2018; Miyazaki et al. 2009; Pollock et al. 2014). Solid appearance is associated with better responses, on the theoretical basis that solid tumors might be more easily delimitated and radiation coverage is more homogeneous, as compared to cystic and mixed lesions (Chung et al. 2000; Kobayashi et al. 2012; Losa et al. 2018). The high targeting precision of SRS and the steep irradiation gradient at lesional boundaries are associated with fewer long-term complications, even though available published data on

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SRS is still too limited to disclose definite conclusions on outcome compared to other RT techniques. In a recent review, complications resulting from SRS have been shown to be minimal with a mean morbidity rate of 4%, most frequently involving endocrine deficiencies and visual deterioration (Iannalfi et al. 2013). Compared to conventional RT, updated reports of SRS series do not describe onset of neurocognitive dysfunction or secondary malignancy. Main restrictions for SRS are the size of the tumor and the proximity to critical structures; indeed, the risk of RION imposes limitations on prescription dose to spare visual function. Hypofractionated SRS is considered as an effective alternative whenever single session SRS is deemed too hazardous for optic pathways tolerance. Otherwise, fractionated stereotactic RT (possibly delivered with modern IMRT techniques) remains the preferred alternative.

11.6.2.5 Intracavitary Brachytherapy Intracavitary brachytherapy consists in stereotactic implantation of beta-emitting radioisotopes (phosphorus-32, yttrium-90, and rhenium-186) into purely cystic or monocystic component of craniopharyngioma, delivering a high radiation dose of 200–270 Gy. The main features of the ideal radioisotope agent include: limited penetrance of emitted radiation which minimizes exposure of critical nearby structures, adequate half-life providing exposure of cystic secretory epithelium to radioactivity, and ease of management (Karavitaki 2014). Phosphorus-32 is the only radioisotope approved for intracavitary therapy in the USA, while yttrium-90 has been preferred in Europe and Japan. Intracavitary brachytherapy applied as primary treatment modality or as salvage option at time of recurrence is associated with local control rates of 70–96% with progressive reduction in fluid production and cyst shrinkage (Derrey et al. 2008; Hasegawa et al. 2004; Lunsford et al. 1994). Solid components have shown to be less responsive to intracavitary irradiation than cystic portions (Julow et al. 2007a, b; Lee et al. 2014). In several studies, deterioration in endocrine function and visual impairment have been

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reported in 3–31.5% and 10–58% of cases, respectively (Iannalfi et al. 2013; Karavitaki 2014). Visual worsening has been imputed to failure of cyst involution, new cysts formation, increase of the solid component, and radiationrelated damage to the optic pathways. In light of the reported control rates and its low mortality and morbidity, intracavitary irradiation may be considered as a safe and effective therapeutic option for predominantly cystic craniopharyngiomas (Backlund et al. 1972; Barriger et al. 2011; Huk and Mahlstedt 1983; Julow et al. 2007a; Julow et al. 1985; Julow et al. 2007b; Karavitaki 2014; Manaka et al. 1985; Pollock et al. 1995; Van den Berge et al. 1992; Voges et al. 1997).

11.6.3 New Therapeutic Modalities 11.6.3.1 Proton Beam Therapy (PBT) PBT is a form of radiotherapy employing beams of accelerated high-energy particles. It represents one of the most highly conformal techniques of irradiation due to the physical principle of Bragg peak. The advantage of PBT is the concentration of maximum dose just over the last few millimeters of the particle’s range during its travel through tissue, without “exit” dose beyond the target. Thus, toxic effects on surrounding normal tissue are limited, while a higher gradient dose is delivered with a precise concentration into the target volume (O’Steen and Indelicato 2018). In the last years, PBT has been increasingly used for the treatment of craniopharyngiomas close to the optic pathways with promising results. Compared to other photon therapy methods, PBT offers a better opportunity to lower the incidence of neurocognitive decline, vascular complications, RION, and second malignancies (Ajithkumar et al. 2018; Alapetite et al. 2012; Beltran et al. 2012; Boehling et al. 2012; Conroy et al. 2015; Friedman et al. 2010; Iannalfi et al. 2013; Merchant et al. 2008). In the most recent series, common grade 1 acute toxicities were represented by cutaneous manifestations, such as dermatitis (33%) and alopecia (27%), headache (27%), and fatigue

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(27%). Grade 2 toxicities were headache (5.6%) and RION (11.1%). During the follow-up, newonset endocrinopathies with panhypopituitarism developed in 38% of cases (Ajithkumar et al. 2018). Cyst enlargement occurring during PBT course was reported in 4–36% of patients (Alapetite et al. 2012; Bishop et al. 2014; Fitzek et al. 2006; Luu et al. 2006). A published review of 40 pediatric craniopharyngiomas treated with PBT demonstrated that 5-year local tumor control and OS rates were 100% (Indelicato et al. 2012). Preliminary experiences with PBT in craniopharyngioma are encouraging, but early clinical results are affected by a low number of published studies including limited number of patients.

11.6.3.2 BRAF Inhibitors Recently, targeted therapies with BRAF inhibitors, such as vemurafenib and dabrafenib, in adults affected by papillary craniopharyngiomas demonstrated promising results (Brastianos et al. 2016; Himes et al. 2018). Current studies aim to predict BRAF and CTNNB1 mutation status before definitive surgery on the basis of noninvasive MRI-based radiomic features, in order to identify subgroups of patients who could potentially benefit from targeted systemic therapies, offering a guidance in clinical decision-making process (Chen et al. 2019; Fujio et al. 2019). Further researches providing insights into pathogenetic mechanisms underlying tumorigenesis in craniopharyngiomas (mostly in adamantinomatous subtype) are needed for clinical validation of these preliminary observations.

11.7

Follow-Up and Prognosis

The principal risk factor that negatively impacts on long-term prognosis is local relapse, mainly in childhood-onset tumors due to prolonged life expectancy. Survival rates at 10 years in patients with tumor recurrence range between 29 and 70%, depending on the adopted treatment strategy (Karavitaki et al. 2006). At the state of the art, there is no general consensus about the optimal therapeutic strategy dealing with

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craniopharyngioma recurrence, which remains extraordinarily challenging (Karavitaki et al. 2006; Losa et al. 2018). Since most of tumor recurrences occur between the first and 4.3 years after surgery, a minimum of five years follow-up is necessary for early detection of tumor relapse (Karavitaki 2014). However, tumor recurrence as late as 30 years after primary treatment has been reported (Karavitaki 2014). After primary treatment, the patient should be referred to endocrinological, neuroophthalmological, neuroradiological, and neurocognitive evaluation every 3–6 months for the first year, every 6 months for the second and third years, and yearly thereafter (Attuati and Picozzi 2016; Di Pinto et al. 2012). Despite the histological benign nature and slow-growing attitude, craniopharyngiomas are locally invasive tumors that tend to relapse even after an attempt at complete surgical resection, due to persistent tumor cells islets in gliotic brain parenchyma close to the lesion (Karavitaki 2014). Recurrence rate is mostly related to the extent of removal: It ranges from 20 to 50% after surgery and is up to 85% in patients undergoing partial resection with postoperative tumor residual (Lee et al. 2014; Mortini et al. 2013a). STR associated with RT has a risk of recurrence close to that of GTR surgery, and fewer morbidity and mortality rates compared to redo surgical debulking. An early postoperative brain MRI is mandatory to better reveal the presence and the amount of tumor residual, and to allow early planning of secondary adjuvant treatment. Additional CT scan can detect any persisting calcification missed in the postoperative MRI, which indicates the presence of tumor residual (Fahlbusch et al. 1999). Other predictive preoperative factors that correlate with an increased recurrence rate are: tumor diameter, extrasellar development, involvement of the third ventricle, presence of hydrocephalus at time of clinical presentation, and high amount of calcification (Attuati and Picozzi 2016; Liubinas et al. 2011).

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With the regard of patient age at time of diagnosis, histological subtype and presence of initial hydrocephalus, several studies disclosed conflicting results both on adult and pediatric cohorts; thus, the prognostic significance of these factors is still matter of debate (Daubenbüchel et al. 2015; Fahlbusch et al. 1999; Karavitaki et al. 2005; Rajan et al. 1993; Tavangar et al. 2004). Overall mortality in craniopharyngioma patients has been reported to be threefold to fivefold higher when compared to the general population (Pereira et al. 2005). OS reported in pediatric cohorts ranges from 83 to 96% at 5 years (Muller et al. 2001), from 65 to 100% at 10 years (Poretti et al. 2004; Visser et al. 2010) and is, on average, 62% at 20 years. In mixed pediatric and adult cohorts, OS is in the range 54–96% at 5 years (Karavitaki et al. 2005; Pereira et al. 2005), 40–93% at 10 years (Karavitaki et al. 2005; Pemberton et al. 2005; Pereira et al. 2005), and 66–85% at 20 years (Pemberton et al. 2005; Pereira et al. 2005). Patients with craniopharyngioma suffer from disabling morbidities that far outweigh the mortality risk. The main issue in successful management of patients affected by craniopharyngioma is optimal QoL and acceptable functional outcome. Despite higher survival rates obtained both in primary and recurrent disease for the advances in microsurgical techniques and radio-oncological treatments, tumor-related and treatment-related sequelae unfavorably impact on QoL in up to 50% of long-term survivors. Visual impairment and hypothalamic dysfunction are the mainstay in influencing functional outcomes; therefore, hypothalamic integrity and visual pathways preservation should be of pivotal importance in treating craniopharyngioma according to riskadapted therapeutic strategies. Furthermore, efforts should be made to assess neuropsychological and cognitive prognosis, mostly in children, for the enduring impact on psychosocial independence.

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Conclusion

Craniopharyngiomas should be considered as a chronic disease, since the negative impact of tumor-related and treatment-related sequelae on patients’ quality of life far exceeds the mortality. In particular, the preservation of functional integrity of hypothalamus, optic apparatus, and neurocognitive structures is of pivotal relevance and should represent the primary focus dealing with these malignancies. Current treatment of craniopharyngiomas encompasses tailored, risk-adapted therapeutic strategies aimed at maximal safe resection. For patients unsuitable for surgical resection, cystcontrolling ancillary procedures are a viable option. A satisfactory tumor control should be pursued through a multimodal approach, including adjuvant RT/SRS in cases of postoperative residual and/or relapse. Due to the rarity of these tumors, it is essential to refer the management of patients with craniopharyngioma to specialized centers, capable of providing multidisciplinary medical resources to enhance the delivery of optimal treatment and careful surveillance, in order to improve the functional outcomes and minimize the long-term morbidity. In the light of the emerging role of brand-new molecular criteria in the histological definition of craniopharyngioma variants, patients enrollment in clinical trials based on innovative targeted therapies should be encouraged to open up the hypothesis of introducing neoadjuvant chemotherapy regimens in the neuro-oncological field.

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328 Rao YJ, Hassanzadeh C, Fischer-Valuck B, Chicoine MR, Kim AH, Perkins SM, Huang J (2017) Patterns of care and treatment outcomes of patients with craniopharyngioma in the national cancer database. J Neurooncol 132:109–117. https://doi.org/10.1007/s11060-0162342-3 Regine WF, Mohiuddin M, Kramer S (1993) Long-term results of pediatric and adult craniopharyngiomas treated with combined surgery and radiation. Radiother Oncol 27:13–21 Rock AK, Dincer A, Carr MT, Opalak CF, Workman KG, Broaddus WC (2019) Outcomes after craniotomy for resection of craniopharyngiomas in adults: analysis of the National Surgical Quality Improvement Program (NSQIP). J Neurooncol 144:117–125. https://doi.org/ 10.1007/s11060-019-03209-9 Rodriguez FJ, Scheithauer BW, Tsunoda S, Kovacs K, Vidal S, Piepgras DG (2007) The spectrum of malignancy in craniopharyngioma. Am J Surg Pathol https://doi.org/10.1097/PAS. 31:1020–1028. 0b013e31802d8a96 Romani R, Niemela M, Celik O, Isarakul P, Paetau A, Hernesniemi J (2010) Ectopic recurrence of craniopharyngioma along the surgical route: case report and literature review. Acta Neurochir (Wien) 152:297– 302; discussion 302. https://doi.org/10.1007/s00701009-0415-1 Rosemberg S, Fujiwara D (2005) Epidemiology of pediatric tumors of the nervous system according to the WHO 2000 classification: a report of 1,195 cases from a single institution. Childs Nerv Syst 21:940– 944. https://doi.org/10.1007/s00381-005-1181-x Rossi A et al (2006) Neuroimaging of pediatric craniopharyngiomas: a pictorial essay. J Pediat Endocrinol Metabol JPEM 19:299-319 Roth CL, Gebhardt U, Muller HL (2011) Appetiteregulating hormone changes in patients with craniopharyngioma. Obesity (silver Spring) 19:36–42. https://doi.org/10.1038/oby.2010.80 Saleem MA, Hashim AS, Rashid A, Ali M (2013) Role of gamma knife radiosurgery in multimodality management of craniopharyngioma. Acta Neurochir Suppl 116:55–60. https://doi.org/10.1007/978-3-7091-13769_9 Samii M, Bini W (1991) Surgical treatment of craniopharyngiomas. Zentralbl Neurochir 52:17–23 Samii M, Tatagiba M (1997) Surgical management of craniopharyngiomas: a review. Neurol Med Chir (Tokyo) 37:141–149. https://doi.org/10.2176/nmc.37. 141 Savateev AN, Trunin YY, Mazerkina NA (2017) [Radiotherapy and radiosurgery in treatment of craniopharyngiomas] Zh Vopr Neirokhir Im N N Burdenko 81:94– 106. https://doi.org/10.17116/neiro201781394-106 Schoenfeld A et al (2012) The superiority of conservative resection and adjuvant radiation for craniopharyngiomas. J Neurooncol 108:133–139 Schwartz TH (2013) A role for centers of excellence in transsphenoidal surgery. World Neurosurg 80:270– 271. https://doi.org/10.1016/j.wneu.2012.11.019

M. Piloni et al. Schwartz TH, Fraser JF, Brown S, Tabaee A, Kacker A, Anand VK (2008) Endoscopic cranial base surgery: classification of operative approaches. Neurosurgery 62:991–1002; discussion 1002–1005. https://doi.org/ 10.1227/01.neu.0000325861.06832.06 Schweizer L et al (2015) BRAF V600E analysis for the differentiation of papillary craniopharyngiomas and Rathke’s cleft cysts. Neuropathol Appl Neurobiol 41:733–742. https://doi.org/10.1111/nan.12201 Sekine S et al (2002) Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol 161:1997–2001. https://doi.org/10.1016/ s0002-9440(10)64477-x Shi X et al (2017) Outcome of radical surgical resection for craniopharyngioma with hypothalamic preservation: a single-center retrospective study of 1054. Patients World Neurosurg 102:167–180. https://doi. org/10.1016/j.wneu.2017.02.095 Shibuya M, Takayasu M, Suzuki Y, Saito K, Sugita K (1996) Bifrontal basal interhemispheric approach to craniopharyngioma resection with or without division of the anterior communicating artery. J Neurosurg https://doi.org/10.3171/jns.1996.84.6. 84:951–956. 0951 Sicignano G et al (2012) Dosimetric factors associated with pituitary function after Gamma Knife Surgery (GKS) of pituitary adenomas. Radiother Oncol 104:119–124. https://doi.org/10.1016/j.radonc.2012. 03.021 Sorva R, Heiskanen O (1986) Craniopharyngioma in Finland. A study of 123 cases Acta Neurochir (Wien) 81:85–89. https://doi.org/10.1007/bf01401226 Sterkenburg AS, Hoffmann A, Gebhardt U, Warmuth-Metz M, Daubenbüchel AM, Müller HL (2015) Survival, hypothalamic obesity, and neuropsychological/ psychosocial status after childhood-onset craniopharyngioma: newly reported long-term outcomes. Neuro-Oncol 17:1029–1038 Stripp DC et al (2004) Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults. Int J Radiat Oncol Biol Phys 58:714–720. https://doi.org/10.1016/S0360-3016 (03)01570-0 Suh JH, Gupta N (2006) Role of radiation therapy and radiosurgery in the management of craniopharyngiomas. Neurosurg Clin N Am 17(143–148):vi–vii. https://doi.org/10.1016/j.nec.2006.02.001 Tavangar SM, Larijani B, Mahta A, Hosseini SM, Mehrazine M, Bandarian F (2004) Craniopharyngioma: a clinicopathological study of 141 cases. Endocr Pathol 15:339–344. https://doi.org/10.1385/ ep:15:4:339 Ulfarsson E, Lindquist C, Roberts M, Rahn T, Lindquist M, Thoren M, Lippitz B (2002) Gamma knife radiosurgery for craniopharyngiomas: long-term results in the first Swedish patients. J Neurosurg https://doi.org/10.3171/jns.2002.97. 97:613–622. supplement Van den Berge JH, Blaauw G, Breeman WA, Rahmy A, Wijngaarde R (1992) Intracavitary brachytherapy of

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cystic craniopharyngiomas. J Neurosurg 77:545–550. https://doi.org/10.3171/jns.1992.77.4.0545 Van Effenterre R, Boch AL (2002) Craniopharyngioma in adults and children: a study of 122 surgical cases. J Neurosurg 97:3–11. https://doi.org/10.3171/jns. 2002.97.1.0003 Visser J, Hukin J, Sargent M, Steinbok P, Goddard K, Fryer C (2010) Late mortality in pediatric patients with craniopharyngioma. J Neurooncol 100:105–111. https://doi.org/10.1007/s11060-010-0145-5 Voges J, Sturm V, Lehrke R, Treuer H, Gauss C, Berthold F (1997) Cystic craniopharyngioma: long-term results after intracavitary irradiation with stereotactically applied colloidal beta-emitting radioactive sources. Neurosurgery 40:263–269; discussion 269–270. https://doi.org/10.1097/00006123-199702000-00006 Weiner HL et al (1994) Craniopharyngiomas: a clinicopathological analysis of factors predictive of recurrence and functional outcome. Neurosurgery 35:1001– 1010; discussion 1010–1001. https://doi.org/10.1227/ 00006123-199412000-00001 Weiss M et al (1989) The role of radiation therapy in the management of childhood craniopharyngioma. Int J Rad Oncol Biol Phys 17:1313–1321 Wijnen M et al (2018) The metabolic syndrome and its components in 178 patients treated for craniopharyngioma after 16 years of follow-up. Europ J Endocrinol 178:11–22 Wijnen M et al (2017) Very long-term sequelae of craniopharyngioma. Eur J Endocrinol 176:755–767 Winkfield KM, Linsenmeier C, Yock TI, Grant PE, Yeap BY, Butler WE, Tarbell NJ (2009) Surveillance of craniopharyngioma cyst growth in children treated with proton radiotherapy. Int J Rad Oncol Biol Phys 73:716–721. https://doi.org/10.1016/j.ijrobp.2008.05. 010 Winkfield KM et al (2011) Long-term clinical outcomes following treatment of childhood craniopharyngioma. Pediatr Blood Cancer 56:1120–1126. https://doi.org/ 10.1002/pbc.22884 Xu Z, Yen CP, Schlesinger D, Sheehan J (2011) Outcomes of Gamma Knife surgery for craniopharyngiomas. J Neurooncol 104:305–313. https://doi.org/ 10.1007/s11060-010-0494-0 Yamada S, Fukuhara N, Oyama K, Takeshita A, Takeuchi Y, Ito J, Inoshita N (2010) Surgical outcome

329 in 90 patients with craniopharyngioma: an evaluation of transsphenoidal surgery. World Neurosurg 74:320– 330. https://doi.org/10.1016/j.wneu.2010.06.014 Yasargil MG, Curcic M, Kis M, Siegenthaler G, Teddy PJ, Roth P (1990) Total removal of craniopharyngiomas. Approaches and long-term results in 144 patients. J Neurosurg 73:3–11. https://doi.org/10. 3171/jns.1990.73.1.0003 Yomo S et al (2009) Stereotactic radiosurgery of residual or recurrent craniopharyngioma: new treatment concept using Leksell gamma knife model C with automatic positioning system. Stereotact Funct Neurosurg 87:360–367. https://doi.org/10.1159/ 000236370 Young SC, Zimmerman RA, Nowell MA, Bilaniuk LT, Hackney DB, Grossman RI, Goldberg HI (1987) Giant Cystic Craniopharyngiomas Neuroradiol 29:468–473. https://doi.org/10.1007/bf00341745 Yu X, Liu Z, Li S (2000) Combined treatment with stereotactic intracavitary irradiation and gamma knife surgery for craniopharyngiomas. Stereotact Funct https://doi.org/10.1159/ Neurosurg 75:117–122. 000048392 Zabramski JM, Kiris T, Sankhla SK, Cabiol J, Spetzler RF (1998) Orbitozygomatic craniotomy. Technical note. J Neurosurg 89:336–341. https://doi.org/10.3171/jns. 1998.89.2.0336 Zacharia BE, Bruce SS, Goldstein H, Malone HR, Neugut AI, Bruce JN (2012) Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program. Neuro Oncol 14:1070–1078. https://doi.org/10.1093/ neuonc/nos142 Zhang S, Fang Y, Cai BW, Xu JG, You C (2016) Intracystic bleomycin for cystic craniopharyngiomas in children. Cochrane Database Syst Rev 7: CD008890. https://doi.org/10.1002/14651858. CD008890.pub4 Zhou J, Zhang C, Pan J, Chen L, Qi ST (2017) Interleukin6 induces an epithelialmesenchymal transition phenotype in human adamantinomatous craniopharyngioma cells and promotes tumor cell migration. Mol Med Rep 15:4123–4131. https://doi.org/10.3892/ mmr.2017.6538

Schwannomas of Brain and Spinal Cord

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Venelin Gerganov, Mihail Petrov, and Teodora Sakelarova

Abstract

Schwannomas are benign tumors originating from the Schwann cells of cranial or spinal nerves. The most common cranial schwannomas originate from the eight cranial nervevestibular schwannomas (VS). VS account for 6–8% of all intracranial tumors, 25–33% of the tumors localized in the posterior cranial fossa, and 80–94% of the tumors in the cerebellopontine angle (CPA). Schwannomas of other cranial nerves/trigeminal, facial, and schwannomas of the lower cranial nerves/ are much less frequent. According to the World Health Organization (WHO), intracranial and intraspinal schwannomas are classified as Grade I. Some VS are found incidentally, but most present with hearing loss (95%), tinnitus (63%), disequilibrium (61%), or headache (32%). The neurological symptoms of VSs are mainly due to compression on the surrounding structures, such as the

V. Gerganov International Neuroscience Institute, Hannover, Germany V. Gerganov . M. Petrov (&) University Multiprofile Hospital for Active Treatment With Emergency Medicine N. I. Pirogov, Sofia, Bulgaria e-mail: [email protected] T. Sakelarova University Hospital St. Anna, Sofia, Bulgaria

cranial nerves and vessels, or the brainstem. The gold standard for the imaging diagnosis of VS is MRI scan. The optimal management of VSs remains controversial. There are three main management options—conservative treatment or “watch-and-wait” policy, surgical treatment, and radiotherapy in all its variations. Currently, surgery of VS is not merely a life-saving procedure. The functional outcome of surgery and the quality of life become issues of major importance. The most appropriate surgical approach for each patient should be considered according to some criteria including indications, risk–benefit ratio, and prognosis of each patient. The approaches to the CPA and VS removal are generally divided in posterior and lateral. The retrosigmoid suboccipital approach is a safe and simple approach, and it is favored for VS surgery in most neurosurgical centers. Radiosurgery is becoming more and more available nowadays and is established as one of the main treatment modalities in VS management. Radiosurgery (SRS) is performed with either Gamma knife, Cyber knife, or linear accelerator. Larger tumors are being increasingly frequently managed with combined surgery and radiosurgery. The main goal of VS management is preservation of neurological function – facial nerve function, hearing, etc. The reported recurrence rate after microsurgical tumor removal is 0.5–5%. Postoperative follow-up imaging is essential to diagnose any recurrence.

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_12

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Keywords

Vestibular schwannomas angle

12.1

. Cerebellopontine

Background and Epidemiology

Schwannomas are benign tumors originating from the Schwann cells of cranial or spinal nerves. The most common cranial schwannomas originate from the eight cranial nerve, vestibular schwannomas (VS). They were erroneously named acoustic neuromas by Virchow due to the frequent hearing loss resulting from their growth. VS account for 6–8% of all intracranial tumors, 25–33% of the tumors localized in the posterior cranial fossa and 80–94% of the tumors in the cerebellopontine angle (CPA) (Chandler and Ramsden 1993; Lanser et al. 1992; Tos 1998). Schwannomas of other cranial nerves including trigeminal, facial and schwannomas of the lower cranial nerves, are much less frequent, they account for 2–3% of the CPA tumors and 8–10% of the intracranial schwannomas (Hamm et al. 2008; Springborg et al. 2008). Vestibular schwannomas are more frequent in females, and the female-to-male ratio ranges from 1:0.8 to 1.5:1 (Reznitsky et al. 2019). Steady increase in the annual incidence of VSs was found in a large population-based study from Denmark with an increased incidence from 2.8 per million people in 1976 to 22.8 per million in 2004 and 33.8 per million in 2015. A study from Minnesota (USA) published in 2016 reported even higher incidence of about 42 VSs per million/annually (Marinelli et al. 2018). These increased numbers do not reflect an actual rise of the incidence of VS but rather the better access of the patients to modern imaging modalities such as magnetic resonance imaging scan (MRI). Earlier and more accurate imaging is the explanation for the dramatic decrease of the mean diagnostic tumor size from 26 mm in 1976 to 7 mm in 2015 (Reznitsky et al. 2019). The median age at diagnosis has increased from

49 years in 1976 to 60 years in 2015 (Reznitsky et al. 2019). Trigeminal schwannomas were first described in 1846 by Dixon (Al-Mefty et al. 2002) but it wasn’t until 1918 when the first successful operative removal of a trigeminal schwannoma was performed by Frazier. Trigeminal schwannomas are the second most frequently encountered intracranial schwannomas (0.8–8%) and quite rare intracranial tumors (0.07–0.5%) (Pan et al. 2005a, b; Samii et al. 1995a, b). Depending on the part of the trigeminal nerve from which the trigeminal schwannoma originates, there are three main types: Type A, originating from the gasserian ganglion and located primarily in the middle cranial fossa; Type B, originating from the root of cranial nerve V and localized mainly in posterior cranial fossa; Type C, hourglass or dumbbell-shaped tumors, located in both middle and posterior fossa (Jefferson 1953). Later a fourth type D was added for trigeminal schwannomas originating from the more distal part of the trigeminal nerve, tumors with small intracranial and larger extracranial part, located in the infratemporal fossa (Arena and Hilal 1976; Lesoin et al. 1986). This type is the least frequently encountered. The clinical significance of this classification is that it helps for the decision of an appropriate neurosurgical approach. Even less common are the oculomotor nerve schwannomas. The first case was reported in 1927 by Kovacs (1927). Around 60 cases have been reported so far (Hironaka et al. 2010; Tanriover et al. 2007; Muhammad and Niemelä 2019). These schwannomas are classified in three groups (Celli et al. 1992) including cisternal, cavernous, and cisternocavernous type. The first case of a trochlear nerve schwannoma was reported in 1976 by King (1976). Up until now, only 38 cases have been published (Lan et al. 2020). This type of schwannomas is also subdivided in three groups as cisternal, cavernous and cisternocavernous. Trochlear schwannomas occupy the interpeduncular or/and the ambient cistern. Abducens nerve schwannomas are even rarer and only around 22 cases have been reported so far (Bing-huan 1981; Li et al. 2015). Tung et al.

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(1991) subdivided these tumors in two groups including tumors arising within the cavernous sinus and all others that arise along the course of the nerve, mainly in the prepontine cistern. Unlike all other schwannomas, the abducens nerve schwannoma does not originate from the glial–Schwann sheath junction (Vachata and Sames 2009). Facial nerve schwannoma was described for the first time in 1930 (Hajjaj and Linthicum 1996). These tumors may originate from every part of the facial nerve, from the CPA to its extracranial part. Lipkin et al. differentiated four groups of facial nerve schwannomas as tympanic, vertical, labyrinthine, and meatal (Lipkin et al. 1987). A more practical is the anatomically based classification (Sarma et al. 2002) as follow: type 1, localized in the CPA; type 2, geniculate; and type 3, tympanomastoid lesions. More frequently, however, facial nerve schwannomas involve more than just one segment of the nerve. Schwannomas of cranial nerve VII comprise only 2% of the intracranial schwannomas and 20% of them are localized in the CPA (Kertesz et al. 2001; Symon et al. 1993). Schwannomas of the lower cranial nerves (glossopharyngeal, vagus and accessory nerve) are also called jugular foramen schwannomas because in most cases the exact origin of the tumor is difficult to determine (Carvalho et al. 2000; Tan et al. 1990). In patients without neurofibromatosis (NF), these tumors comprise only 2.9–4% of the intracranial schwannomas (Tan et al. 1990; Samii et al 1995a, b). Most common are the schwannomas of cranial nerve IX and least frequent from cranial nerve XI. These tumors are more frequent in women and present usually between the fourth and sixth decades of life (Carvalho et al. 2000). Jugular foramen schwannomas are benign slow-growing lesions. However, malignant schwannomas have also been reported in the jugular foramen (Balasubramaniam 1999). JF schwannomas are classified depending on their location according to the jugular foramen as follows: Type A, tumor located mainly intracranially with minimal enlargement of the JF; Type B, tumor primarily in the JF with small intracranial component;

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Type C, primarily extracranial tumor; and Type D, “dumbbell”-shaped tumor (Samii et al. 1995a, b). Hypoglossal nerve schwannoma was reported for the first time in 1933 (Spinnato et al. 1998). They represent less than 5% of all nonvestibular schwannomas (Shimansky et al. 2019). A total of 94 cases have been reported so far (Bindal et al. 2019). Female patients were 64%, and the mean age was 45 years. Hypoglossal nerve schwannomas are divided in three groups including intracranial, intra- and extracranial, and extracranial (Sutay et al. 1993).

12.2

Genetics, Immunology, and Molecular Biology

Vestibular schwannomas could be divided into two groups including unilateral sporadic cases (95%), or bilateral (5%), associated with Neurofibromatosis type 2. The most common genetic mutation in VS affects chromosome 22 causing loss of heterozygosity (LOH). The NF2 gene is in 22q12 region of the chromosome and is responsible for the synthesis of a protein called merlin. Merlin plays an important role in the cell–cell and cell–matrix interactions and when overexpressed could inhibit cell proliferation and the transformation of cells from oncogenes, therefore, merlin functions as a potent tumor suppressor. Mutations leading to the inactivation of the NF2 gene are found in around 66% of sporadic VS and 33% of those associated with NF2 syndrome. Many authors support the “two-hit hypothesis” according to which patients with NF2 syndrome inherit a mutated NF2 allele and during their lifetime acquire a somatic loss in the second allele. In 80–90% of the VS, there is a mutation in one of the alleles, and only in 50–60%, there is a mutation in both. There are studies that have established a correlation between the type of mutation of the NF2 gene and the clinical course of the disease. For instance, nonsense and frameshift mutations are associated with more severe course of the disease, while missense mutations that lead to the stable production of

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nonfunctional merlin are associated with milder form of the disease (Patronas et al. 2001). These correlations appear to be more valid for the familial NF. The severity of disease progression in NF2 syndrome is influenced by the presence of mosaicism (coexistence of two or more populations of cells with different genotypes; this is a result of mutation that occurs after fertilization). Around 25–30% of the patients with NF-2 and healthy patients are due to mosaicism. When mosaicism occurs in a later stage of embryogenesis, the disease has a milder course. On the other hand, offspring of patients with mosaicism experience more severe clinical manifestations as the mutations are present in all their cells (Kluwe et al. 2003). Merlin, a.k.a. Schwannomin, is the protein product of the expression of the NF2 gene. The overexpression of the protein leads to inhibition of cell proliferation and has a protective role over the oncogenic transformation of the cells. Meanwhile, the loss of merlin leads to neoplastic transformation. Merlin interferes not only in the cell cycle, but also in the cell–cell interactions. It has an inhibitory effect over the EGFR /Epidermal Growth Factor receptor/-signaling pathway by internalizing the ErbB2 receptor (Hansen et al. 2006). In VSs associated with NF2 syndrome, EGF is upregulated which could explain the increased growth rate and invasiveness in this subgroup of VS. The more aggressive tumor behavior is also associated with the overexpression of the VEGF (Vascular Endothelial Growth Factor). VEGF and some of the matrix metalloproteinases (MMP), especially MMP9, are potent mediators of tumor progression (Moller et al. 2010). Schwannomatosis is a clinical scenario that is characterized by the predisposition for multiple schwannomas. Schwannomatosis is clinically identical to NF type 2, but it lacks the NF2 gene mutation. On the other hand, gene mutations in a series of tumor suppressor genes (TSG), i.e., SMARCB1 or LZTR1, have been identified as the cause for 86% of the familial cases of schwannomatosis and 40% of the sporadic ones (KehrerSawatzki et al. 2017). In the study of KehrerSawatzki from 2017, it is implied that

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schwannomatosis is a tumor predisposition syndrome for the development of which a concomitant mutation inactivation of at least two TSG is needed. Epigenetic alterations affect gene expression without any change in the sequence of DNA. Four main epigenetic mechanisms are described in the literature including DNA methylation, covalent histone modification, noncovalent mechanism, and nucleosome remodeling. This could also play a role in the development of schwannomas. Epigenetic alterations could lead to dysregulation of gene expression, for instance silencing of TSG could result in developing tumor growths as it was postulated in the schwannomatosis paradigm that was put forward by Kehrer-Sawatzki. Another function of merlin is to inhibit the synthesis of NF-kB which is a transcription factor involved in cell growth and suppression of apoptosis. NF-kB has very potent proinflammatory properties and a major trigger of innate immunity (Elmaci et al. 2017). A plethora of inflammatory cells (macrophages, neutrophils) could be found invading the structure of schwannomas and leading to its degeneration. A hallmark of the ongoing degeneration is cyst formation, hemorrhage, and vascular hyalinization. A few studies are investigating the effects of salicylates, COX-inhibitors and other suppressors of inflammation as medical treatment that halts proliferation and decreases the vitality of VS cells (Kandathil et al. 2014). In conclusion, there seems to be a variety of pathogenic mechanisms that result in schwannoma formation and proliferation. A considerable difference exists between the cellular pathways that result in the development of sporadic cases and those associated with NF2 syndrome.

12.3

Histopathology and Morphology

There are three main types of nerve sheath tumors as follows: schwannoma, neurofibroma, and perineurioma. Schwannomas are comprised

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solely of Schwann cells, while neurofibromas consist of Schwann-like perineural cells and fibroblasts. Neurofibromas are more frequently solitary lesion, except in the case of Neurofibromatosis type 1 (NF1) and involve peripheral nerves. Bilateral VSs are the hallmark of NF2, while multiple neurofibromas are typical for NF1, especially dermal and plexiform neurofibromas. According to the World Health Organization (WHO) intracranial and intraspinal schwannomas are classified as Grade I. Their pathological effect is mainly due to compression of surrounding structures (cranial nerves, brainstem). Schwannomas typically involve sensory nerves, particularly posterior spinal roots. They are result of pathological proliferation of Schwann cells (Murray et al. 1940) due to the aforementioned genetic aberrations. The myelin sheath of the central portion of the cranial nerves (and the whole olfactory and optic nerves) is formed by oligodendrocytes. The peripheral portion is produced by the Schwann cells. The zone between the two parts of the cranial nerves (except cranial nerve I and cranial nerve II) is called Obersteiner–Redlich junction, and it is a frequent location for the schwannomas to arise. Intracranial schwannomas involve more often sensory nerves. The superior (SVN) and inferior vestibular nerves (IVN) are the nerves from which VSs arise and not the cochlear nerve. Therefore, the term acoustic neuroma although commonly used, is not fully correct. VSs originate from the IVN in 70% of the cases and from the SVN in 20% of cases, and only in 10%— from the cochlear nerve. Intracranial parenchymal schwannomas have also been described in the literature. They are extremely rare and are thought to arise from minute nerve fascicles around the vessels (Gupta et al. 2016). Macroscopically, VSs are encapsulated, pale tumors that compress and displace the surrounding structures and enlarge the internal acoustic canal (IAC). Spinal schwannomas enlarge in the direction of least resistance and grow through the intervertebral neuroforamina and assume a shape of a “dumbbell” which is characteristic in neuroimaging.

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Microscopically, schwannomas consist of two main patterns of cell architecture: Antoni type A and Antoni type B (Antoni 1920). (Fig. 12.6a, b) The Antoni type A pattern consists of elongated cells with hyperchromatic nuclei that frequently are arranged parallel to one another and form bundles called Verocay bodies. (Fig. 12.6d) Antoni type B pattern is less compact and consists of pleomorphic cells. Secondary changes, such as hemorrhage and infarction, could also be present in schwannomas. There are three clinically significant histological variants of schwannomas including cellular schwannoma, plexiform schwannoma, and melanotic. Cellular schwannomas as their name suggests have a high cellularity index, Antoni A pattern predominates with variable mitotic activity and are lacking Verocay bodies. These schwannomas are typically located paravertebrally around the pelvis and retroperitoneally. Despite the high cellularity index theses schwannomas should be differentiated from malignant peripheral nerve sheath tumor (MPNST) as they have much better clinical prognosis. However, sacral and intracranial cellular schwannomas recur much more frequently than their peripherally located counterparts. Plexiform schwannomas are commonly located in the derma and have multinodular growth pattern, involving multiple nerve fascicle. Melanotic schwannomas are much less frequent than the previous two types. The Schwann cells in their structure contain true melanin. Histologically, the differential diagnosis between schwannomas and meningiomas is not straightforward. Even Verocay bodies could sometimes be present in meningiomas. In all those cases, immunohistochemistry is of considerable importance. All schwannomas are highly positive for the S-100 protein (Fig. 12.6 e), while neurofibromas have more variable S100 staining. On the other hand, meningiomas stain weakly with S-100 protein but have strong reaction to the epithelial membrane antigen (EMA). Calretinin could be used in the differential diagnosis between schwannomas and neurofibromas, as calretinin is detected in almost all schwannomas and in only few neurofibromas.

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Malignant peripheral schwannomas are much more common than their cranial counterparts. More often they present de novo rather than from a pre-existing lower grade schwannoma. Malignant VSs are extremely rare and only a few cases have been reported so far. The common histological markers of malignancy are also present in malignant schwannomas including increased cellularity, high rate of mitoses, local invasive potential.

12.4

Imaging and Radiologic Features

The gold standard for the imaging diagnosis of VS is MRI. In T1-weighted images, VSs are isointense to slightly hypointense, while on T2weighted images, VSs are hyperintense; they enhance intensely after IV contrast administration. In 50–60% of cases, VSs enhance homogenously, in 30–40% heterogeneously and in only 5–15% cases they are cystic (Fundova et al. 2000). With the administration of gadolinium contrast, even small VS could be detected. With the use of some MRI modalities, like threedimensional Fourier transformation-constructive interference in steady-state sequence (3DFTCISS), the close relationships between the vascular structures, the cranial nerves and the VS in the cerebellopontine angle (CPA) could be assessed. The extension of the VS in the CPA on the MR-imaging could be used for the classification of VSs (See International Neuroscience

Institute (INI) or Samii classification of VS extension, Fig. 12.2). The largest diameter of the extrameatal part of the VS is the basis of the Koos Classification. Some specific MRI sequences could be useful in the preoperative work-up for VSs. A study in 2011 conducted by the senior author (Gerganov et al. 2011) demonstrated that with the use of DTI-based tractography, the course of the facial nerve in the CPA could be predicted in 90% of the cases. This information might be useful especially in large VS where the nerve could be severely displaced. The main differential diagnosis for extra-axial lesions in the CPA includes VSs, meningiomas, and epidermoids. (Table 12.1) On contrastenhanced MR-imaging, VSs have a typical “ice-cream cone”-appearance, with an acute angle between the lesion and the temporal bone. On the other hand, CPA meningiomas are also contrast-enhancing lesion but usually they are asymmetrically situated over the IAC and have a broad attachment to the petrous bone. Moreover, in CPA meningiomas, there is often a hyperostotic bone reaction of the petrous bone readily appreciated on CT imaging. Calcifications are more frequent in meningiomas rather than in VSs. On MR-imaging epidermoids follow the intensity of CSF on T1 and T2 sequences and could be differentiated from arachnoid cysts only on DWI and ADC images. CT scan is invaluable for posterior fossa surgery as it gives neurosurgeons important information about the bony structure of the skull base. The widening of the IAC is pathognomonic for

Table 12.1 Imaging differential diagnosis between VS and meningiomas in the CPA VS

Meningiomas

IAC

. Widened, erosion of the petrous bone . Tumor centered over the IAC

. No change (invasion of the tumor in the IAC only 10–20%)

Contrast enhancement

Yes

Yes

Angle between the tumor and the petrous bone

Acute

Obtuse

Characteristic appearance

“Ice-cream cone”

“Dural tail”

Calcifications

Extremely rare

Frequently

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VSs, and only in rare cases it is encountered in CPA meningiomas. Only on CT scan, it is possible to establish the proximity of the semicircular canals and the IAC, as well as the extend of pneumatization of the temporal bone. In conclusion, when planning VS surgery, it is essential to obtain all possible neuroimaging modalities as they give different information about the posterior fossa anatomy. The neuroradiological features of nonvestibular schwannomas are like that of the VS. However, preoperative differentiation between oculomotor, trochlear, trigeminal, and abducens nerve schwannomas is not possible. CT scan could orient the neurosurgeon on the skull defect caused by the tumor, especially in the case of trigeminal schwannoma. In Type A trigeminal schwannomas, a bone defect involving the foramen oval and spinosum can be observed. In Type B and C trigeminal schwannomas the petrous apex is eroded and to a various extend the inferomedial surface of the petrous bone. CT-angiography or digital subtraction angiography might be helpful when planning operative treatment of lower cranial nerve schwannomas or hypoglossal nerve schwannomas. These diagnostic modalities can orient the neurosurgeon which vertebral artery is dominant, about the caliber of the venous sinuses, and whether some of these vascular structures could be sacrificed.

12.5

Clinical Manifestations

Some VS are found incidentally, but most present with hearing loss (95%), tinnitus (63%), disequilibrium (61%), or headache (32%). The neurological symptoms of VSs are mainly due to compression on the surrounding structures, such as the cranial nerves and vessels, or the brainstem. The clinical symptoms depend on the origin of the schwannoma, the size, the extension of the lesion in the CPA, and the growth rate. The growth of VSs follows a certain pattern that consists of four stages as follows: intrameatal, cisternal, brainstem compressive, and hydrocephalic. Every stage has a set of typical

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neurological symptoms. VSs originate from the vestibular nerve and are located within the IAC. With the gradual enlargement of the tumor, it either fills the IAC and leads to its erosion and widening or grows in the CPA, following the line of least resistance. The widening of the IAC does not correspond to the size of the VS (Yamakami et al. 2002). In the latter study, the IAC was widened in 46% of the cases, extensive erosion was present in 17%, and the IAC was normal in 36% of the cases. The hearing impairment was much more severe in the cases with extensive erosion of the IAC compared to the cases with normal IAC (Yamakami et al. 2002). The pressure within the IAC is one of the factors that lead to damage of the cochlear nerve and hearing impairment (Badie et al. 2001; Satar et al. 2003). The neurological symptoms that are typical for the intrameatal stage of VS are hearing loss, tinnitus, and vestibular dysfunction. Audiograms of patients in this stage show high-frequency sensorineural hearing loss. The auditory impairment has insidious onset, and according to different series, only 3–26% of the patients experience sudden hearing loss (Matthies and Samii 1997; Saunders et al. 1995). The mechanism of hearing impairment is postulated in several theories including mechanical injury of the cochlear nerve due to the compressive force of the VS, mechanical injury of the cochlear apparatus itself, biochemical changes of the fluid in the inner ear, ischemic injury due to occlusion or spasm of the labyrinthine artery, and increase of intracanalicular pressure (Saunders et al. 1995). The combination of all those factors could also be the explanation. In the rare cases when hearing loss has sudden onset, the cause is most likely impairment of the arterial blood supply. Vestibular symptoms (vertigo, dizziness, and unsteady gait) are also present in the intrameatal stage. Most often they are not recognized by the patient but are always present when specially tested for. Unterberger’s stepping test (Moffat et al. 1989) could be routinely used when examining patients with suspected VS. Disequilibrium is rarely disabling due to the compensatory role of the contralateral vestibular apparatus.

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During the second stage, a.k.a. cisternal, auditory impairment is even less profound, and disequilibrium is the main symptom. The VS is occupying to different extent the CPA. (Fig. 12.2) It is centered over the IAC, and its cisternal part is oval, round, or polycyclic. Depending on its size and whether it occupies the cerebello-mesencephalic cistern and the lateral cerebellomedullar cistern, symptoms could be present from the trigeminal nerve (cranial nerve V) and lower cranial nerves, respectively. Symptoms due to cranial nerve V dysfunction are rarely noticed by the patient. They involve most frequently corneal and lower facial hypesthesia. Compression on the lower cranial nerves leads to dysphagia, dysphonia and in the later stages complete ipsilateral bulbar palsy. When a patient with untreated schwannoma in the CPA presents with preoperative facial palsy, it should be kept in mind that this most commonly is a facial nerve schwannoma rather than VS. The most frequently used facial nerve function grading system is proposed by House and Brackmann (House and Brackmann 1985). Compression of the cerebellar hemisphere leads to discoordination of the ipsilateral limbs and ataxic gait with deviation to the side of the tumor. In the third stage due to the compression of the brainstem long-tract, signs could be present. The symptoms could affect the contralateral side of the body. As the VSs enlarges in size, it leads to severe compression of the cerebellum and eventually leads to 4th ventricle compression. This results in obstructive hydrocephalus which is the last stage. The raised intracranial pressure (ICP) and all the symptoms of the latter are characteristic of the last stage of VS development. VSs are slow-growing lesions and the abovementioned symptoms develop gradually and insidiously. However, acute neurological deterioration is also possible. It could be the result of either intralesional hemorrhage or rapid expansion of a tumor cyst (Fundova et al. 2000). Decompensation of the ongoing obstructive hydrocephalus may also be the cause for rapid decrease of the level of consciousness.

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Oculomotor nerve schwannomas are rare tumors. They are mainly located in the interpeduncular cistern and cavernous sinus. They are three main types, as previously mentioned. When the cisternal type of tumors grow, they expand in the prepontine cistern and may lead to brainstem compression (Leunda et al. 1982; Sarma et al. 2002). Almost always, the presenting symptom is diplopia due to different degrees of oculomotor nerve dysfunction. Other symptoms could be due to compression on other cranial nerves. Raised intracranial pressure (ICP) is also common (Netuka and Benes 2003; Tanriover et al. 2007). Common presenting symptoms of patients with trochlear nerve schwannomas are cranial nerve IV palsy, trigeminal nerve symptoms, headache, and if the tumor is large enough to cause brainstem compression long-tract signs could also be present (Abe et al. 1994; Gerganov et al. 2007). However, only half of the patients present with trochlear nerve palsy, which could be due to compensatory mechanisms that ensue during the slow-growth of the tumor (Du et al. 2003; Matsui et al. 2002). The cranial nerve IV palsy persists in more than 40% of the cases postoperatively, though gradual improvement occurs over time. Most common symptom in patients with trigeminal schwannomas is trigeminal sensory impairment including paresthesia or numbness (74–96% of cases), usually in more than one division of the trigeminal nerve; trigeminal motor deficit (33–60%); facial pain (15–34%); headache in 20–44% of cases; diplopia (15–52%) and rarely hearing deficit, and ataxia (Day and Fukushima 1998; Goel et al. 2003). Atrophy of the temporal and pterygoid muscles is frequently observed (24–60% of cases). Corneal reflex could be diminished in 36–82% of the cases. Large trigeminal schwannomas could lead to symptoms of raised ICP. The facial pain caused by trigeminal schwannomas should be differentiated from the pain typical for trigeminal neuralgia. The pain caused by these tumors is constant or paroxysmal lancinating pain, but usually does not have triggering mechanisms, which are typical for trigeminal neuralgia.

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Furthermore, carbamazepine has potential effect in trigeminal neuralgia pain but no effect whatsoever in trigeminal schwannomas (Day and Fukushima 1998; Yonas and Jannetta 1980). Main symptom of patients with abducens nerve schwannoma is diplopia due to cranial nerve VI palsy. In larger tumors, various symptoms due to compression of other cranial nerves or the brainstem could be present (Nakamizo et al. 2019; Tung et al. 1991). A rare case of intratumoral hemorrhage was reported in an abducens nerve schwannoma which presented clinically with sudden headache, nausea and photophobia (Brown et al. 2018). Patients with VSs rarely present with facial palsy. However, this is not the same with facial nerve schwannomas, where varying degree of facial palsy is usually present. Therefore, in a patient with cranial nerve VII palsy and a CPA lesion localized in the IAC should be suspected a facial nerve schwannoma. However, 27–54% of patients do not have facial nerve paresis (Saleh et al. 1995). Other common symptoms are auditory impairment, tinnitus, and vertigo. The interval between the initial symptoms and the diagnosis is usually long, maybe due to the confusion with Bell’s palsy (Sherman et al. 2002). In all patients with progressive cranial nerve VII palsy or patients with Bell’s palsy with no improvement in facial nerve function after 6 months, conducting an MRI scan is recommended (Sherman et al. 2002). Cochlear nerve schwannomas are extremely rare. They are usually identified during surgery. In these patients, the presenting symptom is profound auditory impairment and tinnitus with absence of vertigo (Barbieri et al. 2001). Symptoms of jugular foramen schwannomas are mainly due to compression on surrounding structures. According to Samii, 81% of the patients present with lower cranial nerve deficit, 75% have hearing impairment, 44% have symptoms of cerebellar compression, 31% have tongue hemi-atrophy, 25% have facial palsy, and 13% have alteration in facial sensation (Samii et al. 1995a, b). Preoperatively, based on clinical manifestations and neuroimaging, the differential diagnosis is between VS, JF schwannomas, and

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glomus jugular tumors. Type A JF schwannomas are localized in the CPA and should be differentiated from VS. As was previously mentioned 20–25% of JF schwannomas present with facial nerve palsy, which is considered atypical for VS. The lack of the characteristic changes in the IAC typical of VS could also make the diagnosis of JF schwannoma more probable. Patients with hypoglossal nerve schwannoma usual present with hemi-atrophy of the tongue in 80% of the cases (Bindal et al. 2019). Other common symptoms are suboccipital headache (33%) and foramen jugular symptoms especially in the intracranial group. Symptoms of brainstem compression are also possible when these schwannomas reach considerable size.

12.6

Therapeutic Approaches

The optimal management of VSs remains controversial. Multiple factors must be considered in the decision-making process. These factors are related to the tumor characteristics, such as type, size, and extent of brainstem compression and to the patients’ neurological and general condition. Ultimately, the patient’s expectations should be considered. Currently, surgery of VS is not merely a life-saving procedure. The functional outcome of surgery and the quality of life become issues of major importance. Decision making on the surgical procedures should be based on individualized considerations, indications, risk–benefit ratio, and prognostic impact for each patient. Incidentally diagnosed small VSs are another subgroup of tumors, requiring individual consideration. Three main therapeutic options are available for these tumors including conservative treatment or “watch-and-wait” policy, surgical treatment and radiotherapy in all its variations. The “watch-and-wait” or the “wait-and-scan” strategy consists of conducting regular MRI scans to exclude tumor growth. The rational for this strategy is that the biological behavior of VSs is unpredictable: some do not grow, some grow slowly (less than 2 mm per year) and some exhibit faster growth (>2 mm/year). Initial

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observation is acceptable option in incidentally found small VS, in elderly or patients with multiple comorbidities with small tumors and mild stable symptoms, in patients with small tumors and complete hearing loss, in patients with VS on the only hearing side, or in those unwilling to undergo surgery or radiosurgery. After the diagnosis, a control MRI should be performed in 6 months and then annually for at least 5 years. Most of the studies show that the growth rate is highest in the first year after diagnosis and slowed thereafter. It is suggested that in the first 5 years of observation of a diagnosed VS, there is a growth in 64% of the cases that could be used to predict the natural history of those tumors (González-Orús ÁlvarezMorujo et al. 2014; Hoa et al 2012; Prasad et al. 2018; Raut et al. 2004a, b) There is a tendency of VSs in their cisternal stage to continue growing that should be taken into consideration (Walsh et al. 2000). In most of the studies, there is not established correlation between tumor growth rate and patients’ sex, age, or tumor size (Raut et al. 2004a, b). Importantly, cystic VSs are prone to display rapid and sudden growth that could lead to sudden deterioration of hearing, and all those patients are not suitable for conservative management (Fundova et al. 2000) (Fig. 12.5). The main goal of VS management is preservation of neurological function, facial nerve function, hearing, etc. During the “watch-andwait” period, it cannot be predicted whether hearing would deteriorate because its decline is not always with insidious onset and does not progress gradually like the size of the tumor which is suggested by its multifactorial origin explained above (Fig. 12.1). In young patients with small intrameatal VSs, serviceable hearing and preserved BAEP (brainstem auditory evoked potentials) a hearing preservation surgery might be a better option (Hadjipanayis et al. 2018) (Figs. 12.2, 12.3, 12.4 and 12.5). Microsurgical resection of a VS is the preferred treatment modality for patients with large VSs (diameter > 3 cm), cystic tumors, or those that exert considerable mass effect. In smaller tumors, alternative to microsurgery is

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radiosurgery. The functional outcome of both methods is comparable but only surgery has the potential for definitive healing of the patient. Prerequisite for that is that the surgeon is highly experienced in this area and has sufficient caseload. The goal of surgery is total tumor removal with complete neurological preservation (including auditory and facial nerve function). Anatomical preservation of the facial nerve is achieved in more than 90% of the cases in experienced hands. Functional preservation is achieved in 52–98% of the cases, depending on the tumor size. In a study of Samii et al. published in 2006 in a series of 200 patients operated on for VSs with the retrosigmoid approach, 62% of the patients had excellent facial nerve function and 14% good facial nerve function (HB grade III) 2 weeks postoperatively (Samii et al. 2006). In small-to-medium-sized VS, 98% of the cases had excellent facial nerve function (HouseBrackmann I or II) at 12 months follow-up (Ebersold et al. 1992; Lalwani et al. 1994; Sughrue et al. 2010). Hearing is a vital determinant of good quality of life and should be preserved during VS surgery whenever possible. In the same study, the functional or serviceable hearing preservation was 51%, while the anatomical continuity of the cochlear nerve was preserved in 84% of the cases. The current paradigm in VS surgery is that size affects the auditory impairment. However, in all patients who have good or useful hearing preoperatively, an attempt of cochlear nerve preservation is mandatory whatever the size of the VS. Whether the patient still has serviceable hearing is one of the indications for a certain surgical approach. (Fig. 12.5) Hearing preservation is possible in both the middle fossa approach and the retrosigmoid approach. Generally, the middle fossa approach is suitable for small laterally located VSs, deep in the IAC, while the retrosigmoid approach is suitable for any sized tumors with considerable compression on the cerebellum and the brainstem (Fig. 12.6). Radiosurgery is becoming more and more available nowadays and is established as one of the main treatment modalities in VS management. Radiosurgery (SRS) is performed with

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Fig. 12.1 a–d MRI of a 38-year-old male patient with a 6-month history of tinnitus and sudden deterioration in auditory function on the right side. A VS was observed localized inside the right IAC (Grade I, according to the INI classification), with typical “ice-cream cone” sign. The patient refused surgery or radiosurgery. The follow-

up MRI scan in 6 months showed a marked enlargement of the VS–now grade II, according to the INI classification. The patient underwent operative treatment with total removal of the VS with complete preservation of the facial nerve function (House-Brackmann I)

either Gamma knife, Cyber knife, or linear accelerator (see Sect. 12.6.2). The reported radiographic tumor control after linear accelerator SRS ranges from 88.5 to 100% (Benghiat et al. 2014; Lo et al. 2014) and after Gamma knife SRS—from 71 to 100% (Bush et al. 2008; Vermeulen et al. 1998; Verughese et al. 2012) and at 10 years the reported tumor control is from 65.7 to 91% (Chopra et al. 2007; Llópez Carratalá et al. 2014). In general, the longer the follow-up the lower the tumor control rate. SRS is generally suggested for VS less than 3 cm in

diameter (Puataweepong et al. 2014; Kopp et al. 2011). Larger tumors are being increasingly frequently managed with combined surgery and radiosurgery. In case of large VS, even if the facial nerve has been preserved, the patient may suffer from temporary facial nerve dysfunction, which might decrease his quality of life. To avoid this, it might be reasonable to leave the most strongly attached part of the tumor to the nerve. This part can be subsequently treated radiosurgically. Importantly, the tumor remnant should be as small as possible, so that the risks of

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Grade 1

Grade 3b

Grade 2

Grade 4a

Grade 3a

Grade 4b

Grade 5 Fig. 12.2 International neuroscience institute (INI) or Samii classification of VS extension. /Gratitude for all the cases to department of neurosurgery, university

multiprofile hospital for Active treatment and emergency medicine N. I. Pirogov, Sofia, Bulgaria/

radiosurgery are minimized. Planned partial or intracapsular tumor removal and subsequent radiosurgery cannot be regarded as appropriate

strategy. The volume of the remnant corresponds with the radiotherapy-related morbidity and efficacy. On the other hand, it is impossible to

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Fig. 12.3 Posterior fossa reconstruction with PMMA (polymethyl methacrylate) after retrosigmoid craniectomy

predict preoperatively if the VS’s capsule is strongly attached to the neural structures or not. Hence, an attempt for complete tumor removal is always justified (Pollock and Link 2008; Unger et al. 2002). The patients’ general functional status (for instance measured by Karnofsky performance status, KPS) is much more important than the patients’ age when deciding for a particular treatment mode. For example, a patient with KPS < 70 and age less than 65 years is much more suitable for radiosurgery, while a patient with KPS-100 and age 75 years with no comorbidities could be discussed as a surgical candidate. Another special group of patients are those with Neurofibromatosis type 2. Every patient below the age of 30 who is diagnosed with bilateral VSs or meningioma should be genetically evaluated further whether they have a mutated NF2 gene. The dilemma in the NF2 cases is whether to offer early treatment (surgery or stereotactic radiosurgery (SRS)) with the potential chance to preserve long-term hearing or to postpone surgery until useful hearing is lost. The tumor size is the absolute indication for surgery: large or growing tumors should be removed surgically. In those cases, with small tumors on the side with serviceable hearing in NF2 patients, the decision is more complex and

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multiple factors should be considered. In NF2 patients SRS is an alternative to surgery. However, in the long-term tumor control rates and hearing preservation rates are worse in NF2 patients than in sporadic VS. SRS may be recommended for symptomatic patients with NF type 2 with enlarging VSs. A tumor control rate at 10 years after SRS is reported to be around 81% with hearing preservation of 48% at 5-yearfollow-up (Mathieu et al. 2007). Early operative treatment in NF2 patients, due to their faster growth than their sporadic counterparts, leads to higher hearing preservation (around 40%) and excellent facial nerve preservation according to one of the largest series (Samii et al. 1997; Tysome et al. 2012). The considerable improvement of microsurgical technique in the last few decades has led to remarkable decrease in perioperative morbidity and mortality in trigeminal nerve schwannoma surgery. Furthermore, in the largest series the total or near-total tumor removal was achieved in more than 70% of the cases. Only in the case of absent arachnoidal plane of dissection, or tumor infiltration of the adjacent structure should less than total tumor removal be accepted. Patients with many comorbidities and in bad general condition are candidates for radiosurgery. The achieved tumor control rate with radiosurgery according to one of the latest large studies by Sun and Snyder are respectively 86.5% and 77.3% (Sun et al. 2013; Snyder et al. 2018). The probability of neurological improvement in preexisting symptoms is less likely with SRS and the cranial nerve morbidity is higher (Pan et al. 2005a, b). According to Samii et al. the optimal management for patients with trigeminal schwannomas is complete tumor removal with preservation of neurological function. Subtotal removal and radiosurgery are also a plausible option in case part of the tumor cannot be safely removed. Management of patients with facial nerve schwannomas is also controversial. In incidentally found facial nerve schwannomas with no neurological symptoms, some authors recommend the wait-and-see strategy until neurological deficit develops (Fenton et al. 2004; Liu and

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Fig. 12.4 A 35-year-old male patient presented with diminished hearing on the left for a period of 1 year, ataxia and ipsilateral trigeminal-like pain. The preoperative MRI scan a, b showed a large VS with inhomogeneous internal structure and an irregular surface. (In contrast to the smooth tumor surface, the irregular one is known to correlate with absence of good arachnoidal plane and more severe adhesion of the facial nerve). Edema of the cerebellar peduncle is also seen. A subtotal tumor removal was performed through a left-sided

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retrosigmoid craniectomy, due to the lack of welldefined tumor capsule and absence of good arachnoid plane. Tiny part of the tumor was left along the facial nerve at the porus acusticus internus. The facial nerve was anatomically and functionally preserved. The early postoperative CT presents the small remnant and the persisting slight peduncular edema shown on c. d photograph of the patient on the 9th postoperative day, before being discharged from the hospital, facial nerve function, House-Brackmann Grade II

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Fig. 12.5 A 37-year-old male patient presented after an episode of vertigo a month ago. a His MRI scan showed a cystic VS on the right side (Grade 3b, according to the INI classification). At presentation the patient was completely neurologically intact (preoperative audiogram–b). Due to the cystic characteristic of the VS, it was decided that operative removal has the best chance of hearing and facial nerve preservation. A right-sided retrosigmoid craniectomy was performed. The IAC was opened with a high-speed drill and the facial and the cochlear nerves were recognized, dissected from the tumor, and anatomically preserved without any changes in the neurophysiological parameters that were monitored. The IAC was

plugged with fat tissue and sealed with fibrin glue. The dura was closed in a watertight manner and sealed with fibrin glue. Postoperatively the patient was neurologically intact—preserved hearing on the right, normal facial nerve function—House-Brackmann I. However, a nasoliquorrhea occurred on the 2nd postoperative day. A lumbar drainage was inserted immediately and kept for 7 days. The patient was discharged on the 12th postoperative day with no neurological impairment. A postoperative MRI scan, T1 contrast-enhanced sequence is shown in c. d postoperative audiogram of the patient

Fagan 2001). The explanation for this is that these tumors are slow-growing. Even with some neurological deficit present (House-Brackmann I-II) some neurosurgeons still recommend conservative treatment in the hope of preserving facial nerve function if possible. In patients with facial nerve palsy (House-Brackmann III or

worse) or quickly enlarging tumors, the only reasonable option is operative tumor removal and facial nerve reconstruction (Marzo et al. 2009). On the other hand, other authors recommend operative removal of the tumor immediately after diagnosis to preserve auditory function (Sarma et al. 2002). Some authors recommend only

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Fig. 12.6 Pathological specimens of vestibular schwannomas. a and b Hematoxylin–Eosin (H&E) staining with lower magnification (6A-10x) and higher magnification (6B-40x). On both images on the right Antoni A zones— higher cellularity with formation of Verocay bodies, and on the left Antoni B zones—myxoid hypocellular zone. c —H&E staining, depicts the typical microscopic examination of schwannomas—spindle elongation of the cells, hyperchromic nuclei with dense chromatin, collagenized

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stroma and thin-walled slit-like vessels. On d with H&E staining again are shown the typical Verocay bodies. e shows S-100 protein immunohistochemistry, characteristic for schwannomas—diffusely positive reaction is observed in both the nuclei and the cell cytoplasm. (Gratitude for all the pathological specimens to M. Dochkova MD, Department of pathology, university multiprofile hospital for active treatment and emergency medicine N. I. Pirogov, Sofia, Bulgaria)

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partial tumor removal to preserve facial nerve function. In preexisting facial nerve palsy, more radical surgery is recommended.

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localized in the IAC, age of the patient, neurological status (preservation of hearing), and most importantly surgeon’s experience. The preservation of neurological function and if possible, its recovery is of utmost importance.

12.6.1 Surgical Intervention The neurosurgical removal of schwannomas localized in the CPA is quite challenging. It wasn’t until 1894 when the first successful operation of a tumor localized in the CPA was performed by an English surgeon called Sir Charles Balance (Pellet 2008). The tumor was removed through a right suboccipital craniectomy with the little finger of the surgeon. The patient recovered from surgery and was reported alive 18 years later despite the poor neurological outcome (complete facial nerve palsy) (Stone 1999). The first successful removal of a VS is attributed to the Scottish surgeon Thomas Annandale. Surgery in the CPA was further refined by many neurosurgeons including Victor Horsley, von Eisenberg, and Fedor Krause. Harvey Cushing was the one to propose intracapsular tumor debulking as a method of reducing the perioperative complications and morbidity. Walter Dandy was the one to introduce the concept of complete tumor removal to minimize the recurrence rate, despite the higher perioperative mortality. All these neurosurgeons founded the milestones that led to the modern VS microsurgery. The approaches to the CPA and VS removal are generally divided in posterior and lateral. (Fig. 12.7) At the end of the nineteenth century, Fedor Krause introduced the retrosigmoid suboccipital approach that is still used today (Samii and Gerganov 2008). The lateral approaches include removal to different extent a part of the petrous bone either through a subtemporal route (the middle fossa approach) or through the mastoid (the presigmoid approach, translabyrinthine approach, etc.). The two groups of approaches have various advantages and disadvantages that are shown in Table 12.2. There is a list of factors that should be considered before deciding on the correct approach for the patient including size of the VS, extension in the CPA or

12.6.1.1 The Retrosigmoid Suboccipital Approach The retrosigmoid suboccipital approach is a safe and simple approach. (Fig. 12.7) It could be performed in various positions of the patient on the operating table—semisitting, lateral or supine with the head rotated 90° to the contralateral side. The semisitting position is the preferred positioning by Samii and other groups (Scheller et al. 2019). One of the main advantages of this position is that it allows the surgeon to perform the dissection of the tumor with both hands, as gravitational forces clear the field from blood and irrigation fluid and constant suction is not necessary. Brain retraction is also reduced to a minimum. However, it also has some drawbacks and challenges, such as risk of venous air embolism, which makes this positioning difficult in some institutions, especially with less trained anesthesiology teams (Engelhardt et al. 2006). Preoperative echocardiography of the patient is mandatory to rule out persistent foramen oval and intraoperative transesophageal echocardiography or combined monitoring of end-tidal CO2 and precordial Doppler echocardiography. Tension pneumocephalus is also a possible complication after operations conducted in semisitting position. Nowadays, neurophysiological monitoring is part of the daily neurosurgical practice, especially when it comes to VS surgery. Monitoring of somatosensory evoked potentials (SSEPs) during positioning of the patient is important as it could give feedback if compression of the spinal cord occurs for some reason. Electromyography and direct stimulation of cranial nerve VII is compulsory during VS dissection as it could orient the surgeon of the displacement of the facial nerve by the tumor and guide the neurosurgeon through the dissection. Brainstem auditory evoked potentials (BAER) are monitored

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b Fig. 12.7 Alternative approaches for microsurgical

resection of vestibular schwannomas are shown above. With pink is depicted the craniectomy for the retrosigmoid approach, with purple—the translabyrinthine approach, and with blue—the middle fossa approach. The lower image illustrates the retrosigmoid approach. The patient is placed in lateral position—with thick purple lines is shown the approximate position of the transverse and sigmoid sinuses; the dotted line demarcates the slightly curved skin incision. 2 With the skin retractor in place a burr hole is performed at the

349 approximate intersection of the transverse and sigmoid sinus or slightly inferior and medial to that point, with dotted line are shown the boundaries of the craniectomy. 3 After the craniectomy is finished 2 mm of the transverse sinus is visible cranially and 2 mm of the sigmoid sinus, laterally. The dural incision is marked with a dotted line and follows the venous sinuses, approximately 2 mm inferior and medial to them to have enough space to perform a watertight suture at the end of the operation /Copyright of all illustrations is owned by Denitsa Peneva/

Table 12.2 Advantages and disadvantages of anterior and lateral approaches for VS surgery

a

Advantages

Disadvantages

Posterior approaches (Retrosigmoid suboccipital craniectomy)

. Safe and simple approach . Panoramic view of the CPA . Easy and precise dissection close to the brainstem . Low procedure-related morbidity . Possible hearing preservation even in large VS . The facial nerve could be reconstructed during the same procedure

. Cerebellar retractiona . Difficult visualization of the most lateral part of the IACa . Higher rate of postoperative headache (minimized with cranioplasty)a

Lateral approaches (Translabyrinthine approach)

. . . .

. Higher approach-related morbidity . Restricted access to the CPA . Difficult dissection and hemostasis close to the brainstem . Poor access to the lower cranial nerves . Sacrifice of hearing . Higher CSF leak rate

Lateral approach (Middle fossa approach)

. Direct access to the lateral part of the IAC . Possible hearing preservation . Low risk for CSF leak

Shorter distance to the tumor Good visualization Minimal brain retraction Early identification of CN VII

. Appropriate only for small tumors (up to 2 cm in the CPA) . Temporal lobe retraction . Risk to the vein of Labbe . Restricted access to the CPA

(Relative disadvantage) with appropriate technique they can be avoided

only in patients with preserved serviceable hearing. Monitoring of other cranial nerves is performed depending on the clinical case. A slightly curved skin incision is performed 2–3 cm medial to the mastoid process. (Fig. 12.7) Subcutaneous fat tissue can be harvested during the approach and used later for the watertight closure of the opened mastoid air cells. The asterion, despite the historical belief, is unfortunately not a reliable anatomical landmark for the underlying angulus venosus (Bozbuga et al. 2006). The location of the transverse sinus

is quite variable, but the sigmoid sinus is much more constant in its location as it descends along a line over the mastoid groove. An initial burr hole placed medial and caudal to the aforementioned lines is considered safe (Bozbuga et al. 2006). (Fig. 12.7-2) The choice between craniectomy and craniotomy is a matter of personal preference. The one-piece craniotomy is not recommended in less experienced hands due to the risk of venous sinus injury. The superior and lateral borders of the approach should be reached with a high-speed drill, only 1-2 mm of

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the transverse and sigmoid sinus should be exposed. (Fig. 12.7-3) A key step of the approach is the inferolateral portion of the craniectomy and enough bone should be removed to provide access to the cerebellomedullary cistern. The dural incision should be approximately 2 mm medial and along the venous sinuses. This allows primary watertight dural closure. The first step after dural opening is evacuation of sufficient CSF from the cerebellomedullary cistern, this leads to relaxation of the cerebellum. In this way, the self-retaining retractor only supports the cerebellum and does not compress it, thus avoiding retraction-related injury. The arachnoid plane should always be preserved. The arachnoid layer protects the underlying structures and does not allow bone dust from drilling of the IAC to enter in the subarachnoid space. Early in the microscopic stage of the neurosurgical procedure, the intrameatal portion of the VS is exposed. The posterior lip of the IAC is stripped off from its dura with a scalpel and a platelet knife. In this part of the operation, it is very important to have performed a preoperative CT scan to exclude a high jugular bulb. The injury of the jugular bulb with the high-speed drill could lead to brisk venous bleeding that is difficult to control and might lead to unpredictable neurological consequences. In the case of a high jugular bulb, the skeletonization should proceed extremely carefully. If the jugular bulb is lacerated, the opening could be closed with a piece of fat and fibrin glue. The posterior and superior walls of the IAC are reduced gradually with a diamond high-speed drill under constant irrigation. The extent of lateral opening of the IAC depends on the extension of the intrameatal VS part. The last 2 mm to the fundus of the IAC are left untouched to preserve the structures of the inner ear. After opening of the IAC, the facial nerve can be identified both anatomically and neurophysiologically by direct nerve stimulation (DNS). Quite rarely the facial nerve is displaced anteriorly, but it is essential in this stage of the operation to rule out this possibility by DNS. Internal decompression of the VS

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is the next step of the procedure. It is usually performed with an ultrasonic aspirator. If the tumor lacks a well-defined capsule the “onion skin technique” could be used. The layers of the tumor are removed one by one, starting from the center, and proceeding outwards. This technique prolongs the operation but leads to functional preservation of all cranial nerves in the CPA and excellent postoperative results. When sufficient internal decompression is performed, the tumor is dissected in its arachnoid plane. Bipolar coagulation should be reduced to a minimum in the dissection phase of the operation and used only at the end while performing hemostasis. Even then, the lowest possible current of the bipolar should be used. The part of the VS that is just medial to the IAC is the most difficult part to dissect. That is why it is left until the end when all the structures are identified around the VS. In this area coagulation should be avoided. After removing the tumor, copious irrigation is applied, the blood pressure is elevated, and hidden sources of bleeding are identified. Afterward, the opened mastoid air cells are plugged with pieces of fat tissue harvested in the beginning of the operation and sealed with fibrin glue. With this method of sealing the IAC, the risk of postoperative CSF leak is further reduced (up to 2.2% in some series) (Lüdemann et al. 2008). However, even despite all these measures if CSF leak occurs, our recommendation is to insert a lumbar drain immediately and leave it for minimum 7 days. If the CSF leak persists after the lumbar drain is removed, a revision surgery might be necessary. The bone defect is reconstructed with PMMA (polymethyl methacrylate) (Fig. 12.3). It is shown that the cranioplasty reduces the postoperative headache. Another possibility for the reconstruction of the posterior cranial fossa is with the bone dust collected during the drilling, which is spread across the bone defect and fixed with fibrin glue. This prevents the attachment of the muscles to the dura mater, reconstructs the shape of the occipital region of the head, and leads to a good cosmetic result.

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12.6.1.2 The Translabyrinthine Approach The translabyrinthine approach was introduced by Panse in 1904, but due to the high mortality was abandoned for more than half a century. The approach was reintroduced by William House in 1964. An important anatomical landmark for this approach is the Trautmann’s triangle. Its boundaries are the superior petrosal sinus superiorly, the sigmoid sinus posteriorly, and the jugular bulb inferiorly. There is a considerable bone removal during this exposure which minimizes the cerebellar retraction. It is used for various skull base tumors, including VS of any size, but mainly above 25 mm. The approach could be further increased cranially by opening the dura of the middle fossa and dividing the tentorium or the approach could be increased posteriorly by dividing the sigmoid sinus. The latter is only possible if preoperative venography has proven that the contralateral sigmoid sinus is dominant. The major disadvantage of this approach is the sacrifice of hearing. Moreover, any infection of the middle ear, or recent perforation of the tympanic membrane or mastoiditis is a contraindication for this approach as the risk of meningitis is considerable. For technical consideration of the translabyrinthine approach, see Fig. 12.8. 12.6.1.3 The Middle Fossa Approach The middle fossa approach was first described by Parry in 1904 and reintroduced by House for VS surgery in the 1960s (Parry 1904; Monfared et al. 2010). It allows direct access to the IAC, and it is therefore indicated mainly for VSs confined to the IAC and/or extending not more than 5 mm into the CPA. It is mainly preferred for VS extending to the fundus of the IAC, where the access would be difficult with the other approaches (Brackmann et al. 1994). However, it has been criticized for the limited exposure and the complications that it entails including temporal lobe epilepsy, dysphasia, intracerebral hematoma, possible injury of the vein of Labbé (Gantz et al. 1986). Furthermore, the access to the CPA

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is quite limited and removing this part of the tumor is quite a challenge, securing hemostasis even more. For technical consideration of the middle fossa approach, see Fig. 12.9.

12.6.1.4 The Retrosigmoid Suprameatal (Samii) Approach The retrosigmoid suprameatal (Samii) approach that is frequently used for trigeminal nerve schwannomas consists of standard retrosigmoid craniectomy, as described above (Fig. 12.7), and intradural resection of the petrous apex (Samii et al. 2000). Initially, after retraction of the cerebellum the trigeminal schwannoma is seen through the upper corridor above the complex of cranial nerves VII, CN VIII, and AICA. Internal debulking is performed with ultrasonic aspirator, as in VS surgery. After that the bone located above and anterior to the IAC, called suprameatal tubercle, is removed with a small diamond burr of the high-speed drill. The amount of bone that must be drilled depends on the extent of the tumor and the anatomical characteristics of the petrous bone. Anatomical studies have shown that by removing the suprameatal tubercle the approach is increased with up to 13 mm (Chanda and Nanda 2006). Vital structures that are in the proximity and need to be preserved are the petrous carotid artery anterolaterally, the superior petrosal sinus, and the superior semicircular canal laterally. The approach can be further enlarged by the incision of the tentorium, prior to which the trochlear nerve should be identified. Various neurosurgical approaches are suitable for patients with trigeminal schwannomas depending on their specific type. Type A trigeminal schwannomas that are predominantly located in the middle cranial fossa could be removed by using pterional transsylvian approach or an infratemporal extradural technique. Type B trigeminal schwannomas located predominantly in the posterior cranial fossa could be removed by using standard retrosigmoid approach, as described above, or the modified

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Fig. 12.8 For the translabyrinthine approach the patient is placed supine with the head turned 45° contralaterally. A curved skin incision is planned just behind the mastoid process. 1 The pericranial flap is reflected anteriorly and the mastoid process is exposed. 2 An extensive mastoidectomy is performed with a highspeed drill (Day et al. 2004; Lanman et al. 1999). Superiorly, the superior petrosal sinus should be seen and the middle fossa dura and posteriorly the sigmoid sinus which should be carefully skeletonized. The lateral semicircular canal is one of the anatomical landmarks for the horizontal part of the facial nerve which lies deeper and anterior. The facial nerve should be followed inferior with extreme caution. When the descending portion of the facial nerve is skeletonized, the anterior border of the approach is done. Inferiorly, the jugular bulb should be also skeletonized and the posterior fossa dura at the lower angle of Trautmann’s triangle (marked with red dotted line) the exposure should be sufficient to allow

mobilization of the lower part of the tumor. 3 A labyrinthectomy is performed by removing the semicircular canals and the vestibule until the dura of the IAC is reached. All three walls (posterior, superior, and inferior) of the IAC should be removed. When drilling the anterior aspect of the superior wall of the IAC it should be paid special attention as the facial nerve lies just beneath the dura in the anterosuperior quadrant of the IAC. The vertical crest, a.k.a. Bill’s bar, is an anatomical landmark that would help us identify the facial nerve. A T-shaped dural incision is conducted. 3a The tumor and the superior vestibular nerve (SVN) are gently displaced inferiorly, and the location of the facial nerve is confirmed with direct electrical stimulation. Initially internal debulking of the tumor is performed with ultrasonic aspirator, especially in larger VSs occupying the CPA. 3b The dura is closed watertightly. (Copyright of all illustrations is owned by Denitsa Peneva)

retrosigmoid suprameatal approach. With the latter approach could be removed also Type C dumbbell-shaped trigeminal schwannomas with or without the additional incision of the tentorium. The application of an endoscope is extremely useful when removing this type of schwannomas because it could provide an angled view of the supratentorial component of the

tumor and assist in its removal. Type D trigeminal schwannomas with mainly infratemporal localization could be removed by extradural subtemporal-infratemporal approach with additional removal of the zygomatic arch, an approach favored by Samii et al. Unlike vestibular schwannomas, surgery for oculomotor nerve schwannomas is not so well

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Fig. 12.9 For the middle fossa approach the patient is positioned in lateral position with the head turned 90° to the contralateral. Either U-shaped, or a question-mark skin incision is performed just above the ear with a craniotomy 4 X 5 cm. The craniotomy should be level with the middle cranial fossa and located 2/3rds anterior and 1/3rd posterior to the external auditory meatus. 1 The elevation of the dura mater should begin posteriorly to avoid undue stretch to the greater superficial petrosal nerve (GSPN). 2 Damage of the GSPN could lead to the so called “dry eye” syndrome. Anteriorly, the dura should be elevated until foramen spinosum is localized and the middle meningeal artery is coagulated. Medially, the superior petrosal sinus should be reached, carefully elevated to identify the posterior surface of the temporal bone. The arcuate eminence should be identified. Anteromedial to the arcuate eminence there is a flat bony surface called “meatal plane”, it lies just above to the IAC (Rhoton and Tedeschi 2008). The location of the IAC is identified anatomically or using neuro-navigation (Fisch 1970; Garcia-Ibanez and Garcia-Ibanez 1980; House and Shelton 1992). The roof of the IAC is around 3–4 mm thick. It is recommended to start bone removal from the “meatal plane”, drilling directly at the angle between GSPN and superior semicircular canal is considered

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dangerous due to the possible injury of the cochlea (Brackmann et al. 1994; Garcia-Ibanez and Garcia-Ibanez 1980). A wide exposure of the IAC should be obtained. The medial part of the temporal bone should also be removed and achieved access to the posterior fossa dura. Laterally, the superior semicircular canal should be carefully reached and skeletonized, and the labyrinthine segment of the facial nerve localized. Identifying Bill’s bar and the transverse crest means that the fundus of the IAC is reached and facilitated in identifying CN VII and CN VIII. Continuous EMG monitoring of the facial nerve assures the neurosurgeon that no harm is done during the drilling stage of the operation. Dural incision is performed over the posterior fossa, between the posterior aspect of the porus acusticus and the superior petrosal sinus. CSF is evacuated and the incision is elongated along the posterior aspect of the IAC and reflected anteriorly. The facial nerve is located anterosuperiorly. Dissection around the porus acusticus should be extremely careful. If the tumor is small, it could be removed piecemeal with meticulous microsurgical dissection. Bipolar coagulation should be reduced to a minimum to preserve the arterial supply to the cochlea and preserve auditory function. (Copyright of all illustrations is owned by Denitsa Peneva)

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studied due to the limited number of cases and only around 60 cases were reported so far (Hironaka et al. 2010; Muhammad and Niemelä 2019; Tanriover et al. 2007). Cisternal oculomotor schwannomas could be removed with a good chance of nerve preservation. However, in most of the cases this is not possible with their cavernous counterparts. There is the possibility of cranial nerve III sacrifice with its entailing postoperative neurological deficit. In the 45 cases that were operated 73% had cranial nerve III palsy postoperatively, while only 22% had some improvement after surgery. So, it is very important to discuss this possibility preoperatively with the patient and their relatives. Jugular foramen schwannomas are rare lesions, and few centers have the experience to make recommendations on their proper management. The goal of JF schwannomas surgery, like in VS surgery, is complete tumor removal with preservation of cranial nerve function. Type A JF schwannomas are approached with a retrosigmoid craniectomy, as described above. (Fig. 12.7) Type B and D JF schwannomas are operated with a single-stage combined lateral suboccipital intra-extradural transmastoid infralabyrinthine and cervical approach. JF schwannomas are benign lesions, but nevertheless they produce extensive bone destruction that should be kept in mind during the surgical exposure. Some of these tumors are quite vascular and preoperative endovascular embolization is a good option. JF schwannomas rarely infiltrate the cranial nerves, thus with meticulous microsurgical technique these tumors could be removed with anatomical preservation of the cranial nerves. Cystic JF schwannomas are special entity and should be emphasized that if the cystic component is evacuated early in the operation, the arachnoid plane is lost, and the dissection of the surrounding structures becomes much more difficult. Therefore, it is recommended that the initial step is identification of the dissection plane around the tumor. In the biggest series of Samii and Fukushima, complete removal of the tumor was achieved in almost all patients. In both series, there were no new postoperative cranial nerve deficit; it was emphasized that

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preoperatively impaired cranial nerve function could become worse, but the worsening was transient (Bulsara et al. 2008; Samii et al. 1995a, b). Expertise in skull base surgery is fundamental for operative treatment of JF schwannomas (Nowak et al. 2014). In the series of Fukushima of 53 patients, only 5.7% experienced tumor recurrence (Bulsara et al. 2008). Prognosis in patients with hypoglossal nerve schwannomas is overall favorable. In the review of 94 cases, 93% were operated on with residual mass documented in less than 30% of the cases (Bindal et al. 2019). Hypoglossal nerve deficit was present in 67% of the patients but it was well tolerated.

12.6.2 Radiotherapy Conventional external beam radiotherapy (EBRT) has been used in the past as an adjuvant treatment after subtotal resection of VSs. EBRT with doses in the range of 50-55 Gy has led to dramatic decrease in the probability of recurrence of operated VSs (Wallner et al. 1987). However, RT had no influence on recurrence rate in VSs that were resected more than 90% and is related to multiple side effects of RT that need to be mentioned (cranial nerve palsies, brain stem edema, brain stem ischemia, cognitive decline, secondary neoplasms). It wasn’t until 1969 when stereotactic radiosurgery (SRS) with Gamma knife was introduced for VS therapy by Leksell (1971) (Prasad et al. 2000). Since then, SRS has established as one of the main treatments for VSs (Prasad et al. 2000). SRS refers to a highly precise delivery of highdose radiation in a small target area in the brain. It could be either conducted by using Gamma rays emitted from 60Co (Gamma knife) or X-rays emitted by a linear accelerator (LINAC). It could also be performed in a single fraction which is referred as SRS or in multiple fraction which is called stereotactic radiotherapy (SRT). The term stereotactic is used to highlight the precision of the procedure (from Greek “stereos” means three dimensional and ‘taxis’ means arrangement, order). Back in 1969, Leksell used a stereotactic

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frame to achieve this high precision. Nowadays, frameless SRS is mainly used. In general, only lesions below 30 mm should be treated with SRS. A radiation dose of < 13 Gy is delivered to the VS in a single fraction for a period of 10–20 min. Most of the studies show that there is no difference in tumor control rate whether the radiation delivered to the tumor bed is < 13 Gy or > 13 Gy (Hasegawa et al. 2013; Prasad et al. 2000). However, the more important fact leading to the use of smaller dose fraction is the likelihood of hearing preservation which is higher with the lower radiation dose (Andrews et al. 2009; Williams 2002). In order to avoid auditory impairment, it is essential what radiation dose will be applied to the cochlea. The cochlear dose is emphasized as a cornerstone of hearing preservation (Massager et al. 2007). The mean cochlear dose in patients with preserved hearing was 3.7 Gy, while the mean cochlear dose was 5.33 Gy in those with auditory impairment. Delivering enough radiation to the VS to achieve tumor control and minimal cochlear radiation dose is the goal of contemporary SRS. A cochlear radiation dose less than 3 Gy is reported to be a favorable prognostic factor for hearing preservation (Baschnagel et al. 2013). The achieved tumor control after single fraction SRS after 10 yearsfollow-up is 90.8% (Windisch et al. 2019). A recent study with almost 7 yearfollow-up of patients after SRS with GK reports a radiological control of around 78.6% for VSs larger than 10cm3 and estimated radiological control of 83.2% for VSs smaller than 20 cm3 (Mezey et al. 2020). They also put forward the idea that size might not be a contraindication for SRS treatment. Due to the high operative risk of cranial nerve III palsy during operative treatment of oculomotor nerve schwannomas, SRS seems like a reasonable alternative. In a review of 7 patients with oculomotor nerve schwannomas that have undergone SRS, a progression-free interval of almost 2 years is observed in around 90% of the cases (Muhammad and Niemelä 2019). In larger tumors or tumors with considerable mass effect where operative treatment is indicated, a subtotal

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resection with preservation of cranial nerve function and postoperative SRS is a reasonable treatment plan. A small series of patients (5) with trochlear and abducens nerve schwannomas from Lausanne, Switzerland, published in 2017 showed some promising results from GK-SRS of these rare nerve-sheet tumors (Peciu-Florianu et al. 2017). They reported 100% tumor control rate and around 30% improvement in patients’ symptoms. Only one of the patients had previous surgery as a volume-reduction measure, and all the patients received a dose of 12 Gy (PeciuFlorianu et al. 2017). Stereotactic radiosurgery has been proposed as an alternative or as an adjunct to operative treatment of trigeminal nerve schwannomas. A tumor shrinkage after SRS was shown in 88.5% of the patients with trigeminal schwannomas with diameter less than 30 mm (Pan et al. 2005a, b). However, cranial nerve morbidity is higher with SRS, and the improvement of preexisting neurological function is less likely. Patients with jugular foramen schwannomas could also be treated with GK-SRS. However, the experience with this treatment of JF tumors is still limited, and unfortunately, the vast experience gained on VS SRS could not be extrapolated to these schwannomas, as they originate from different cranial nerves and have different localization. A tumor control was achieved in 96% of the cases (44% had decrease in tumor size) in a series of 27 patients with JF schwannomas treated with GK-SRS, after application of 14.6 Gy (Zhang et al. 2007, 2002). In a series of 92 patients with JF schwannomas who underwent GK-SRS with 12.5 Gy, the reported progression-free survival at 3 years was 93%, at 5 years 87%, and at 10 years 82% (Kano et al. 2018). This study proved that SRS could be a viable option for management of patients with JF schwannomas. However, greater permanent cranial nerve deficit was observed after GK-SRS in patients with JF schwannomas than in patients with VS, despite the lower radiation dose (Ruangkanchanasetr et al. 2018). In general, our recommendation is to reserve radiosurgery for

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elderly patients, for patients with multiple comorbidities, unfit for surgery, and for patients that are unwilling to be operated on.

12.6.3 New Therapeutic Modalities Chemotherapy has little role in vestibular schwannoma treatment so far. However, new therapies might be emerging on the horizon. They might be especially helpful in NF2 cases since in those patients the genetic defect predisposes to a lifelong formation of multiple CNS tumors (i.e., meningiomas). Angiogenesis has a central role in tumor growth. Vascular endothelial growth factor (VEGF) is essential in neoangiogenesis. Bevacizumab is a monoclonal antibody against VEGF. A lot of studies and reports support the use of Bevacizumab as a monotherapy in patients that are unfit or refuse surgery or SRS (SRT) (Huang et al. 2018a, b; Liu et al. 2016; Plotkin et al. 2009). A radiographic tumor regression and hearing improvement were reported after I.V administration of 5 mg/kg/2 weeks Bevacizumab in 88% of the cases on the 1st year and in 54% on the 3rd year (Mautner et al. 2010; Plotkin et al. 2009). The continuous use of Bevacizumab may lead to the desired tumor control with the cost of some serious side effects including hypertension, proteinuria, thrombosis, and hemorrhage (Plotkin et al. 2012). The side effects and the slow penetration of Bevacizumab through the blood–brain barrier led to the idea of super-selective intraarterial application of the antibody (Riina et al. 2012). A combination of two kinase inhibitors has been proposed as a novel chemotherapy regimen for VSs. AZD2014 is a dual inhibitor of mTORC1 and mTORC2 pathways and Dasatinib which is a multi-kinase inhibitor (Sagers et al. 2020). The two mTOR pathways are activated in meningiomas with loss of NF2. The two drugs (AZD2014 and Dasatinib) both inhibit tumor growth, but in combination, a synergistic effect has been elicited over the suppression of VS cell growth. This novel therapy has yet to be FDAapproved.

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It has been suggested for further investigation the immunomodulator Pomalidomide, a derivative of Thalidomide, after it has been reported to lead to reduction of the size of a spinal schwannoma of a patient with NF2 (Kunnel Jomon et al. 2020). The patient was treated with Pomalidomide for a multiple myeloma, while on control imaging a reduction of the preexisting spinal schwannoma was confirmed.

12.7

Follow-Up and Prognosis

Over the last few decades, the management of VS advanced considerably. From a merely lifesaving procedure previously, currently its goal is to preserve the quality of life of the patient. This goal can be achieved in most of the patients with the available treatment options or combination thereof, as described earlier. According to the largest series of patients, complete tumor removal is achieved in 90–99% (Arthurs et al. 2011; Brackmann and Green 2008; Gjuric et al. 2001; Lanman et al. 1999; Samii et al. 2006; Wiet et al. 2001). The size of the remaining tumor is an important predictor of tumor recurrence. The reported recurrence rate after microsurgical tumor removal is 0.5–5%. Postoperative follow-up imaging is essential to diagnose any recurrence. The first postoperative MRI should be performed within 6 months after surgery and then annually. After this initial 3-year period of annual control in case of gross total removal, the follow-up can be in 2 or 3 years. In case of tumor remnant, the follow-up MRI should be performed annually. After SRS the recommended follow-up imaging during the first year is done every 3– 4 months (Nagano et al. 2010; Okunaga et al. 2005) to every 6 months (van de Langenberg et al. 2012; Huang et al. 2018a, b). During the 2nd to 5th year, most studies recommend annual MRI scans or every six months. After the 5th year, the recommendation is to perform annual MRI scan or every 2 years (Meijer et al. 2003; Mindermann and Schlegel 2013). During the follow-up period after SRS if there are radiological signs for tumor progression, the patient

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should be considered for either microsurgical tumor resection, or further SRS. There are few studies for SRS retreatment that show a tumor regression or tumor control from 81.8% to 100% of the cases (Dewan and Norén 2008; Kano et al. 2010; Liscak et al. 2009).

12.8

Conclusion

The management of brain and spinal schwannomas advanced considerably over the past decades. The focus previously was on preservation and prolongation of life, while currently the goal is to preserve all neurological functions and provide a good quality of life. The selection of the best management option including radical surgery, subtotal tumor resection, and radiosurgery or radiosurgery has to be taken individually in each case in order to achieve that goal.

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361 Samii M, Gerganov VM (2008) Surgery of extra-axial tumors of the cerebral base. Neurosurgery 62(6 Suppl 3):1153–66; Discussion 1166–8 Sarma S, Sekhar LN, Schessel DA (2002) Nonvestibular schwannomas of the brain: a 7-year experience. Neurosurgery 50(3):437–448; Discussion 438–439 Satar B, Yetiser S, Ozkaptan Y (2003) Impact of tumor size on hearing outcome and facial function with the middle fossa approach for acoustic neuroma: a metaanalytic study. Acta Otolaryngol 123(4):499–505 Saunders JE, Luxford WM, Devgan KK, Fetterman BL (1995) Sudden hearing loss in acoustic neuroma patients. Otolaryngol Head Neck Surg 113(1):23–31, S0194-5998(95)70140-0 [pii] Scheller C, Rampp S, Tatagiba M, Gharabaghi A, Ramina KF, Ganslandt O, Bischoff B, Matthies C, Westermaier T, Pedro MT, Rohde V, von Eckardstein K, Strauss C (2019) A critical comparison between the semisitting and the supine positioning in vestibular schwannoma surgery: subgroup analysis of a randomized, multicenter trial. J Neurosurg 3:1–8 Sherman JD, Dagnew E, Pensak ML, van Loveren HR, Tew JM Jr (2002) Facial nerve neuromas: report of 10 cases and review of the literature. Neurosurgery 50 (3):450–456 Shimansky VN, Shevchenko KV, Poshataev VK, Tanyashin SV, Abdurakhimov FD (2019) Hypoglossal schwannoma: case report and literature review]. Zh Vopr Neirokhir Im N I’m Burdenko 83(5):51–57 Snyder MH, Shepard MJ, Chen CJ, Sheehan JP (2018) Stereotactic radiosurgery for trigeminal schwannomas: a 28-year single-center experience and review of the literature. World Neurosurg 119:e874–e881 Spinnato S, Talacchi A, Musumeci A, Turazzi S, Bricolo A (1998) Dumbbell-shaped hypoglossal neurinoma: surgical removal via a dorsolateral transcondylar approach. A case report and review of the literature. Acta Neurochir (Wien) 140(8):827–832 Springborg JB, Poulsgaard L, Thomsen J (2008) Nonvestibular schwannoma tumors in the cerebellopontine angle: a structured approach and management guidelines. Skull Base 18(4):217–227 Stone JL (1999) Sir Charles Ballance: pioneer British neurological surgeon. Neurosurgery 44(3):610–31; Discussion 631–2. Review Sughrue ME, Yang I, Rutkowski MJ, Aranda D, Parsa AT (2010) Preservation of facial nerve function after resection of vestibular schwannoma. Br J Neurosurg 24(6):666–671 Sun J, Zhang J, Yu X, Qi S, Du Y, Ni W, Hu Y, Tian Z (2013) Stereotactic radiosurgery for trigeminal schwannoma: a clinical retrospective study in 52 cases. Stereotact Funct Neurosurg 91(4):236–242 Sutay S, Tekinsoy B, Ceryan K, Aksu Y (1993) Submaxillary hypoglossal neurilemmoma. J Laryngol Otol 107(10):953–954 Symon L, Cheesman AD, Kawauchi M, Bordi L (1993) Neuromas of the facial nerve: a report of 12 cases. Br J Neurosurg 7(1):13–22

362 Tan LC, Bordi L, Symon L, Cheesman AD (1990) Jugular foramen neuromas: a review of 14 cases. Surg Neurol 34(4):205–211. 0090-3019(90) 90130-H [pii] Tanriover N, Kemerdere R, Kafadar AM, Muhammedrezai S, Akar Z (2007) Oculomotor nerve schwannoma located in the oculomotor cistern. Surg Neurol 67(1):83–88 Tos M (1998) Increasing incidence of vestibular schwannoma: is it real and realistic? Ugeskr Laeger 160 (45):6538 Tung H, Chen T, Weiss MH (1991) Sixth nerve schwannomas. Report of two cases. J Neurosurg 75 (4):638–641 Tysome JR, Macfarlane R, Durie-Gair J, Donnelly N, Mannion R, Knight R, Harris F, Vanat ZH, Tam YC, Burton K, Hensiek A, Raymond FL, Moffat DA, Axon PR (2012) Surgical management of vestibular schwannomas and hearing rehabilitation in neurofibromatosis type 2. Otol Neurotol: Official Publ Am Otological Soc, Am Neurotol Soc [and] Eur Acad Otol Neurotol 33(3):466–472 Unger F, Walch C, Papaefthymiou G, Feichtinger K, Trummer M, Pendl G (2002) Radiosurgery of residual and recurrent vestibular schwannomas. Acta Neurochir 144(7):671–677 Vachata P, Sames M (2009) Abducens nerve schwannoma mimicking intrinsic brainstem tumor. Acta Neurochir (wien) 151(10):1281–1287 van de Langenberg R, Dohmen AJ, de Bondt BJ, Nelemans PJ, Baumert BG, Stokroos RJ (2012) Volume changes after stereotactic LINAC radiotherapy in vestibular schwannoma: control rate and growth patterns. Int J Radiat Oncol Biol Phys 84 (2):343–349 Varughese JK, Wentzel-Larsen T, Pedersen PH, Mahesparan R, Lund-Johansen M (2012) Gamma knife treatment of growing vestibular schwannoma in Norway: a prospective study. Int J Radiat Oncol Biol Phys 84(2):e161–e166

V. Gerganov et al. Vermeulen S, Young R, Posewitz A, Grimm P, Blasko J, Kohler E, Raisis J (1998) Stereotactic radiosurgery toxicity in the treatment of intracanalicular acoustic neuromas: the Seattle Northwest gamma knife experience. Stereotact Funct Neurosurg 70(Suppl 1):80–87 Wallner KE, Sheline GE, Pitts LH, Wara WM, Davis RL, Boldrey EB (1987) Efficacy of irradiation for incompletely excised acoustic neurilemomas. J Neurosurg 67(6):858–863. PubMed PMID: 3681424 Walsh RM, Bath AP, Bance ML, Keller A, Tator CH, Rutka JA (2000) The natural history of untreated vestibular schwannomas. Is there a role for conservative management? Rev Laryngol Otol Rhinol (Bord) 121(1):21–26 Wiet RJ, Mamikoglu B, Odom L, Hoistad DL (2001) Long-term results of the fi rst 500 cases of acoustic neuroma surgery. Otolaryngol Head Neck Surg 124 (6):645–651, S0194599801514382 [pii] Williams JA (2002) Fractionated stereotactic radiotherapy for acoustic neuromas. Acta Neurochir (Wien) 144 (12):1249–54; Discussion 1254 Windisch PY, Tonn JC, Fürweger C, Wowra B, Kufeld M, Schichor C, Muacevic A (2019) Clinical results after single-fraction radiosurgery for 1002 vestibular schwannomas. Cureus 11(12):e6390 Yamakami I, Uchino Y, Kobayashi E, Saeki N, Yamaura A (2002) Prognostic significance of changes in the internal acoustic meatus caused by vestibular schwannoma. Neurol Med Chir (Tokyo) 42(11):465– 70; Discussion 470–1 Yonas H, Jannetta PJ (1980) Neurinoma of the trigeminal root and atypical trigeminal neuralgia: their commonality. Neurosurgery 6(3):273–277 Zhang N, Pan L, Dai JZ, Wang BJ, Wang EM, Cai PW (2002) Gamma knife radiosurgery for jugular foramen schwannomas. J Neurosurg 97(5 Suppl):456–458 Zhang H, Cai C, Wang S, Liu H, Ye Y, Chen X (2007) Extracranial head and neck schwannomas: a clinical analysis of 33 patients. Laryngoscope 117(2):278–281

Other Nerve Sheath Tumors of Brain and Spinal Cord

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Mihail Petrov, Teodora Sakelarova, and Venelin Gerganov

Abstract

The three main types of nerve sheath tumors are schwannomas, neurofibromas and perineuriomas. Multiple neurofibromas throughout the body are the hallmark of Neurofibromatosis type 1 (NF1). Spinal nerve sheath tumors are classified in the group of intradural extramedullary spinal cord tumors, in which they are the most common type (25–30%). Their incidence is 3–4 per 1 million people. Spinal schwannomas are encountered sporadically or in the context of Neurofibromatosis type 2, while neurofibromas are typical for patients with Neurofibromatosis type 1. Neurofibromas are composed predominantly of Schwann cells and fibroblasts, alongside which are also found axons, perineurial cells, mast cells and extracellular matrix. Most of the neurofibromas are asymptomatic. Any increase in the size of a neurofibroma or the presence of pain is an indicator of a possible

M. Petrov (&) . V. Gerganov University Multiprofile Hospital for Active Treatment With Emergency Medicine N. I. Pirogov, Sofia, Bulgaria e-mail: [email protected] T. Sakelarova University Hospital St. Anna, Sofia, Bulgaria V. Gerganov International Neuroscience Institute, Hannover, Germany

malignant degeneration. Neurofibromas are treated surgically. Neurofibromas involve the whole nerve and cause its fusiform enlargement which makes it impossible to preserve the nerve’s functions if complete tumor removal is performed. Hence, such tumors are initially observed. In case of progressive growth, the options are either resection of the tumor and immediate reconstruction with a peripheral nerve graft (e.g., nerve suralis interposition graft) or subtotal removal and follow-up. Malignant peripheral nerve sheath tumors (MPNST) are very rare tumors with incidence of around 1 per 1,000,000 people. MPNST account for 3–10% of all soft-tissue sarcomas. The most common initial symptom of MPNST is a painless mass. Any rapid increase in a subcutaneous mass or rapid onset of symptoms should raise the suspicion of a malignant tumor. In patients with diagnosed NF1, the recent rapid increase in a known lesion should raise the suspicion of malignant degeneration of the lesion and opt for active treatment. In the case of MPNST a wide surgical excision is advocated. The resectability depends greatly on the location of the tumors and varies from around 20% in paraspinal MPNST and reaches 95% in MPNST localized in the extremities. MPNST are a rare disease and should be managed by a multidisciplinary team of neurosurgeons, radiologists and oncologists.

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_13

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Keywords

Nerve sheath tumors MPNST

13.1

. Neurofibromas .

Background and Epidemiology

The three main types of nerve sheath tumors are schwannomas, neurofibromas and perineuriomas. Neurofibromas consist of Schwann-like cells and fibroblasts. Multiple neurofibromas throughout the body are the hallmark of Neurofibromatosis type 1 (NF1). This disease was described for the first time by an English poet called Akenside in (1768). He reported a case of a 60-year-old male patient with multiple cutaneous tumors that were also observed in the patient’s father. Later this disease was named after Friedrich Daniel von Recklinghausen, a German pathologist, who named these cutaneous tumors neurofibromas (von Recklinghausen 1882). The frequency of NF1 is approximately 1 in 2500–3000 live births. No gender prevelance has been identified. Perineuriomas (PN) are benign peripheral nerve sheath tumors comprised of welldifferentiated neoplastic perineural cells. These tumors were described for the first time in 1978 by Lazarus and Trombetta (1978). They are two main types including extraneural PN that are encountered in the soft tissues and skin and intraneural PN that are confined to the boundaries of the peripheral nerves (Macarenco et al. 2007; Uerschels et al. 2020). PN are more frequently encountered in adults; however, some cases have been reported in children (Balarezo et al. 2003). Spinal nerve sheath tumors are classified in the group of intradural extramedullary spinal cord tumors, in which group they are the most common type (25–30%) (Seppälä et al. 1995). Their incidence is 3–4 per 1 million people. They are subdivided in two main categories, schwannomas and neurofibromas. Spinal schwannomas are encountered sporadically or in the context of Neurofibromatosis type 2, while

neurofibromas are typical for patients with Neurofibromatosis type 1. Unlike the cranial schwannomas, the female-to-male ratio of the spinal schwannomas is reported to be almost 1:1. Some studies report a slight male predominance (Tish et al. 2019); other studies report the opposite (Himmiche et al. 2019). The median age at diagnosis is between the fourth and fifth decades (Lenzi et al. 2017). Spinal nerve sheath tumors originate usually from the dorsal nerve root. Most frequently they are located intradurally and extramedullary (58%), extradurally (27%), dumbbell-shaped with an intradural and extradural component (15%) and rarely intramedullary (90%) due to a germline monoallelic pathogenic mutation in the VHL tumorsuppressor gene (3p25.3), an evolutionarily preserved gene located on the short arm of chromosome 3 (Latif et al. 1993). Up to 20% of cases are due to de novo pathogenic variants and, therefore, without a family history. The pathogenetic role of this gene in VHL was discovered almost thirty years ago (Latif et al. 1993); since that point, research about the pathogenetic and molecular processes in VHL disease has flourished. The involved VHL gene variants are heterogeneous, including single or multi-exon deletions (30–40% of cases), truncating mutations (30% of cases), and missense variants (Maher and Sandford 2019). VHL type 1 disease is associated with CNS and retinal HBs and RCC, while pheochromocytomas and paraganglioma are rare; VHL type 2 is associated with frequent pheochromocytomas or paragangliomas (Gossage et al. 2015; Nielsen et al. 2016). Phenotypic variability is a prominent feature of VHL disease, and genotype–phenotype correlations are a well-known feature of VHL (Maher and Sandford 2019). The VHL gene encodes a tumor-suppressor protein forming a complex (VCB-CUL2) with elongin C, elongin B, Cul-2, and Rbx1, which acts as a ubiquitin–protein ligase, finally determining ubiquitin-dependent proteolysis of cellular proteins. In VHL, the mutations are concentrated around the a-domain,

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which contains a binding site of elongin C (Stebbins et al. 1999), and around the b-domain with its binding site of hypoxia-inducible factor (HIF) (Maxwell et al. 1999). HIF enhances the glucose uptake and increases the expression of angiogenic, growth, and mitogenic factors, and it plays a pivotal role in regulating and coordinating cellular response to hypoxia. The VHL-HIF signaling pathway is critical in CNS hemangioblastomas angiogenesis (Nguyen et al. 2018). The main target of VCB-CUL2 complex is exactly the HIF: the VHL protein complex had a critical role in regulating the expression of the asubunits of HIF-1 and HIF-2 (Maher and Sandford 2019), which in hypoxic conditions promote transcription of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The deletion or mutations of the VHL gene determine the loss of protein complex function; therefore, HIF does not undergo the VHL-mediated degradation and activates dysregulated transcription of these growth factors, thus promoting tumorigenesis in VHL. The VHL protein-defective cells produce high levels of hypoxia-inducible messenger RNAs as VEGF, platelet-derived growth factor polypeptide (PDGF), transforming growth factor (TGF), and erythropoietin (EPO), explaining also the onset of polycythemia. This pathway involves a prolyl hydroxylase domain protein 2 (PHD2), which targets HIF-2a for degradation by the VHL protein. Hypoxia may result in the stabilization of HIF-2a and transcriptional activation of the EPO gene, thus leading to the expansion of red cell mass. The mutations in PHD2 and VHL or the gain of function mutations in HIF-2a and EPOR are well-established causes of erythrocytosis, thus explaining the association between the VHL protein pathway and the polycythemia (Lappin and Lee 2019). The polycythemia related to VHL is characterized by increased circulating levels of EPO, differently from polycythemia vera, a primary form with low serum EPO, due to mutations expressed within the erythroid progenitors (Lappin and Lee 2019; Pastore et al. 2003). Interestingly, the Chuvash polycythemia is instead an autosomal recessive

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form of erythrocytosis (endemic in patients from Chuvashia, Russian Federation) (Ang et al. 2002), associated with a mutation in the VHL gene (Lenglet et al. 2018), without HBs or RCC (Gordeuk et al. 2004). More recently, next to the classic VHL-HIF pathway, the role of other signal pathways in the HBs tumorigenesis has been postulated. HBs, in particular the stromal cells, express several mesodermal markers consistent with the hemangioblasts progenitor cell (Ostrom et al. 2019), and the neoplastic originating cells of HBs are probably the mesoderm-derived embryonic hemangioblasts (Gläsker et al. 2006; Park et al. 2007; Takada et al. 2018a, b; Vortmeyer et al. 1997; Wang et al. 2018), in which the binding between VHL protein and elongin C has determined JAK2 ubiquitination and inhibition of the JAK-STAT pathway (Stebbins et al. 1999). Therefore, hemangioblast progenitor cells may differentiate to neoplastic cells, also through the inhibition of the JAK-STAT pathway (Kanno et al. 2018). Although all these mechanisms adequately explain the origin of HBs in VHL, their role in sporadic HBs is less clear. The biallelic inactivation of the VHL gene with all consequent alterations of the HIF pathway is the leading cause of the pathogenesis of syndromic HB, and the rates of biallelic inactivation of VHL gene in sporadic HBs are ranged between from 10 to 33% of cases (Gläsker et al. 2006). Using more advanced techniques as the next-generation sequencing, the rates of VHL mutation and biallelic inactivation rise to 56% and 46%, respectively (Shankar et al. 2014). Therefore, in sporadic HBs, the classic pathogenetic mechanisms are not enough to explain tumorigenesis. Moreover, Takayanagi et al. reported a rate of biallelic VHL inactivation of 64% in VHL-related HBs and 52% in sporadic forms (Takayanagi et al. 2017), although the percentage of biallelic VHL inactivation was higher in other VHL-related tumors (such as clear cell RCC) than among syndromic HBs. Other epigenetic or unknown mechanisms may play roles in the pathogenesis of syndromic and sporadic HBs. Loss of heterozygosity (LOH) on chromosome 3 was

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found in 64% and 57% of VHL-related and sporadic HBs (Takayanagi et al. 2017), while the hypermethylation of the VHL promoter was observed only in sporadic tumors, in which epigenetic suppression of VHL expression may contribute to VHL inactivation. Recent studies with whole-genome and whole-exome sequencing analysis identified novel candidate genes possibly involved in the pathogenesis of RCCs: polybromo 1 (PBRM1), BRCA-1 associated protein 1 (BAP1), and SET domain containing 2 (SETD2), located on chromosome 3p (Dalgliesh et al. 2010; Varela et al. 2011). Another interesting finding, always in sporadic HBs, is the higher frequencies of LOH on chromosomes 6 and 10, suggesting a possible role of some genes located in these chromosomes, in addition to the classic VHL gene in the 3p25.3 (Takayanagi et al. 2017). As reported in 2017, LOH in chromosome 6 or 10 could be found in 43% of sporadic HBs (Takayanagi et al. 2017), mainly in 10q, where is located a gene encoding one of the most commonly involved tumor suppressors in human cancers, the phosphatase and tensin homolog (PTEN) (Chen et al. 2005; Goncalves et al. 2018). Therefore, the exact mechanism of HBs’ tumorigenesis remains partially unknown, especially about sporadic forms.

14.3

Histopathology and Morphology

HBs can present various morphological aspects: they can appear solid, solid-cystic, or mainly cystic with a small mural, vascularized node composed of stromal cells and a dense capillary network (Kuharic et al. 2018; Lohle et al. 2000). The pathologically increased vascular permeability within the hemangioblastoma leads to ultrafiltrate extravasation into the interstitial spaces, finally determining the development of peritumoral edema (Lohle et al. 2000). There are high similarities in histologic characteristics of mainly cystic and/or solid tumor subtypes; therefore, differentiation is often challenging. HBs contain rich vascularity with tightly packed thin-walled capillary-type vessels, separated by

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stromal cells. The stromal cells are the neoplastic cells harboring the genetic alterations involved in tumorigenesis, although they account only for 20% of the tumor (Vortmeyer et al. 1997). Macroscopically, HBs present as highly vascularized lesions, well-demarcated from the surrounding tissue, often partly cystic. The cut surface appears red–yellow variegated. The tumor shows a biphasic pattern with two main components at the histological examination, being composed of large vacuolated stromal cells and a dense vascular network of capillary proliferation. A different proportion of these components is characterized as the “cellular”, with predominant stromal cells and “reticular” variants that could also have different genetic pathways (Rickert et al. 2006) (Fig. 14.1). The stromal cells represent the neoplastic component of the tumor with occasional atypical and hyperchromatic nuclei varying in size. The typical “clear cell” morphology of capillary HBs in paraffin-embedded histological specimens is due to the presence of numerous lipid-containing vacuoles on stromal cells. This feature can underlie the differential diagnosis of metastatic renal cell carcinoma or capillary HBs, which is a complex challenge because the patients with VHL disease have a predisposition to RCC (Kim et al. 2019; Zheng et al. 2020). The

adjacent parenchyma may present piloid gliosis and Rosenthal fibers, mimicking a pilocytic astrocytoma. The mitotic and the proliferation indices (with Ki67/MIB1) are low, mostly less than 1%. At the immunohistochemical analysis (Fig. 14.2), the vascular components express endothelial markers, such as CD34, von Willebrand factor (or factor VIII-related antigen), and VEGF, with the corresponding endothelial expression of its receptors VEGFR-1 and -2, suggesting an angiogenesis activation, driven by the hypoxia-inducible factor which presents in the nuclei of stromal cells. The stromal cells highly express Vimentin, an intermediate filament of the cytoskeleton, and inhibin, helpful in distinguishing HB from other clear cell tumors, as the RCC. Moreover, stromal cells express, with different degrees of intensity, a variety of other markers as S100, neural cell adhesion molecule (NCAM), neuron-specific enolase (NSE), epidermal growth factor receptor (EGFR), CXCR4, and aquaporin-1. The genetic basis of HBs pathogenesis is the mutation on VHL, the tumor-suppressor gene that causes VHL disease; however, somatic mutations of VHL were also found in sporadic forms. The VHL gene encodes for a protein involved in the degradation of HIF-1 and HIF-2, promoting

Fig. 14.1 Histological features of hemangioblastomas (hematoxylin–eosin staining). The reticular variant (a), with several thin vessels and stromal cells, shows the

typical “clear cell” morphology due to the accumulation of lipid droplets. The cellular variant is instead characterized by dense stromal tumor cells (b)

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Fig. 14.2 Hemangioblastomas immunophenotype. a CD34 immunostaining of endothelial cells showing the dense capillary network. b Abundant VEGF

expression on vessels and stromal cells. c Stromal cells immunoreactivity for inhibin

transcription of proangiogenic factors, such as VEGF and PDGF, in hypoxic conditions. When this regulator function of VHL protein is lost, the result is an activation of these growth factors promoting HBs’ tumorigenesis. Pathological vessel remodeling arises from the dysregulation of HIFs and VEGF. This mechanism is similar among VHL-related and sporadic tumors. Alternative pathways may exist for tumorigenesis of sporadic forms (Roh et al. 2019; Takayanagi et al. 2017; Wang et al. 2017).

14.4.1.1 MR Findings The mural nodule is isointense on both T1- and T2-weighted images and enhances strongly and homogeneously after contrast media injection (Fig. 14.3). Prominent flow voids are present in some cases. The cystic component is hypointense on T1-weighted images and hyperintense on T2weighted images, with slightly or markedly low signal on DWI. Perfusion MRI reveals high relative cerebral blood volume ratios, with values significantly higher than those encountered in metastases.

14.4

14.4.1.2 Angiography Findings Angiography is rarely performed because diagnosis is made easily by magnetic resonance. Dilated feeding arteries and prolonged tumor blush highlight the vascular nature of these tumors (Fig. 14.3).

Imaging and Radiologic Features

14.4.1 Cerebral Hemangioblastomas HBs are composed of cysts and mural nodules in 60% of cases. In the remaining 40% of cases, the tumor is solid without cysts. Dimensions vary from tiny to several centimeters. On a non-contrast scan, the mural nodule is isodense/hyperdense and enhances intensely after injection of contrast media. The mural nodule is surrounded by low-density cysts with nonenhancing walls; calcifications and hemorrhage are rare. CT angiography may demonstrate the arterial feeders.

14.4.2 Spinal Hemangioblastomas Spinal hemangioblastomas are solid in 25% of cases, whereas the rest usually have mixed solid and cystic components. Tumors are typically located superficially on the cord's dorsal surface and can be associated with a syrinx or syringohydromyelia. Sometimes, larger syringomyelic

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Fig. 14.3 Cerebellar HB. Cerebellar axial T2-weighted (a) and T1-weighted (b) images showed a heterogeneous cerebellar mass with prominent flow voids (white arrows)

and surrounding edema. Axial T1 post-contrast MR image (c) depicted a marked enhancement of the mass. Vertebral angiograms (d–f) revealed an intense tumor blush

cavities could be related to small nodular HBs, mainly in symptomatic patients. Spinal HBs are located more frequently in the thoracic segment and more rarely in the cervical spine. CT is not used routinely because the visualization of the spinal cord nodules is limited. In some cases, it is possible to detect a bone remodeling. CT angiography imaging is helpful for preoperative planning and intraoperative guidance.

heterogeneous enhancement (Fig. 14.4). Intratumoral flow voids and prominent posterior draining veins are detected often on T1- and T2weighted images, especially in large lesions. A hypointense rim on T2-weighted images is the consequence of hemosiderin deposition. Surrounding edema within the cord can also be seen. In patients with multiple HBs, extensive edema involves a large area of the spinal cord, producing venous hypertension similar to that occurring in spinal dural arteriovenous fistulae.

14.4.2.1 MR Findings Small tumors (50% relative to those before stereotactic radiosurgery) received higher doses ( ≥ 14 Gy) than those with partial tumor shrinkage or no change.

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and symptoms secondary to the mass effect (Bhatt et al. 2019; Brennan et al. 2001). The first description of this tumor in neurosurgery dates back to 1980. Pearl suggested three possible pathways of CNS involvement in his original paper: as a scalp mass with drainage into the intracranial venous sinuses, an intracranial mass arising from the dura, and an epidural spinal mass determining spinal cord compression (Pearl et al. 1980). Spinal forms can be asymptomatic and incidentally discovered, but a common presenting symptom is a local and irradiated pain. Histologically, several forms are described, including Kaposi form, epithelioid, spindle cell, and composite form (Bhatt et al. 2019). In immunohistochemical studies, tumor cells stained strongly and diffusely positive for CD31 but not for CD34. Due to their rarity, the best treatment for these lesions, including the role of adjuvant therapies, is not yet characterized. The primary treatment is local removal, usually not followed by chemoradiotherapy. Despite the generally good prognosis, a small percentage of the most aggressive subtype may metastasize distally (Díaz et al. 2004). In some cases, RT alone has been described as a choice treatment (Scott et al. 2014).

14.8.3 Solitary Fibrous Tumor 14.8.2 Hemangioendothelioma Epithelioid hemangioendothelioma is an intermediate entity between hemangioma and aggressive, sarcomatous forms as the angiosarcoma. This vascular originating tumor is generally considered to carry a low malignancy potential. Nonetheless, it can determine local recurrence, and rarely, a metastatic spread is described (Díaz et al. 2004). Hemangioendotheliomas have only rarely been encountered in the CNS, originating from the brain (Wen et al. 1991) and spinal cord (Abdullah et al. 2002; Munson et al. 2013). However, when arising from surrounding bone structures, mainly the spine, they also can determine neurologic signs

The 2016 revision of WHO classification (Louis et al. 2016) has overcame the long-lasting differentiation between hemangiopericytoma and solitary fibrous tumors. The recognition that both entities share the fusion between the NAB2 and STAT6 genes, which leads to STAT6 nuclear expression detectable by immunohistochemistry (Chmielecki et al. 2013; Schweizer et al. 2013), led to the understanding that solitary fibrous tumors and hemangiopericytomas are overlapping entities. For this reason, the 2016 WHO classification proposed the combined term solitary fibrous tumor/hemangiopericytoma (SFT/HPC) to describe this entity. The same revision of CNS tumor classification assigned three grades to SFT/HPC: a grade I, in case of highly collagenous,

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relatively low cellularity, spindle cell lesion (representing the previous SFT); a grade II in case of more cellular and less collagenous tumor, corresponding to the previous HPC, and a grade III in case of malignancy, corresponding to the anaplastic HPC. The 2021 WHO classification has finally retired the term “hemangiopericytoma”, and the tumor is now called Solitary Fibrous Tumor (SFT) only (Louis et al. 2021). SFT is exceptionally rare, accounting for less than 1% of all CNS tumors (Lavacchi et al. 2020). They can be misdiagnosed as meningiomas at neuroradiological imaging, whereas advanced MRI techniques can help in differentiating the two entities (Chen et al. 2020). Surgery, with the aim of a gross total resection, is the main treatment. SFT has a high rate of local recurrence, and the occurrence of intracranial metastases has been reported (Lavacchi et al. 2020). Extracranial metastases are also described, up to 28% of cases, mainly involving bone, lung, and liver (Ratneswaren et al. 2018). Anaplastic SFT presents a very poor prognosis (Mosquera and Fletcher 2009; Tan et al. 2019). Spine and spinal cord locations are even less frequent than cranial involvement. Spinal SFTs are often intradural extramedullary tumors (Singla et al. 2020), but intramedullary SFTs can be rarely described (Yang et al. 2019). In a multicentric series of 90 patients harboring 133 SFTs, stereotactic radiosurgery determined a reasonable rate of local tumor control, with neurological stability or improvement in the majority of patients (Cohen-Inbar et al. 2017). A chemotherapy regimen based on cyclophosphamide, doxorubicin, and vincristine has been used in advanced or relapsing cases (Chamberlain and Glantz 2008), although SFT usually shows a modest response. Another chemotherapy combination, with some benefit, was based on Temozolomide and Bevacizumab (Park et al. 2011). More promising results have been obtained with Sunitinib, the tyrosine kinase inhibitor active against PDGF and VEGF receptors (Stacchiotti et al. 2012). In all cases of SFTs, despite the treatment, a close flow-up is necessary due to the high probability of local recurrence and distant metastases.

I. G. Vetrano et al.

14.8.4 Angiosarcoma Primary cerebral angiosarcomas are extremely rare malignant tumors (Gao et al. 2019; Zakaria et al. 2015) arising from vascular endothelial cells. Sometimes, the brain may constitute a secondary location from other organs, mainly from cardiac angiosarcoma (Drosos et al. 2020; Lin et al. 2017). The epidemiology, characteristics, and clinical course of this aggressive tumor are not well understood, whereas the prognosis is usually poor due to its local aggressiveness and metastatic spreading (Zakaria et al. 2015). Exceptionally, they can also present during childhood and can also involve the surrounding soft tissues and the skull (Lee et al. 2020b). Rarely, the diagnosis is concomitant with the onset of tumoral hemorrhage (Lee et al. 2020a). Angiosarcoma typically expresses endothelial markers CD31, CD34, factor VIII-related antigen, and VEGF. More recently, the IGF2BP3, an oncofetal protein highly expressed in fetal tissue and gonads but rarely in other adult benign tissues, has been used to distinguish at immunohistochemistry malignant and intermediate forms (angiosarcoma and hemangioendothelioma) from benign vascular tumors as hemangioma (Okabayshi et al. 2020). The treatment usually comprises a multidisciplinary approach involving surgery to extensive resection, radiation therapy, and chemotherapy. VEGF-receptor inhibitors have been proposed to treat angiosarcomas, but the results are still to be confirmed (Liu et al. 2019).

14.9

Conclusion

The diagnosis of CNS HBs not automatically determines the need for neurosurgical or other treatments: a precise balance is necessary between the possible neurological postoperative deficits and the possible static or slow-growing pattern of these tumors. Whereas this is particularly true for sporadic forms, VHL-related tumors need a strict follow-up during their lifetime. A multidisciplinary perspective is necessary to establish optimal timing and better options for

14

Hemangioblastomas and Other Vascular Originating …

397

Suggestive for VHL disease?

Neuroradiological Diagnosis

Spinal

Intracranial

VHL mutations Retinal HBs, RCC, PHC, familial screening, genetic counseling Symptoms or signs? YES

Preoperative embolization?

Surgery (maximal safe resection)

Radiosurgery in small or recurrent HBs (mainly VHL)

NO

Follow-up

VHL

abdominal imaging, ophthalmological evaluations, catecholamines dosage, etc.

Cyst’s formation and growth, edema, new signs and symptoms

Fig. 14.7 Suggested flow chart for brain and spinal cord HBs’ management. Considering their rarity, the management of the other vascular originating tumors as hemangiomas, hemangioendotheliomas, angiosarcomas, or

solitary fibrous tumor/hemangiopericytoma needs specific consideration for each single patient. HBs: hemangioblastomas; PHC: pheochromocytoma; RCC: clear cell renal cell carcinoma; VHL: von Hipple-Lindau disease

each patient. The proposed flowchart (Fig. 14.7) may represent a valid support for managing sporadic and VHL-related HBs of the brain and spinal cord.

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Brain and Spinal Cord Tumors of Embryonic Origin

15

Marios Lampros and George A. Alexiou

Abstract

Embryonal tumors (ETs) of the central nervous system (CNS) comprise a large heterogeneous group of highly malignant tumors that predominantly affect children and adolescents. Currently, the neoplasms classified as ET are the medulloblastoma (MB), embryonal tumors with multilayered rosettes (ETMR), medulloepithelioma (ME), CNS neuroblastoma (NB), CNS ganglioneuroblastoma (GNB), atypical teratoid/rhabdoid tumors (AT/RT), and CNS embryonal tumors with rhabdoid features. All these tumors are classified as malignant-grade IV neoplasms, and the prognosis of patients with these neoplasms is very poor. Currently, except for the histological classification of MB, the recently utilized WHO classification accepts a novel molecular classification of MBs into four distinct molecular subgroups: wingless/ integrated (WNT)-activated, sonic hedgehog (Shh), and the numerical Group3 and Group 4. The combination of both histological and genetic classifications has substantial prog-

M. Lampros Department of Neurosurgery, University Hospital of Ioannina, Ioannina, Greece G. A. Alexiou (&) Department of Neurosurgery, School of Medicine, University of Ioannina, 45500 Ioannina, Greece e-mail: [email protected]

nostic significance, and patients are categorized as low risk with over 90% survival, the standard risk with 75–90% survival, high risk with 50–75% survival, and very high risk with survival rate lower than 50%. Children under three years are predominantly affected by AT/RT and represent about 20% of all CNS tumors in this age group. AT/RT is typically located in the posterior fossa (mainly in cerebellopontine angle) in 50–60% of the cases. The pathogenesis of this neoplasm is strongly associated with loss of function of the SMARCB1 (INI1, hSNF5) gene located at the 22q11.23 chromosome, or very rarely with alterations in (SMARCA4) BRG1 gene. The cells of this neoplasm resemble those of other neuronal tumors, and hence, immunochemistry markers have been utilized, such as smooth muscle actin, epithelial membrane antigen, vimentin, and lately antibodies for INI1. ETMRs are characterized by the presence of ependymoblastic rosettes formed by undifferentiated neuroepithelial cells and neuropil. The tumorigenesis of ETMRs is strongly related to the amplification of the pluripotency factor Chr19q13.41 miRNA cluster (C19MC) present in around 90% of the cases. Additionally, the expression of LIN28A is a highly sensitive and specific marker of ETMR diagnosis, as it is overexpressed in almost all cases of ETMR and is related to poor patient outcomes. The treatment of patients with ETs includes a

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_15

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combination of surgical resection, radiotherapy (focal or craniospinal), and chemotherapeutic agents. Currently, there is a trend to reduce the dose of craniospinal irradiation in the treatment of low-risk MBs. Novel targeted therapies are expected in the treatment of patients with MBs due to the identification of the main driver genes. Survival rates vary between ET types and their subtypes, with ganglioneuroblastoma having over 95% 5-year survival rate, while ATRT is probably linked with the worst prognosis with a 30% 5-year survival rate. Keywords

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.

Embryonal tumors Medulloblastoma Atypical teratoid rhabdoid tumors Embryonal tumors with multilayered rosettes Molecular classification

15.1

.

.

Background and Epidemiology

Embryonal tumors (ET) of central nervous system (CNS) comprise a large heterogeneous group of highly malignant tumors that predominantly affect children and adolescents. They possess a neuroectodermal origin from poorly differentiated (embryonal) cells that have little to no phenotypic markers of nerve cells compared to the mature fully differentiated cells of CNS. Histologically, they have the appearance of small blue round cells with abundant cellularity and high mitotic activity (Kumar et al. 2015). ET represents the most frequent tumor category that affects children under 3 years of age and the second most common in the pediatric age group, comprising approximately 12% of all CNS tumors (Alexiou et al. 2011; Stefanaki et al. 2012). The median age of patients with ET is 7– 8 years with the majority being under 10 years upon diagnosis (Stefanaki et al. 2012). Several genetic syndromes such as Li-Fraumeni, Gorlin, and Turcot syndromes have been associated with increased risk of ET development (Stefanaki et al. 2012). Medulloblastoma is the most common neoplasm of this group and additionally the

most common CNS malignancy in childhood (20%) (Juraschka and Taylor 2019). The classification of ET has been subjected to continuous alterations in past years due to the novelties of the molecular and genetic mechanisms involved in the pathogenesis of these neoplasms. The 2016-WHO (World Health Organization) Classification of CNS tumors has gone beyond the classical histological classification of ET to additionally encompass their molecular features. This generated multiple ET subtypes and especially in the classification of medulloblastoma. Currently, the neoplasms classified as ET include the medulloblastoma (MB), embryonal tumors with multilayered rosettes (ETMR), medulloepithelioma (ME), CNS neuroblastoma (NB), CNS ganglioneuroblastoma (GNB), atypical teratoid/ rhabdoid tumors (AT/RT), and CNS embryonal tumors with rhabdoid features. All these tumors are classified as malignant-grade IV neoplasms. The subtypes of these tumors will each be discussed separately (Kram et al. 2018; Louis et al. 2016). The term “primitive neuroectodermal tumors” (PNET) is no longer utilized to describe non-MB ET (Louis et al. 2016). The clinical manifestations are related to neurological deficits due to tumor invasion or to symptoms of raised intracranial pressure (ICP), especially in children with MB. The treatment of these ET is a combination of surgical resection, radiotherapy (focal or craniospinal), and chemotherapeutic agents (Alexiou et al. 2011). Survival rates vary between ET types and their subtypes, with AT/RT linked with the worst prognosis with a 30% 5-year survival rate (Table 15.1) (Tulla et al. 2015).

15.2

Genetics, Immunology, and Molecular Biology

15.2.1 Medulloblastoma The MB is a tumor with highly variable clinical behavior and prognostic features, even among tumors with similar histological features. The latter indicates the involvement of distinct signaling pathways in the tumorigenesis of

Percentage of ET (%)

70

20

7–9

Case reports

Case reports

Tumor type

MB

AT/RT

ETMR

ME

CNS NB and GNB

Cerebral lobes

Periventricular areas Infants and children

Children under 10 years

Children under 4 years

Children under 3 years

Posterior Fossa

Supratentorial structures (70%)

Children (mean: 7 years)

Age group affected

Cerebellum

Location in CNS

Seizures, deficits

Hydrocephalus, seizures, deficits

Nonspecific, solid, and cystic components

Signal heterogeneity, enhancement in the progress of the disease

Solid tumor, signal heterogeneity, intratumoral cysts, and hemorrhages

GTR + Chemotherapy

GTR+ Adjuvant Radiotherapy

GTR + Adjuvant Chemo/Radiotherapy

Favorable, less favorable in GNB

Very poor, 30% 5–year survival

Mean survival 2–3 years after diagnosis

Very poor, 30% 5-year survival

GTR+ Adjuvant Chemo/Radiotherapy

Nonspecific, heterogeneous signal, generally low in T2, hemorrhagic areas (high T1signal)

Hydrocephalus, ataxia, cranial nerve palsy Hydrocephalus, seizures, ataxia

80–90% 5-year survival in standard risk

Prognosis

GTR + Adjuvant Chemo/Radiotherapy

Treatment

Midline lesion, clear borders. Iso- to highintense T2 signal. Presentation of enhancement, the pattern varies

Imaging features

Hydrocephalus, ataxia

Clinical features

Table 15.1 Comparative characteristics of CNS embryonic tumors

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ependymomas. Indeed, the involvement of these pathways was confirmed by the results of several molecular studies that identified the main molecular pathways associated with the pathogenesis of MBs. Additionally, the prognosis of patients with MB was found to be strongly associated with the activation of each specific signaling pathway. The genetic landscape of these neoplasms was mainly enlightened by the novel study of Northcott et al., who molecularly classified these neoplasms. The recently utilized WHO classification accepts a novel molecular classification of MBs into four distinct molecular subgroups: wingless/integrated (WNT)-activated, sonic hedgehog (SHH), Group 3, and Group 4. This classification is discussed in detail in Sect. 15.3.1.1. The WNT-activated MB is related with a favorable prognosis and is characterized by somatic mutation in the exon 3 of CTNNB1 gene in around 90% of patients in this subgroup. These mutations lead to the stabilization of beta-catenin and its intracellular accumulation. When the cytoplasmic concentration of beta-catenin becomes significantly increased, it is translocated into the nucleus and activates the family of TCF/LEF1 transcription factors, leading to the activation of target genes involved in cellular growth and proliferation. Chromosome 6 monosomy is a frequent cytogenic alteration in the WNT-activated and is strongly related to the CTNNB1 gene mutations. Mutations in the APC gene are usually found in patients with nonmutated CTNNB1 genes. The APC gene is a tumor suppressor gene that is involved in the ubiquitylation of beta-catenin. Hence, in patients with this mutation, the beta-catenin is accumulated and activates the WNT target genes. Patients who have germline mutations in the APC (e.g., patients with FAP syndrome) are found at an increased risk for the occurrence of WNT-activated MB. Other mutations less frequently related to WNT-MB include mutations in the DDX3X, SMARCA4, and TP53 genes (Northcott et al. 2017). The SHH group accounts for around 30% of all MB cases. This subgroup is related to hyperactivation in the SHH signaling pathway due

M. Lampros and G. A. Alexiou

to germline or somatic mutations or amplifications in its components. The most frequently found genetic alterations in the SHH-MB pathway as found by Kool et al. include LOF or deletions in the PTCH1 (most common) or SUFU gene, activations in SMO, and GLI-1, GLI-2 amplifications (Kool et al. 2014). Recently, Begemann et al. found that germline mutations in the GPR161 are found in 6% of children in the SHH group. The SHH group has a highly variable biological behavior indicating the existence of different tumorigenic mechanisms among the patients of the same molecular subgroup (Begemann et al. 2020). Another study classified the patients with SHH into different molecular subgroups: SHHa, SHHb, SHHc, and SHHd. SHHa usually concerns children and is related to TP53 mutations and amplifications in MYCN, GLI2, and YAP1. Cytogenetic alterations found in this subgroup include losses in 9q (PTCH1 gene located), 10q (SUFU gene located), and in 17p. The SSHb and SHHc occur in infants, with SSHb subgroup being highly metastatic (30% of cases) and is related to more favorable outcome, while the SHHc is related with a balanced genome and more favorable outcome (Northcott et al. 2017). This group is characterized by metastases only in 9% of the cases. Finally, the SHHd accounts for the vast majority of adult SHH-MB and is also related to a favorable outcome and strongly related to mutations in TERT promoters. Finally, patients who fall in this subgroup usually have germline mutations in the TP53 gene (e.g., Li-Fraumeni syndrome) and genetic counseling is recommended. Group 3 and Group 4 MBs are numerically designed groups characterized by the lack of a distinct molecular pathway responsible for their pathogenesis. Metastases are usually found in around 40% of patients, and they are related with a less favorable outcome compared to the WNT and SHH groups. MYC amplification occurs in around 17% of patients with Group3MB, while it is very rare in the other MB groups. The presence of MYC amplification is related with a poor patient outcome. Genes that are frequently found mutated in these patients include SMARCA4, KBTBD4, KMT2D, GLI1,

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OTX2, and enhancer hijacking mediated upregulation of the transcriptional repressors GFI1, GFI1B. Frequent cytogenetic alterations include isochromosome 17q, gain 18, and loss of 8 and 10q. The tumorigenesis of grade 4-MBs is mainly unknown, with several genes being involved. However, none of these genes were found to be mutated in a significant percentage of the patients with Group 4 MBs. Similar to Grade 4 MBs, the enhancer jacking activations appear to be an important mechanism related to the pathogenesis of these neoplasms. Specifically, enhancer-mediated overexpression of PRDM6 gene was observed in around 17% of patients in this group. The latter is probably correlated with focal-tandem duplication in the SNCAIP gene. An association of the hijacking enhancement of GFI1 and GFI1b has been observed in up to 10% of patients in this group. Other genetic alterations in this group include mutations in the KDM6A, ZMYM3, KBTBD4 genes, amplification in MYCN, OTX2, isochromosome 17, and gain of 18q, and loss of X,8p,11p (Begemann et al. 2020; Kool et al. 2014; Northcott et al. 2017).

15.2.2 Atypical Teratoid/Rhabdoid Tumors and CNS Embryonal Tumors with Rhabdoid Features The pathogenesis of this neoplasm is strongly associated with loss of function of the SMARCB1 (INI1, hSNF5) gene located on 22q11.23 chromosome, or very rarely with alterations in BRG1 (SMARCA4) gene. The presence of a CNS neoplasm with features of AT/RT but without the presence of mutations in the INI1 or BRG1 genes set the diagnosis for CNS embryonal tumors with rhabdoid features. These genes encode components of the SWItch/sucrose non-fermentable (SWI/SNF) tumor suppressor complex that is involved in the ATP-dependent chromatin remodeling. Torchia et al. studied the molecular subgroups of these neoplasms and classified them into two numerical subgroups: Group 1 and Group 2. Group 1 concerns supratentorial AT/RT, while Group 2 concerns infratentorial.

409

The expression of achaete-scute homolog 1 (ASCL1), a Notch regulator involved in neural differentiation, is associated with a more favorable prognosis and is more frequently expressed in Group 1. In contrast, Group 2 was characterized by significant gene enrichment in genes involved in mesenchymal stem cell differentiation, mainly in bone morphogenetic protein (BMP) pathway components, and in genes involved in cell adhesion and migration (Torchia et al. 2015). In another study, Johann et al. by performing whole-genome DNA and RNA sequencing, classified AT/RT into three distinct subgroups: (1) ATRT-TYR (infratentorial tumors, SMARCB1 deletions, melanosomal genes), (2) ATRT-SHH (SMARCB1 aberrations, SHH pathway), (3) ATRT-MYC (supratentorial, focal SMARCB1 deletions, MYC expression) (Johann et al. 2016). Recently, Holdhof et al. found that ATRT-SMARCA4 composes a molecular subgroup with different features from those observed in the previously mentioned categories and recommend creating a distinct Group 4 to include these neoplasms (Holdhof et al. 2021). Regarding the methylation status, Group1 and Group2 are hypermethylated, while Group 3 and Group 4 are hypomethylated (Holdhof et al. 2021; Johann et al. 2016).

15.2.3 Embryonal Tumors with Multilayered Rosettes The tumorigenesis of ETMRs is strongly related with amplification of the pluripotency factor Chr19q13.41 miRNA cluster (C19MC) being present in around 90% of the cases and with overexpression of LIN28A, which is an RNA binding protein that enhances IGF-2 translation. The overexpression of C19MC in patients with ETMR-C19MC altered is probably related to the translocation and fusion with Tweety Family Member 1 (TTYH1) that is involved in the differentiation of neural stem cells. Some authors suggest that the C19MC is involved in cell proliferation and migration. However, our knowledge of the exact normal function of this gene

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remains in its infancy, mainly because this gene is only expressed in early neural stem cells and placenta. The expression of LIN28A is a highly sensitive and specific marker of ETMR diagnosis, as it is overexpressed in almost all cases of ETMR and is related to poor patient outcomes (Korshunov et al. 2012; Lambo et al. 2020). Finally, biallelic mutations in the DICER gene are frequently found in patients with ETMRnegative for the C19MC amplification. Lately, the potential role of alternative splicing in the biology of ETMR neoplasms has been noted, with the potential involvement of pathways such as mTOR and MAPK (Hesham and El-Naggar 2020).

15.2.4 Other Embryonal Tumors The genetic landscape of the other ETs remains unclear mainly due to the rarity of these neoplasms. Korshunov et al. found that the expression of SOX10 (a transcription factor involved in CNS development) and ANKRD55 (encodes Ankyrin repeat domain 55) is highly specific for CNS-NB with Foxr2 activation and can help in the differential diagnosis from other PNET-like neoplasms (Korshunov et al. 2021). Ito et al. described a patient with CNSganglioneuroblastoma who harbored the MYO5A-NTRK3 fusion usually found in melanocytic tumors (Ito et al. 2020).

15.3

Histopathology and Morphology

15.3.1 Medulloblastoma MB is the most common CNS malignancy (Grade IV/WHO) in childhood, accounting for 20% of all CNS neoplasms and 70% of all embryonal CNS tumors, and is by definition exclusively located in the cerebellum (Juraschka and Taylor 2019). The average age of children with MB is approximately 7 years at the time of diagnosis, with the majority of patients being

between 3 and 8 years of age (Farwell et al. 1984). There exists a male predilection with the male-to-female ratio being 1.5. Nevertheless, the average age of patients affected by MB and the gender predilection varies between the subtypes of MB (Kram et al. 2018; Stefanaki et al. 2012). The 2016-WHO classification of CNS neoplasms suggests two different classifications of MB subtypes, the histological and the genetic. The histological classification includes MB-classic, MB-desmoplastic/nodular, MB with extensive nodularity, and MB-large-cell/anaplastic. The genetic classification includes MB-WNT (wingless)-activated, MB-SHH (sonic hedgehog)-activated with the subtypes of TP53 mutant and TP53 wild-type, MB-Group3, and MB-group4. The combination of both histological and genetic classifications has substantial prognostic significance, and patients are categorized as low risk with over 90% survival, standard risk with 75– 90% survival, high risk with 50–75% survival, and very high risk with survival rate lower than 50% (Kram et al. 2018; Louis et al. 2016).

15.3.1.1 Histologic Classification of Medulloblastoma In terms of histology, the MB-classic is the most frequent subtype (70%) with sheets of cells of pleomorphic appearance that fall into the category of small blue cells. Homer-Wright rosettes may be present in this subtype. All genetic subtypes may occur as MB-Classic. The desmoplastic/nodular variant is characterized by nodules of differentiated neurocytic cells (pale zones) surrounded by areas with undifferentiated cells rich in reticulin between the nodules. The extensive nodularity type has similar features with the desmoplastic variant, but the nodules are abundant with only a few internodular space. The MB-SHH-activated (TP53-wildtype) is related to the manifestation of nodular and extensive nodular subtypes. Anaplastic/large cells account for 20% of MB subtypes and as expected anaplastic features are present with abundant mitosis and apoptotic bodies. Survival is poor in children with anaplastic MB. MB-Group 3 and MB-SHH (TP53 mutant and wildtype)-activated

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Brain and Spinal Cord Tumors of Embryonic Origin

may occur with the anaplastic variant (Borowska and Jóźwiak 2016; Eberhart and Burger 2003; Kram et al. 2018; Louis et al. 2016).

15.3.1.2 Genetic Classification of Medulloblastoma In genetic classification, the WNT subgroup comprises 10% of MB and is related to excellent survival rates (over 95%) with little to none metastatic potential. Children over the age of 4 and adolescents are chiefly affected, while there is no sex predilection. They are usually located in the cerebellar or cerebellopontine angle. MBs that occur in Turcot syndrome are related to this subtype. MB-SHH-activated (30% of MB) usually occurs in the cerebellar hemispheres and affects infants and adults. The mutant TP53 type in MB-SHH-activated is related to metastatic lesions, and patients of this category are classified as high risk. MB-Group 3 (20–30% of MB) and Group 4 (30–40% of MB) are not related to any specific pathogenetic pathway, despite the 17q-isochromosome is observed in approximately half of the patients in Group 3. Group 3 affects children and infants and is linked to less favorable prognosis of under 60% in 5-year survival. Group 4 accounts for 40% of MB and thus is the most frequent subtype, affecting predominantly children and adolescents. The prognosis varies in Group 4, with metastatic lesions occurring in 40% of the patients. MBs of Group

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3 and Group 4 are located in the midline (Juraschka and Taylor 2019; Kram et al. 2018; Louis et al. 2016) (Table 15.2).

15.3.2 Atypical Teratoid/Rhabdoid Tumors and CNS Embryonal Tumors with Rhabdoid Features AT/RT is a highly malignant (Grade IV/WHO) neoplasm of CNS comprising 20% of all embryonal CNS tumors. Children under 3 years are predominantly affected by AT/RT and represent about 20% of all CNS tumors in this age group. AT/RT is typically located in the posterior fossa (mainly in cerebellopontine angle) in 50– 60% of the cases, or in supratentorial structures in approximately 20–30% of the cases. The spinal and pineal locations are rare with only a few cases having been reported in the literature. In terms of histology, many cell populations are observed in rhabdoid tumors as rhabdoid cells, epithelial cells, cells of mesenchymal origin, and a population of small blue round cells. The cells of this neoplasm resemble those of other neuronal tumors, and so differential diagnosis based solely upon histological findings may be impossible. Immunochemistry markers have been utilized for this reason as smooth muscle actin, epithelial membrane antigen, vimentin, and lately

Table 15.2 Characteristics of medulloblastoma subtypes Genetic subtype of MB

Frequency percentage of subtype (%)

Age group affected

Associated histological subtypes

Associated genetic syndrome/ Mutations

Prognosis

MBWNT

15

5–18 years

Classic

Turcot’s Syndrome

Low-risk

MB-SHH

25

Under 3 and over 16 years

Classic, Anaplastic, Desmoplastic, Extensive nodularity

Gorlin, LiFraumeni Syndrome

Favorable (except anaplastic variant)

MBGroup 3

20–30

Infants and children

Classic, Desmoplastic, Anaplastic

17qisochromosome

Standard to (Very) High risk/ Poor prognosis

MBGroup 4

30–40

5–18 years

Classic

CDK6 and MYCN amplification

Standard risk

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antibodies for INI1. Nevertheless, the only definite way to set the diagnosis of AT/RT is by locating the alterations in INI1 gene (Alexiou et al. 2011; Ginn and Gajjar 2012; Kram et al. 2018; Louis et al. 2016; Moeller et al. 2007; Oka and Scheithauer 1999; Reddy 2005; Stefanaki et al. 2012; Strother 2005).

15.3.3 Embryonal Tumors with Multilayered Rosettes (ETMR) ETMR encompasses a group of neoplasms from small blue round cells, which were classified as separate entities in previous WHO classifications. The term embryonal tumors with abundant neuropil and true rosettes (ETANTR) and ETMR were considered synonyms in previous revisions. However, in recent years, the observation that other embryonal tumors such as ependymoblastomas and ME may share some histological features with ETMR, along with the discovery that almost all of these tumors, including ETANTR, display the C19MC amplification on chromosome 19q13.42, led to merging of all those entities into the single denomination of “ETMR, C19MC altered.” Nevertheless, some ETMR do not display the previous amplification and are recognized as “ETMR, NOS” (non-other specified), or if they display features characteristic of ME may instead be recognized as ME. However, the term ME includes all ME, with or without C19MC amplification (Louis et al. 2016). Under light microscopy, ETMRs are characterized by ependymoblastic rosettes, with cellular and acellular areas formed by undifferentiated primitive neuroepithelial cells and neuropil areas of necrosis or calcification, and the presence of cells with ganglionic or neurocytic differentiation. Immunochemistry is usually positive for vimentin, cytokeratin, EMA, and CD99. The expression of these markers varies between the tumors areas, and the expression of vimentin is more prominent in the neuroepithelium, while the cytokeratin, EMA, and CD99 are expressed in small-cell areas (Ceccom et al. 2014; Pei et al.

M. Lampros and G. A. Alexiou

2019b). However, as noted in Sect. 15.2.3, the reactivity for LIN28A is the most specific marker for diagnosing these neoplasms. ETMR is an exceedingly rare malignant (Grade IV/WHO) neoplasm of CNS that typically affects children under 4 years, with no sex predilection. The majority are localized in supratentorial (70%) or infratentorial (30%) structures. It is noted that approximately half of the infratentorial ETMR falls in the category of ETMR, NOS. The spinal location is very uncommon, but a few cases have been reported.

15.3.4 Medulloepithelioma CNS ME is a rare malignant (Grade IV/WHO) embryonal tumor that arises from cells of the embryonal medullary cavity. Children under 8– 10 years are chiefly affected by ME. As mentioned above, CNS-ME with amplification of C19MC may also be classified as “ETMR, C19MC altered.” CNS ME is located in intracranial structures with a predilection for periventricular areas. Typical histological features found in ME are trabecular and tubular formations that resemble those of the neural tube. Non-ciliary pseudostratified epithelial cells located around a lumen are typically observed in the tubular formations (Bansil et al. 2016; Molloy et al. 1996; Müller et al. 2011).

15.3.5 CNS-Neuroblastoma (NB) and CNSGanglioneuroblastoma (GNB) CNS NB is one of the rarest CNS neoplasms, and our knowledge of them is limited to a few literature reports. The 2016-WHO classification of CNS tumors recognizes CNS-NB and CNS-GNB as distinct entities from the rest of embryonal tumors and they belong to the group of FOXR2activated neoplasms. CNS-NB is an embryonal tumor with partial neuroepithelial differentiation and originates from cells that are found in the second stage of neurocytogenesis. It is

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considered a malignant (Grade IV/WHO) neoplasm, but its mortality is approximately 10– 15%, significantly lower compared to most of the other embryonal neoplasms. Children and young adults are mainly affected. The neoplasm is located in intracranial structures such as the frontal, parietal, and occipital lobes (Berger et al. 1983; Bianchi et al. 2018; Steenberge and Prayson 2014; Yariş et al. 2004). CNS-GNB is a neoplasm with a histological resemblance to CNS-NB but with a population of differentiated ganglionic cells in addition to the population of poorly differentiated neuroepithelial cells typical of CNS-NB. The exact cell of origin of this neoplasm is still under research and very little is known about the genetic characteristics of this neoplasm. Nevertheless, the MYO5A-NTRK3 fusion was recently detected within the cells of this tumor. Up to date, fewer than 20 cases of CNS-GNB have been described worldwide. Generally, the tumor affects infants and children with a possible potential for rapid growth within a few hours or days. Similar to the CNS-NB, CNS-GNB is mainly located in intracranial structures, but the prognosis seems to be less favorable than CNS-GNB. Despite that, a survival benefit is observed with tumor resection and adjuvant radio/chemotherapy (Ito et al. 2020; Mirza et al. 2018; Steenberge and Prayson 2014).

Significant and inhomogeneous enhancement is observed in the anaplastic variant, while the presence of multiple markedly enhanced nodules is suggestive of the MB-extensive nodularity variant. Intratumoral cysts are another common imaging feature of MB and represent areas of necrosis or cystic degeneration, but in the majority of cases concern adult MB. The spread of the tumor follows the flow of CSF from the cerebellum to the spinal cord, but the involvement of supratentorial structures is not uncommon. Consequently, MRI imaging of the whole neuraxis should be performed to highlight the presence of leptomeningeal spread in the brain and spinal cord. Hydrocephalus with dilation of the ventricles should be expected in most patients due to the obstruction of CSF flow from the neoplasm (Baroni et al. 2020; Massimino et al. 2016; Robinson et al. 2018). Computed tomography (CT) is rarely used for the diagnosis of MB in the era of MRI. The only possible role of CT is in the event of an emergency neurological complication of MB. In CT, the MB typically appears as a midline cerebellum lesion, which occupies the fourth ventricle, with clear margins, hyperdense to the normal cerebellar parenchyma, with homogenous enhancement (Koeller and Rushing 2003; Massimino et al. 2016).

15.4

15.4.1 Medulloblastoma

15.4.2 Atypical Teratoid/Rhabdoid Tumors and CNS Embryonal Tumors with Rhabdoid Features

Magnetic resonance imaging (MRI) features of MB include a midline cerebellar lesion in approximately 80% of cases, with clear borders and typically with a hypointense signal in T1weighted images and isointense to hyperintense in T2-weighted images. The hyperintense T2 signal is suggestive of the anaplastic variant. All MB variants display Gd (Gadolinium)enhancement with different patterns of enhancement related to tumor type (Fig. 15.1).

Imaging features of AT/RT are considered nonspecific with a generally heterogeneous signal, T2 signal is low to isointense, and T1 signal is high in areas with hemorrhages that are very frequently observed in this neoplasm. The signal heterogeneity is attributed mainly due to the presence of many areas of necrosis, hemorrhages, or calcifications. After contrast administration, these neoplasms are heterogeneously enhanced. The tumor usually possesses an infratentorial

Imaging and Radiologic Features

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Fig. 15.1 a Sagittal T1-weighted and a gadolinium-enhanced T1-weighted (b) MRI

intra-axial location, but a multifocal position is not unexpected. When the tumor has an extraaxial location, it is usually located in the cerebellopontine angle. In MR spectroscopy, the tumor may have increased choline and decreased N-acetyl aspartate (NAA) levels. In CT, the tumor has a heterogeneous signal intensity and enhancement pattern. Calcifications are observed in around half of the cases. Because this tumor mainly occurs in children, a CT is usually performed in cases of tumor complications. Hence, the presence of hydrocephalus and ventricular dilation due to fourth ventricle obstruction or leptomeningeal dissemination is not uncommon when a CT scan is performed (Arslanoglu et al. 2004; Oka and Scheithauer 1999; Reddy 2005; Rorke et al. 1996; Strother 2005).

15.4.3 Embryonal Tumors with Multilayered Rosettes (ETMR) ETMR are solid neoplasms that usually possess an extra-axial location and can have either a supratentorial or infratentorial location. Regarding their imaging features, they usually appear as

large, well-circumscribed masses with little to no mass effect. In MRI, the tumor usually has a homogenous signal that is hypointense in T1, hyperintense in T2, while in CT the tumor signal density varies and calcifications can be found in up to 50–70% of the cases. After contrast administrations, they display little to no enhancement. The lack of degenerative features such as necrosis and hemorrhages as well as the absence of enhancement can help in the differential diagnosis from other malignant neoplasms of the CNS that occurs in the pediatric age group (e.g., MB, ATRT) (Dangouloff-Ros et al. 2019).

15.4.4 Medulloepithelioma In CT, MEs usually appear as well-defined lesions, hypodense to the normal parenchyma, while in MRI they typically have low signal in T1-sequences and high signal in T2 sequences. The enhancement pattern of the lesion is generally unpredictable, with some MEs having no enhancement, while others appear enhanced later during the progress of the disease (Bansil et al. 2016; Molloy et al. 1996; Müller et al. 2011).

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15.4.5 CNS-Neuroblastoma (NB) and CNSGanglioneuroblastoma (GNB) Due to their rarity, no specific imaging features have been described for these neoplasms. Yariş et al. described a case of a child with CNS-NB located in the frontotemporal region that presented as a large tumoral mass in the CT (Yariş et al. 2004). A similar case of a supratentorial CNS-GNB was described by Ito et al. (Ito et al. 2020). Pedram et al. described a case of a child with a CNS-NB located in the fourth ventricle. The tumor had radiological features resembling MB, and the patient presented with symptoms of increased intracranial pressure due to obstruction in the CSF flow (Pedram et al. 2013).

15.5

Clinical Manifestation

15.5.1 Medulloblastoma Initial clinical manifestations of patients with MB mainly include symptoms of raised ICP due to the obstruction of cerebrospinal fluid (CSF) flow on the level of the fourth ventricle, such as headache, nausea, vomiting, and papilledema. The prodrome period of symptoms is approximately 2 weeks to 3 months. Symptoms from the cerebellum may occur as limb and truncal ataxia or nystagmus. Acute neurological symptomatology could be the result of a spontaneous intratumoral hemorrhage. Cauda equina syndrome may occur due to drop metastasis but is rarely observed as an initial symptom (Hoffman and Park 1983).

15.5.2 Atypical Teratoid/Rhabdoid Tumors and CNS Embryonal Tumors with Rhabdoid Features Clinical manifestations are related to the tumor location, and usually, the prodrome period is short due to the aggressive nature of this neoplasm. Symptoms of raised ICP (nausea, vomiting,

415

lethargy, and headaches) are observed in patients with AT/RT in the posterior fossa. Despite that, hydrocephalus may be present in AT/RT of the spinal cord from tumor leptomeningeal infiltration. Symptoms from cerebellar dysfunction such as ataxia or nystagmus are observed, while cranial nerve palsy from tumor pressure or infiltration may also be observed when the tumor is located in the cerebellopontine angle. The cauda-equina syndrome is the main presentation in AT/RT with spinal location. Metastatic lesions may be present in approximately 20–60% of patients at the time of diagnosis.

15.5.3 Embryonal Tumors with Multilayered Rosettes (ETMR) Clinical features of ETMR are related to the tumor site, and as with other embryonal tumors include symptoms of raised ICP due to obstruction of CSF flow, ataxia, seizures, and hemiplegia. The patients typically manifest a rapidly deteriorating clinical picture within a few weeks due to the aggressive development of the neoplasm. Imaging features are similar to other embryonal tumors, with the neoplasm being predominantly solid with signal heterogeneity but intratumoral cystic and hemorrhagic areas may be observed (Bouali et al. 2018; Lambo et al. 2020; Pei et al. 2019a).

15.5.4 Medulloepithelioma Clinical manifestations of ME are linked to the tumor location and include focal neurological deficits, seizures, or symptoms of raised ICP (nausea, vomiting, and lethargy).

15.5.5 CNS-Neuroblastoma (NB) and CNSGanglioneuroblastoma (GNB) Symptoms of raised ICP, seizures, and hemiplegia are observed in patients with CNS-NB. They

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may have solid and cystic components, with the recurrence rate being lower in cystic CNS-NB.

15.6

Therapeutic Approaches

15.6.1 Surgical Intervention The treatment of MB encompasses a combination of surgical resection, radiotherapy, and chemotherapy. Surgical resection together with radiation treatment is the most important factors in terms of survival and has dramatically altered the prognosis of children with MB. The goal of surgical resection should be the gross total resection (GTR), but in cases where this has not been achieved, near to total resection (NTR) (defined as residual tissue less than 1.5 cm3) was found to have similar results in overall survival (OS). Nevertheless, in terms of progressive-free survival (PFS), the GTR displays a more favorable outcome. Cerebellar mutism is a wellknown postoperative complication of MB removal (Juraschka and Taylor 2019). A permanent ventriculoperitoneal (VP) shunt will be placed in approximately 30% of the patients, with the possible risk of tumor seeding in the peritoneal cavity (Massimino et al. 2016). Surgical removal of the tumor with an aim for GTR is typically attempted for ATRT, but ultimately, GTR or NTR will be achieved in about 30% of the cases due to the infiltrative nature of the tumor (Richards et al. 2020). Tekautz et al. performed a survival analysis in 31 patients with ATRT. The mean event-free survival and overall survival rates at two years were 31% and 40%, respectively. The outcome rates were more favorable in children over 3 years compared to infants. A correlation between the extent of resection and the overall survival was reported (GTR/NTR vs STR; P = 0.053). The most important finding of that study was that the combination of adjuvant radiotherapy and radiotherapy was associated with a dramatic increase in the event-free survival and overall survival compared to the group treated only with chemotherapy (Tekautz et al. 2005). The extent of resection and the age at the time of

surgery were additionally found to be correlated with a more favorable outcome in another recent study (Richards et al. 2020). The management of children with ETMR is contentious, due to the limited number of patients with ETMR and the lack of prospective cohorts in the literature. The same principles as with other embryonal neoplasms apply and include tumor resection, chemotherapy, and radiotherapy. The tumor may be adhesive to the dura matter and there is often not clear excision plane from the surrounding parenchyma. In a systematic review of the literature, Alexiou et al. found that GTR or NTR will be achieved in approximately 45%, STR in 35%, and only biopsy of the lesion will be performed in 20% of the cases. The authors did not observe a statistically significant difference in OS between the group of patients treated with GTR/NTR and STR, but a statistically significant difference was observed when comparing the survival of patients who were treated with surgical resection (GTR or NTR or STR) vs patients who treated with biopsy only (14 months vs. 6 months; P = 0.006). Additionally, the authors found a survival benefit for patients who were treated with adjuvant radiotherapy or adjuvant chemotherapy with sequential autologous hematopoietic stem cell rescue. Treatment of ME includes surgical resection, radiotherapy, and chemotherapy. The GTR is the most important factor that influences patients’ survival. It is of crucial significance that the surgeon maximizes the extent of resection as a 75% benefit in 5-year survival is observed in GTR vs non-GTR groups. GTR is attempted in the majority of cases of NB and GNB, but may be difficult to achieve in solid NB.

15.6.2 Chemotherapy and Radiotherapy MB is an extremely radiosensitive neoplasm, thus radiotherapy, when feasible, is of crucial significance to patient survival. The typical protocol includes craniospinal irradiation (CSI) and focused high-dose irradiation of posterior fossa.

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One of the biggest dilemmas in the treatment of MB is whether or not to irradiate infants under 3 years of age due to the effects of irradiation in infant CNS. The latter has been associated with significant deficits in intellectual growth, with drops in intelligence quotient and endocrinological disorders (Alexiou et al. 2011; Juraschka and Taylor 2019). Chemotherapy has also been found to improve the survival rates of patients with MB. Currently, the most accepted chemotherapeutic protocol for children over 3 years is that of Children’s Oncology Group (COG) with a multiagent regimen that includes platinum agents, vincristine, and cyclophosphamide (Alexiou et al. 2011; Farwell et al. 1984; Massimino et al. 2016). In infants under 3 years who have not undergone irradiation, or the irradiation could not be completed successfully due to the associated side effects, various alternative treatment schemes have been proposed. Nevertheless, there is no consensus in the literature in regard to the optimal treatment. Intraventricular or intrathecal administration of methotrexate and intensified chemotherapy protocols with autologous hematopoietic transplantation are among the most common methods of treatment (Baroni et al. 2020; Robinson et al. 2018). CSI and local irradiation have shown a positive overall impact on survival of ATRT, but the effects of irradiation in the youngest age group of AT/RT are frequently considered unacceptable due to the resulting neurocognitive impairments. Consequently, and similarly to MB, other intensified treatments with intraventricular/intrathecal administration of methotrexate or high-dose chemotherapy with hematopoietic transplants have been proposed as possible alternatives. Regarding the ETMR, the dilemma of CSI remains, but data from the literature support the use of irradiation to prolong PFS and OS. Several chemotherapy regimens have been utilized that include agents such as vincristine, cisplatin, etoposide, cyclophosphamide, and lomustin. CSI followed by focal irradiation is another treatment intervention that has a positive impact on patients’ survival, especially in non-resectable MEs, such as those located in the brain stem. The effect of chemotherapy in overall survival

417

remains controversial (Bansil et al. 2016; Molloy et al. 1996; Müller et al. 2011). Adjuvant multiagent chemotherapy is administered in non-metastatic CNS-NB, while singledose chemotherapeutic agents are utilized in metastatic CNS-NB. The role of radiotherapy is contentious and is preferred in older children (over 3 years). The 3-year survival is approximately 60% (Berger et al. 1983; Bianchi et al. 2018; Steenberge and Prayson 2014; Yariş et al. 2004).

15.6.3 New Therapeutic Modalities 15.6.3.1 Medulloblastoma Despite the efficacy of CSI in the treatment of MB, it is associated with significant adverse effects such as neurocognitive and endocrine impairment. Currently, there is a trend to reduce the dose of CSI in some low-risk subtypes of newly diagnosed MBs aiming to mediate these complications. The St. Jude’s trial (NCT01878617) is the largest of them, with 625 patients. In that study, the patients with newly diagnosed WNT-MB (low-risk) receive low-dose CSI (15–51 Gy). Furthermore, patients with SHH-MB receive a combination of conventional chemotherapy regimens (cyclophosphamide, cisplatin, and vincristine) and vismodegib. The vismodegib is a smoothened receptor (SMO) inhibitor. The SMO is a component of the SHH pathway that is mainly utilized in the treatment of basal cell carcinoma, and its inhibition impairs the activation of GLI1/2 transcription factors and the activation of SHH pathway target genes. The combination of vismodegib with temozolomide compared to treatment with temozolomide alone in adult patients with recurrent SHH-MB was tested in the MEVITEM trial (NCT01601184). However, the trial was terminated due to early failure. A similar attempt to reduce the dose of CSI in WNT-MB is tested in two other clinical trials: COG ACNS1422 (NCT02724579), SIOPPNET-5 (NCT02066220). A small trial (NCT02212574) with 13 patients attempted to study the effect of no CSI irradiation in patients with WNT-MB. However, the trial is currently

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suspended due to early failures. The HeadStart4 trial is another trial that tests the effect of the dose-intensive tandem consolidation compared to single-cycle consolidation via randomization. The study concerns children under 10 years old with high-risk MB (NCT02875314) (Non-WNT, Non-MB) (Thompson et al. 2020).

15.6.3.2 Other Embryonal Tumors Due to their rarity, only preliminary research has been performed on developing novel treatments for the rest of embryonal tumors. Currently, in a phase 3 trial (NCT00653068) of COG, an improvement in the outcome of patients with ATRT was observed with the combination of chemotherapy, three-dimensional conformal radiation therapy, and an autologous peripheral blood stem cell transplant (Reddy et al. 2020). The potential role of alisertib, an Aurora kinase A inhibitor, in treating young patients with ATRT is studied in an ongoing phase 2 trial (NCT02114229). Except for ATRT and MB, only a limited number of patients diagnosed with the rest of embryonal tumors have been reported in the literature. Hence, the conduction of large clinical trials to study the efficacy of potential novel therapies is currently not feasible.

15.7

Follow-Up and Prognosis

The prognosis of non-metastatic MB in standardrisk patients is excellent, with approximately 80–90% 5-year survival. Nevertheless, the prognosis remains poor for infants, except for those that fall into MB-SHH group. Recurrence of MB either locally or with dissemination into leptomeninges or outside of CNS (mainly as metastasis in bones and lymph nodes) is related to poor prognosis that is not significantly improved despite the applied treatment protocols. The understanding of the genetic alterations which indicate the metastatic potential of MB might lead to the development of novel targeted therapies for the treatment of metastatic MB (Fruhwald and Plass 2002; Koeller and Rushing 2003; Stefanaki et al. 2012).

Unfortunately, the prognosis of children with AT/RT remains very poor despite the intensified protocols that are currently applied, and the 5year survival is approximately 30% (Ginn and Gajjar 2012; Reddy 2005; Rorke et al. 1996). The prognosis of patients with ETMR is extremely poor, and the vast majority of these patients will expire within the first 2–3 years after diagnosis. There is some evidence that ETMR, NOS is related to worse prognosis, but further studies should be performed for confirmation (Lambo et al. 2020). The overall 5-year survival of MEs remains poor, approximately 30%. It is paradoxical that the survival rate is significantly lower than that of ocular MEs, which have an excellent prognosis after enucleation (Bansil et al. 2016; Molloy et al. 1996; Müller et al. 2011).

15.8

Conclusion

ETs are malignant neoplasms that usually occur in children and are associated with very poor patients’ outcomes. The MB is the most common neoplasm of this group. Large molecular studies performed in the last five years helped discover the molecular landscape of these aggressive neoplasms. However, heterogeneity in the biological behavior of non-WNT/non-SHH MBs has been observed, indicating the existence of further subgroups with distinct pathogenetic mechanisms. Understanding these mechanisms is crucial for developing novel targeted therapies because these molecular subgroups are related to a poor outcome. Lately, a trend to reduce the dose of CSI in patients with low-risk MB, aiming to prevent longterm neurocognitive and endocrinological complications, is observed in ongoing clinical trials. Progress has been also observed in understanding the molecular mechanisms involved in the tumorigenesis of ATRT, and three distinct molecular subgroups have been identified. Finally, the introduction of novel targeted therapies against the components of the responsible molecular pathways is expected to treat patients with MB and ATRT within the following years.

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419 Ginn KF, Gajjar A (2012) Atypical teratoid rhabdoid tumor: current therapy and future directions. Front Oncol 2:114 Hesham D, El-Naggar S (2020) Transcriptomic analysis revealed an emerging role of alternative splicing in embryonal tumor with multilayered rosettes. Genes 11. https://doi.org/10.3390/genes11091108 Hoffman M, Park T (1983) Medulloblastoma: clinical presentation and management. J Neurosurg 8:543–552 Holdhof D et al (2021) Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases. Acta Neuropathologica 141:291–301. https://doi.org/10.1007/ s00401-020-02250-7 Ito J et al (2020) Central nervous system ganglioneuroblastoma harboring MYO5A-NTRK3 fusion. Brain Tumor Pathol 37:105–110. https://doi.org/10.1007/ s10014-020-00371-1 Johann PD et al (2016) Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29:379–393. https://doi.org/10.1016/j.ccell.2016.02.001 Juraschka K, Taylor MD (2019) Medulloblastoma in the age of molecular subgroups: a review. J Neurosurg Pediatr 24:353–363. https://doi.org/10.3171/2019.5. peds18381 Koeller KK, Rushing EJ (2003) From the archives of the AFIP: medulloblastoma: a comprehensive review with radiologic-pathologic correlation. Radiographics 23:1613–1637 Kool M et al (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25:393–405. https://doi.org/10.1016/j.ccr.2014.02.004 Korshunov A et al (2021) Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation. Acta Neuropathologica Commun 9:20. https://doi.org/10.1186/s40478-021-01118-5 Korshunov A et al (2012) LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR). Acta Neuropathologica 124:875–881. https://doi.org/10.1007/s00401-0121068-3 Kram DE, Henderson JJ, Baig M, Chakraborty D, Gardner MA, Biswas S, Khatua S (2018) Embryonal tumors of the central nervous system in Children: the era of targeted therapeutics. Bioengineering (Basel, Switzerland) 5. https://doi.org/10.3390/bioengineering5040078 Kumar A, Abbas AK, Jon C (2015) Aster: Robbins and Cotran pathologic basis of disease. Professional Edition Lambo S, von Hoff K, Korshunov A, Pfister SM, Kool M (2020) ETMR: a tumor entity in its infancy. Acta Neuropathologica, 1–18 Louis DN et al (2016) The World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https:// doi.org/10.1007/s00401-016-1545-1

420 Massimino M et al (2016) Childhood medulloblastoma. Crit Rev Oncol/Hematol 105:35–51 Mirza FA, Synder B, Smith VD, Vasquez RA (2018) Pediatric supratentorial ganglioneuroblastoma: case report and review of literature. World Neurosurg 113:261–266 Moeller KK, Coventry S, Jernigan S, Moriarty T (2007) Atypical teratoid/rhabdoid tumor of the spine. Am J Neuroradiol 28:593–595 Molloy PT et al (1996) Central nervous system medulloepithelioma: a series of eight cases including two arising in the pons. J Neurosurg 84:430–436 Müller K et al (2011) Curative treatment for central nervous system medulloepithelioma despite residual disease after resection. Strahlenther Onkol 187:757– 762 Northcott PA et al (2017) The whole-genome landscape of medulloblastoma subtypes. Nature 547:311–317. https://doi.org/10.1038/nature22973 Oka H, Scheithauer BW (1999) Clinicopathological characteristics of atypical teratoid/rhabdoid tumor. Neurologia Medico-chirurgica 39:510–518 Pedram M, Vafaie M, Fekri K, Haghi S, Rashidi I, Pirooti C (2013) Cerebellar neuroblastoma in 2.5 years old child. Iran J Cancer Prevention 6:174–176 Pei Y-C et al (2019a) Embryonal tumor with multilayered rosettes, C19MC-altered (ETMR): a newly defined pediatric brain tumor. Int J Clin Exp Pathol 12:3156 Pei YC et al (2019b) Embryonal tumor with multilayered rosettes, C19MC-altered (ETMR): a newly defined pediatric brain tumor. Int J Clin Exp Pathol 12:3156– 3163 Reddy AT (2005) Atypical teratoid/rhabdoid tumors of the central nervous system. J Neurooncol 75:309–313 Reddy AT et al (2020) Efficacy of high-dose chemotherapy and three-dimensional conformal radiation for atypical teratoid/rhabdoid tumor: a report from the children’s oncology group trial ACNS0333. J Clin Oncol (Official Journal of the American Society of Clinical Oncology) 38:1175–1185. https://doi.org/10. 1200/jco.19.01776 Richards A et al (2020) Outcomes with respect to extent of surgical resection for pediatric atypical teratoid rhabdoid tumors. Child’s Nerv Syst (ChNS: Official Journal of the International Society for Pediatric

M. Lampros and G. A. Alexiou Neurosurgery) 36:713–719. https://doi.org/10.1007/ s00381-019-04478-5 Robinson GW et al (2018) Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 19:768–784 Rorke LB, Packer RJ, Biegel JA (1996) Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85:56–65 Steenberge SP, Prayson RA (2014) Pediatric cerebral ganglioneuroblastoma. J Clin Neurosci 21:2023–2025 Stefanaki K, Alexiou GA, Stefanaki C, Prodromou N (2012) Tumors of central and peripheral nervous system associated with inherited genetic syndromes. Pediatr Neurosurg 48:271–285. https://doi.org/10. 1159/000351546 Strother D (2005) Atypical teratoid rhabdoid tumors of childhood: diagnosis, treatment and challenges. Expert Rev Anticancer Therapy 5:907–915 Tekautz TM et al (2005) Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and highdose alkylator-based chemotherapy. J Clin Oncol (Official Journal of the American Society of Clinical Oncology) 23:1491–1499. https://doi.org/10.1200/jco. 2005.05.187 Thompson EM, Ashley D, Landi D (2020) Current medulloblastoma subgroup specific clinical trials. Transl Pediatr 9:157–162. https://doi.org/10.21037/ tp.2020.03.03 Torchia J et al (2015) Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol 16:569–582. https://doi.org/10.1016/s14702045(15)70114-2 Tulla M, Berthold F, Graf N, Rutkowski S, von Schweinitz D, Spix C, Kaatsch P (2015) Incidence, trends, and survival of children with embryonal tumors. Pediatrics 136:e623-632. https://doi.org/10. 1542/peds.2015-0224 Yariş N, Yavuz MN, Reis A, Yavuz AA, Okten A (2004) Primary cerebral neuroblastoma: a case treated with adjuvant chemotherapy and radiotherapy. Turk J Pediatr 46:182–185

Brain and Spinal Tumors Originating from the Germ Line Cells

16

Tai-Tong Wong, Min-Lan Tsai, Hsi Chang, Kevin Li-Chun Hsieh, Donald Ming-Tak Ho, Shih-Chieh Lin, Hsiu-Ju Yen, Yi-Wei Chen, Hsin-Lun Lee, and Tsui-Fen Yang

Abstract

Primary central nervous system germ cell tumors (CNS GCTs) are part of the GCTs in children and adults. This tumor entity presents with geographic variation, age, and sex predilection. There are two age peaks of incidence distribution at the first few months of life and in adolescence. CNS GCTs are heterogeneous in histopathological subtypes, locations, and tumor marker (AFP, b-hCG) secretions. In the WHO CNS tumor classification, GCTS are classified as germinoma and T.-T. Wong (&) Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan e-mail: [email protected] T.-T. Wong . M.-L. Tsai . H. Chang . K. L.-C. Hsieh . H.-L. Lee Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei 110, Taiwan T.-T. Wong Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan

nongerminomatous GCT (NGGCT) with different subtypes (including teratoma). Excluding mature teratoma, the remaining NGGCTs are malignant (NGMGCT). In teratoma, growing teratoma syndrome and teratoma with somatic-type malignancy should be highlighted. The common intracranial locations are pineal region, neurohypophysis (NH), bifocal pineal-NH, basal ganglia, and cerebral ventricle. Above 50% of intracranial GCTs (IGCTs) present obstructive hydrocephalus. Spinal tumors are rare. Age, locations,

K. L.-C. Hsieh Department of Medical Imaging, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan D. M.-T. Ho . S.-C. Lin Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan D. M.-T. Ho Department of Pathology and Laboratory Medicine, Cheng Hsin General Hospital, Taipei 112, Taiwan

Neuroscience Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan

H.-J. Yen Division of Pediatric Hematology and Oncology, Department of Pediatrics, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan

M.-L. Tsai Department of Pediatrics, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan

Y.-W. Chen Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_16

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hydrocephalus, and serum/CSF titer of b-hCG correlate with clinical manifestations. Delayed diagnosis is common in tumors arising in neurohypophysis, bifocal, and basal ganglia resulting in the increasing of physical dysfunction and hormonal deficits. Staging work-up includes CSF cytology for tumor cells and contrast-enhanced MRI of brain and spine for macroscopic metastasis before treatment commences. The therapeutic approach of CNS GCTs integrates locations, histopathology, staging, tumor marker level, and therapeutic classification. Treatment strategies include surgical biopsy/excision, chemotherapy, radiotherapy (single or combination). Secreting tumors with consistent imaging may not require histopathological diagnosis. Primary germinomas are highly radiosensitive and the therapeutic aim is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination. Primary NGNGCTs are less radiosensitive. The therapeutic aim is to increase survival utilizing more intensive chemotherapy and radiotherapy. The negative prognostic factors are residue disease at the end of treatment and serum or CSF AFP level >1000 ng/mL at diagnosis. In refractory or recurrent NMGGCTs, besides high-dose chemotherapy, new therapy is necessary. Molecular profiling and analysis help for translational research. Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction, physical S.-C. Lin . Y.-W. Chen Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan H.-L. Lee Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 110, Taiwan Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan T.-F. Yang Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan Department of Physical Therapy and Assistive Technology, National Yang-Ming University, Taipei, Taiwan, ROC

T.-T. Wong et al.

disability, pituitary hormone deficiency, and other CNS complications after cranial radiotherapy. Continuous surveillance and assessment may lead to improvements in treatment protocols, transdisciplinary interventions, after-treatment rehabilitation, and quality of life. Keywords

.

.

Central nervous system Intracranial Germ cell tumor Germinoma Nongerminoma Treatment

.

16.1

.

.

Background and Epidemiology

16.1.1 Background In humans, germ cell tumors (GCTs) develop in gonads, coccyx, mediastinum, retroperitoneum, brain, and spine (rare) (Gobel et al. 2000; Jennings et al. 1985; Matsutani et al. 1997). Primary central nervous system (CNS) GCTs consist of 18% of all GCTs in children with male predilection. Two age peaks of incidence in both sexes are found. The first peak and the second peak distribute around the time of birth and in adolescence, respectively (Goodwin et al. 2009). The vast majority of CNS GCTs arise intracranially. Intraspinal tumors are rare. Intracranial GCTs (IGCT) occur in all ages with a median age of 16 years (Goodwin et al. 2009). In spinal GCTs, the median age of presentation is 24 years with no sex predilection (Biswas et al. 2009). The six leading clinical factors of CNS GCTs diagnosis and treatment are: age at presentation, tumor location, histopathology, tumor markers, hydrocephalus, and staging (Biswas et al. 2009; Goodwin et al. 2009; Matsutani et al. 1997; Murray et al. 2015). In the first age peak of incidence, congenital teratomas (exclusively immature teratomas) are the most common and mainly distributed within cerebral ventricles (Isaacs 2002; Wong et al. 2005). IGCTs arise mainly in the pineal,

16

Brain and Spinal Tumors Originating from the Germ Line Cells

neurohypophyseal (NH), multifocal (including bifocal), basal ganglia (BG), cerebral ventricle, and other rare sites (Biswas et al. 2009; Krueger et al. 2016; Matsutani et al. 1997; Wong et al. 2005; Yang et al. 2014). Intraspinal GCTs often distribute in the thoracic and thoracolumbar regions (Biswas et al. 2009). The histopathology of CNS GCTs is heterogeneous consisting of germinoma and nongeminomatous GCT [NGGCT] with different degrees of malignancy (Louis et al. 2016; Matsutani et al. 1997). Both germinoma and NGGCT can secret protein markers [a-fetoprotein (AFP) and/or human chorionic gonadotropin (b-hCG)] in serum or cerebrospinal fluid [CSF]. The titers differ in different histopathological subtypes (Allen et al. 1979; Hu et al. 2016; Matsutani et al. 1997; Wong et al. 2005). About 60% of IGCTs presented obstructive hydrocephalus at diagnosis (Wong et al. 2011b). Staging of CNS GCTs comprises the work-up of CSF cytology staging and radiological staging at the time of diagnosis before treatment commence (Murray et al. 2015). The clinical manifestations in patients with CNS GCTs correlates with age at diagnosis, tumor location, b-hCG titer, and hydrocephalus (Rivarola et al. 2001; Sandow et al. 2004; Sethi et al. 2013; Starzyk et al. 2001). Delayed diagnosis is common for intracranial tumors (Sethi et al. 2013; Sonoda et al. 2008). Apart from CT scan, magnetic resonance imaging (MRI) of brain and spine is currently the most common and sensitive diagnosed tool for CNS GCT (Chang et al. 1989; Fujimaki et al. 1994; Murray et al. 2015). Diagnostic brain MRI features can aid the preoperative differential diagnosis of germinoma from NGGCTs and other tumor entities (Kinoshita et al. 2016; Lee et al. 2016; Wu et al. 2017). Age, histopathology, tumor location, serum/CSF markers (AFP and b-hCG), hydrocephalus, and staging comprise the integrated therapeutic approaches of CNS GCT. The proposed therapeutic classification of IGCTs is the principal guideline for the treatment of these tumors with different degrees of malignancy (Matsutani et al. 1997). Histopathological diagnosis is essential for accurate classification through surgical resection (biopsy, radical

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resection). Non-secreting teratoma and NGGCT with growing teratoma syndrome (GTS) may be cured after total resection (Matsutani et al. 1997; Tsuyuguchi et al. 2020). Hypervascular IGCTs exist and may impact the risk of tumor surgery (Monroy-Sosa et al. 2018; Tsuyuguchi et al. 2020). Besides non-secreting teratoma and NGGCT with GTS, CNS germinomas and malignant NGGCTs are treated with radiotherapy with/without chemotherapy of different intensity (Calaminus et al. 2013, 2017; Goldman et al. 2015). Compared with malignant NGGCTs (NGMGCTs), the survival rates of germinomas and mature teratomas are high. For highly malignant NGGCTs, the survivals are poor (Matsutani et al. 1997; Sawamura et al. 1998; Takami et al. 2019). For germinomas, the therapeutic aim is to maintain a high survival rate applying optimal radiotherapy regimen. In NGMGCTs, the therapeutic aim is to increase survival. Impact of neurocognitive dysfunction, pituitary hormone deficiency, physical disability, and other late effects of anticancer treatment occur in children with IGCT at diagnosis and in survivors (Liang et al. 2013; Margelisch et al. 2015; Sawamura et al. 1998). Except cognitive function, other late radiation complications include cerebral necrosis, occlusive vasculopathy of intracranial large vessels, cavernoma, and secondary neoplasm occurred with increase of cumulative incidence (Acharya et al. 2015; Burn et al. 2007; Heckl et al. 2002; Lee et al. 2018b; Sawamura et al. 1998). Physical disability was also noted (Sawamura et al. 1998). Primary prevention by early diagnosis, protective treatment, lifelong surveillance, and intervention management of survivors are crucial.

16.1.2 Epidemiology The reported age standardized incidence rates (ASR per million person-year) and the incidences of GCTs in CNS tumors differ according to geographic regions, registries, cohort series, time period, and age spans (Table 16.1). In children (aged 0–14 or 0–19 years), Asian

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T.-T. Wong et al.

countries/regions (e.g., Korea, Japan) have higher ASRs (4.5–4.9 per million) (Kang et al. 2019; Makino et al. 2013) and incidences in CNS or brain tumors are reported about 10.6–14.0% (Kang et al. 2019; Makino et al. 2013; Wong et al. 2005). In Taiwan (registered malignant tumor only) and Hong Kong, the reported ASR was 2.3, and 5.7 per million, respectively (Hung et al. 2015; Liu et al. 2020). The ASR (5.7) and incidence in childhood brain tumors (21.9%) in Hong Kong were extraordinarily high (Liu et al. 2020). In Western countries, represented by Canada and USA, the reported ASRs in children were 1.06 and 2.3 per million, respectively (Keene et al. 2007; Ostrom et al. 2019). In the ethnic group of Asian-Pacific Islander in the USA, the ASR was 3.6 per million person-year (Ostrom et al. 2019) that was close to the ASRs of Korea and Japan. In age groups including children and adults, the ASRs and incidence in CNS tumors in Japan (Kumamoto prefecture) were 1.7 per million and 1.1% compared with 1.0 per million and 0.4% in the USA (Makino et al. 2013; Ostrom et al. 2019), respectively. CNS GCTs have two age peaks in incidence, at the first few months of life and in adolescence. Male predilection occurs in the age span of 9–30 years (Goodwin et al. 2009). In children aged 0–14 or 0–19, the sex ratios vary from 1.6 to 3.8 (Table 16.1) (Bao et al. 2009; Brain Tumor Registry of Japan (2001–2004) 2014; Carlos Chung et al. 2013; Goodwin et al. 2009; Hung et al. 2015; Kakkar et al. 2016; Kang et al. 2019; Keene et al. 2007; Liu et al. 2020; Makino et al. 2013; Ostrom et al. 2019; Wong et al. 2005).

Murray et al. 2017). In the molecular era, understanding the molecular biology and microenvironment of both germinoma and NGGCTs is indispensable. Molecular prognostic markers and therapeutic targets identification will contribute to personalized and precise treatment, and the development of biological targeted therapy and immunotherapy (Galvez-Carvajal et al. 2019). Some new advancements were reported.

16.2

16.2.2 The Distinction of Genetic Mutation Between Pure Germinoma and NGGCT

Genetics, Immunology, and Molecular Biology

CNS GCTs are heterogeneous in arising locations, histopathology, and secreting markers. The response of radiotherapy with/without combined chemotherapy for localized, metastatic disease, and relapse for germinomas and NGMGCTs are different (Calaminus et al. 2013, 2017; Callec et al. 2020; Chen et al. 2012; Fangusaro et al. 2019; Khatua et al. 2010; Modak et al. 2004;

16.2.1 KIT-RAS-MAPK and AKT-MTOR Pathways Novel mutations in intracranial GCT (IGCT) have been identified. Among them, KIT-RASMAPK and KIT-AKT-mTOR signal pathways are well-known. Overall, 53% of IGCTs have one or more genetic variations in these two pathways. There are 26% of tumors showing mutation in KIT and 19% in KRAS/NRAS which locate at the downstream of KIT receptor tyrosine kinase, activating the MAPK pathway. A separate downstream pathway of the KIT receptor consists of AKT1 and mTOR. Amplification of AKT1 in 19% and genetic alteration of mTOR in 6.5% were observed. Contrary to the report of Wang et al., KIT mutation was identified in 6 out of 54 NGGCTs (11.1%) (Ichimura et al. 2016; Wang et al. 2014). Mutations of NF1, CBL, and other genes involving MAPK pathway were also found (Ichimura et al. 2016). CBL is a negative regulator of receptor tyrosine kinase such as KIT. Its inactivation could affect both KIT-RAS and AKT-mTOR pathways.

Mutations of KIT-RAS-MAPK and AKT-mTOR occur predominantly in pure germinomas but less frequently in NGGCTs. In germinomas, mutually exclusive mutations of KIT and RAS were observed (Fukushima et al. 2014a). According to the genetic features of IGCT, 40% of pure germinomas had mutations involving KIT but only

1989–2011 2001–2004

31/251

312/13,431

48/435

Japan (Brain tumor registration of Japan (2001-2004))

Taiwan (Hung et al. 2015)

1543/405740

USA (Ostrom et al. 2005)

121

638

USA (Goodwin et al. 2009)

21

Canada (Keene et al. 2007)

95

Australia (Carlos Chung et al. 2013)

138

Cohort series/N

India (Kakkar et al. 2016)

Taiwan (Wong et al. 2005)

Country/city

111/508 (Chinese)

Hong Kong, China (Liu et al. 2020)

951/24931

13/609

Shanghai, China (Bao et al. 2009)

166/832

1989–2011

70/6615

1973–2004

1990–2004

1997–2007

1999–2013

1975–2004

1.06

ASR (per million-person)

1.4

Black 151 Time period

3.6 2.4

API

2.3

4.8

0.43

14.0

Incidence rate (%)

3.8

0.4

100

79.3

100

100

75.5

Histological diagnosis (%)

0–29

0–17

0–48

0–17

Study age span (years)

0–19

0–19

0–19

0–19

0–85+

0–17

5.7 1.0

0–14

1.9

0–19

0–9

0–100

0–14

0–60

0–19

Study age span (years)

10–19

81.1

Histological diagnosis (%)

2.3

21.9

2.3

12.4

1.1

10.6

Incidence rate (%)

3.28

1.08

4.5

1.7

4.9

ASR (per millionperson)

White 1221

2012–2016

1999–2016

2002–2005

1995–2009

2005–2014

641

Kumamoto, Japan (Makino et al. 2013)

Time period

Korea (Kang et al. 2019)

Cohort series/N

Registry/N

Country/city

11.6 (mean age)

13

12

10.6 (mean age)

Median age

16

13.1

Median age

10–12

10–14

10–14

Peak incidence (years of age)

10–14

10–19

10–14

10–19

10–14

10–19

10–14

Peak incidence (years of age)

3.31

3.5

2.5

1.97

3.8

Sex ratio

2.17

2.17

1.6

2.24

2.77

1.10

4.67

2.44

2.33

2.4

Sex ratio

Table 16.1 Age standardized incidence rates (ASRs per million person-year) and the incidences of GCTs in CNS tumors in reported registries and cohort series of different geographic regions, time period, and age spans

16 Brain and Spinal Tumors Originating from the Germ Line Cells 425

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6% in NGGCTs (Fukushima et al. 2014a). RAS mutations were observed in 20% of pure germinomas and only 3% in NGGCTs. In fact, many NGGCTs having KIT-RAS mutations were actually mixed GCTs. Therefore, unlike pure germinoma, the genetic mutation of NGGCTs seems to be independent from KAT-RAS and AKT-mTOR signal pathways (Fukushima et al. 2017).

16.2.3 BCORL1 and JMJD1C As IGCTs show geographic (East Asian countries), sex, and age predilections, a genetic susceptibility has been considered. Recent studies identified a recurrent somatic mutation in BCORL1 (a transcriptional corepressor and tumor suppressor located on the X-chromosome) and a rare germline variant of JMJD1C [a chromatin modifier gene and coactivator of androgen receptor (AR)]. Interestingly, the significant enrichment of JMJD1C was observed in Japanese population and further enriched (about fivefold) in Japanese IGCT patients (Wang et al. 2014; Wolf et al. 2007). Indicating a strong association between JMJD1C variants and the risk of developing IGCTs. Through interaction with AR, JMJD1C may account for the increased incidence of IGCTs in East Asia and male predominance.

16.2.4 Chromosomal Aberrations and Intracranial Germ Cell Tumors (IGCTs) In testicular GCT (TGCT), a gain of chromosome 12p [i(12p) mainly] is observed in almost all the tumors (Reuter 2005). However, chromosome 12p gain occurred much less in IGCT (Okada et al. 2002; Phi et al. 2018; Sukov et al. 2010). Other common chromosomal aberrations with clinical significance including of chromosomes X and 21 that associate with Klinefelter syndrome and Down syndrome, respectively, in extragonadal (including CNS) GCTs (Bonouvrie et al. 2020; Miyake et al. 2017; Okada et al. 2002).

T.-T. Wong et al.

16.2.5 Epithelial Mesenchymal Transition (EMT) Signatures and Immunology EMT gene signatures and immunology are involved in IGCTs. In a mRNA array study of 14 IGCTs (6 germinomas and 8 NGGCTs), OCT4 and NANOG were highly expressed in germinomas. Oppositely, in NGGCTs, the two key EMT regulators, SNAI2 and TWIST2 were abundantly expressed. In gene set enrichment analysis according to Gene Ontology (GO) classification, the overexpression genes in germinomas were in the DNA damage checkpoint and genes associated with the immune system process, whereas in NGGCTs, significant enrichment of differentiation and morphogenesis (especially neurogenesis) genes were observed (Wang et al. 2010a). Applying fluorescent immunohistochemistry (FIHC) and gene expression profiling in a cohort series of testicular GCTs (TGCTs), seminomas were associated with increased CD3 + T-cell infiltration, decreased regulatory T-cells (Tregs), increased PD-L1, and increased PD-1/PDL-1 spatial interaction. Non-seminoma showed high neutrophils and macrophage enrichment. TGCTs of advanced stage are associated with decreased Tcell and NK-cell signatures, and increased signatures of Treg, neutrophil, mass cell, and macrophage (Siska et al. 2017). In a study of intratumor landscape of 100 intracranial germinomas, 93.8% expressed PD-1 in immune cells, while 73.5% exhibited PD-L1 in tumor cells (Takami et al. 2020a). Association of EMT signature with prognosis and tumor microenvironment in head and neck squamous cell carcinoma was reported (Jung et al. 2020). These studies provide rationale for immunotherapy to refractory and recurrent intracranial NGMGCTs (Kalavska et al. 2020).

16.3

Histopathology and Morphology

In the 2016 WHO classification, CNS GCTs were classified as germinoma, teratoma (mature, immature), teratoma with somatic-type

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malignancy (TSM), embryonal carcinoma (EC), yolk sac tumor (YST), choriocarcinoma (CC), and mixed GCT (Louis et al. 2016). This classification is the same as the classification of GCTs in the gonads and other extragonadal sites. In testis and ovary, germinoma is termed as seminoma and dysgerminoma, respectively. GCTs other than germinoma are collectively called nongerminomatous GCTs (NGGCTs). Histologically and morphologically, GCTs recapitulate primordial germ cell (PGC) and/or various stages of embryonic and extraembryonic development (Ho and Liu 1992; Sato et al. 2009; Vasiljevic et al. 2015). The distribution of histopathological subtypes differs in their arising locations (Table 16.4) (Matsutani et al. 1997; Wong et al. 2005).

16.3.1 Germinoma The tumor cells of germinoma resemble PGCs and are arranged in sheets or lobules. They are large round or polygonal and have a moderate amount of faint eosinophilic or clear cytoplasm. Their nuclei are round, central, and vesicular and have a prominent nucleolus or sometimes a few smaller nucleoli. Mitoses are frequent. Mature lymphocytes, which are non-neoplastic, could be abundant or scant, are always present. Histiocytes, some of which aggregate to form granulomas, could also be seen. In extreme examples, lymphocytes and/or histiocytes could be prominent, and the germinoma cells are concealed among the reactive cells. In this situation, immunohistochemical stains, e.g., PLAP (placental alkaline phosphatase; mainly on cell membrane and some cytoplasmic), c-kit/CD117 (membranous stain) or OCT3/4 (octamer-binding transcription factor 3/4, nuclear stain), are helpful to identify germinoma cells. Otherwise, the lesion could be mislabeled as lymphocytic or granulomatous inflammation (Schmalisch et al. 2012; Utsuki et al. 2005; Vasiljevic et al. 2015). Scarce syncytiotrophoblastic giant cells (STGCs), which are b-HCG immunoreactive, could be seen. Germinoma with STGCs is highlighted because of the association with

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serum/CSF marker (HCG) (Sato et al. 2009; Vasiljevic et al. 2015) (Fig. 16.1).

16.3.2 Teratoma and Growing Teratoma Syndrome 16.3.2.1 Teratoma Teratoma is composed of admixture of various tissues representing the three embryonic germ layers (i.e., ectoderm, mesoderm and endoderm). It is further classified into mature teratoma, immature teratoma, and teratoma with somatictype malignancy (TSM). Mature teratoma is composed of entirely adult or fully differentiated tissues including skin and its appendages, respiratory tissue, gastrointestinal tissue, adipose tissue, bone, cartilage, skeletal muscle, nervous tissue, choroid plexus, etc. Immature teratoma is the teratoma containing embryonic or fetal tissues, and could also have mature tissues (Fetcko and Dey 2018). It could contain any forms of immature tissues, of which neuroectodermal tissue and primitive mesenchymal tissue are the most frequently encountered. TSM is the teratoma with malignant change of its epithelial component (carcinoma) or mesenchymal component (sarcoma) (Biskup et al. 2006; Freilich et al. 1995; Scheckel et al. 2019). Teratomas present similar antigens to the native somatic counterparts on immunohistochemically. Alphafetoprotein (AFP) could be demonstrated in the gastrointestinal tissue and liver tissue in immature teratomas, and it is not demonstrated in mature teratoma. Teratoma is commonly seen in mixed GCT. As the treatment of mature teratoma is surgical resection and immature teratoma always needs combined chemoradiotherapy, histopathological distinguishing between mature and immature forms is important (Fig. 16.2). 16.3.2.2 Growing Teratoma Syndrome (GTS) A syndrome was described in a small subset of patients with GCTs, which contained teratoma components in the resected tissue at initial diagnosis. Subsequently, radiological recurrences developed with normalized tumor markers during

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Fig. 16.1 a–d Germinoma, a germinoma with lymphocytic background (H&E X400), b with granuloma (H&E X100), c with syncytiotrophoblastic giant cells (STGCs)

(H&E X400), and d germinoma tumor cells with nuclear immune-reactivity of OCT3/4 (OCT3/4, X100)

Fig. 16.2 a–e Mature teratoma, a mature squamous epithelium (H&E X200), b mature intestinal mucosa (H&E X200), c mature chondroid, osseous and mesenchymal tissue (H&E X100), and d mature adipose and

smooth muscle tissue (H&E X100). Immature teratoma, e immature teratoma with immature neuroepithelial element (arrow) (H&E X40)

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therapy or after treatment completion. Upon pathological examinations on the enlarging mass, mature teratoma component was exclusively identified (Logothetis et al. 1982). The unique syndrome had been reported in adults (Panda et al. 2014) and children (Goldman et al. 2015; Li et al. 2016) having intracranial (Goldman et al. 2015) or extracranial GCTs (Li et al. 2016; Panda et al. 2014).

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ground substance is noted in the stroma. Eosinophilic hyaline globules could be found intracellularly and extracellularly. When arranged in a solid sheet, it should be differentiated from germinoma. As AFP is secreted in YST, and not in germinoma, AFP is a helpful immunohistochemical marker to distinguish them. Immunoexpression of glypican 3 is also a useful marker for YST (Preda et al. 2011; Rueda-Pedraza et al. 1987; Vasiljevic et al. 2015) (Fig. 16.3).

16.3.3 Yolk Sac Tumor 16.3.4 Choriocarcinoma Yolk sac tumor (YST) is a type of GCT having yolk sac differentiation. Morphologically, the tumor cells ranged from flattened to cuboid. The most common pattern is the reticular pattern. Other patterns include solid, cystic, alveolarglandular, poly-vesicular vitelline, tubular, and papillary. The presence of Schiller-Duval body consisting of a vessel surrounded by tumor cells lying in a cystic space is diagnostic. Myxoid

Choriocarcinoma (CC) is very rare and shows trophoblastic (placental) differentiation (Matsutani et al. 1997; Vasiljevic et al. 2015). It is composed of cytotrophoblastic and syncytiotrophoblastic components arranged in a biphasic pattern. Cytotrophoblastic cells are round to polygonal mononucleated cells with clear cytoplasm. Syncytiotrophoblastic cells are

Fig. 16.3 a–d Yolk sac tumor, a endodermal sinus pattern (H&E X200), b Schiller-Duval bodies (H&E X200), c microvesicular pattern (H&E X200), d hyaline globules. (H&E X400)

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Fig. 16.4 a–d Choriocarcinoma, admixture of syncytiotrophoblastic, cytotrophoblastic and intermediate trophoblastic cells within a hemorrhagic background. a H&E X40, b H&E X400, c b-hCG X400, and d OCT3/4 X400

multinucleated cells with eosinophilic cytoplasm. The presence of only syncytiotrophoblastic components is not qualified to make such a diagnosis. Necrosis and hemorrhage are common. Immunohistochemical staining of b-hCG is helpful to confirm syncytiotrophoblastic components. CC commonly is presented as a component of mixed germ cell tumor (Fig. 16.4).

rarest in IGCT. It is rarely pure and is primarily one of the components of mixed GCTs. It grows in solid, glandular or papillary patterns. The tumor cells are primitive, large and have pleomorphic nuclei and prominent nucleoli. Mitotic figures are frequent. Immunohistochemical stain for CD30 is helpful to confirm this diagnosis (Fetcko and Dey 2018; Vasiljevic et al. 2015) (Fig. 16.5).

16.3.5 Embryonal Carcinoma 16.3.6 Mixed Germ Cell Tumors Embryonal carcinoma (EC), (Fetcko and Dey 2018; Ho and Liu 1992; Matsutani et al. 1997; Sato et al. 2009; Vasiljevic et al. 2015) more commonly occurs in testicular GCTs and is the

Intracranial mixed GCTs are GCTs composed of more than one component. About 10–30% of IGCTs are mixed tumors (Matsutani et al. 1997;

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a

b

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c

Fig. 16.5 a–c Embryonal carcinoma, a with irregular glandular pattern and tumor cells marked nuclear pleomorphism, and solid or syncytial pattern (H&E X200),

b tumor cells are immune-reactive for CD30 (CD30, X200), c nuclear expression of OCT3/4 (OCT3/4 X200)

Sawamura et al. 1998; Wong et al. 2005). According to the consisted components and malignancy, these tumors are further categorized as germinoma and teratoma, germinoma and/or teratoma (mainly) along with other malignant elements, and malignant GCTs (YST, CC, or EC mainly) associated with other elements (Matsutani et al. 1997). In IGCTs, only germinoma and teratoma are likely to be encountered as pure tumor types (Vasiljevic et al. 2015) and the other types are mostly part of mixed GCTs (Vasiljevic et al. 2015). Immunostains of mixed GCT are like those of the pure GCT.

respectively). Lower elevated titers of b-hCG and/or AFP occurred in immature teratoma (30– 590 mIU/ml and 7.5–500 ng/ml, respectively), embryonal carcinoma (EC) (83 mIU/ml and 183– 700 ng/ml, respectively), mixed germinoma and teratoma (61 mIU/ml and 7.3–143 ng/ml, respectively), and mixed EC (mainly) (110 mIU/ml and 58 ng/ml, respectively) (Matsutani et al. 1997). Correlation with levels of serum and CSF tumor markers in patients with synchronized samples, linear correlation between serum and CSF b-hCG and AFP was observed (Hu et al. 2016). Secreting GCT was defined by SIOP with serum and/or CSF AFP >25 ng/ml or serum and/or CSF b-HCG >50 mIU/ml (Biassoni et al. 2020; Seregni et al. 2002). Treatment may be initiated without diagnostic surgery for a secreting tumor (Murray et al. 2015). In the SIOP-CNSGCT-96 trial for intracranial germinoma, the serum/CSF AFP levels of the patient had to be ≤ 25 ng/ml and HCG levels ≤ 50 mIU/ml (Calaminus et al. 2013). Serum/CSF AFP >1000 ng/ml in NGGCT is considered as highrisk disease, and intensified chemotherapy is required (Biassoni et al. 2020). In infants, it should be interpreted serum or CSF AFP levels carefully because of high AFP levels in newborn and decreasing levels with age. Research showed that serum AFP is normally elevated at birth in term (mean serum level 41,687 ng/ml) and preterm babies before 37 gestational weeks (mean serum level 158,125 ng/ml) and gradually declines into an average of 8 ng/ml between 6 months and 2 years of age (Blohm et al. 1998).

16.3.7 Tumor Markers Except pure germinoma and mature teratoma, other intracranial GCTs are capable of secreting tumor markers including AFP and/or b-hCG that can be detected in serum and CSF (Calaminus et al. 1994; Hu et al. 2016; Matsutani et al. 1997). Among 92 patients with primary IGCTs, serum AFP and/or HCG elevated in 36 patients (Matsutani et al. 1997). The range of marker elevation relates to histopathological subtypes. Elevated titers of serum b-hCG were observed in germinoma with STGCs (40–690 mIU/ml). In choriocarcinoma (CC) and mixed GCT (mainly CC), highly elevated b-hCG titers were observed (2120–32,000 mIU/m and 6000 mIU/ml, respectively). Yolk sac tumor (YST) and mixed GCT (mainly YST) had highly elevated serum AFP titers (2700–9500 ng/ml and 3380–6700 ng/ml,

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16.3.8 Staging Staging serves to define localized or disseminated CNS GCTs. The work-up of staging includes CSF cytology for tumor cells and MRI of brain and spine for macroscopic dissemination (Murray et al. 2015). Metastasis IGCT in the SIOP-CNS96 trial was defined as the presence of >1 intracranial focus (besides bifocal tumor), spinal metastasis, metastasis outside CNS, or tumor cells in CSF (Calaminus et al. 2013, 2017). Including macroscopic metastasis and/or positive CSF cytology, the incidence of metastasis in germinomas (n = 235) and NGGCT (n = 149) was 19.1% (n = 45) and 22% (n = 33), respectively (Calaminus et al. 2013, 2017).

16.3.9 Histogenesis In human, totipotent cells are derived from the fertilization egg. As proceeding to the early blastocyst, inner cell mass (ICM) and trophoblast (trophectoderm) are formed. Embryonic stem cells (ESCs) are identified in ICM. At late blastocyst, ICM gives rise to lineages of epiblast and primitive endoderm (hypoblast) (Hackett and Surani 2014). The trophectoderm forms the future fetal part of placenta, the hypoblast generates the yolk sac, and the pluripotent epiblastderived stem cells (EpiSC) give rise the three germ layers of the future embryo and primordial germ cell (PGC) (De Miguel et al. 2009). The ‘germ cell theory’ was at first summed up by Teilum. He hypothesized that gonadal GCTs were transformed from primordial germ cells (PGCs) with differentiation to seminoma or different types of NGGCTs (Teilum 1968). Sano in 1998 doubted the validity of single cell theory through his clinical observations in intracranial GCTs (IGCTs). Compared with the most differentiated GCTs (EC, YST, and CC), germinoma (the most undifferentiated GCT) behaves like a benign tumor and demonstrates the highest survival rate among all malignant IGCTs. He assumed that in GCTs, germinoma might be the only true tumor derived from PGCs. The other

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NGGCT might be derived from the enfolded and misplaced embryonic cells in different stages of embryogenesis (Sano 1999). Oosterhuis and Looijenga reported a comprehensive developmental pathogenetic model for the origin of all GCTs (Oosterhuis and Looijenga 2019). The authors highlighted that the different histological types of GCT were determined by the latent developmental and reprogramming potential of their cells of origin (Oosterhuis and Looijenga 2019). Germinoma is characterized by global hypomethylation in which indicates its PGC origin. In a combined genomic and epigenomic study of 61 histologically verified IGCTs and testicular GCTs, the authors considered that MAPK/PI3K pathway mutations are the main drivers for most types of IGCTs. They proposed that ICGT development arose from the mutation harboring PGC. Germinoma may be initiated directly from the mutated PGCs. Other types of IGCT are developed by the differentiation of the mutated PGCs through epigenetic reprograming in addition (Fukushima et al. 2017). PGCs migrate after specification. In mouse, PGCs appear first in the posterior primitive streak at E7.5 that migrate through the path of endoderm, hind gut tissue, mesoderm (E8–E9.5) and then move to the gonadal ridges bilaterally as a component of gonad formation (E10.5–E11). PGCs stop migration as arriving the gonads (Richardson and Lehmann 2010; Anderson et al. 2000; Molyneaux et al 2001). The migration of PGCs in human is similar to mouse. A study was performed using human specimens of 5– 14 weeks post-conception (wpc). From 6 wpc forward, the migration of PGCs from the hid gut to the bilateral gonadal ridges passes through the established connections of the developing nerve fibers in high gut with the sympathetic system (Mamsen et al. 2012). For the survived PCGs that fail to reach the gonadal ridge, ectopic migration along the sympathetic trunk and body midline may occur and stop in extragonadal tissues (including CNS) that give rise extragonadal germ cell tumor (Richardson and Lehmann 2010; Oosterhuis and Looijenga 2019; Oosterhuis et al. 2007; Arora et al. 2012).

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16.4

Imaging and Radiologic Features

16.4.1 Location The location of CNS GTCs correlates with age at diagnosis, clinical manifestations, and histopathological subtypes distribution. Intracranial GCTs (IGCTs) are located in the pineal region, neurohypophysis (NH), multiple sites (including bifocal tumors), basal ganglia (BG), cerebral ventricle, and other rare locations. Cerebral ventricle GCTs (mostly immature teratoma) are diagnosed especially in the early postnatal period (Isaacs 2002; Wong et al. 2005) (Figs. 16.6 and 16.7). Intraspinal tumors (mainly germinomas) are rare and mainly distribute in the thoracic or thoracolumbar region (Biswas et al. 2009). Germinoma with diffuse subependymal spread is a unique entity in multiple sites (Krueger et al. 2016) (Fig. 16.8). Bifocal tumors are mainly pineal-NH tumors. The main part of these tumors may be seen at the pineal or NH region (Matsutani et al. 1997) (Fig. 16.9). BG

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GCTs can be unilateral or bilateral (rare) (Oyama et al. 2005) (Fig. 16.10). A comparison of the arising locations of IGCTs is shown in Table 16.2 (Keene et al. 2007; Matsutani et al. 1997; Oyama et al. 2005; Wong et al. 2005). The incidence of childhood IGCTs in the five most common intracranial locations was pineal region (71.2–80.8%) (Oi et al. 1998; Wong et al. 2011a), NH (sellar-suprasellar compartment) (19.1%) (Wong et al. 2005), bifocal pineal-NH (95.5% unreported data from Taipei VGH), BG (70.8%, unreported data from Taipei VGH), and cerebral ventricle (8.5%) (Table 16.3) (Wong et al. 2005). In non-secreting IGCT, we have to differentiate with other tumor entities arising in these locations (Figs. 16.11, 16.12 and 16.13). The sex ratio of GCTs arising in the pineal region, BG, bifocal, and cerebral ventricle is much higher than GCTs in NH region (Goodwin et al. 2009; Wong et al. 2005). The distributions of GCT subtypes in different intracranial anatomical locations were similar between the reported cohort series I (Matsutani et al. 1997) and the reported series II (Wong et al. 2005). However, in

Fig. 16.6 Contrast-enhanced T1WI reveal different sites of origin of intracranial germ cell tumors including tumor in the a NH (suprasellar region), b pineal region, c bifocal tumor, d basal ganglia, (e) hypothalamus, and f cerebellum

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Fig. 16.7 Congenital immature teratoma in a 3-monthold boy. Contrast-enhanced T1WI a–c showed a large heterogeneously enhanced tumor occupying the bilateral

lateral ventricles. d Follow-up CT image after radical resection of the tumor

series II, 7 ventricular immature teratomas occurred in first year of life (Table 16.4). CT brain scan is the earliest tool for radiological investigation of intracranial GCTs (IGCTs) (Chang et al. 1989). Gadoliniumenhanced MRI of the brain and spinal axis is presently the most powerful. It helps the diagnosis and differentiation of CNS GCTs from other tumor entities in different intracranial locations and radiological staging (Chang et al. 1989; Fujimaki et al. 1994; Kinoshita et al. 2016; Murray et al. 2015; Wu et al. 2017). Radiological features (germinoma and NGGCTs), associated hydrocephalus, vascularity, macroscopic metastasis status, and recurrence can be identified. The enhancement of germinoma can be homogeneous or heterogeneous. NGGCTs are exclusively heterogeneously enhanced and very often associated with small or large cysts (Liang et al. 2002).

16.4.2 Germinoma (See 16.3.1) In CT scan, germinoma is a well-demarcated isodense to hyperdense mass with homogeneous enhancement in the solid part (Chang et al. 1989; Fujimaki et al. 1994). On MRI, it is usually a well-defined, round, ovoid, or lobulated mass with isointensity to hypointensity signal compared to gray matter on both T1WI and T2WI (Figs. 16.12a and 16.14). Homogeneous enhancement and restricted diffusion are usually noted in the solid portion. Heterogeneous enhancement is often seen if the tumor is large, probably due to microcyst formation and necrosis (Douglas-Akinwande et al. 2009; Fujimaki et al. 1994; Liang et al. 2002; Wu et al. 2017) (Fig. 16.15). Small cysts to solitary cystic components may present (Fig. 16.16). Locational specific radiological features may help the predicting diagnosis of germinoma, such as

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Table 16.2 Comparison of intracranial germ cell tumor locations in five selected cohort series Cohort series

(Matsutani et al. 1997)

NCC Japan (Takami et al. 2020a)

Mayo Clinic (Takami et al. 2020a)

Taipei VG (Wong et al. 2005)

Canadian Cohort (Liu et al. 2020)

Total cases

N = 153

N = 154

N = 80

N = 138

N = 121

Mean age (years)

16.1

10.6

11.6

3–18

Median age (years)

17.6

16.9

15

17

Age range (years)

2–45

0–60

0–56

0–17

Male to female ratio

3.9:1

5.4:1

5.7:1

3.8:1

3.5:1

Histological Dx (%)

100

99.4

86.3

75.5

79.3

Locations

Number of cases (%)

Pineal

78 (51)

81 (52.6)

40 (50.0)

58 (42)

65 (53.1)

NH

46 (30.1)

20 (13.0)

17 (21.3)

36 (26.1)

37 (30.6)

Multiple

13 (8.5)

22 (14.3)

18 (22.5)

Bifocal

12 (7.8)

7 (4.5)

15 (18.8)

9 (6.5)

10 (8.3)

a

6 (5)

Pineal mainly

5 (3.3)

NH mainly

7 (4.6)

Bifocal + 3rd lesion DVWI

7 (4.5) 1 (0.7)

Others Basal ganglia

5 (3.3)

8 (5.2)

3 (3.8%)

13 (8.4)

0 (0)

25 (18.1)

Cerebral ventricle

3 (2)

7 (5.1)

Cerebellum

3 (2)

1 (0.7)

Corpus callosum

1 (0.7)

Other

9 (5.8)

a

2(1.4)

5 (6.3)

3 (2.5)

DVWI diffuse ventricular wall infiltration; N number of patients; NH neurohypophysis, sellar-suprasellar compartment; hemisphere GCTs 27 (19.6%) including basal ganglia GCT 25 (18.1%) and other sites 2 (1.4%)

a

Cerebral

Table 16.3 Proportions of intracranial germ cell tumors and other tumor entities in the five common neuroanatomical locationsa Locations

No. of cases

Cerebral hemisphereb

194

NH

189

Pineal and Pineal-NH

74

Ventricle

82

a

Cases of tissue diagnosis 179 166 54 79

Cases of clinical diagnosis 7 17 15 2

Types and percentage (%) of tumors Ast

GCT

Epen

Gang

Oli

49

13.9

10.3

7.2

6.2

Cran

Ast

GCT

Pit

Ham

43.4

21.2

19.1

5.3

4.2

GCT

PB

Ast

PC

79.8

9.5

2.4

1.2

Epen

CPT

SEGA

GCT

Men

43.9

23.2

14.6

8.5

4.9

Adopted from Table 8 (Wong et al. 2005) The vast majority of GCT tumors in cerebral hemisphere locate in basal ganglia (see Table 16.2). Ast astrocytic tumor; CPT choroid plexus tumor; Cran craniopharyngioma; Epen ependymal tumor; Gang ganglioglioma; GCT Germ cell tumor; Ham hamartoma; Men meningioma; NH neurohypophysis, sellar-suprasellar compartment; Olig oligodendroglial tumor; PB pineoblastoma; PC pineocytoma; Pit: pituitary adenoma; SEGA subependymal giant cell astrocytoma

b

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Fig. 16.8 Germinoma with diffuse subependymal spread in a 16-year-old boy, contrastenhanced T1WI showed diffuse subependymal spreading of tumor involving bilateral lateral and 3rd ventricles (arrows in a and b)

thickened pituitary stalk (neurohypophyseal tumor), diffuse subependymal infiltration (multifocal tumor), shrinkage of basal ganglia-thalamus and cerebral peduncle (basal ganglia tumor), and local infiltration (pineal tumor) (Figs. 16.8, 16.10, 16.12a, 16.14b and 16.17).

16.4.3 Teratoma and Intracranial Growing Teratoma Syndrome (GTS) (See 16.3.2) CNS teratomas always present with heterogeneous appearance with variable attenuations and signal intensities. In CT scan, teratoma usually appears as a tumor with different degree of calcification, fat and cystic components (Liang et al. 2002). In MRI, teratomas are usually hypo- to isointense on T1WI and hyperintense on T2WI. The solid part of tumor is always well-enhanced. In mature teratoma, a well-marginated mass with fat is a diagnostic feature (Fig. 16.18a, b). Immature teratoma has less calcification and cystic component comparing to mature teratoma. In immature or malignant teratoma (teratoma with somatic-type malignancy), the tumor margin is obscure with irregular contour, homogeneous enhancement, and sometimes perifocal edema in surrounding brain tissues. Fat and calcified components are not seen, which is very different from their benign counterparts (Kyritsis 2010) (Fig. 16.18c, d). Intracranial congenital

teratoma commonly demonstrates large heterogeneous tumors with multi-cystic components (Koen et al. 1998). Intradural spinal teratoma is very rare and may be associated with spinal dysraphism (Keykhosravi et al. 2020; Koen et al. 1998) (Fig. 16.7). The radiological characteristics of NGGCT with GTS demonstrates increasing honey-comb-shaped multi-cysts with normalized tumor markers during/after adjuvant treatment (Kim et al. 2011).

16.4.4 Other Nongerminomatous Malignant GCT (NGMGCT) (See 16.3.3– 16.3.5) Pure intracranial NGMGCTs including yolk sac tumor (YST), choriocarcinoma (CC), and embryonal carcinoma (EC) are very rare and arise mainly in the pineal region. YST is the most common (Matsutani et al. 1997; Wong et al. 2005). The radiological manifestations can be nonspecific. In non-enhancing MRI, YSTs show an irregular hypointense to isointense lesion. The enhancing image may show either homogeneous or heterogeneous enhancement with tumoral hemorrhage and necrosis (Macvanski et al. 2012; Zhao et al. 2014) (Fig. 16.19). On plain CT, CC shows heterogeneous hyperattenuation. Contrast enhancement is prominent (Lv et al. 2010) (Fig. 16.20a, b). The presence of blood products showing in T2 sequences and intrinsic high T1

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Fig. 16.9 Pineal mainly (a) and NH mainly (b) bifocal germ cell tumors in contrast-enhanced T1WI

Fig. 16.10 a–c Basal ganglia germinoma (predictive diagnosis) with normal serum b-hCG titer. T2WI shows typically a small infiltrative lesion with shrinkage of basal

ganglia, thalamic region (white arrows) and cerebral peduncle atrophy (black arrows) on the right side

signal may be a differentiation from germinoma (Smirniotopoulos et al. 1992). ECs are very rare but aggressive (Jiang et al. 2017). MRI shows slight hypointense on T1WI and heterogeneous signal on T2WI with potential of intratumoral hemorrhage. Homogeneous to heterogeneous enhancement after contrast medium administration were reported (Jiang et al. 2017).

useful to detecting teratoma components, particularly fatty components, which is helpful for diagnostic prediction (Fig. 16.19c, d).

16.4.5 Mixed GCT (See 16.3.6) Mixed GCTs arise in all common intracranial locations (Keene et al. 2007; Matsutani et al. 1997; Takami et al. 2020b; Wong et al. 2005). Although definite histological diagnosis cannot be achieved by CT and/or MRI alone, imaging is

16.5

Clinical Manifestations

The clinical symptoms of CNS GCT correlate with age of patient, size of the lesion, tumor location, associated hydrocephalus, and b-hCG titer in serum or CSF. The diagnosis of intracranial GCTs (IGCTs) is often delayed, regardless of the apparent malignant nature in most of them. Symptoms may be present for months to years prior to diagnosis along with tumor progression (Rushing et al. 2006; Sethi et al. 2013; Sonoda et al. 2008). The delay from

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Fig. 16.11 a–f Contrast-enhanced T1WI depict differential tumor entities besides germ cell tumors involving pineal region: a pineocytoma, b pineoblastoma,

c astrocytoma, d anaplastic astrocytoma, e atypical teratoid/rhabdoid tumor, and f meningioma

symptom onset to treatment vary with tumor locations, as 31.6 months, 27.9 months, 21.7 months, and 8.1 months in neurohypophysis (NH), basal ganglia (BG), bifocal (pinealNH), and pineal GCTs, respectively (Sonoda et al. 2008). Patients with IGCTs may present symptoms of increased intracranial pressure (IICP) for a large tumor or associated tumoral hydrocephalus. Macrocephaly is often seen in infants with congenital intracranial teratoma (Isaacs 2002; Koen et al. 1998). b-hCG secreting GCTs may cause precocious puberty in boys and in girls (Nascimento et al. 2012; Rivarola et al. 2001; Starzyk et al. 2001). Pineal GCTs most commonly presented with hydrocephalus and IICP signs. An important eye sign, Parinaud syndrome, occurs in approximately around 50% of patients. Central diabetes insipidus (DI) may also be presented (Echevarria et al. 2008). Patients with NGGTCs tend to have larger tumors and more severe neurologic

compromise at the time of diagnosis (Packer et al. 2000). Neurohypophyseal (sellarsuprasellar compartment) GCTs may be local or widely infiltrated and cause pituitary/hypothalamic dysfunction. The most common symptoms are central diabetes insipidus (CDI), followed by IICP, visual symptoms, abnormal sexual development, panhypopituitarism, and isolated growth failure (Esfahani et al. 2020; Jennings et al. 1985; Wang et al. 2010b). Short stature, precocious puberty, excess body weight gain or loss may be presented prior to diagnosis. In bifocal pineal-NH GCTs, patients may present Parinaud syndrome and hydrocephalus in addition (Esfahani et al. 2020). The most common symptom for basal ganglia GCTs is hemiparesis (Sonoda et al. 2008). Extrapyramidal signs (e.g., choreoathetosis), CDI, and precocious puberty may occur (Oyama et al. 2005; Sonoda et al. 2008). In bilateral tumors, patients usually present spastic

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Fig. 16.12 a–f Neurohypophyseal (sellar-suprasellar compartment) tumors. Contrast-enhanced T1WI depicts different entities of tumors: a germinoma (predictive diagnosis with thickened pituitary stalk and normal serum

titers of AFP and b-hCG in a 12-year-old girl with central DI, b mixed germ cell tumor in a 9-year-old girl with central DI, c, d craniopharyngioma and e, f optic glioma

hemiparesis, dysarthria, and mental deterioration (Oyama et al. 2005).

applied to patients according to this classification (Calaminus et al. 2013, 2017; Matsutani et al. 1997; Sawamura et al. 1998). In both secreting and non-secreting CNS GCTs, surgical intervention helps to relieve symptoms, to obtain accurate histopathological diagnosis, and to investigate molecular biology for precise targeted treatment and the development of new therapeutic modalities (Echevarria et al. 2008; Matsutani et al. 1997; Murray et al. 2015; Takami et al. 2019). Patients with consistent image of IGCTs and serum/CSF markers (AFP and/or bhCG) above national-defined protocol threshold may not need histological diagnosis before treatment (Murray et al. 2015). In the SIOPCNS-GCT-96 trial for intracranial germinoma, the serum/CSF AFP levels had to be ≤ 25 ng/mL and HCG levels ≤ 50 IU/L to treat for germinomas (Calaminus et al. 2013). Teratomas (non-secreting) and NGGCTs with growing teratoma syndrome (GTS) can be cured

16.6

Therapeutic Approaches

The therapeutic approach of CNS GCTs integrates location, histopathology, staging, tumor marker level (see 16.3.1–16.3.7) and therapeutic classification (Matsutani et al. 1997). Other clinical factors (e.g., size, vascularity, hydrocephalus) should be considered in addition. The therapeutic classification of IGCT initiated by Dr. Matsutani in 1997 (Matsutani et al. 1997) is a fundamental guideline for the treatment of intracranial GCTs (IGCTs) with different malignance. Based on the subtypes of pure GCTs and the components of mixed GCTs, three therapeutic prognostic groups (good, intermediate, and poor) are classified (Matsutani et al. 1997). Different intensities of cytotoxic regimens are

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Fig. 16.13 a–e Basal ganglia tumors. Contrast-enhanced T1WI depicts different entities of tumors: a Germinoma, b Non-germinomatous germ cell tumor, c ganglioglioma, d astrocytoma, and e anaplastic astrocytoma

Fig. 16.14 a–c Pineal germinoma. a A small T2 hyperintense tumor at the pineal region (arrow) of a 12-year-old boy of normal serum b-hCG titer. b, c Another two well-enhanced pineal germinomas in contrast-enhanced T1WI (arrows)

Fig. 16.15 a–c Variable tumor size, location, enhancement, cystic components, and sellar-suprasellar extension of neurohypophyseal germinomas detected on contrast-enhanced T1WI

after total tumor resection (Kim et al. 2011; Matsutani et al. 1997; Takami et al. 2019). Germinomas are highly radiosensitive, whereas nongerminomatous malignant GCTs (NGNGCTs) are less radiosensitive. The

therapeutic aim for primary germinomas is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination (Calaminus et al. 2013; Chen et al. 2012; O’Neil et al. 2011). In primary

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Fig. 16.16 a–c Contrast-enhanced T1WI (a, b) and T2WI (c) depict characteristic microcysts in a suprasellar germinoma

Fig. 16.17 a, b Basal ganglia germinoma. A round tumor with heterogeneous hypo- to hyperintensity on T2WI (arrow in a) and well enhancement on contrast-enhanced T1WI (arrow in b)

Fig. 16.18 a–d Teratoma. a, b A large mature teratoma with heterogeneous signal in both T1WI and T2WI (arrow in b) with the presence of fat signal (arrow in a). Fat tissue and tooth structure were found in tumor specimens. c, d A

solid suprasellar immature teratoma with small focus of high signal in T1WI (arrow in a). Heterogeneous enhancement after administration of contrast medium is noted (arrow in b)

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Fig. 16.19 a, b Pineal yolk sac tumor in a 16-year-old boy. A small irregular-shaped tumor at the pineal region is detected. Heterogeneous high signal intensity within the tumor was found in T1WI (arrow in a), which is corresponding to tumor hemorrhage. Heterogeneous enhancement after administration of contrast medium is noted (arrow in b). c, d A mixed germ cell tumor in a 9-

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year-old boy with large well marginated tumor at pineal region. Heterogeneous signal with high-intensity fatty component within the tumor was found in T1WI (arrow in c). Mild enhancement of the solid portion after infusion of contrast medium is noted (arrow in d). Histological features showed a mixed germ cell tumor with germinoma, teratoma, and yolk sac tumor components

Fig. 16.20 a, b Choriocarcinoma in a 9-year-old boy with a heterogeneous iso to hyperintense T1 signal tumor at pineal region (arrow in a). Heterogeneous enhancement is noted on contrast-enhanced T1WI (arrow in b)

NGMGCTs, the aim is to increase survival utilizing more intensive chemotherapy and radiotherapy (Calaminus et al. 2017).

16.6.1 Surgical Intervention The surgical strategies of IGCTs cover biopsy, radical resection, and shunting procedures. For biopsy w/o image guidance, the surgical techniques include neuroendoscopy, stereotaxy, and open biopsy. Neuroendoscopic biopsy is used for the diagnosis of non-secreting IGCTs located at neurohypophyseal (NH), pineal, multifocal/bifocal, and other periventricular regions (Oertel and Keiner 2019; Onuma et al. 2012; Wong et al.

2011a). Endoscopic endonasal transsphenoidal surgery (EETS) is limited for NH or bifocal tumor involving sella turcica (Day et al. 2020; Esfahani et al. 2020). Stereotactic biopsy can be selectively performed in basal ganglia or pineal tumors (Esfahani et al. 2020; Regis et al. 1996). Tumoral bleeding during or after tumor biopsy may occur (Wong et al. 2011a). Radical resection of non-secreting teratomas and NGGCTs with GTS helps to achieve cure of the diseases. Besides, in NGGCTs especially in mixed GCTs, radical resection contributes to early symptom relief and provides adequate tumor samples for accurate histopathology and molecular biology studies (Matsutani et al. 1997; Phi et al. 2018; Sawamura et al. 1998; Takami et al. 2019; Takami et al. 2020a).Residual tumor

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after end of treatment in NGMGCTs associated with relapse and poor prognosis, surgical resection is recommended (Calaminus et al. 2013). The approaches and complications for radical resection of IGCTs vary according to their location, size, and extension. For pineal NGGCTs, the established surgical approaches for radical excision included parietal transcallosal approach (Dandy 1921), occipital transtentorial approach (Jamieson 1971), posterior transventricular approach (Van Wagenen 1931), transchoroidal approach (Viale et al. 2001), transcallosal interforniceal approach (Winkler et al. 2000), and infratentorial supracerebellar approach (Stein 1971). An alternative lateral infratentorial/supracerebellar approach in lateral position was lately developed (Kulwin et al. 2016). In large pineal tumors, a combined supra/infratentorial approach may be required (Ziyal et al. 1998). The relative position of the tumor with the internal cerebral vein should be considered for an optimal surgical approach (Azab et al. 2014). For solitary NH NGGCTs, it is a selection of endoscopic endonasal transsphenoidal approach or open craniotomy approach for tumor resection according to the presence of tumor extension into the sella turcica (Esfahani et al. 2020). For sizable basal ganglia NGGCTs, radical resection is performed utilizing the techniques of preoperative pyramidal tract identification, and intraoperative neuronavigation along with subcortical mapping (Quan et al. 2015). NGGCTs arising in cerebral ventricles are mainly immature teratomas in infants and rarely mixed GCTs (Goetz et al. 2002; Wong et al. 2005). Teratomas within cerebral ventricles require radical resection, but hypervascular tumors may cause perioperative mortality (Wong et al. 2005). Hypervascular IGCTs are occasionally encountered and may impact the risk of tumor resection (Monroy-Sosa et al. 2018; Wang et al. 2013). Preoperative embolization, chemotherapy or radiosurgery may avoid the technically challenging surgical resection (Lee et al. 2018a; Razzaq and Cohen 1997; Wang et al. 2013). Above 60% of IGCTs presented obstructive hydrocephalus at diagnosis. The incidence rate

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differs with tumor location (Wong et al. 2011b). The management is a selection of radical tumor resection, endoscopic third ventriculostomy (ETV), temporarily long tract external ventricular drainage (EVD), and ventriculoperitoneal shunt (VP) implantation (Buatti and Friedman 2002; Wong et al. 2011a, b).

16.6.2 Chemotherapy and Radiotherapy Excluding mature teratoma and growing teratoma syndrome (GTS) in NGGCT, radiotherapy with/without chemotherapy is applied in both CNS germinoma and NGGCTs. For localized GCTs, traditionally, both germinoma and NGMGCT were treated with craniospinal irradiation (CSI) and tumor-bed boost (Bamberg et al. 1999; Calaminus et al. 1994, 2013, 2017; Goldman et al. 2015). Neoadjuvant chemotherapy was given to NGMGCTs (secreting tumors) in addition (Calaminus et al. 1994; Goldman et al. 2015). To reduce the long-term toxicities of radiotherapy (e.g., neurocognitive dysfunction and endocrinopathies) (Sawamura et al. 1998), alternative treatment strategies including chemotherapy only, focal radiotherapy preceded by chemotherapy, and reduced dose ventricular irradiation after chemotherapy have been investigated.

16.6.2.1 Primary Chemotherapy Chemotherapy only for the treatment of both germinomas and NGMGCTs is not effective with about 50% recurrence or progression (Balmaceda et al. 1996; Bamberg et al. 1999). 16.6.2.2 Treatment Strategies for Localized Tumors For localized tumors, neoadjuvant chemotherapy followed by focal radiation has been applied in IGCTs. In germinomas, the SFOP study achieved event-free survival of 84%. But 8 in a total of 10 patients with relapses had tumor recurrences in the periventricular area outside the radiation field (Alapetite et al. 2010). In NGMGCTs, a SIOP trial (CNS-GCT-96) also evaluated the feasibility

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of neoadjuvant chemotherapy followed by 54 Gy radiation to primary tumor bed. The 5-year progression-free survival was 72% (Calaminus et al. 2017). Neoadjuvant chemotherapy followed by ventricular irradiation has been utilized for this purpose. In germinomas, reduced dose ventricular irradiation (21.6–25.5 Gy) and primary tumor-bed boost (30–30.6 Gy) with/ without preceding chemotherapy produced a 3year event-free survival of 90% (Chen et al. 2012; Khatua et al. 2010) and yet preserved neurocognitive functioning (O’Neil et al. 2011). In NGMGCTs, a COG trial (ACNS1123) applied reduced dose and volume (30.6 Gy over ventricular field and 54 Gy over tumor bed) radiotherapy. The 3-year progression-free survival in 62 patients was comparable to the results of ACNS0122. But eight patients relapsed as distant spinal seeding (Fangusaro et al. 2019).

16.6.3 Metastasis (at Diagnosis), Relapsed, or Refractory Tumors For GCT with metastasis at diagnosis, craniospinal axis irradiation (CSI) is essential (Calaminus et al. 2013, 2017). For relapsed germinoma, salvage CSI is effective for survival (Calaminus et al. 2013; Hu et al. 2012). For refractory or relapsed NGMGCTs, low tumor burden and high dose chemotherapy with autologous stem cell rescue (HDC-ASCR) help to improve survival (Callec et al. 2020; Modak et al. 2004). AFP >1000 ng/mL in serum or CSF is a negative prognostic marker and intensified chemotherapy is needed (Biassoni et al. 2020).

16.6.4 New Therapeutic Modalities 16.6.4.1 Targeted Biologic Therapy KIT-RAS-MAPK and KIT-AKT-mTOR signal pathways are frequently involved in intracranial GCTs (IGCTs) (see 16.2.1) with 6.5–8% showing mTOR mutation (Ichimura et al. 2016; Wang et al. 2014). The mutated mTOR upregulates AKT pathway protein (AKT and 4EBP1)

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phosphorylation that enhances soft-agar colony formation. This event can be suppressed by mTOR inhibitor (pp242) (Ichimura et al. 2016) with potentiality of targeted therapy for refractory IGCTs. Highly expressed CDK4 and CDK6 were identified in pediatric and adult GCTs, respectively (Skowron et al. 2020). Furthermore, strong retinoblastoma protein (pRB) expressions were demonstrated in more differentiated GCTs (Vaughn et al. 2015). Phosphorylation of the pRB by CDK4/6 (in association with cyclin D) results in a cell’s passage through the G1-S interface (Harbour et al. 1999). The pathogenesis of many malignancies may be related to the dysregulation of CDKs (overexpression or amplification) (Hall and Peters 1996). CDK4/6 inhibition, prevents the phosphorylation of pRB, and induces cell cycle arrest and apoptosis in both pediatric and adult GCTs. A potent CDK4/6 inhibitor, in a phase 2 trial, Palbociclib was used in 29 evaluable patients with refractory extracranial GCTs achieving a favorable prognosis (Vaughn et al. 2015). Although stabilization by Palbociclib was documented in 1 patient with intracranial GTS presenting high pRB expression, the absorption of Palbociclib across the blood–brain barrier is relatively poor (compared to Abemaciclib) (O’Leary et al. 2016). Further analyses of CDK4/6 and pRB expressions in IGCT may be necessary for its application to treat patients with refractory IGCT or GTS.

16.6.4.2 Immunotherapy (See 16.2.5) Immunotherapy has been used in treatmentrefractory testicular GCTs (TGCTs). Clinical trials targeting anti-PD-1 (Pembrolizumab) and anti-PD-L1 (Avelumab) were terminated due to inefficacy (Adra et al. 2018; Kalavska et al. 2020; Mego et al. 2019). No response in Durvalumab or low response rate in Durvalumab plus Tremelimumab trial targeting anti-PD-L1 was observed (Kalavska et al. 2020; Necchi et al. 2019). There are other ongoing clinical trials evaluating immunotherapy utilized in cancer patients and GCT patients (Kalavska et al. 2020).

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16.7

Follow-Up and Prognosis

16.7.1 Follow-Up Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction months to years after treatment. The risk factors include host factors (young age at diagnosis, physical disability, comorbidity, genetic predisposition syndromes, pre-existing neurodevelopmental state, neurological and pituitary hormone deficits), surgical-related complications, cranial irradiation, and chemotherapy (Butler et al. 1994; Castellino et al. 2014; Sawamura et al. 1998). Continuous surveillance and assessment of physical disability, pituitary hormone deficiency, and quality of life may lead to improvements in treatment protocols, transdisciplinary interventions, and after-treatment rehabilitation.

16.7.1.1 Cognitive Dysfunction Young age and cranial irradiation are the most important factors of cognitive dysfunction (Aarsen et al. 2009; Grill et al. 1999; Qaddoumi et al. 2011). CNS GCTs may occur in young infants (mainly teratoma) (Murray et al. 2015). In noninfant patients, the majority are germinoma and NGMGCTs (Goodwin et al. 2009). The treatment requires radiotherapy of different dosage and volume with/without additional chemotherapy. In relapsed or refractory tumors, more intensive salvage treatment (HDC-ASCR, reirradiation) are needed for tumor control (Calaminus et al. 2013, 2017; Matsutani et al. 1997). The anatomical structures involved by IGCTs in non-infant patients are critical to normal sexual and cognitive development. Reduction of long-term disability is a major challenge. Early diagnosis may alleviate part of the tumorrelated risk factors (Ono et al. 1994). Significant neurocognitive disorder occurs in patients with IGCTs before and after radiotherapy that attributes to tumor location. Patients with basal ganglia tumors performed significantly worse than other locations in most domains of neurocognitive function (Liang et al. 2013; Park et al. 2017). Besides, tumor location (basal

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ganglia), and irradiation field/dosage appeared to be the crucial factors associated with certain neuropsychological, emotional, behavioral dysfunctions, and quality of life (Liang et al. 2013). The adverse effect of chemotherapy (in addition to radiation) for intracranial germinoma is relatively limited (Osuka et al. 2007).

16.7.1.2 Other Late CNS Complications After Cranial Radiotherapy Late CNS complications after anticancer treatment occur at more than 6 months to years after irradiation (Soussain et al. 2009). In CNS GCTs, among 85 survivors with a median follow-up of 86 months, post-irradiation cerebral atrophy/ necrosis, occlusive vasculopathy of large intracranial vessels, and secondary tumors were observed in 19, 3, and 4 patients, respectively. The secondary tumors included two glioblastomas and two meningioma (Sawamura et al. 1998). The SEER 1973–2004 CNS GCTs data analysis recruited 405 germinomas and 94 NGGCTs. The inclusion criteria were: age at diagnosis of 0–30 years and survival of at least 5 years after initial diagnosis. Comparison with peers, in germinomas, there was a nearly 59 fold increase in risk of death from stroke. For the whole cohort, at 25 years, the cumulative incidence of subsequent malignant neoplasms (SMN) was 6.0% and sarcomas were more common in germinomas (Acharya et al. 2015; Lee et al. 2018b). 16.7.1.3 Physical Disability and Pituitary Hormone Deficiency In an outcome measure of 25 IGCTs survivors in children aged ≥ 6 years, panhypopituitarism was the most common long-term complication and significant physical disability was observed (Tso et al. 2019). Among 85 survivors of CNS GCTs, 87% (74/85) of patients had physical sequelae with low Karnofsky performance scale in 26 patients due to severe motor paresis, visual impairment, or cognitive dysfunction. Hormonal replacement was required in 68% (58/85) of

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patients. All of the patients with neurohypophyseal tumors and some patients with pineal tumors had pituitary dysfunction (Sawamura et al. 1998).

16.7.2 Prognosis In IGCTs, following treatment according to therapeutic classification (Matsutani et al. 1997) with reference to tumor markers and staging, the 5-year overall survivals (OS) of germinomas, germinoma with syncytiotrophoblastic giant cell (STGC), mature teratomas, and NGMGCTs ranged from 95.4–98.6%, 83.3%; 93–100%; and 76.1%, respectively (Matsutani et al. 1997; Takami et al. 2019). In the clinical trial studies of SIOP-CNS-GCT 96, the OS of localized germinoma in patients receiving craniospinal radiotherapy with/without combined chemotherapy, the 5-year OS was 0.95 ± 0.02 and 0.96 ± 0.03, respectively (P = 0.72). Compared with localized disease and metastasis disease, there was no survival difference (Calaminus et al. 2013). For the OS survival of localized and metastatic NGMGCTs, the 5-year OS was 0.82 ± 0.04 and 0.75 ± 0.08, respectively, with no survival difference (P = 0.37) (Calaminus et al. 2017). An analysis was performed utilizing the United States SEER database on 5-year survivors of CNS germinoma and NGGCT with age at diagnosis of 0–30 years. Among 405 germinoma survivors, the OS at 10 years, 20 years, and 30 years of follow-up was 92.3%, 84.1%, and 61.9% respectively. Among 83 NGGCT survivors, the 10 years, 20 years, and 30 years of survivals was 92.7%, 86.7%, and 86.7%, respectively. If OS of all GCTs is stratified by decades of diagnosis, there was no improvement of survival in more recent treatment. The causes of deaths were attributable to recurrence, progression of primary disease, second tumor, stroke, and others (Acharya et al. 2015) (Table 16.4). The prognosis of NGMGCTs differs from histopathological subtypes. The 5-year survival of immature teratoma and pure NGMGCTs (i.e., embryonal carcinoma, yolk sac tumor, and choriocarcinoma) was 86%, and 27.3%,

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respectively (Matsutani et al. 1997; Sano 1999). The 3-year survival rate of teratoma with malignant transformation, yolk sac tumor, and embryonal carcinoma was 50%, 33%, and 20%, respectively. Patients with choriocarcinoma died within one year (Sano 1999). The survival of spinal mature teratoma was as good as its intracranial counterpart (Agrawal et al. 2010). In mixed tumors, the prognosis differs from histological components and the presence of somatictype malignancies. Three subgroups of mixed tumors were divided according to the malignancy and proportion of histological components (mixed germinoma and teratoma, mixed tumor mainly consisting of germinoma or teratoma, and mixed tumor mainly consisting of CC, EC, or YST). The 5-year survival rate was 84.7%, 52.5%, and 9.3%, respectively (Matsutani et al. 1997). For intracranial germinoma, negative prognostic factors are atypical site of tumor location (basal ganglia and cerebral cortex) (Takami et al. 2019), chromosomal instability (gain of 2q and 8q, and loss of 5q, 9p/q, 13q, and 15q) (Takami et al. 2019), and NOS2 expression (Takami et al. 2020a). Positive prognostic factors are lower tumor cell count (higher immune cell infiltration), and high expression of CD4 (Takami et al. 2020a). Tumor metastasis (Calaminus et al. 2013), residue tumor at the end of treatment (Calaminus et al. 2013), serum HCG level (Ogino et al. 2005), and tumor with STGC (Shibamoto et al. 1997) do not influence the prognosis. For fetal intracranial teratomas, the majority of these fetuses died before or immediately after birth. Moreover, the overall survival rate was 7.8% in 90 fetuses who had intracranial teratoma (Isaacs 2014). The prognosis for intracranial growing teratoma syndrome (GTS) is crucial for timely radical resection (Kim et al. 2011). For intracranial NGMGCTs, the negative prognostic factors are residue disease at the end of treatment, diagnostic serum or CSF AFP level >1000 ng/mL (Calaminus et al. 2017), and logarithmic decrease of serum AFP or HCG in response to chemotherapy (Kawaguchi et al. 2011). Metastatic disease has no prognostic significance in both germinomas and NGMGCTs (Calaminus et al. 2013, 2017).

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Table 16.4 Comparison of the distribution of intracranial GCT subtypes according to intracranial locations Histology

Tumor location [Cohort series I(I) and Cohort series II (II)] (Matsutani et al. 1997; Wong et al. 2005)

Germinoma Germinoma w/ STGCs

No. of cases

Pineal region

I

I

II 55

75

8

NH II

23

29

1

I 19

II 19

5

Multiple sites

Basal ganglia

Ventricles

Other sites

I

II

I

I

II

I

II

8

7

3

0

2

2

2

II 18

0

ND ND

0

NGGCT

90

63

53

29

22

17

3

2

5

6

ND

7

9

2

Teratoma

30

22

21

11

4

1

0

0

0

2

ND

7

5

1

Mature

19

8

17

7

0

0

0

0

0

0

0

2

1

Immature

7

14

3

4

3

1

0

0

0

2

7

1

0

Malignant u

4

ND

1

ND

1

MD

0

ND

0

ND

ND

2

0

Choriocarcinoma

3

ND

2

ND

1

ND

0

ND

0

ND

ND

0

ND

ND

Embryonal carcinoma

5

ND

1

ND

1

ND

0

ND

1

ND

ND

ND

2

ND

Yolk sac tumor

3

10

3

4

0

5

0

0

0

0

ND

0

0

1

49

19

27

8

16

6

3

1

1

4

ND

0

2

0

0

2

0

1

0

1

0

0

0

0

ND

0

ND

0

0

10

0

5

0

4

0

1

0

0

ND

0

ND

0

138

78

58

46

36

13a

9b

5

24

0

7

11

4

Mixed tumor Unclassified GCT Diagnostic by markers Total

153

ND no data; STGCs: syncytiotrophoblastic giant cells; a Multiple sites, including 8 cases of bifocal pineal mainly or neurohypophysis mainly tumors; b Multiple sites, all of the 9 cases were bifocal pineal mainly or neurohypophysis mainly tumors; u Malignant teratoma: teratoma with malignant transformation (teratoma with somatic-type malignancy)

16.8

Conclusion

In children, the age standardized incidence rate (ASR) is higher in Asian countries (Korea, Japan) and the ethnic group of Asian Pacific Islander in the USA (Kang et al. 2019; Makino et al. 2013; Ostrom et al. 2019). The incidence rate of GCTs in the cohort series of CNS tumors in children is higher in Asian countries (Japan, Korea, Taiwan) (Kang et al. 2019; Makino et al. 2013; Wong et al. 2005). CNS GCTs are heterogeneous in histopathological classification, locations, tumor marker secretion (Goodwin et al. 2009; Matsutani et al. 1997; Sawamura et al. 1998; Wong et al. 2005), genetics, molecular biology, immunology, and cell-type enrichment in tumor microenvironment (Bonouvrie et al. 2020; Fukushima et al. 2014b; Fukushima et al. 2017; Jung et al. 2020; Kalavska et al. 2020; Miyake et al. 2017; Okada et al. 2002; Phi et al. 2018; Reuter 2005; Siska et al. 2017; Sukov et al. 2010; Takami et al. 2020a; Wang et al. 2010a; Wang et al. 2014; Wolf et al. 2007). The diagnosis and management involve clinical manifestations, diagnostic

imaging, tumor location, histopathological diagnosis, staging, level of tumor marker at diagnosis, molecular prognostic factors, and residue tumor at-end-of treatment. In localized germinomas, reduced dose ventricular and tumor-bed boost radiotherapy with/without preceding chemotherapy produced a 3-year event-free survival of 90% (Calaminus et al. 2017; Chen et al. 2012; Khatua et al. 2010) and preserved neurocognitive functioning (O'Neil et al. 2011). For relapsed germinoma, salvage CSI is effective for survival (Calaminus et al. 2013; Hu et al. 2012). In the SIOP-CNS-GCT 95 study, among 235 intracranial germinomas, staging of tumors showed that 30 cases had macroscopic metastasis and in other 15 cases that a diagnosis of metastasis was based on positive cytology (Calaminus et al. 2013). For germinoma with metastasis at diagnosis, craniospinal axis irradiation (CSI) is reported to be essential (Calaminus et al. 2013). However, the possible effect of whole brain irradiation (WBI) in CSI in overall intellectual performance should be aware as it is given in the group of germinoma patients with metastasis diagnosed by positive CSF cytology alone (Liang et al. 2013). For

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refractory or relapsed NGMGCTs, low tumor burden and high dose chemotherapy with autologous stem cell rescue (HDC-ASCR) help to improve survival (Callec et al. 2020; Modak et al. 2004). Development of new treatment is necessity

in this group of patients. The diagnostictherapeutic algorithm of CNS GCTs is summarized in Fig. 16.21 with exclusion of patients having M1 metastasis (positive CSF cytology alone).

CNS Germ Cell Tumors Symptoms

Diagnostic

MRI (Brain and Spine) Imaging Features Serum Tumor Markers: AFP, βHCG

Intracranial Tumors

Serum Tumor Markers: AFP, βHCG

Hydrocephalus

CSF (LP) Tumor Markers: AFP, βHCG

Intraspinal Tumors

Non-Consistent Imaging Features

Consistent Imaging Features

≈*

Therapeutic

Biopsy/Resection HV Molecular Profiling

NGMGCT

Germinoma ↑**, M0

↑**, M2,3

↑*, M0

M2,3 CMT + CSI

CMT + RT

CMT + RT Relapse

Residue Tumor

Refractory/Relapse

Resection

HDCT/New Therapy

≈*, Tumor with normal institution established value of serum/CSF AFP and β-hCG; *, serum/CSF AFP ≤25ng/ml and serum/CSF β-hCG ≤50mIU/ml; **, serum/CSF AFP >25ng/ml and serum/CSF β-hCG < or >50mIU/ml;

Fig. 16.21 Diagnostic-therapeutic algorithm of CNS germ cell tumors

CSI

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Acknowledgements The authors thank for the license provided from John Wiley and Sons and Copyright Clearance Center for the reuse of a table (Table 8) from the publish paper titled ‘Primary pediatric brain tumors’ in Cancer. This table is reused in this chapter of a new book titled ‘Human brain and spinal cord tumors: from bench to bedside. Volume 2—the path to bedside management.

Funding This work was supported by Ministry of Health and Welfare grant (MOHW109-TDU-B-212-134010 and MOHW110TDU-B-212-144010 to A.L.Y. and T.-T.W.); Ministry of Science and Technology grant (MOST108-2314-B-038061-MY3 to T.-T.W.), Taipei Medical University Hospital grant (109TMU-TMUH-15 to T.-T.W.), Taipei Medical University grant (DP2-109-21121-03-C-02-01; DP2-11021121-03-C-02-01 to T.-T.W.).

Abbreviations

CMT CSF CSI HDCT HV ICM Mo M1 M2 M3 PGC *

"* "**

Chemotherapy Cerebrospinal fluid Cerebrospinal irradiation High-dose chemotherapy Histopathological verification Inner cell mass CSF cytology tumor cell negative CSF cytology tumor cell positive Intracranial macroscopic metastasis Intraspinal macroscopic metastasis Primordial germ cell Tumor with normal institution established value of serum/CSF AFP and b-hCG Serum/CSF AFP ≤ 25 ng/ml and serum/CSF b-hCG ≤ 50 mIU/ml Serum/CSF AFP >25 ng/ml and serum/CSF b-hCG < or > 50 mIU/ml

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Benign Brain and Spinal Tumors Originating from Bone or Cartilage Abhishek Gami, Andrew Schilling, Jeff Ehresman, and Daniel M. Sciubba

Abstract

Benign osseocartilaginous tumors of the spine are overall uncommon, representing between 1 and 13% of all primary bone tumors and less than 10% of all spinal tumors. Tumors in this category include osteoblastic lesions such as the related osteoid osteoma and osteoblastoma, and cartilage-forming lesions including osteochondroma, chondroma, and chondroblastoma. Aneurysmal bone cysts, giant cell tumors of bone, and eosinophilic granulomas also comprise benign tumors of the spine arising from bone. There is significant heterogeneity in the epidemiology, molecular biology, imaging features, and optimal treatment of these lesions. For example, osteoid osteoma is characterized by high expression of the cyclooxygenase enzymes, making it amenable to treatment with anti-inflammatory drugs

A. Gami . A. Schilling . J. Ehresman . D. M. Sciubba (&) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected] A. Gami e-mail: [email protected] A. Schilling e-mail: [email protected] J. Ehresman e-mail: [email protected]

initially, whereas other lesions such as osteoblastoma may require intralesional curettage or en bloc resection sooner. Generally, en bloc resection is preferred when possible to minimize risk of recurrence. Further, some tumors may arise in the setting of syndromic conditions, such as multiple chondromas arising in Ollier disease or Maffucci syndrome, or as part of genetic disorders, such as osteochondromas in the context of hereditary multiple exostosis. These lesions may present with local pain, cause neurological compromise or be discovered incidentally on routine imaging. The Enneking classification and Weinstein-Boriani-Biagini system are routinely used to classify lesions and assist in surgical planning. More novel techniques such as radiofrequency ablation and laser photocoagulation have been applied for the treatment of osteoid osteoma and may have utility in the treatment of other lesion types. A multidisciplinary approach is critical in the management of benign lesions of the spine, and both chemotherapeutic and surgical approaches are routinely used. Keywords

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Benign spine tumors Osteoid osteoma Osteoblastoma Osteochondroma Aneurysmal bone cyst Giant cell tumor of bone Eosinophilic granuloma Fibrous dysplasia

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© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_17

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17.1

A. Gami et al.

Background and Epidemiology

Benign osseocartilaginous tumors of the spine are overall uncommon, representing between 1 and 13% of all primary bone tumors and less than 10% of all spinal tumors (Kelley et al. 2007; Thakur et al. 2012). Benign tumors of the spine include osteoblastic lesions, such as osteoid osteoma and osteoblastoma, and cartilage-forming lesions, including osteochondroma, chondroma, and chondroblastoma, in addition to aneurysmal bone cysts, giant cell tumors of bone, and eosinophilic granulomas. These benign lesions may be discovered incidentally but frequently can cause pain, radiculopathy, and spinal instability, and treatment includes observation, ablation, or surgical resection. Due to the heterogeneity of these lesions, understanding of their epidemiology, molecular biology, and imaging features is important in guiding therapeutic approaches. Osteoid osteoma and osteoblastoma are histologically similar, yet have distinct clinical presentations and distribution in the skeleton. Both are benign bone-forming neoplasms characterized by the production of osteoid or mature bone. 10–12% of all benign bone tumors are osteoid osteoma, and 10% of all osteoid osteomas occur in the spine (Atesok et al. 2011; Greenspan 1993; Kadhim et al. 2017). Osteoblastoma accounts for 3% of all benign bone tumors, and 40% of all osteoblastomas occur in the spine (Elder et al. 2016). Both osteoid osteoma and osteoblastoma typically present in the first three decades of life and have a decisive male predominance (Greenspan 1993). Osteochondroma, or osteocartilaginous exostosis, is the most common benign tumor of bone and account for 40% of all benign bone tumors and can have sporadic or hereditary origins. 1– 4% of solitary and 3–9% of hereditary osteochondromas occur in the spine. Osteochondromas are usually not identified until adulthood, with a mean age of 31–39 years at diagnosis (Gunay et al. 2010; Sciubba et al. 2015; Thakur et al. 2012). Chondroma comprises 5% of all

primary bone tumors and rarely affects the spine, with fewer than 4% of chondromas originating in the vertebral column. These lesions exhibit a strong male predominance and typically present between the third and fifth decades of life. However, multiple chondromas can be present in childhood in patients with multiple chondromatosis syndromes such as Ollier disease or Maffucci syndrome (McLoughlin et al. 2008). Aneurysmal bone cysts (ABCs) are osteolytic neoplasms characterized by blood filled cavities with septations and comprise 1% of all primary bone tumors, and 10–30% of all ABCs are found in the spine (Boriani et al. 2014). ABCs have a female predominance and more commonly affect children, with 60–90% of cases occurring in those younger than twenty (Ameli et al. 1985; Saccomanni 2008). Giant cell tumor (GCT) of bone accounts for approximately 5% of all primary bone tumors, and 2–8% of all GCTs present in the spine. GCTs typically present between ages 20–45 and have higher frequency in females (Luther et al. 2008; Martin and McCarthy 2010). Fibrous dysplasia involves the spine in 2.5% of cases (Harris et al. 1962). The disease may affect a single bone or multiple bones and typically affects younger children (Ropper et al. 2011). Bone hemangiomas occur in the spine in approximately 10% of cases with a slight female predominance; however, the majority of these hemangiomas are incidentally discovered (Rodallec et al. 2008). Eosinophilic granulomas are manifestations of Langerhans cell histiocytosis and are rare bone lesions that primarily affect young children (Ropper et al. 2011).

17.2

Genetics, Immunology, and Molecular Biology

17.2.1 Osteoid Osteoma Osteoid osteoma consists of a nidus surrounded by sclerotic bone tissue. High levels of prostaglandin synthesis have been reported in the nidus of osteoid osteoma. Several studies have demonstrated high levels of expression of cyclooxygenase-1 and

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cyclooxygenase-2 enzymes in the tumor tissue, which are both enzymes responsible for the synthesis of prostaglandins. The presence of local pain as an initial sign of osteoid osteoma is likely related to these inflammatory mediators (Healey and Ghelman 1986). Studies have also demonstrated the high vascularity and presence of nervous fibers in osteoid osteoma which may also mediate pain (Greenspan 1993). Though osteoblastoma resembles osteoid osteoma, this entity does not express high levels of prostaglandin, possibly explaining its poor response to oral salicylates (Berry et al. 2008).

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(IDH) have been identified in both solitary and syndromic enchondromas. IDH1 and IDH2 mutations lead to excess production of 2hydroxyglutarate leading to altered DNA methylation. IDH mutations have been identified in 87% of enchondromas in patients with Ollier disease and 77% of tumors in patients with Maffucci syndrome. Gain of function mutations lead to somatic mosaicism and the development of multiple enchondromas in these disorders (Schaefer et al. 2018). c-Myc amplification and polysomy 8 are associated with transformation of chondroma to chondrosarcoma (McLoughlin et al. 2008).

17.2.2 Osteochondromas Osteochondromas can occur as solitary spontaneous lesions, but approximately 15% of osteochondromas occur in the context of hereditary multiple osteochondroma/exostosis (HME), a disorder with an autosomal dominant inheritance pattern. HMEs are caused by mutations in the tumor suppressor genes exostosis-1 (EXT1) located on chromosome 8 or exostosis-2 (EXT2) on chromosome 11 (Sciubba et al. 2015). Biallelic inactivation of the EXT1 gene is also linked to solitary nonhereditary osteochondroma. The EXT1 and EXT2 proteins function in heparan sulfate proteoglycan (HSPG) synthesis. HSGPs are essential for the normal signaling of the epiphyseal growth plate, and abnormal processing of HSPGs may prevent diffusion of Hedgehog factors which regulate chondrocyte differentiation and endochondral ossification (Kitsoulis et al. 2008).

17.2.4 Aneurysmal Bone Cysts (ABCs) The pathogenesis of aneurysmal bone cysts (ABCs) is controversial. ABCs were hypothesized to occur as reactive lesions following an insult that altered interosseous blood flow (Ameli et al. 1985). However, genetics have also been implicated in the pathogenesis of ABC, and recent work has demonstrated that ABCs may harbor a 17p13 translocation of TRE17/USP6, leading to activation of the transcription factor NF-kB which activates matrix metalloproteases. Xenograft studies have also demonstrated TRE17 can induce formation of tumors with features of ABCs, such as high vascularity (Ye et al. 2010).

17.2.5 Giant Cell Tumor (GCT) 17.2.3 Chondromas Chondromas are classified according to their site of origin: enchondromas arise from the medullary cavity, while periosteal or juxtacortical chondromas arise from the cortical surface. Though chondromas usually occur as isolated lesions, they can present as multiple lesions in Ollier disease or Maffucci syndrome. Mutations in genes encoding isocitrate dehydrogenase

Giant cell tumor (GCT) of bone contain neoplastic cells that are osteoblast precursors, which arise from mononuclear cells of macrophage origin. The tumors are made of osteoclastic cells expressing receptor activator of nuclear factor kappa-B (RANK) and neoplastic cells expressing RANK ligand (RANKL). RANKL leads to multinuclear osteoclast formation and subsequent bone resorption that is typical of GCT (van der Heijden et al. 2017).

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17.2.6 Fibrous Dysplasia Fibrous dysplasia may occur in association with McCune-Albright syndrome, which is characterized by a triad of fibrous dysplasia, café-au-lait macules, and endocrinopathies such as precocious puberty (Ropper et al. 2011). The underlying defect in this syndrome involves somatic mutations of the GNAS gene and the Gs alpha cAMP regulating protein (Dumitrescu and Collins 2008).

17.2.7 Langerhans Cell Histiocytosis Langerhans cell histiocytosis takes the form of Hand–Schuller–Christian disease, Letterer–Siew disease, and eosinophilic granulomas and occurs due to proliferation of Langerhans histiocytes, which are antigen presenting cells of the skin (Ropper et al. 2011). Mutations of the BRAF oncogene have been identified to occur in cases of Langerhans cell histiocytosis, however, a definite pattern of inheritance has not been identified (Zeng et al. 2016).

17.3

Histopathology and Morphology

17.3.1 Osteoid Osteoma Osteoid osteomas most commonly occur in the lower extremity, especially the femur and tibia, but can involve the spine, often in the posterior elements. Grossly, osteoid osteomas are less than 1.5 cm in diameter and are composed of a central red nidus composed of osteoid tissue or mineralized immature bone that is surrounded by denser sclerotic bone tissue. The nidus is surrounded by a rich stroma that has prominent osteoblastic and osteoclastic activity responsible for local bone remodeling. Osteoid osteoma is a benign lesion and has no potential for malignancy (Atesok et al. 2011; Healey and Ghelman 1986). Osteoblastoma is frequently found in the axial skeleton, and 34% of cases involve the

spine, most often in the posterior elements of the vertebrae and in the sacrum (Atesok et al. 2011; Healey and Ghelman 1986). Osteoblastoma resembles osteoid osteoma histologically; however, osteoblastoma are markedly larger with an average diameter of 4 cm. Osteoid production is generally greater in osteoblastoma than in osteoid osteoma, and osteoblastoma also exhibit a less organized pattern of growth. Additionally, osteoblastoma may be locally aggressive and may be associated with large epithelioid osteoblasts that are more mitotically active compared to osteoid osteoma and less aggressive osteoblastoma. Osteoblastoma has no malignant or metastatic potential. Both osteoid osteomas and osteoblastomas can occur in intramedullary, intracortical, and periosteal sites (Atesok et al. 2011; Greenspan 1993; Healey and Ghelman 1986) (Fig. 17.1).

17.3.2 Osteochondroma Osteochondromas are lesions thought to form when fragments of epiphyseal growth plates or cartilage herniate through bone and undergo ossification and maturation. Osteochondroma frequently occurs in the long bones, but can occur in the spine, most frequently in the posterior elements of the cervical and thoracic regions. Grossly, osteochondromas are usually 1–2 cm in diameter. They demonstrate pediculated or sessile growth of hyaline cartilage. The lesion contains a central growth of hyaline cartilage that is demarcated peripherally by perichondrium that is continuous with the periosteum of the underlying bone. The rate of malignant transformation for osteochondroma is less than 1% for solitary cases and 3–5% in hereditary cases, and a thick and irregular cartilage cap may indicate malignant transformation. Other features that may indicate malignant transformation include irregular mineralization, soft tissue bands, loss of architecture of cartilage, necrosis, or other atypia of chondrocytes (Kitsoulis et al. 2008; Sciubba et al. 2015) (Fig. 17.2).

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Fig. 17.1 a, b H&E staining of osteoid osteoma and osteoblastoma showing trabeculae of woven bone surrounded by osteoblasts. Reprinted from Lam et al. (2020) with copyright permission from Springer Nature (open Access)

Fig. 17.2 H&E staining of resected osteochondroma showing an overlying cartilage cap. Reprinted from Fukushi et al. (2017) with copyright permission from Springer Nature under license number 5118391266046

17.3.3 Chondromas Chondromas can be classified into enchondromas and periosteal chondromas. Chondromas occur mostly in the small bones but can be found in the vertebral column. All portions of the vertebrae can be affected, and the thoracic region is reported to have a higher incidence of chondroma. Chondromas are typically small tumors,

and a diameter greater than 7 cm is suggestive of malignant transformation. Grossly, chondromas appear as lobules of firm, mature, cartilage that are well-circumscribed from adjacent bone. Enchondromas typically produce an expansive growth pattern, while periosteal chondromas are exophytic. Histologically, chondromas have small and uniform cells with dark, round nuclei that form lobules separated by vascular septa in a

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myxoid or hyaline background (McLoughlin et al. 2008; Palaoglu et al. 1988).

17.3.4 Aneurysmal Bone Cysts (ABCs) Aneurysmal bone cysts commonly occur around the knee but can also occur in the vertebral column, with 70% of cysts occurring in the thoracolumbar legion and 25% in the cervical spine, typically in the pedicles, laminae, and spinous processes (Saccomanni 2008). Grossly, ABCs appear as vascular tumors less than 2 mm in diameter, and histology shows hemorrhagic spaces separated by septa consisting of spindle cells, inflammatory cells, fibroblasts, and multinucleated osteoclast-like giant cells. A background of osteoid and new bone formation may also be appreciated (Ameli et al. 1985; Rapp et al. 2012) (Fig. 17.3).

17.3.5 Giant Cell Tumor (GCT) Giant cell tumors typically occur at the end of the long bones but can also occur in the sacrum and spine, most commonly in the vertebral bodies. Grossly, GCTs are yellow, soft, friable lesions with areas of hemorrhage. Histologically, GCTs demonstrate multinucleated osteoclastic giant cells with nuclei that resemble those of mononuclear cells (Luther et al. 2008; Sanjay et al. 1993) (Fig. 17.4).

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17.3.6 Fibrous Dysplasia Fibrous dysplasia lesions consistent of woven bone in a background of fibroblasts. Other features include hemorrhage and foamy macrophages (Gogia et al. 2007) (Fig. 17.5).

17.3.7 Hemangioma Hemangiomas appear as multiple small blood vessels woven among bone and may be categorized as capillary hemangiomas or cavernous hemangiomas (Ropper et al. 2011).

17.3.8 Langerhans Cell Histiocytosis Eosinophilic granulomas demonstrate features of Langerhans cell histiocytosis, including Birbeck granules, which are described as tennis-racketshaped entities in the cytoplasm. Immunohistochemistry also shows CD1a positivity (Ropper et al. 2011) (Fig. 17.6).

17.4

Imaging and Radiologic Features

Computed tomography (CT) is preferred study for the evaluation of osteoid osteoma and osteoblastoma, though plain radiographs, bone scintigraphy, and MRI also have utility. On CT,

Fig. 17.3 a, b, c Histological types of ABC showing hemorrhagic spaces within bone. Reprinted from Zhao et al. (2019) with copyright permission from Springer Nature under license number 5130960932471

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Fig. 17.4 a, b Histology of giant cell tumor of bone showing osteoclast-like giant cells with multiple nuclei. Reprinted from Scotto di Carlo et al. (2018) (open access)

osteoid osteoma demonstrates a radiolucent nidus surrounded by an area of sclerosis (Fig. 17.7). Osteoblastomas tend to be irregularly shaped radiolucent lesions demonstrating areas of mineralization and expansile bone remodeling in an intact surrounding shell of bone. Bone scintigraphy is highly sensitive for both osteoid osteoma and osteoblastoma with strong uptake at the nidus occurring in both lesions (Fig. 17.8) (Atesok et al. 2011; Berry et al. 2008; Healey and Ghelman 1986). The characteristic finding of osteochondroma on imaging is the continuity of the lesion with the cortex and medullary cavity of bone. Multiple imaging techniques are leveraged for diagnosis including CT and MRI. CT is the technique of choice for osteochondroma of the spine and demonstrates cortical-medullary continuity with underlying bone as well as a cartilage cap. T2weighted MRI may demonstrate a high signal in the water-rich cartilaginous cap and low signal on T1-weighted MRI. MRI with gadolinium contrast

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may also demonstrate peripheral enhancement due to the fibrovascular tissue overlying the cartilage cap, which can help resolve vascular complications caused by the tumor and assist in differentiating malignant chondrosarcoma from osteochondroma (Fig. 17.9) (Kitsoulis et al. 2008; Sciubba et al. 2015). Malignant transformation of osteochondroma to chondrosarcoma is a serious complication, and imaging findings should focus on changes in a previously stable tumor, local aggressiveness, and the hyaline cartilage cap, with a cartilage cap thickness of >1.5– 2 cmon CT and MRI serving as sensitive indicator for chondrosarcoma (Sinelnikov and Kale 2014). Plain radiography of chondroma reveals wellcircumscribed lytic lesions without reactive sclerosis, but may also demonstrate deformities such as foraminal widening. CT of chondroma reveals a radiolucent, erosive lesion with cartilage appearing as regions of low attenuation. Stippled patterns of calcification may also be visualized. MRI has utility in differentiating benign chondroma and malignant chondrosarcoma, and enhancement on MRI may be consistent with chondrosarcoma (Fig. 17.10) (McLoughlin et al. 2008; Palaoglu et al. 1988). ABC may be initially evaluated using plain radiography and can demonstrate a radiolucent cystic lesion. CT may further reveal a “soapbubble” appearance, or the lesions’ ballooning lytic nature. The lesion may be accompanied by pathologic fracture of a vertebral body or partial or complete collapse. MRI of ABC can help elucidate internal septations within the lesion with characteristic fluid–fluid lines on T2weighted imaging representing accumulation of blood (Fig. 17.11) (Brastianos et al. 2009; Rapp et al. 2012; Saccomanni 2008). Plain radiography of GCT shows an eccentric, lytic lesion with a sharply defined border, and is often a first step in the diagnosis of GCT. CT may be used to further evaluate the anatomy of GCT and CT-guided core biopsy is indicated following identification of the lesion. MRI of GCT shows a low to moderate intensity in the spinal cord with heterogenous contrast

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Fig. 17.5 Histology of fibrous dysplasia showing woven bone in a background of fibroblasts. a, b H&E stain, c, d Trichrome stain. Reprinted from Kushchayeva et al. (2018) (open access)

Fig. 17.6 a–b Eosinophilic granuloma showing eosinophilic infiltration with mononuclear cells/osteoclast-like giant cells. c Bone marrow biopsy showing granulocyte proliferation. Reprinted from Zhao et al. (2019) (open access)

enhancement based on the extent of paraspinal or epidural involvement (Fig. 17.12) (Luther et al. 2008; van der Heijden et al. 2017). Fibrous dysplasia demonstrates a groundglass appearance with sclerotic margins on plain radiograph. CT may show a lytic lesion associated with a pathological fracture (Pons

Escoda et al. 2020; Medow et al. 2007). MRI of fibrous dysplasia may show low intensity on T1 imaging and variable intensity on T2 (Fig. 17.13) (Ropper et al. 2011). Hemangiomas have a “honeycomb” pattern on radiography, and CT shows thickened trabeculae that has been dubbed as a “polka dot” pattern (Ropper et al. 2011;

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Fig. 17.7 Osteoid osteoma in a 23-year-old showing a lesion in the C4 arch. a, b Showing a hypointense lesion in the C4 arch. c–f Bone scan showing uptake in the cervical spine. g, j CT showing lesion in the cervical

spine. h, i, k SPECT/CT imaging showing uptake in the cervical spine. Reprinted from Bhure et al. (2019), with copyright permission from Springer Nature under license number 5113630716294

Medow et al. 2007). MRI shows high signal intensity on T1 and T2-weighted imaging, and angiography shows the high vascularity of these tumors (Ropper et al. 2011). Eosinophilic granulomas have a higher incidence in the skull and imaging shows lytic lesions with signature “beveled edges” and “hole within a hole” signs. MRI demonstrates a T2intense lesion with possible surrounding edema (Fig. 17.14) (Pons Escoda et al. 2020).

pain that is typically more apparent and severe in the nighttime and that can be relieved with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been reported that pain relieved by NSAIDs is apparent in more than 75% of cases of osteoid osteoma (Greenspan 1993; Kadhim et al. 2017). The pain may last weeks to months before presentation and may be described by patients as a dull and aching pain. In pediatric cases, osteoid osteoma may present with rapidly progressive scoliosis when the spine is involved (Atesok et al. 2011). On the other hand, the pain associated with osteoblastoma rarely interferes with sleep and is typically not relieved with the use of NSAIDs. Further, osteoblastoma may also present with local swelling and tenderness. In patients with

17.5

Clinical Manifestations

Pain is the most common presenting symptom in patients with osteoid osteoma and osteoblastoma. In osteoid osteoma, patients present with local

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Fig. 17.8 A 42-year-old man with osteoblastoma. a Bone scan showing uptake at T7. b Radiograph demonstrating lesion at T7. c, d CT demonstrating lesion with replacement of bone trabeculae. e, f T2- and T1-

weighted MR imaging. Reprinted from Liu et al. (2020), with copyright permission from Springer Nature (open Access)

spinal osteoblastoma, scoliosis is a common presenting sign, and spinal lesions may cause neurologic deficits ranging from muscle weakness, numbness, tingling, radicular pain, and paraplegia (Atesok et al. 2011; Greenspan 1993). Osteochondromas are generally asymptomatic as they generally arise from the posterior spinal elements. They may be found incidentally, present with nonmechanical spinal pain or tumor-

related pain, or in the case of spinal invasion, present with compressive myelopathy and sciatica. Generally, neurological deficits due to osteochondromas are rare and are seen in only 0.5–1% of all cases (Sciubba et al. 2015; Sinelnikov and Kale 2014). However, multiple osteochondromas can be present in hereditary exostosis syndrome in the first decade of life or in newborns with limb undergrowth, ankle

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Fig. 17.9 a Radiograph showing osteochondroma of cervical spine. b CT showing tumor arising from C3. c T2weighted MR imaging showing extension of tumor into spinal canal with cervical cord compression. d T2weighted MR imaging, axial view. Reprinted from Fukushi et al. (2017), with copyright permission from Springer Nature under license number 5118391266046

valgus, genu valgum, and spinal compression syndrome (Kitsoulis et al. 2008). Spinal cord compression may occur in solitary osteochondroma as well and may present with upper motor neuron signs. Other uncommon presentations include dysphagia, Horner syndrome, and vascular deformity (Sinelnikov and Kale 2014). Patients presenting with spinal chondromas typically exhibit local tenderness at the site of the lesion with or without a palpable mass. Because chondromas are slow growing, neurological symptoms may develop insidiously. Chondromas may present with radiculopathy or myelopathy in the event of direct compression. In certain cases, pathologic fractures may also be present. Chondromas can also be associated with multiple

chondromatosis syndromes including Ollier disease and Maffucci syndrome in childhood. These syndromes are associated with skeletal deformity, limb-length discrepancy, and pathologic fractures. Maffucci syndrome can be distinguished from Ollier disease by the presence of cutaneous hemangiomata (McLoughlin et al. 2008; Palaoglu et al. 1988). These syndromes are associated with a higher risk for sarcomatous transformation of chondroma. Aneurysmal bone cysts are rapidly growing lesions with an average duration of symptoms of approximately four months. They may present with rapid worsening of symptoms or may present insidiously and become quiescent (Ameli et al. 1985). The main symptoms of ABC of the

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Fig. 17.10 Chondroma a T1-weighted MR imaging and b T2-weighted MR imaging showing a wellcircumscribed lesion. c Heterogenous enhancement

following Gd-DTPA administration. Reprinted from Guo et al. (2017) (open access)

Fig. 17.11 Aneurysmal bone cyst a, b CT showing aneurysmal bone cyst at L4, c, d MR imaging showing high intensity on T2-weighted imaging. Reprinted from

Zhao et al. (2019), with copyright permission from Springer Nature under license number 5130960932471

spine are pain, a tender, palpable mass, and spinal cord compression. The pain may progress and increase in severity as the lesion expands, and neurological symptoms due to spinal cord compression can range from paresthesia to complete paraplegia (Ameli et al. 1985; Boriani et al. 2014). GCT of the spine most commonly presents with back pain, and in cases of tumor growth, with weakness due to compression of the spinal cord or nerve roots. In a series of twenty-four patients with giant cell tumors of the spine, all

presented with pain for an average period of five months (Luther et al. 2008; Sanjay et al. 1993). Fibrous dysplasia may occur in the context of McCune–Albright syndrome, and underlying endocrinopathies should be studied to evaluate for calcium disorders. Hemangiomas are often discovered incidentally on spine imaging in many cases, however, may cause neurologic deficits secondary to bone expansion (Ropper et al. 2011; Acosta et al. 2008). Many cases of hemangiomas of the spine can be observed; however, in cases of worsening

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Fig. 17.12 Giant cell tumor arising from the clivus with invasion at C1. Reprinted from Scotto di Carlo et al. (2018) (open access)

Fig. 17.13 Fibrous dysplasia. a Craniofacial fibrous dysplasia, b, c fibrous dysplasia in the proximal femur and skull. Imaging may demonstrate mixed sclerotic/lytic lesions. Reprinted from Kushchayeva et al. (2018) (open access)

neurological symptoms, treatment may be pursued. Cases of eosinophilic granuloma typically present with pain, depending on the location of the pathology.

17.6

Therapeutic Approaches

Appropriate treatment for benign tumors of the spine arising from cartilage or bone can include observation, medication, radiotherapy,

chemotherapy, and surgical resection. The appropriate treatment is based on the natural history of the lesion, patient characteristics, and patient symptoms including pain and neurological deficits. Biopsy is often indicated for primary spine tumors, and needle/core biopsy, incisional biopsy, and excisional biopsy are performed (Traina et al. 2015). Biological grade and tumor extension can be then used to stage the tumor. Benign spine tumors can be classified using the Enneking system, which was developed for the surgical staging of primary musculoskeletal

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Fig. 17.14 Eosinophilic granuloma in a 4-year-old boy. a Radiographic showing lytic lesions. b, c CT imaging showing a lesion with associated soft tissue invasion. Reprinted from Gomez et al. (2018) (open access)

tumors. The Enneking classification divides benign tumors into latent (S1), active (S2), or aggressive (S3) tumors. Stage S1 lesions generally require no management unless for decompression or stabilization, while stage S2 lesions can be treated with intralesional excision and S3 lesions can be treated with en bloc resection. However, the Enneking classification does not consider the complexities of the spine, such as involvement of the epidural space (Chan et al. 2009; Enneking 1986; Versteeg et al. 2017). The Weinstein–Boriani–Biagini (WBB) system has been proposed to stage spinal tumors and to recommend the appropriate surgical procedure. This system divides the vertebrae into twelve radiating sectors (in a clockwise direction) and five tissue layers (ranging from paravertebral to

dural extension) to assist in surgical planning (Hart et al. 1997) (Table 17.1). Intralesional excision, also referred to as curettage, refers to the piecemeal removal of tumor without wide excisional margins. En bloc resection refers to an attempt to remove the entire tumor in one piece with a perimeter of healthy tissue. En bloc resection is further categorized based on histologic studies into intralesional, marginal, or wide resection; with intralesional referring to dissection within the tumor mass, marginal referring to dissection along the tumor pseudocapsule, and wide referring to separation outside the pseudocapsule and into the healthy surrounding tissue (Boriani et al. 1997). En bloc resection typically requires a total vertebrectomy or spondylectomy.

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Table 17.1 Characteristics of tumors arising from the spine and cartilage Lesion

Epidemiology

Morphology

Radiology

Clinical features

Therapy

Osteoid osteoma

10–12% of all benign bone tumors, 45 Gy) have been associated with better PFS (Weng et al. 2018). Adjuvant radiation therapy for spinal and sacral GCTs is also controversial with some of the largest studies

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showing no benefit to adjuvant radiotherapy (Ruggieri et al. 2010; Xu et al. 2013). As such, this is often considered only when other options have failed.

18.6.3.3 New Therapeutic Modalities The lack of a standard of care, particularly in chemotherapeutic regimens and radiation therapy make giant-cell tumors an active area of research. The use of denosumab and other biologic agents is actively being studied with several ongoing clinical trials. Also, parsing out the types of effective radiotherapy, whether it be IMRT, EBRT, or stereotactic radiosurgery, are also active topics of study.

18.6.4 Osteosarcoma 18.6.4.1 Surgical Intervention Osteosarcoma found outside the central nervous system is almost universally treated with surgical resection as a mainstay of the treatment protocol. Surgical outcomes have been positively correlated with wide, en-bloc resections with negative margins (Casali et al. 2018). Depending on the tumor location within the skull and skull base, en-bloc or gross total resection with negative margins may not be possible. Raza et al. showed that GTR with negative margins was associated with improved disease specific survival and progression free survival of 144.5 versus 31.2 months and 170 versus 15.3 months, respectively, compared to those with positive margins in skull base OSCs (Raza et al. 2020). The strategy of en-bloc or gross total resection has also been applied to OSCs of the spine and sacrum. Dekutoski et al. showed that patients with spinal OSCs when treated with en-bloc resection had improved median survival of 6.8 years compared to 3.7 years for patients that had just intralesional resection (Dekutoski et al. 2016). Also, patients with intralesional resection had a higher rate of local recurrence compared to those with en-bloc resection (Dekutoski et al. 2016).

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18.6.4.2 Chemotherapy and Radiotherapy Systemic chemotherapy is a necessity in osteosarcoma. Over 80% of patients who are treated with surgery alone will go on to develop metastasis. Currently, there is no definitive benefit of neoadjuvant versus adjuvant chemotherapy for OSCs, but many centers imply both. Typically, a three-drug regimen is preferred over two drugs (Anninga et al. 2011). For children and adolescents, the standard initial regimen is methotrexate, doxorubicin, and cisplatin (MAP regimen) (Link et al. 1991). Adults over the age of 40 are often offered doxorubicin plus cisplatin (Souhami et al. 1997). Osteosarcoma is relatively radioresistant; therefore, radiation therapy is typically reserved for patients with incomplete resection or where GTR was not feasible, such as in the skull and spine. Ciernik et al. analyzed radiotherapy in OSC patients with unresectable or incompletely resected tumors and showed that with radiotherapy (average dose of 68.4 Gy) there was a local control rate of 82 and 72% at 3 and 5 years and a disease-free survival of 65% at 5 years—a fair number of these patients had OSCs of the skull and spine (Ciernik et al. 2011). However, there was a lower local control rate ( 3 cm) or causing neurologic deficits in which case surgical removal followed by radiation is the mainstay of treatment. Although fractionated radiation has typically been the primary treatment for skull base metastases, radiosurgery with either gammaknife or cyber-knife for smaller tumors is growing in popularity due to their high tumor specificity and low side-effect profile (Mitsuya et al. 2011). Spinal metastasis can be treated with either surgical resection and/or radiation therapy. Neurologic deficit, patient prognosis, bone quality, pain,and patient preoperative condition are all incorporated into the decision-making tree for the treatment of spinal metastasis (Chang et al. 2020). As it is for skull metastases, stereotactic spine radiosurgery is becoming the mainstay in the treatment of spinal metastasis (Barzilai et al. 2018). Kyphoplasty or vertebroplasty can be a good palliative option for spinal metastases and can serve as a route for biopsy when needed. Chemotherapy and immunotherapy regimens are typically directed by the primary tumor pathology and genetics for both skull and spinal metastases. Other treatments such as androgen deprivation therapy play a primary role in tumors like prostate cancer (Gilligan and Kantoff 2002). 18.6.5.4 Cholesterol Granuloma Chemotherapy and radiation options do not exist for CGs. The standard therapy for these lesions is surgical drainage via open surgery (middle fossa or transmastoid), endoscopic endonasal surgery, or stereotactic aspiration. An innovative new approach to lesions of the petrous apex, including CGs, is the contralateral transmaxillary approach which allows for improved access to the petrous done with decreased need for manipulation of the carotid artery (Patel et al. 2018).

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18.7

Z. C. Gersey et al.

Follow-Up and Prognosis

18.7.1 Chordoma Follow-up for chordoma varies from institution to institution. However, it is recommended that MRI be performed immediately and then three months and 9 months after surgery. Then, if the disease shows no progression/recurrence, this can be spaced out to a minimum of yearly—all with MRIs at each visit. These intervals can be shortened for dedifferentiated or poorly differentiated tumors. The median survival of chordoma at all anatomic sites is 4.7 years with a mean survival of 6.1 years. The median survival is higher in cranial cases compared to spinal and sacral cases, and spinal cases have a higher median survival than sacral cases, although these are not statistically significant. In multivariate analysis female sex, younger age at diagnosis, and use of surgery as first course of treatment were all protective in terms of overall survival. When broken down by year of diagnosis, there is a trend for increased survival in those patients treated within the past two decades (1990–2011) compared to the prior two decades (1973–1989), therefore hinting that treatment modalities may be improving over the years (Communications).

18.7.2 Chondrosarcoma Follow-up for chondrosarcomas is typically like that of chordoma, with MRI every three to six months after surgery spreading out to yearly. Overall, chondrosarcomas of the skull base have a much better prognosis than that of chordomas. According to surveillance epidemiology and end results (SEER) analysis, overall survival at 5 years and 10 years is 82 and 50%, respectively. In multivariate analysis, age, earlier decade of diagnosis, and mesenchymal subtype were associated with worse survival in patients with skull base chondrosarcoma. The most favorable survival outcomes of approximately 91% 5-year survival was observed in patients under 60 years

of age with non-mesenchymal subtype (Bohman et al. 2014). In addition, a recent study classified conventional chondrosarcomas by preoperative vascular encasement and age into 3 distinct prognostic groups with dramatically different progression free survival. In this paper, young patients (15% and 9p21 homozygous deleted: >25%

No

Radiation. Consider chemotherapy with denosumab

Observation if negative margins. If positive margins, consider further surgery if possible. If not possible, radiation

Gross Total Resection?

Giant Cell Tumor

Yes

Biopsy vs close clinical follow-up

Growth, symptoms, and/or biopsy confirming tumor appropriate for resection

No / unsure

Fig. 18.10 Diagnostic and therapeutic algorithm for malignant brain and spinal tumors originating from bone or cartilage

No

Yes

No further treatment unless Grade 3

Gross Total Resection?

Chondrosarcoma

Pathology

Maximal, safe resection with negative margins as goal

Yes

Imaging characteristics consistent with tumor appropriate for resection

New bony skull base tumor

No

Yes

Radiation. Chemotherapy regardless of EOR

If positive margins, consider further surgery if possible. If not possible, radiation. Chemotherapy regardless of EOR

Gross Total Resection?

Osteosarcoma

18 Malignant Brain and Spinal Tumors Originating from Bone or Cartilage 499

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SEER database, skull OSCs have a 5-year survival rate of 51.5%. Older age (>50 years), no surgical treatment, and progression of disease are associated with decreased overall survival. Patients that did not have radiotherapy were associated with superior survival, but this is likely due to the fact that patients with incomplete resection or no resection are those that receive radiotherapy (Martin et al. 2019). 5-year survival for spinal osteosarcoma is about 30– 40%. Factors that increase survival were wide surgical resection combined with chemoradiation, carbon ion radiotherapy, and 3-drug chemotherapy regimens (Katonis et al. 2013).

Z. C. Gersey et al.

18.7.5.3 Metastasis Due to advances in chemotherapy, immunotherapy, radiotherapy, and radiosurgery, the prognosis for patients with metastasis is dictated by the pathology of the primary tumor rather than the presence of brain, skull, or spine metastasis (Park et al. 2021). 18.7.5.4 Cholesterol Granuloma CGs are typically followed with serial imaging and treatment based on patient symptoms. This is true for both patients that have and have not undergone surgery. Currently, recurrence rates after surgery are 5–14.7% based on both imaging and clinical findings (Brackmann and Toh 2002; Gore et al. 2011; Patel et al. 2021).

18.7.5 Miscellaneous 18.7.5.1 Multiple Myeloma and Plasmacytoma Multiple myeloma/plasmacytoma patients are closely followed by an oncologist on a regular basis throughout their treatment course. Patients with known metastasis to their skull or spine will typically only undergo routine imaging of these areas based on symptomatology. The overall prognosis for MM/plasmacytoma has improved dramatically over the years. Depending on revised international staging system (RISS), patients with R-ISS I, II, and III have an estimated overall survival of 82, 62, and 40% at five years, respectively (Palumbo et al. 2015). 18.7.5.2 Fibrous Dysplasia The majority of cases of fibrous dysplasia do not progress or require treatment. Progression/ recurrence and malignant transformation are the main factors affecting patient prognosis in FD. Recurrence is common in symptomatic craniofacial FD with nearly 50% of all patients requiring repeat surgery (Lustig et al. 2001). Malignant transformation to osteosarcoma occurs in 0.4% (monostotic) to 6.7% (in McCuneAlbright syndrome (Qu et al. 2015) and the risk can increase with radiation exposure or in patients with polyostotic FD (Riddle and Bui 2013).

18.8

Conclusion

In conclusion, malignant tumors of the skull and spine originating from bone and cartilage are rare and extremely difficult entities to treat. Depending on their location, these tumors can cause headaches, brainstem compression, cranial nerve palsies, spinal cord compression, radiculopathy and an array of symptoms that can have significant effects on patients’ lives. The typical treatment for these tumors starts with safe but maximal resection. This is usually followed by radiation for chordoma and some chondrosarcomas. Chemotherapy is necessary for osteosarcoma, may have a role in giant-cell tumors, but is currently lacking for chordoma and chondrosarcoma. Current research and trials are focused on understanding the molecular and genetic underpinnings of these rare tumors to better provide targeted therapies in the future (Fig. 18.10).

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506 Sciubba DM, Petteys RJ, Dekutoski MB et al (2010) Diagnosis and management of metastatic spine disease: a review. J Neurosurg Spine 13:94–108. https:// doi.org/10.3171/2010.3.SPINE09202 Scotto di Carlo F, Divisato G, Iacoangeli M et al (2018) The identification of H3F3A mutation in giant cell tumour of the clivus and the histological diagnostic algorithm of other clival lesions permit the differential diagnosis in this location. BMC Cancer 18:358. https://doi.org/10.1186/s12885-018-4291-z Sekhar LN, Pranatartiharan R, Chanda A, Wright DC (2001) Chordomas and chondrosarcomas of the skull base: results and complications of surgical management. Neurosurg Focus 10:E2. https://doi.org/10. 3171/foc.2001.10.3.3 Sharifnia T, Wawer MJ, Chen T et al (2019) Smallmolecule targeting of brachyury transcription factor addiction in chordoma. Nat Med 25:292–300. https:// doi.org/10.1038/s41591-018-0312-3 Shives TC, McLeod RA, Unni KK, Schray MF (1989) Chondrosarcoma of the spine. J Bone Joint Surg Am 71:1158–1165 Smeele LE, Snow GB, van der Waal I (1998) Osteosarcoma of the head and neck: meta-analysis of the nonrandomized studies. Laryngoscope 108:946. https://doi.org/10.1097/00005537-199806000-00030 Souhami RL, Craft AW, Van der Eijken JW et al (1997) Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 350:911–917. https://doi.org/10.1016/S0140-6736(97)02307-6 Stark AM, Eichmann T, Mehdorn HM (2003) Skull metastases: clinical features, differential diagnosis, and review of the literature. Surg Neurol 60:219–225. https://doi.org/10.1016/S0090-3019(03)00269-6 Stephens PJ, Greenman CD, Fu B et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40. https://doi.org/10.1016/j.cell.2010.11.055 Szuhai K, Cleton-Jansen A-M, Hogendoorn PCW, Bovée JVMG (2012) Molecular pathology and its diagnostic use in bone tumors. Cancer Genet 205:193–204. https://doi.org/10.1016/j.cancergen.2012.04.001 Thomas D, Henshaw R, Skubitz K et al (2010) Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 11:275–280. https://doi.org/10.1016/S1470-2045(10)70010-3 Thumallapally N, Meshref A, Mousa M, Terjanian T (2017) Solitary plasmacytoma: population-based analysis of survival trends and effect of various treatment modalities in the USA. BMC Cancer 17:13. https:// doi.org/10.1186/s12885-016-3015-5 Tosi P (2013) Diagnosis and treatment of bone disease in multiple myeloma: spotlight on spinal involvement. Scientifica (Cairo) 2013:104546. https://doi.org/10. 1155/2013/104546 Tzortzidis F, Elahi F, Wright DC, et al (2006) Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base

Z. C. Gersey et al. chondrosarcomas. Neurosurgery 58:1090–1098 (discussion 1090–1098). https://doi.org/10.1227/01.NEU. 0000215892.65663.54 Venteicher AS, McDowell MM, Goldschmidt E et al (2020) A preoperative risk classifier that predicts tumor progression in patients with cranial base chondrosarcomas. J Neurosurg 1–9. https://doi.org/ 10.3171/2019.10.JNS191672 Walcott BP, Nahed BV, Mohyeldin A et al (2012) Chordoma: current concepts, management, and future directions. Lancet Oncol 13:e69-76. https://doi.org/10. 1016/S1470-2045(11)70337-0 Walker BA, Leone PE, Chiecchio L et al (2010) A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood 116:e56-65. https://doi.org/10.1182/blood-201004-279596 Weng J-C, Li D, Wang L et al (2018) Surgical management and long-term outcomes of intracranial giant cell tumors: a single-institution experience with a systematic review. J Neurosurg 131:695–705. https:// doi.org/10.3171/2018.4.JNS1849 Werner M (2006) Giant cell tumour of bone: morphological, biological and histogenetical aspects. Int Orthop 30:484–489. https://doi.org/10.1007/s00264006-0215-7 Wold LE, Laws ER (1983) Cranial chordomas in children and young adults. J Neurosurg 59:1043–1047. https:// doi.org/10.3171/jns.1983.59.6.1043 Xu W, Li X, Huang W et al (2013) Factors affecting prognosis of patients with giant cell tumors of the mobile spine: retrospective analysis of 102 patients in a single center. Ann Surg Oncol 20:804–810. https:// doi.org/10.1245/s10434-012-2707-6 Yap FHX, Amanuel B, Van Vliet C et al (2021) Malignant transformation of fibrous dysplasia into osteosarcoma confirmed with TP53 somatic mutation and mutational analysis of GNAS gene. Pathology 53:652–654. https://doi.org/10.1016/j.pathol.2020.08.027 Zenonos GA, Fernandez-Miranda JC, Mukherjee D et al (2018) Prospective validation of a molecular prognostication panel for clival chordoma. J Neurosurg 1–10. https://doi.org/10.3171/2018.3.JNS172321 Zenonos GA, Wang EW, Tyler-Kabara EC et al (2016) Endoscopic endonasal surgery for clival chordomas. J Neurol Surg B Skull Base 77:FP-11–5–11. https:// doi.org/10.1055/s-0036-1592493 Zhang Z, Xu J, Yao Y et al (2013) Giant cell tumors of the skull: a series of 18 cases and review of the literature. J Neurooncol 115:437–444. https://doi.org/ 10.1007/s11060-013-1242-z Zhang K, Zhou M, Chen H et al (2015) Expression of IMP3 and IGF2 in giant cell tumor of spine is associated with tumor recurrence and angiogenesis. Clin Transl Oncol 17:570–575. https://doi.org/10. 1007/s12094-015-1280-4 Ziu E, Viswanathan VK, Mesfin FB (2021) Spinal Metastasis. In: StatPearls. StatPearls Publishing, Treasure Island (FL)

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Brain Tumors Affecting the Orbit Globe and Orbit Tumors Affecting the Brain Alfio Spina, Nicola Boari, Francesco Calvanese, Filippo Gagliardi, Michele Bailo, Martina Piloni, and Pietro Mortini

Abstract

Brain tumors affecting the orbit and orbital tumors affecting the brain are a heterogeneous group of lesions, with histological features, behaviors, diagnostic criteria, and treatments varying from each other. Dermoid cyst and cavernous hemangiomas are considered the most frequent benign lesions, while non-Hodgkin lymphoma is the most common malignant tumor in this region. Sharing the same anatomical region, clinical manifestations of orbital lesions may be often common to different types of lesions. Imaging studies are useful in the differential diagnosis of orbital lesions and the planning of their management. Lesions can be classified into ocular or extra-ocular ones: the latter can be further differentiated into extraconal or intraconal, based on the relationship with the extraocular muscles. Surgical therapy is the treatment of choice for most orbital lesions; however, based on the degree of removal, their histology and extension, other treatments, such as chemotherapy and radiother-

A. Spina (&) . N. Boari . F. Calvanese . F. Gagliardi . M. Bailo . M. Piloni . P. Mortini Department of Neurosurgery and Gamma Knife Radiosurgery, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, Milan, Italy e-mail: spina.alfi[email protected]

apy, are indicated for the management of orbital lesions. In selected cases, chemotherapy and radiotherapy are the primary treatments. This chapter aimed to discuss the orbital anatomy, the clinical manifestations, the clinical testing and the imaging studies for orbital lesions, and the principal pathological entities affecting the orbit together with the principles of orbital surgery. Keywords

. .

.

Orbital tumor Brain tumor Orbital malignancies Orbital cavernomas Meningioma

19.1

.

Background and Epidemiology

Orbital lesions (OLs) include different types of tumors and tumor-like lesions that have the same anatomical location and clinical manifestations. The orbit is made of six bones: the frontal and zygomatic bones, the maxilla, the ethmoid, the sphenoid, the lacrimal, and palatine bones (Schuenke et al. 2010). These bones form several foramina that house the link between the orbital cavity and the intracranial space, such as the supraorbital foramina, the superior orbital fissure (SOF), the inferior orbital fissure (IOF), the optic canal, and the anterior and posterior ethmoidal foramens (Schuenke et al. 2010). Several

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_19

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muscles are responsible for ocular movements: the superior rectus muscle, the inferior rectus, the medial and the lateral rectus muscles, the superior and the inferior oblique muscles, and the levator palpebrae muscle. The rectus muscles and their intermuscular septae define the muscle cone (Darsaut et al. 2001). The base of the cone is represented by the ocular globe, while the apex is represented by the optic canal (Darsaut et al. 2001). The canal length varies from 5 to 10 mm, with an average height and width of about 5 mm (Gardner et al. 2017). The optic strut is a bony ridge between the anterior clinoid process and the sphenoid bone and sinus, representing the inferior lateral border of the optic canal, which separates it from the SOF. The falciform ligament extends above the optic nerve (ON) before entering the optic canal. The dura mater after entering the canal gives origin to the dural of the ON and the periosteal layer of the periorbital (Gardner et al. 2017). The orbit can be divided into 4 compartments: the globe, intraconal space, conal (muscle) space, and extraconal space. The intraconal space is the area defined by the surrounding extraocular muscles; the muscle cone is composed of the extraocular muscles, whereas the extraconal space is located externally to the extraocular muscles. Benign and malignant lesions can affect the orbit alone or can spread into the intracranial space through the abovementioned anatomical structures. OLs can be classified based on their origin in primary orbital tumors (OT), originating from the orbit; secondary OT, extending from the intracranial space or paranasal sinuses to the orbit; metastatic tumors (Darsaut et al. 2001). Moreover, OT can be classified into intraconal or extraconal, according to the relationship with the abovementioned muscle cone (Darsaut et al. 2001). Primary OTs are rare and their reported incidence is about 1 case/100,000/year (Montano et al. 2018). The most common benign lesions are dermoid cyst and cavernous hemangiomas, while the most common malignant tumor is represented by non-Hodgkin lymphoma (Montano et al. 2018).

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This chapter aims to discuss the principal pathological entities affecting the orbit and to review the main clinical, radiological, and therapeutic features of these lesions.

19.2

Genetics, Immunology, and Molecular Biology

OLs are a wide range of pathologies, ranging from benign to malignant ones. Hematologic or inflammatory diseases may rarely interest the orbit. Genetic predisposition has been identified only for a discrete number of pathologies, while in most cases, these lesions have to be considered sporadic. The identification of some characteristic chromosomal translocations may help in the differential diagnosis of those lesions with poor differentiation or with overlapping morphological features. Specific chromosomal alterations have been identified for lymphoproliferative neoplasms, soft tissue masses, and a few benign tumors (Khong et al. 2009) (see Sect. 19.8).

19.3

Histopathology and Morphology

OLs comprise vascular and lymphatic lesions, osseous or cartilaginous tumors, and lesions originating from nervous structures and their covering. Based on the specific features of each type of OL, the morphology of the lesion together with the histopathology features has been discussed separately (see Sect. 19.8).

19.4

Imaging and Radiologic Features

Magnetic resonance imaging (MRI) is the most accurate imaging technique in this matter, but to study bone involvement, detect possible calcifications, or when MRI cannot be performed, computed tomography (CT) is typically used in the clinic (Aviv and Casselman 2005; Purohit et al. 2016).

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Brain Tumors Affecting the Orbit Globe and Orbit Tumors Affecting the Brain

On MRI, the extraocular muscles are T1hypointense or isointense and T2-hypointense, and after contrast administration, they are visualized symmetrically enhanced. Normal optic nerves are T1- and T2-hypointense; the cerebrospinal fluid, which connects with the intracranial subarachnoid space, does not enhance. The intact vitreous body is T1hypointense and T2-hyperintense (Aviv and Casselman 2005; Tailor et al. 2013). The first step in the radiologic evaluation of OLs has to be aimed to understand whether the lesion is ocular or non-ocular. Retinoblastoma or orbital melanomas are located within the ocular globe (Aviv and Casselman 2005; Tailor et al. 2013). Nonocular lesions can be present in the intraconal, conal, or extraconal spaces (Aviv and Casselman 2005). Intraconal space is involved in cases of optic nerve sheath meningioma and optic glioma (Aviv and Casselman 2005; Aviv and Miszkiel 2005; Mohammadi et al. 2021; Tailor et al. 2013). Conal space is usually affected in the case of thyroid ophthalmopathy, while Langerhans cell histiocytosis is typically extraconal. Secondary OT may involve more than one compartment. This compartmental approach to OT is useful to provide a differential diagnosis, because of the different contents of each orbital compartment (Aviv and Casselman 2005; Aviv and Miszkiel 2005). Once the location of the lesion and radiologic features has been defined, it can be possible to provide a series of differential hypotheses, considering clinical presentation and patients’ age, as given in Table 19.1. Furthermore, the eventual spread of the disease beyond the orbit to the adjacent bone or soft tissues, to

the cavernous sinus, cerebrum, or the presence of distant metastasis should be considered. The typical radiological characteristics of each type of lesion will be discussed in the following sections (see Sect. 19.8).

19.5

Clinical Manifestations

Accurate clinical history and patient’s age represent two important factors in directing the differential diagnosis of OT. Certain pathologies are typical of childhood, such as retinoblastomas, whereas others only present in adulthood, such as lymphomas (Purohit et al. 2016). Clinical manifestations of OT are often common to different types of lesions (Darsaut et al. 2001). Careful clinical and ophthalmologic evaluations are therefore essential in the diagnosis of OLs (Karcioglu and Jenkins 2015). Moreover, a neuroradiological examination is helpful in differential diagnosis and surgical planning (Boari et al. 2011). Pain is usually related to malignant conditions because of perineural invasion, while slowgrowing benign lesions, such as meningiomas, usually do not cause pain, except if exposure keratopathy is present (Nabavi et al. 2019). Facial evaluation of patients may reveal different information about the symmetry of the eye, eyelid, and orbital content. Eyelid and periorbital distances should be evaluated (Karcioglu and Jenkins 2015). Furthermore, other periorbital/orbital changes, abnormal eyelid configuration, skin lesions, edema, chemosis, and the appearance of conjunctival vessels should be

Table 19.1 Summary of lesions of the orbit based upon orbital compartment and its content Orbital compartment

Content

Type of lesion

Extraconal

Bone, fat, lacrimal gland

Tumors of the bone, lymphoma, carcinoma, metastasis, neurofibroma, SOM, dermoid/epidermoid, ACC

Conal

Extraocular muscles

Rhabdomyosarcoma

Intraconal

ON, arteries, veins, fat, lymph nodes, nerves

Vascular lesions, ON meningioma, ON glioma, schwannoma

Ocular globe

509

Retinoblastoma, metastasis, melanoma

ON Optic nerve; SOM Spheno-orbital meningioma; ACC Adenoid cystic carcinoma

510

carefully checked together with motility abnormalities of the eyelids and the status of the lacrimal drainage system. Exophthalmos or proptosis consists of a bulge of the eyeball beyond the eyelid rim. It can be defined as when the ocular bulb is simply pushed forward, or when a lateral displacement is present. Usually, axial proptosis is related to intraconal lesions, while coronal proptosis is related to extraconal lesions; lobe displacement is usually contralateral to the lesion (Nabavi et al. 2019). Metastatic orbital lesions can cause enophthalmos (Nabavi et al. 2019). Diplopia can be caused by compression or infiltration of extraocular muscles, motor neuron dysfunction, or orbital content displacement. Malignant lesions may infiltrate cranial nerves III, IV, or VI. Benign tumors usually only compress these nerves, while schwannoma or neurofibromas take origin from them (Nabavi et al. 2019). Orbital apex tumors may cause ophthalmoplegia and visual loss. Ocular pressure can be elevated in case of thyroid disease or carotidcavernous fistulas (Lee and Gersztenkorn 2015). Furthermore, eyeball compression and deformation can cause myopic or astigmatic visual changes, which may improve after surgery (Singh et al. 2012). Visual acuity alterations, usually associated with color vision deficit, are directly related to the degree of optic nerve involvement, retinal changes, or the presence of high-grade myopic/ astigmatic alterations (Singh et al. 2012). Visualevoked potentials amplitude variations are directly related to the visual acuity deficit (Bianchi et al. 2013; Singh et al. 2012). OT causing optic neuropathy usually triggers visual field defect ipsilateral to the tumor; lesions that exceptionally present an intracranial extension may cause also contralateral visual field loss, because of chiasm involvement (Lee and Gersztenkorn 2015). Confrontation visual testing can be easily performed; however, kinetic manual perimetry such as Goldmann perimetry, automated computed perimetry, and Humphrey visual test gives more objective and useful information (Lee and Gersztenkorn 2015). Pupillary changes can be caused by a deficit in afferent and efferent

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pupillary pathways; making pupillary light response testing mandatory (Lee and Gersztenkorn 2015). Compressive optic neuropathy can be present in OT with associated optic disc edema, which can be detected at optical coherence tomography (OCT); intracranial lesions rarely produce optic disc edema, while in the case of a large lesion, papilledema may occur (Lee and Gersztenkorn 2015). Retinal vascular changes are rare in OT except for carotid-cavernous fistulas (Lee and Gersztenkorn 2015).

19.6

Therapeutic Approaches

19.6.1 Surgery of Orbital Lesions Choosing the best surgical approach is based on tumor characteristics and extension, rather than the tumor type (Boari et al. 2011; Gardner et al. 2017). As mentioned above, preoperative imaging is pivotal to define these features (Aviv and Miszkiel 2005; Bejjani et al. 2001; Boari et al. 2011, 2013, 2018; Cockerham et al. 2001; Montano et al. 2018; Mortini et al. 2012; Purohit et al. 2016). Different surgical transcranial and transorbital approaches have been developed to reach lesions located alongside the orbit and the intracranial compartment (Rhoton 2002). Axial and coronal MRI or CT images have to be carefully evaluated in order to define tumor size, location, and extension (Boari et al. 2011). On axial plane, orbital apex lesions are located posterior to a plane passing through the greater wings of the sphenoid, at the level of the anterior border of the middle cranial fossa, orthogonal to the Frankfurt plane (Fig. 19.1a); tumors anterior to this plane are classified on the coronal plane according to their position concerning the optic nerve: the orbit is therefore divided into three 120°-angled sectors by three lines intersecting in correspondence of the optic nerve (Fig. 19.1b) (Boari et al. 2011). According to this topographical location, lesions lying in the orbital apex and in the sector B can be removed through a transcranial approach, such as fronto-orbitozygomatic approach (Boari et al. 2011, 2013, 2018; Mortini et al. 2012, 2019; Mortini and

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Brain Tumors Affecting the Orbit Globe and Orbit Tumors Affecting the Brain

Giovanelli 2002); whereas tumors located in the sectors A and C can be removed by a lateral orbitotomy, such as Krönlein approach (Boari et al. 2011; Spina et al. 2019). From a general perspective, the main criterion to select a surgical corridor for the orbital tumor is to avoid working across or around nerves (Gardner et al. 2017). Tumors with an intracranial extension should be approached through a fronto-temporo-orbital craniotomy with or without an orbito-zygomatic osteotomy to improve surgical exposure (Boari et al. 2013, 2018; Gardner et al. 2017; Mortini et al. 2012, 2019; Mortini and Giovanelli 2002; Paluzzi et al. 2015). Regarding medial lesions, together with cranio-orbito-zygomatic approaches, medial orbitotomy or transconjunctival approaches allowing direct access to the lesion, have to be considered (Boari et al. 2011; Gardner et al. 2017; Montano et al. 2018; Mortini et al. 2019). However, when approaching posterior intraconal medial lesions with an anterior approach, it is possible to perform a lateral orbitotomy with medial rectus muscle detaching to allow cone mobilization (Park and Yang 2013). Medial approaches are usually performed by ophthalmic surgeons and are not discussed in this chapter. More recently, with the development of endoscopic techniques, several endoscopic approaches to the orbit have been described (Gardner et al. 2017; Montano et al. 2018;

511

Paluzzi et al. 2015). Advantages of endoscopic approaches are the possibility to reach the medial and inferior compartments of the orbit and the orbital apex, limiting neurovascular structures and globe manipulation, and the absence of skin scars (Montano et al. 2018; Raza et al. 2012). The main disadvantages are the risk of postoperative enophthalmos and nasal morbidity; moreover, the endoscopic route can be performed only in selected cases (Paluzzi et al. 2015). Another important issue regarding surgery of orbital lesions is the role of optic nerve decompression (OND). Surgery of tumors with intracranial extension or intracranial tumor extending into the optic canal and in the SOF may require mobilization and dissection of the optic nerve, which may put it at risk of injury (Mortini et al. 2012). In these cases, extradural OND performed by unroofing the optic canal bone or by an extradural clinoidectomy allows for an early nerve mobilization and decompression, thus reducing the risk of nerve injury during tumor dissection (Mortini et al. 2012). Moreover, OND is recommended for tumors causing hyperostosis and possible narrowings of the optic canal, like en plaque meningioma and fibrous dysplasia. In our experience, two main approaches have to be considered for the management of pure orbital or intra-extra-orbital lesions: the lateral orbitotomy and the fronto-orbito-zygomatic approaches.

Fig. 19.1 Preoperative radiological evaluation on axial a and coronal b CT scans

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19.6.1.1 Lateral Orbitotomy Krönlein approach which is lateral orbitotomy, and its modifications allow direct approach to the lateral orbital content. This method is safe and has not the remarkable morbidity rate of a transcranial or transorbital route (Krönlein 1889; Mohsenipour 1994; Sekhar and Fessler 2016; Sindou 2009; Spina et al. 2019). The patient is placed in a supine position with the head turned 45° on the contralateral side. From the lateral third of the eyebrow to the zygomatic-temporal suture, the incision of the skin is performed in an italic S-shaped cut. The underlying superficial temporal fascia is exposed and preserved. First, the periorbita should be dissected from the inner orbital wall. Then, the deep part of the temporal muscle is subperiosteally dissected and retracted to the posterior. An osteotomy of the lateral wall of the orbit and zygomatic osteotomy, starting from the frontozygomatic suture (FZS) to the base of the frontal process of the zygoma should be done. In order to expose the periorbita, the greater wing of the sphenoid bone should be drilled (Fig. 19.2). The periorbita then should be cut in an x-shaped, while the underlying lateral rectus muscle is preserved. The zygomatic osteotomy is repositioned and fixed with screws and plates. 19.6.1.2 Fronto-Orbito-Zygomatic Approach Fronto-orbito-zygomatic (FOZ) approach allows wide exposure to intraorbital space and anterior and medial cranial fossae. Moreover, through the FOZ approach, it is possible to perform the extradural unroofing of the optic canal (Bejjani et al. 2001; Boari et al. 2018; Mortini et al. 2012, 2019; Mortini and Giovanelli 2002). The bicoronal skin incision begins less than 1 cm anterior to the tragus on the side of the craniotomy and it is extended, staying behind the hairline, to the contralateral frontal area to allow enough reflection of the skin flap to expose the orbital rim. The fat layer in between the 2 temporal fascia layers should be dissected deeply to preserve the frontal branch of the facial nerve. The dissection should be subperiosteally continued until the larger part of the frontal process of

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the zygoma is exposed. The muscle, in a retrograde direction of the fibers, is elevated from its attachment site. A standard fronto-temporal craniotomy is performed. The sphenoid wing is rongeur and drilled. The orbito-meningeal artery is then identified, and thereafter coagulated, and cut. At this stage, it is possible to identify the base of the anterior clinoid. The frontal and temporal parts of dura should be dissected from their attachments to the roof and lateral wall of the orbit. The SOF is identified extradurally just medial to the entrance point of the orbitomeningeal artery. The periorbita is thereafter elevated from the lateral wall and the roof of the orbit for at least 3 cm posteriorly from the orbital rim. The supraorbital nerve and vessels course along with the medial third of the superior orbital rim. The bundle should be spared with a chisel and mallet when it runs in a notch or a bony canal. The first sagittal incision is made at the superior orbital rim and a second one is on the lateral orbital rim exactly superior to the body of the zygoma toward the inferior orbital fissure using a thin saw blade. These 2 cuts can be connected by a high-speed drill with a cutting burr starting from the IOF on the lateral orbital wall to a posteroanterior sagittal direction (Fig. 19.3). After the resection of the lesion, titanium miniplates are used to fix the orbital flap. Also, in order to avoid postoperative skin depression, the bone flap of the vault should be in contact with the orbitotomy flap in the frontal region.

19.6.2 Chemotherapy and Radiotherapy OLs may arise from different orbital structures and surgical management may cause the risk of vision loss and aesthetic sequelae. Based on these findings, especially in the case of malignancies, radical surgery may be difficult to be achieved. In these cases, a multidisciplinary management is mandatory to reduce the risk of local recurrence. (Hu et al. 2019). Radiation therapies (RTs), such as intensitymodulated radiotherapy or Gamma Knife

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Fig. 19.2 Schematic representation of the lateral orbitotomy

Fig. 19.3 Schematic representation of fronto-orbito-zygomatic approach

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radiosurgery, can be considered as an adjuvant therapy after surgical resection. Depending on tumor type, other radiation treatment modalities can be used, based on the response rate of each lesion (Hu et al. 2019). Chemotherapy may be a further possible adjuvant therapy depending on the tumor type, sometimes used in combination with RT. Specific adjuvant therapies have been discussed separately in the next sections.

19.6.3 New Therapeutic Modalities Several new combined protocols of chemotherapy and RT are ongoing as adjuvant or neoadjuvant treatment of OLs before surgery. No definitive data are available to this day to support their use. Furthermore, selected immunotherapeutic agents and target therapies are being studied to test their effectiveness and the ability to positively modify the outcome of some orbital pathologies.

19.7

Follow-Up and Prognosis

The prognosis of OLs is strictly related to the type of lesion. Surgery may be curative in most benign lesions, while for malignant ones, the prognosis is related to histology, tumor size and its location, patients’ characteristics, treatment type, the extent of resection, and presence of metastasis (Mouriaux et al. 1999). The principal aim of surgery for malignancies is to resect the entire visible tumor with free margins if possible (Mouriaux et al. 1999). Regardless of the type of lesion, orbital malignancies may show a 4 years overall survival rate of 45%. Local relapses and metastasis are more common in patients with transacted margins than free margins (p = 0.01). The survival rates are poorer in case of recurrence of distant metastasis (P = 0.0025) (Mouriaux et al. 1999). Based on the abovementioned features, a regular follow-up is mandated in the case of OLs. In benign lesions, a clinical and radiological follow-up every 6 months to one year is

recommended, while in case of malignancies, a stricter follow-up, every 3 to 6 months, may be suggested based on the histology, the tumor stage, and the history of treatments (Fig. 19.4).

19.8

Orbital Lesions

As mentioned above, despite sharing the same anatomical region, orbital lesions include large and varied types of tumors and tumor-like lesions. In the next sections, the most common lesions encountered in the neurosurgical practice are described.

19.8.1 Vascular Lesions 19.8.1.1 Cavernous Malformations Orbital cavernous malformations (CMs) represent the most common intraconal primary tumors in the adult population, accounting for 4% of all orbital tumors and about 9–13% of all intracranial cavernomas (Boari et al. 2011). Orbital OCMs are usually unilateral and affect more commonly females in their fourth and fifth decade of life (Yang and Yan 2014). CMs consist of mulberry-like ectopic thrombosed venous structures characterized by thin elastic endothelial, fibrous degeneration by previous hemorrhages, and thrombosis with small feeding arteries and veins (Boari et al. 2011; Hejazi et al. 1999). They cause progressive proptosis, compressive optic neuropathy, and diplopia (Boari et al. 2011; Brusati et al. 2007). Compared to intracranial lesions, orbital CMs seem to have a more stationary behavior and the risk of hemorrhage is lower, because they show regular smooth vessel walls (Hejazi et al. 1999). Regarding the radiological features, CMs appear as round well-circumscribed intraconal masses (Fig. 19.5a) (Boari et al. 2011). On CT scan, they appear as hyperdense lesions with mild enhancement after contrast administration, whereas in MRI studies, orbital CMs are isointense to the white matter in T1-weighted images and hyperintense on T2-weighted images, with internal enhancement not present at the periphery

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Fig. 19.4 Management algorithm of orbital lesions Fig. 19.5 Preoperative a and postoperative b T2-weighted MRI acquisition of an orbital cavernous malformation

of the lesion (Boari et al. 2011; Hejazi et al. 1999). According to their clinical symptoms and size, orbital CMs can be conservatively managed or surgically treated. Indications for surgical treatment are visual impairment, diplopia due to ocular movement impairment, progressive and disfiguring unilateral proptosis, and severe retroorbital pain related to the orbital cavernoma (Boari et al. 2011). Intraoperatively, orbital CMs are well-encapsulated lesions dipped in intraconal fat, separated from but sometimes adherent

to the optic nerve and the extraocular muscles (Hejazi et al. 1999). The capsule has a hard consistency, which makes a feasible smooth dissection from surrounding tissue; extraocular muscles overstretching or contusion have to be avoided in order to prevent postoperative palpebral ptosis and diplopia (Boari et al. 2011). Surgery is curative and a gross-total resection (GTR) can be usually accomplished (Fig. 19.5b) (Acciarri et al. 1993; Boari et al. 2011; Brusati et al. 2007; Hejazi et al. 1999; Yang and Yan 2014).

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19.8.1.2 Lymphangioma Lymphangiomas are benign malformations of the lymphatic system. They account for up to 8% of orbital masses with non-gender predilection (Santiago and Fay 2019). The pathophysiology is still unknown and they are located in the subconjunctival and periocular areas (Santiago and Fay 2019). Lymphangiomas can have no flow or venous components with swelling during Valsalva maneuvers (Santiago and Fay 2019). Unilateral proptosis, ptosis, and intraorbital hemorrhage are the main symptoms, which can have a sudden onset presentation (Santiago and Fay 2019). Lesions look like multilobulated and septated masses, with intralesional hemorrhage (Santiago and Fay 2019). On MRI studies, lymphangiomas show hypointensity on T1-weighted images and hyperintensity on T2-weighted. Surgery represents the treatment of choice. Alternatively to the surgical treatment or as a neo-adjuvant therapy, sclerosing agents, including doxycycline and bleomycin, can effectively shrink the lesions, allowing a safer and extended surgical resection (Santiago and Fay 2019). GTR is the goal of surgery and it is associated with a low recurrence rate, whereas partially resected lesions show a high recurrence rate. For partially removed lesions, orbital decompression should be warranted to preserve vision (Santiago and Fay 2019). 19.8.1.3 Hemangiopericytomas Hemangiopericytoma (HPC) is a rare tumor with aggressive behavior. These tumors show ovoid cells and sinusoid space formations (Furusato et al. 2011; Santiago and Fay 2019). HPCs show high cellularity and dense vascularization (Brum et al. 2018; Furusato et al. 2011; Goldsmith et al. 2001; Spina et al. 2016a; Valentini et al. 2004). According to the WHO classification, HPCs are distinct in grade II or III, based on the number of mitotic activities, necrosis, hemorrhage, and nuclear atypia; the two grades have different local aggressive behavior and tendency to distant metastasis (Spina et al. 2016a, b). HPCs affect adults. They are usually unilateral, presenting with slowly progressive proptosis, pain, and visual loss. Patients with tumors of intracranial

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extension may experience symptoms from cavernous sinus invasion (Brum et al. 2018; Santiago and Fay 2019). On CT imaging, HPCs are isodense lesions with collateral bony involvement, whereas on MRI, hypointense well-circumscribed mass, with hyperintensity and multiple flow voids on T2-weighted acquisitions (Santiago and Fay 2019). Tumor blush and quick contrast washout can be seen on angiographic imaging (Brum et al. 2018; Goldsmith et al. 2001; Sagiv et al. 2019; Santiago and Fay 2019). GTR is the standard treatment because partially resected lesions show a high tendency to recur (Spina et al. 2016a, b; Valentini et al. 2004). Adjuvant radiation therapies, such as Gamma Knife radiosurgery (GKRS), seem to reduce the recurrence rate after both GTR and partial tumor resection (PTR) (Spina et al. 2016a, b).

19.8.1.4 Capillary Hemangiomas and Orbital Arteriovenous Malformations Capillary hemangiomas, also known as infantile hemangiomas, are extraconal lesions situated in the upper-medial quadrant (Aviv and Miszkiel 2005). They are congenital and may grow and regress thereafter at the age of 7–10 (Aviv and Miszkiel 2005). Capillary hemangiomas can cause amblyopia, optic nerve compression, and corneal exposure (Krema 2015; Sullivan 2018). Surgery is considered only for those cases causing serious visual symptoms, whereas betablockers, such as propranolol, can dramatically shrink the tumor with amblyopia recovery in most cases (Krema 2015; Sullivan 2018). Arteriovenous malformations (AVMs) are high-flow malformations causing pain, acute swelling after thrombosis, and ecchymosis by intraorbital hemorrhage (Rootman et al. 2014). Treatment aims are to safely remove the nidus, to avoid AVM recurrence. Understanding the hemodynamics of the AVMs is pivotal to identify the nidus and choose the optimal treatment strategy, which includes surgery, endovascular embolization or alcohol sclerotherapy, or a combination of them (Colletti et al. 2019; Rootman et al. 2014).

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19.8.2 Tumors Originating from Bone and Cartilaginous Structures 19.8.2.1 Osteoma Osteomas are rare and slow-growing lesions, accounting for 1% of all bony tumors (Abou AlShaar et al. 2015; Jorgensen and Heegaard 2018; Wei et al. 2014). Generally, these tumors originate from the frontal, ethmoid, sphenoid, and maxillary bones, which can extend into the orbit in up to 24% of cases; primary orbital osteomas are very rare (Bagheri et al. 2019; Jorgensen and Heegaard 2018; Wei et al. 2014). Etiology is still unknown (Wei et al. 2014). Based on their histology, osteomas are classified as ivory or compact, mature or cancellous, or mixed types (Wei et al. 2014). On CT scan, they appear as welldefined masses and sclerotic bone lesions (Wei et al. 2014). Surgical resection is usually considered for osteoma causing functional or aesthetic deficits (Wei et al. 2014). Specifical indications for surgical treatment are: large or growing lesions, an associated complication such as mucocele, neurologic symptoms, and evident facial deformity (Georgalas et al. 2011). Through surgery, we can remove the tumor partially or completely, particularly the central core that is the originating point, and also cosmetic outcomes can be improved via the bone defect reconstruction (Abou Al-Shaar et al. 2015; Bagheri et al. 2019; Naraghi and Kashfi 2003; Wei et al. 2014). Clinical outcome is generally favorable (Naraghi and Kashfi 2003; Wei et al. 2014). 19.8.2.2 Fibrous Dysplasia Fibrous dysplasia (FD) is a rare benign disorder of the bone, in which due to the absence of normal differentiation and maturation of osteoblasts, the normal bone marrow is replaced with immature fibro-osseous tissue (Leong and Ming 2015). This pathologic process is occurred because of a mutation in the GNAS1 gene on chromosome 20. FD becomes clinically evident during the first three decades of life, while later presentations are usually uncommon (Leong and Ming 2015).

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FD can be distinguished in monostotic forms, with a single dysplastic focus, or polyostotic forms, in which different foci of bone dysplasia can be detected along the body (Bertin et al. 2020; Bibby and McFadzean 1994; Dumont et al. 2001; Leong and Ming 2015; Ricalde and Horswell 2001). Ocular problems are reported in 20–35% of cases, and proptosis, diplopia, pain, and visual loss are the most common symptoms (Leong and Ming 2015). Visual loss is probably due not only to the direct compression of the optic nerve but also to the increased pressure of the retinal veins affecting retinal perfusion (Dumont et al. 2001; Leong and Ming 2015). CT represents the main diagnostic modality. Regarding the radiological features, three different patterns can be identified: the pagetoid mixed pattern (about 40%) characterized by the “ground-glass” appearance of the pathologic bone and the cranial base foramina involvement; the sclerotic pattern (35%), and the cystic pattern (uncommon), which show inhomogeneous bone texture (Dumont et al. 2001; Leong and Ming 2015). FD usually stabilizes or slows down in progression after skeletal maturity (Leong and Ming 2015). Conservative management has been advocated for those cases with no or mild deformation, while surgery is indicated in case of facial and orbital deformity or in case of visual symptoms (Dumont et al. 2001; Leong and Ming 2015; Ricalde and Horswell 2001). Through surgery, the nervous structure can be decompressed, and FD with free margins can be resected if possible. Also, a functional and aesthetic reconstruction can be provided (Dumont et al. 2001; Ricalde and Horswell 2001). Medical management with bisphosphonates can be considered for pain control, and to control FD growth, however, there is no reported effective visual symptoms relief (Leong and Ming 2015).

19.8.3 Aneurysmal Bone Cyst Aneurysmal bone cysts (ABCs) are rare benign osteolytic lesions of the bone (Cakirer et al.

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2002; Citardi et al. 1996; Johnson et al. 1988; Marcol et al. 2006; Menon et al. 1999; Spina et al. 2016b). They exhibit a non-neoplastic nature and progressive growth with the destruction of the surrounding normal bone (Spina et al. 2019). ABCs usually affect young patients and can be primary or secondary to other bone lesions, such as osteoblastomas and FD (Cakirer et al. 2002). ABCs may cause proptosis and visual symptoms because of the mass effect (Cakirer et al. 2002). Surgery is indicated for symptomatic lesions (Cakirer et al. 2002; Citardi et al. 1996; Johnson et al. 1988; Marcol et al. 2006; Menon et al. 1999; Spina et al. 2016b).

19.8.4 Tumors Originating from Nervous Structures and Their Covering 19.8.4.1 Peripheral Nerve Sheath Tumors Within the orbit, peripheral nerve sheath tumors (PNTs) arise from the neuroectoderm and the neural crest, involving branches of the oculomotor cranial nerves of the ophthalmic branch of the trigeminal nerve (Sweeney et al. 2017). Neurofibromas account for 0.4–3% of all orbital tumors (Fig. 19.6), schwannomas 0.7–2–3%, and malignant peripheral nerve sheath tumors (MPNSTs) account for 0 to 0.2% of cases (Karcioglu and Jenkins 2015; Sweeney et al. 2017). Pure intraorbital PNTs are related to neurofibromatosis 1 (NF1) or familiar cases in about 20% of cases, while extra-orbital ones are the frequent manifestation of NF1 (Kinori et al. 2018; Sweeney et al. 2017). Neurofibromas originate from non-myelinated Schwann cells, whereas schwannomas arise from myelinproducing Schwann cells (Sweeney et al. 2017). MPNSTs may originate de novo or from a preexisting neurofibroma or schwannoma. The originating cells are still unknown and sometimes may exhibit similar features to plexiform neurofibromas (Sweeney et al. 2017; Yong et al. 2020; Yu et al. 2019). Clinically, more often, neurofibromas and schwannomas show proptosis with associated

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palpebral ptosis, decreased vision, and diplopia. Visual loss is a late symptom and can be related to MPNST progression. SOF extension for neurofibromas is reported in more than 30% of cases, while schwannomas are less common (Sweeney et al. 2017). MPNSTs show rapid progression of symptoms and may metastasize to the cranium (Sweeney et al. 2017). On MRI, neurofibromas, schwannomas, and MPNSTs show isointense signal on T1-weighted images and hyperintense signal of T2-weighted acquisitions (Sweeney et al. 2017; Yong et al. 2020). Nonetheless, enhancement after contrast administration is similar for neurofibromas and schwannomas, with well-defined homogeneous to heterogenous patterns, while MPNSTs show diffuse and intense enhancements with irregular shapes (Sweeney et al. 2017; Yong et al. 2020). Surgery is the mainstay in the treatment of neurofibromas and schwannomas. These tumors are well-circumscribed and encapsulated, hence, GTR is often achievable. One of the main surgical issues is to avoid a motor nerve sacrifice; early intraoperative identification of the originating nerve is therefore recommended (Sweeney et al. 2017; Yong et al. 2020 #113). Another limiting factor is the removal of the tumor around the SOF, where the oculomotor nerves can be injured. For benign tumors located in the orbital apex, orbital decompression alone may relieve optic symptoms (Sweeney et al. 2017). In the case of partially resected lesions, fractionated stereotactic RT has to be considered (Yong et al. 2020). For MPNSTs, aggressive surgical resection with free margin is not often possible, due to the presence of local or regional metastasis (Sweeney et al. 2017). In these cases, orbital exenteration can be recommended. The role of RT for MNPSTs has not been clearly understood and these tumors are still considered radio-resistant (Sweeney et al. 2017).

19.8.4.2 Optic Nerve Gliomas Optic nerve gliomas (ONGs) represent the most common tumor of the optic nerve, representing about 2–5% of childhood central nervous system tumors and 1% of all intracranial tumors (Farazdaghi et al. 2019; Nair et al. 2014). ONGs are

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Fig. 19.6 Axial a, coronal b, and sagittal contrast enhanced MRI imaging of a left orbital schwannoma

benign lesions in up to 90% of cases, while the remaining are malignant (Nair et al. 2014). ONGs can occur sporadically or in the context of NF1 (Kinori et al. 2018). From 10 to 80% of children with ONGs suffer from NF1, while ONGs incidence in NF1 is about 20% (Farazdaghi et al. 2019; Nair et al. 2014). About onefourth of optic pathway gliomas are purely intraorbital, while the remaining arise from the optic chiasm, optic tract, or hypothalamus (Giustina et al. 2017). Despite the similar nomenclature, ONGs represent a wide heterogeneity of lesions because of different factors affecting the epidemiology, the clinical manifestations, and the prognosis (Shofty et al. 2017). Patient’s age, sex, NF1 status, tumor’s genetic profile, solid or cystic lesion, and hypothalamic or optic chiasm involvement represent the main factors that can significantly influence the natural history of ONGs (Miller 2016; Mudhar et al. 2016; Pour-Rashidi et al. 2021; Shofty et al. 2017). Benign ONGs are commonly present in the first decade of life. Tumors are usually unilateral with a female predominance (Ghassibi et al. 2017; Nair et al. 2014). Histologically, they are defined as juvenile pilocytic astrocytomas (WHO grade I) (Ghassibi et al. 2017). Malignant lesions are high-grade astrocytomas, such as anaplastic astrocytoma (WHO grade III) or glioblastoma (WHO grade IV) (Traber et al. 2015). Progressive visual loss is the main symptom, which can have a sudden onset and can be followed by proptosis (Ghassibi et al. 2017; Nair

et al. 2014). Based on the tumor extension, patients may experience strabismus, vertical nystagmus, bilateral visual loss, and/or endocrinological disturbances (Farazdaghi et al. 2019; Giustina et al. 2017; Nair et al. 2014; Shofty et al. 2017). On MRI, they appear hypo to isointense in T1-weighted images, whereas they have a hyperintense signal on T2-weighted acquisitions (Ghassibi et al. 2017; Nair et al. 2014; Shofty et al. 2017). The optic nerve is not discernable from the tumor, contrary to what happens in meningiomas (Ghassibi et al. 2017). Because of the abovementioned features, the current treatment of ONGs is still challenging. The natural history of childhood tumors is always benign, with self-limiting slow-growing and possible spontaneous regression (Nair et al. 2014). Chemotherapy has been advocated to treat progressive tumors in children, however, no definitive effectiveness has been reported, hence, chemotherapy has to be considered as an upfront therapy to delay more invasive ones (Farazdaghi et al. 2019). Radiation therapy (RT) is able to dramatically improve progression-free survival rate, however, administration of RT to children may cause some adverse effects or worsens the quality of life permanently (Farazdaghi et al. 2019; Nair et al. 2014). About half of tumors may shrink, while visual improvement has been reported in approximately 30% of patients (Farazdaghi et al. 2019; Ghassibi et al. 2017; Nair et al. 2014; Shofty et al. 2017; Traber et al. 2015). Surgery is considered only for cases with

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severe proptosis and/or with evidence of tumor progression (Nair et al. 2014; Shofty et al. 2017). Surgical removal has a high risk to worsen residual visual function. For those lesions extending to the optic chiasm, surgery is not recommended. No effective treatment is available for malignant tumors. RT alone or combined with chemotherapy may be considered a palliative treatment (Nair et al. 2014; Traber et al. 2015).

19.8.4.3 Meningiomas Meningiomas involving the orbit are mainly represented by optic nerve sheath meningiomas (ONMs) and spheno-orbital en plaque meningiomas (SOMs). ONMs are benign lesions arising from the meninges surrounding the optic nerve (Parker et al. 2018; Santiago and Fay 2019). They represent approximately 2% of all orbital tumors, with female predominance and mean age of 40 years (Parker et al. 2018). Primary ONMs are rare, accounting for 10% of cases, while the remaining represent the intraorbital extension of an intracranial tumor (Parker et al. 2018). ONMs are usually unilateral lesions, while bilateral tumors are reported in 5% of cases (Parker et al. 2018). They are strongly associated with neurofibromatosis type 2 and show slow progression (Parker et al. 2018). Clinically, visual loss is the most common presenting symptom; however, visual field defects, diplopia, and proptosis are other common findings (Parker et al. 2018; Santiago and Fay 2019). Optic disc swelling or atrophy can be detected in OCT studies and pain can be also present (Parker et al. 2018). The gold standard imaging is MRI, which shows welldefined lesions with contrast enhancement, arising from the optic nerve (Parker et al. 2018). Radical resection of ONMs is related to a high risk of visual impairment and amaurosis because the tumor shares the same blood supply as the nerve. For this reason, PTR is recommended with a sheath incision to provide OND, when feasible (Parker et al. 2018). For aggressive tumors without residual visual function, en bloc resection of the tumor, eyeball, and the nerve can be considered (Parker et al. 2018). For partially resected ONMs or none-operable lesions, radiotherapy has

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to be considered to control tumor volume (Adeberg et al. 2011). RT seems to preserve visual function better than surgery or observation alone, with an overall complication rate of about 33%, such as temporal lobe atrophy, radiation retinopathy, or vascular occlusion, compared to 67% of surgical treated cases (Adeberg et al. 2011; Parker et al. 2018; Saeed et al. 2003; Smee et al. 2009). Fractionated Gamma Knife or Cyber Knife radiosurgery represents as emerging primary treatments for ONMs, which seem to be burdened by a lesser risk of visual deterioration if compared with surgery and can provide tumor control in about 95% of cases. SOMs arise from the meningeal layers lining at the level of the greater sphenoid wing. These tumors are typically hyperostotic, slow-growing, and rare (Fig. 19.7a, b) (Boari et al. 2013). The hyperostotic reaction is usually disproportionate to the intradural tumor volume, but it is considered the main underlying reason responsible for the clinical symptoms (Fig. 19.8) (Boari et al. 2013; Charbel et al. 1999). Meningiomatous cells invade the Haversian canals of the bone causing bone response (Charbel et al. 1999). Typically, SOMs interest the lateral orbital wall, squamous temporal bone, the orbital roof, and the frontal bone (Floyd and Demonte 2012). Moreover, hyperostosis can spread to the anterior clinoidal process, the SOF, the optic canal, extending into the cavernous sinus and the paranasal sinuses (Boari et al. 2013; Floyd and Demonte 2012; Freeman et al. 2017; Jorgensen and Heegaard 2018; Terrier et al. 2018). The most common symptoms are proptosis and visual impairment, while orbital pain, diplopia, and oculomotor palsy are less frequent (Boari et al. 2013; Floyd and Demonte 2012; Freeman et al. 2017; Terrier et al. 2018). Proptosis has a multifactorial genesis: the progressive invasion of the orbit by the hyperostotic bone and the soft portion of the tumor together with the reduction of the venous drainage by the infiltration of the SOF is the main causes (Terrier et al. 2018). The combination of MRI and CT imaging is essential to determine both the soft tumor component and the bone extension of the hyperostotic portion (Fig. 19.9a) (Boari et al. 2013;

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Fig. 19.7 Preoperative axial a and coronal b, and postoperative axial c CT scan of a case of spheno-orbital en plaque meningioma

Fig. 19.8 Axial a, coronal b and sagittal contrast enhanced MRI imaging of a left spheno-orbital en plaque meningioma

Terrier et al. 2018). Despite conservative management, with the progression of microsurgical technique and craniofacial reconstruction, it has been historically advocated that surgery is considered the treatment of choice for OSMs (Boari et al. 2013; Floyd and Demonte 2012; Freeman et al. 2017; Terrier et al. 2018). Surgical resection aims to safely remove the tumor as much as possible and provides orbital, optic nerve, and oculomotor nerve decompression. It is not suggested to remove the tumor around the cavernous sinus and the SOF, due to the high risk of postoperative ophthalmoplegia (Boari et al. 2013; Freeman et al. 2017; Terrier et al. 2018). Furthermore, it has been demonstrated that PTR followed by adjuvant radiotherapy, such as Gamma Knife radiosurgery, is able to provide a higher overall and progression-free survival than surgery alone (Boari et al. 2013; Freeman et al.

2017; Terrier et al. 2018). Proptosis usually improves in almost all cases (Boari et al. 2013; Freeman et al. 2017; Terrier et al. 2018), while visual function usually improves in up to 85% of cases (Boari et al. 2013; Terrier et al. 2018). Occasionally, postoperative enophthalmos and orbital pain were reported (Boari et al. 2013). Reconstruction represents an important surgical step in determining functional and the aesthetic outcomes (Figs. 19.8c and 19.9b). The resected orbital wall and fronto-spheno-temporal junction can be reconstructed by using titanium mesh (Boari et al. 2013). Satisfactory aesthetic outcomes, low postoperative enophthalmos rate, and lesser temporal muscle atrophy have been reported by carefully reconstructing the bone gap in different series (Boari et al. 2013; Floyd and Demonte 2012; Freeman et al. 2017; Terrier et al. 2018).

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Fig. 19.9 Preoperative a and postoperative b CT scan of a case of left spheno-orbital en plaque meningioma

19.8.5 Miscellaneous Tumors 19.8.5.1 Dermoid and Epidermoid Cysts Dermoid and epidermoid cysts are the most prevalent orbital tumors in children and they are usually located in the FZS. They are congenital choristomas originating from the embryonic fusion of mesoderm (Bajric and Harris 2019). Mainly, these lesions can be found in intraorbital or periorbital space or can extend to the temporal fossa, as in the case of dumbbell cysts (Bajric and Harris 2019). Six different growth patterns have been identified, which determine the clinical symptoms and surgical approach: anterior to the FZS, superior to the FZS, medial to the FZS, traversing the FZS (dumbbell), nasoglabellar, and sinus tract (Bajric and Harris 2019). On CT scan, they appear as a cyst with adjacent bony changes (Purohit et al. 2016; Pushker et al. 2020). Surgical resection is the treatment of choice (Bajric and Harris 2019; Pushker et al. 2020; Santiago and Fay 2019). Early total tumor removal can limit bony changes and improve the overall outcome because the inflammatory response of the adjacent bone can complicate the surgical excision (Pushker et al. 2020).

Partially resected lesions have the risk of recurrence at follow-up because of the young age of patients. Surgery of recurrent lesions may have higher risks of morbidity: in these cases, cyst marsupialization can be recommended (Bajric and Harris 2019).

19.8.5.2 Adenoid Cystic Carcinomas Adenoid cystic carcinomas (ACCs) are rare malignant masses arising from the lacrimal gland (Crawford and Sharma 2017; Han et al. 2018; Wolkow et al. 2018). The perineural invasion and spread into the nerves can be detected in these tumors. Accordingly, local recurrence and distant metastasis, commonly in lungs, liver, and bones, are usually reported in patients (Crawford and Sharma 2017). The treatment of choice in this tumor is aggressive surgical excision with free margins (orbital exenteration), followed by adjuvant RT (Crawford and Sharma 2017; Han et al. 2018; Wolkow et al. 2018). This treatment protocol can prolong progression-free and overall survival (Crawford and Sharma 2017; Han et al. 2018; Wolkow et al. 2018). Recently, a more conservative surgical management with eyesparing or globe-preserving techniques followed by proton beam therapy showed a similar outcome to conventional approaches (Han et al. 2018; Wolkow et al. 2018).

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19.9

Conclusion

OLs represent a wide group of pathological entities, which include benign lesions, primary tumors of the orbit, cranial tumors that can invade the orbit, and secondary tumors. In this chapter, we have discussed the anatomy, principles of surgery, and the main pathological entities that can affect this particular anatomical location. Management and prognosis are strictly related to the histology and the treatment modality. As discussed, the importance of a prompt and correct diagnosis along with multidisciplinary treatment is fundamental in the management of these lesions.

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Lymphomas of Central Nervous System Kiyotaka Yokogami, Minako Azuma, Hideo Takeshima, and Toshinori Hirai

Abstract

Central nervous system (CNS) lymphoma consists of primary central nervous system lymphoma (PCNSL) and secondary CNS involvement by systemic lymphoma. This chapter focuses on the former. PCNSL is a relative rare disease, accounting for approximately 2.4–4.9% of all primary CNS tumors. It is an extra-nodal variant of non-Hodgkin's lymphoma (NHL), confined to the brain, leptomeninges, spinal cord, and eyes, with no systemic involvement. Recently, elderly patients ( ≥ 60 years) are increasing. Histologically, B cell blasts, which originate from late germinal center exit B cell, are growing and homing in CNS. Immunohistochemically, these cells are positive for PAX5, CD19, CD20, CD22, and CD79a. PCNSL shows relatively characteristic appearances on CT, MR imaging, and PET. Treatment first line of PCNSL is HD-MTX-based chemotherapy with or without rituximab and irradiation. Severe side-effect of this treatment is delayed

K. Yokogami (&) . H. Takeshima Departments of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan e-mail: [email protected] M. Azuma . T. Hirai Departments of Radiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan e-mail: [email protected]

onset neurotoxicity, which cause of cognitive impairment. Therefore, combined chemotherapy alone or chemotherapy with reduced-dose irradiation is more recommended for elderly patients. There is no established standard care for relapse of the PCNSLs. Temsirolimus, lenalidomide, temozolomide, and Bruton's tyrosine kinase (BTK) inhibitor ibrutinib are candidates for refractory patients. The prognosis of PCNSL has significantly improved over the last decades (median OS: 26 months, 5-year survival: 31%). Younger than 60 age and WHO performance status less than < or = 1 are associated with a significantly better overall survival. Keywords

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Primary central nervous system lymphoma PCNSL Epidemiology Genetic and epigenetic alteration Radiographic imaging Chemotherapy Irradiation Prognosis

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20.1

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Background and Epidemiology

Primary central nervous system (CNS) lymphoma (PCNSL) is a mostly diffuse large B cell lymphoma (DLBCL) only occurs in the CNS. PCNSL is excluded from systemic lymphomas with secondary involvement of CNS and immunodeficiency-associated CNS lymphoma such as AIDS, post-transplant conditions, and

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_20

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congenital immunodeficiencies. PCNSL accounts for 4–6% of all extra-nodal lymphomas, up to 1% of all lymphomas and 2.4–4.9% of all brain tumors (Brain Tumor Registry of Japan (2005–2008) 2017; Cai et al. 2019; Villano et al. 2011). Intraocular lesions occur in 15–25% of patients with PCNSL and are often associated with refractory onset and delayed diagnosis (Chan et al. 2011). Recently, an increased incidence has been reported in patients aged > 50 years (> 60 years is 62%) (Brain Tumor Registry of Japan (2005–2008) 2017; Villano et al. 2011). The median patient age is 56 years, and male-to-female ratio is 3:2.

20.2

Genetics, Immunology, and Molecular Biology

In order to understand the histological origin of PCNSL cells, it is useful to reproduce the differentiation of cells under physiological conditions (Fig. 20.1). The cells of PCNSLs have rearranged and somatically mutated immunoglobulin (IG) genes with somatic hypermutation (SHM) (Montesinos-Rongen et al. 1999; Pels et al. 2005; Thompsett et al. 1999). Sixty to eighty percent of PCNSLs expresses the BCL6 protein which is confined to germinal center (GC) B cells (Montesinos-Rongen et al. 2008). Cell-surface expression of IGM and IRF4, which is expressed on a subset of GC and plasma cells, but not plasma cell surface marker (CD38, CD138) indicates that the cells of PCNSLs are late GC exit B cells (Deckert et al. 2014). GC reaction is one of the targets of PCNSL. Under physiological conditions, BCL6 is a key regulator of the GC reaction and inhibits B cell exit from the GCs. Continuously activated BCL6 by translocations, which are detected in 17–47% of PCNSLs, is considered to contribute to keeping the tumor cells of PCNSL in the GC stage and can have tumorigenic effects (Basso and Dalla-Favera 2012; Deckert et al. 2014; Montesinos-Rongen et al. 2008, 2009, 2002). BCL6 overexpression is reported to associate with poorer survival and refractory PCNSL condition (Braaten et al. 2003; Levy et al. 2008; Rubenstein et al. 2013). Although aberrant SHM

(aSHM) is not confined to IG and BCL6 genes, aSHM activates oncogenes or inactivates tumor suppressor genes including PAX5 (60%), TTF (70%), CMYC (60%), and PIM1 (50%) (Montesinos-Rongen et al. 2004). These genes are often involved in the regulation of B cell activity, proliferation, and apoptosis. aSHM's other targets include genes encoding TBL1XR1, TRDM1, BTG2, and PRDM1 (Braggio et al. 2015). Nonconservative gene mutations, which are not associated with GC reaction, are found in ATM, TP53, PTEN, PIK3CA, JAK3, CTNNB1, PTPN11, and KRAS by next-generation sequencing (NGS) analysis. These genes are suggested to associate with pathogenesis, poor survival, and relapse (Cai et al. 2019; Todorovic Balint et al. 2016).

20.2.1 Epigenetic Alterations in PCNSL Epigenetic silencing by DNA hypermethylation was observed in CDKN2A, DAPK, p14ARF, p16INK4a, RFC, and MGMT (Chu et al. 2006; Ferreri et al. 2004; Gonzalez-Gomez et al. 2003; Mrugala et al. 2009). The presence of methylated MGMT promoter sequences was correlated with improved overall survival (OS) in patients who received high-dose chemotherapy. In addition, elder patients with recurrent PCNSL whose MGMT promoter were methylated demonstrated to have an excellent response to temozolomide (Adachi et al. 2012; Kurzwelly et al. 2010; Toffolatti et al. 2014). Although microRNA (miRNA) expression in PCNSL is still limited, several reports showed that miRNA may also play an important role in the PCNSL pathogenesis. PCNSL would express significantly higher levels of miR-10a and MiR-17-5p, which targets the proapoptotic E2F1 gene, in comparison with to nodal DLBCL (Robertus et al. 2009). Fischer et al. described that miR-17-5p, miR-20a, and miR-9, upregulated in PCNSL, were associated with the Myc pathway. Both miR-9 and miR30b/c were associated with inhibition of terminal B cell differentiation. The expression of cancer-

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Fig. 20.1 Histogenetic origin and molecular pathogenesis of PCNSL. The genotypic and phenotypic features of PCNSL tumor cells indicate that they are derived from late GC exit B cells. These cells correspond to mature B cells arrested in their final B cell differentiation. Different mechanisms of genetic alteration are involved in the pathogenesis of the PCNSLs. Abbreviations: aSHM aberrant somatic hypermutation; SHM somatic hypermutation; IGH immunoglobulin heavy locus; STAT6 signal transducer and activator of transcription 6; MDM2 murine double minute 2; CDK4 cyclin-dependent kinase 4; GLI1 GLI family zinc finger 1; HLA human leukocyte antigen; CDKN2A cyclin-dependent kinase inhibitor 2A; PTPRK protein tyrosine phosphatase receptor type K; PRDM1 PR/SET domain 1; TNFAIP3 TNF alpha induced protein 3;

NF-kB nuclear factor-kappa B; BCL6 BCL6 transcription repressor; PIM1 pim-1 proto-oncogene, serine/threonine kinase; PAX paired box 5; RhoH/TTF ras homolog family member H; MYC MYC proto-oncogene; ATM ATM serine/threonine kinase; PTEN phosphatase and tensin homolog; PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; JAK3 janus kinase 3; CTNNB1 catenin beta 1; PTPN11 protein tyrosine phosphatase non-receptor type 11; KRAS KRASprotooncogene; BTG2 BTG anti-proliferation factor 2; MYD88 MYD88 innate immune signal transduction adapter; MALT1 MALT1 paracaspase; CARD11 caspase recruitment domain family member 11; DAPK death associated protein kinase; RFC replication factor C; MGMT O-6methylguanine-DNA methyltransferase

suppressive miRNAs (miR-199a, miR-214, miR193b and miR-145) was down-regulated in PCNSL. (Fischer et al. 2011).

reduced patient survival (Rimsza et al. 2004). Deletions of the chromosomal region 6q21-23 (Braggio et al. 2011) are also common. Loss of this region containing: (1) PTPRK, a protein tyrosine phosphatase involving in cell adhesion signaling; (2) PRDM1, a suppressor of tumor activity and regulator of B cell differentiation; and (3) A20 (TNFAIP3), which downregulates nuclear factorkB (NF-kB) signaling, has been identified as prognostic factor (Rickert et al. 1999). Deletions of the chromosomal region 9p21, which encodes cell cycle regulator CDKN2A, are also common (Braggio et al. 2011). Chromosome recurrent insertions of the 12q region, which contains genes encoding STAT6, MDM2, CDK4, and GLI1, were reported as well (Rubenstein et al. 2005). In

20.2.2 Insertions and Deletions of Genetic Material The most frequent genomic alteration in PCNSL is heterozygous and even homozygous loss of chromosomal region 6p21.32 carrying the genes encoding MHC class II, HLA-DRB, HLA-DQA, and HLA-DQB (Gonzalez-Aguilar et al. 2012; Schwindt et al. 2009). Loss of MHC class II gene and protein expression in DLBCL is associated with impaired tumor immune surveillance and

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PCNSL, CNAs of 9p24.1/PD-L1/PD-L2 are frequently found, as well as translocations of these loci. (Chapuy et al. 2016). These findings may suggest the presence of immune escape mechanism.

20.2.3 Activated Pathway in PCNSLs Janus kinase (JAK)/STAT, BCR, Toll-like receptor (TLR), and NF-kB signaling pathways are activating synergically in PCNSLs. Upregulated IL-4 and IL-10 and downstream JAK/STAT signaling correlate with aberrant activation of MYD88 of TLR signaling pathway (Ngo et al. 2011). The BCR signaling, which induces differentiation and proliferation of B cells, and the TLR signaling pathway is affected by common mutations introduced by aSHM, particularly genes encoding MYD88 and CD79B (Montesinos-Rongen et al. 2012). When the MYD88 gene is expressed, the signaling adaptor protein would be responsible for activation induction of some other factors including NF-kB and the JAK/STAT pathway after stimulation of TLR, interferon-b production, and IL-1/IL-18 receptors. In these pathways, NF-kB signaling is suggested as the core pathway (Braggio et al. 2015; Bruno et al. 2014; Chapuy et al. 2016; Nakamura et al. 2016; Vater et al. 2015). Comparative study between nonmalignant germinal center centroblasts and PCNSLs shows that several transcriptomes (BAX, BCLXL, BCL2, MALT1, CARD9, CARD10, CARD11, CARD14, CCND2, cFLIP, RELA, RELB, NFKB1, NFKB2, and IRF4) of NF-kB signaling pathways, which contribute to high proliferative activity and the low level of apoptosis, are higher in PCNSL (Courts et al. 2007).

20.3

Histopathology and Morphology

PCNSLs show highly cellular and pattern-less growing with perivascular cuffing (Fig. 20.2). From these perivascular cuffs, tumor cells invade the brain. Tumor cells are large atypical cells

with large round, oval, irregular, or pleomorphic nuclei. Immunohistochemically, tumor cells are positive for PAX5, CD19, CD20, CD22, and CD79a. Most cells are positive for BCL6 (60– 80%) and MUM1/IRF4 (90%), indicating that tumor cells are moving away from GC, but repress the exit of B cells from GCs (Basso and Dalla-Favera 2012). Thus, tumor cells are negative for plasma cell marker CD38 and CD138. CD10 positivity is less than 10% in PCNSLs and more frequent in systemic lymphoma. The impairment in B cell maturation could be a result of the CD10 − BCL6 + IRF4/MUM1 + phenotype, which is consistent with the observed phenotype in the late germinal center B cells (Camilleri-Broet et al. 2006) and correlates with poor prognosis (Deckert et al. 2014). Mitotic activity is brisk; accordingly, the Ki-67 proliferation index is usually 70 to 90%.

20.4

Imaging and Radiologic Features

PCNSL shows relatively characteristic appearances on CT, MR imaging, and positron emission tomography (PET). This is related to its hypercellularity, disruption of the blood–brain barrier, and hypermetabolism. PCNSL prefers the periventricular and superficial regions. Additionally, imaging findings of PCNSL vary with immune status of patients.

20.4.1 CNS Lymphoma Features on CT Scan On unenhanced CT, PCNSLs typically appear hyper- to iso-attenuation compared to normal brain in both immunocompetent and immunocompromised patients (Haldorsen et al. 2011). White matter or basal ganglia lesions in contact with a CSF surface are typical. Peritumoral edema is usually present but less prominent than that in malignant gliomas or brain metastases (Haldorsen et al. 2009; Schlegel et al. 2000). Hemorrhage, calcification, and necrosis are thought to be rare in immunocompetent patients

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a

b

c

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Fig. 20.2 Histopathology: geographical necrosis and perivascular cuffing of the tumor cells a Strong nuclear expression of the MUM1/IRF4 protein b Expression of

the BCL6 protein c Expression of the cell surface marker CD79a d

(Coulon et al. 2002; Haldorsen et al. 2009). PCNSL in immunocompetent patients typically shows homogenous enhancement on enhanced CT, while irregular ring enhancement is often seen in immunocompromised patients (Haldorsen et al. 2009; Thurnher et al. 2001).

perivascular spaces is highly suggestive of PCNSL (Chamberlain 2006). In immunocompromised patients, intratumor hemorrhage with T1 shortening, “blooming” on T2*-weighted images, and ring enhancement surrounding a nonenhanced area of necrotic tissue are often seen (Haldorsen et al. 2011, 2008; Sakata et al. 2015; Thurnher et al. 2001).

20.4.2 CNS Lymphoma Features on Conventional MR Imaging PCNSL shows typically hypo- or isointense on T1-weighted images and iso- to hyperintense on T2-weighted images (Haldorsen et al. 2011). PCNSL in immunocompetent patients typically presents as a solitary homogeneously enhancing parenchymal mass in supratentorial regions of the brain (Fig. 20.3a). Linear enhancement along

20.4.3 CNS Lymphoma Features on Advanced MR Imaging PCNSL lesions typically show hyperintensity on diffusion-weighted images and hypointensity (restricted diffusion) on apparent diffusion coefficient (ADC) maps (Zacharia et al. 2008) (Figs. 20.3b, c). They often have more restricted

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a

b

d

e

c

Fig. 20.3 A 74-year-old woman diagnosed with PCNSL. A lesion in the splenium of corpus callosum shows relatively homogenous enhancement on contrastenhanced T1-weighted image a. The lesion has high signal intensity on diffusion-weighted image (b = 1000

s/mm2) b with corresponding low-signal intensity (restricted diffusion) on the ADC map c. Perfusion MR image shows low perfusion within the contrast-enhanced lesion on the rCBV map d. The lesion shows an increased uptake of 18F-FDG on FDG-PET/CT e

diffusion and lower ADC values than high-grade gliomas and brain metastases. On perfusion MR imaging, PCNSLs demonstrate low relative cerebral blood volume (rCBV) (Fig. 20.3d), calculated as a ratio to contralateral normalappearing white matter, and a characteristic intensity time curve, which is related to a massive leakage of contrast media into the interstitial space (Hartmann et al. 2003). Maximum rCBV measured in tumor tissue is typically lower for lymphomas than other brain tumors (e.g., glioblastoma). On MR spectroscopy, solid lesions of PCNSL have usually elevated lipid peaks combined with high Cho/Cr ratios (Zacharia et al. 2008). Susceptibility-weighted imaging (SWI) is sensitive for the visualization of small veins, blood products, and calcifications, which appear as low-signal intensity structures (Mittal et al. 2009). Since intratumoral hemorrhages are rare in PCNSLs but frequent in high-grade gliomas, SWI may be helpful for differentiating the two types of tumors (Peters et al. 2012).

20.4.4 CNS Lymphoma Features on Nuclear Imaging PCNSL is typically shown as hypermetabolic lesions with an increased uptake of 18F-FDG on FDG-PET (Go et al. 2006) (Fig. 20.3e). FDGPET may be suitable for early evaluation of a therapeutic response (Kasenda et al. 2013). CNS lymphoma has higher uptakes of 11C-methionine (methionine PET) in PET. (Ogawa et al. 1994). The enhancing area on CT/MR imaging corresponds to this uptake lesions. Radiation therapy decreases both the size and degree of methionine accumulation in the tumor tissue.

20.4.5 Differential Diagnosis of CNS Lymphoma The major differential diagnosis of PCNSL with immunocompetent patients is glioblastoma. Hemorrhage, necrosis, irregular ring enhancement with heterogenous thickness, and high rCBV are

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common in glioblastoma (Haldorsen et al. 2011; Peters et al. 2012; Yamashita et al. 2013). The second most common differential diagnosis of PCNSL is brain metastasis. Brain metastasis is typically located in corticomedullary junction and prominent peritumoral edema (Krumina 2005). In immunocompromised patients, the major differential diagnosis of PCNSL is toxoplasmosis. Compared to toxoplasmosis, PCNSL shows lower ADC value and higher uptake of FDG on FDG-PET (Liu 2011). The second most common differential diagnosis in immunocompromised patients is progressive multifocal leukoencephalopathy (PML). Contrast-enhanced MR images usually do not show enhancement in PML lesions (Bag et al. 2010).

20.5

Clinical Manifestations

The clinical manifestations of PCNSL are usually associated with relatively rapidly progressive focal neurological symptoms related to the neuroanatomical localization of the tumor. The symptoms of PCNSL in the majority of patients are caused by periventricular lesions. Patients present focal neurologic deficits (70%) such as hemiparesis or speech disturbances, neuropsychiatric symptoms (43%) such as personality changes, depression, apathy, psychosis, confusion, memory impairment, psychomotor slowness, or visual hallucinations. Signs of intracranial hypertension (33%) such as headaches, seizures (14%) are observed. Ocular symptoms (4%) like blurred vision or eye floaters suggest ocular involvement (Bataille et al. 2000; Batchelor and Loeffler 2006; Korfel and Schlegel 2013). Concomitant leptomeningeal dissemination occurs in approximately 11–20% of patients, usually without any symptoms. Primary leptomeningeal lymphoma without involvement of the cerebrospinal cord is less than 10% of cases.

20.6

Therapeutic Approaches

20.6.1 Surgical Intervention As a general rule, stereotactic biopsy or subtotal resection of tumor is performed to confirm the

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diagnosis. PCNSL is multifocal and invasive, with a tendency to extend beyond the visible zone of invasion, making surgical treatment less effective (Lai et al. 2002). Only in patients with impending cerebral herniation, total or subtotal resection is recommended; however, the total or partial resection of the macroscopic lesion does not affect the prognosis. Therefore, the role of resection in the treatment of PCNSL has not been established (Grommes and DeAngelis 2017; Hoang-Xuan et al. 2015; Weller et al. 2012). Preoperative steroid administration leads to rapid shrinkage of the tumor, which may make it difficult for detecting tumor cells. In addition, as it may alter the sensitivity of histopathological diagnosis, steroid treatment should be avoided as much as possible before surgery (Hoang-Xuan et al. 2015) (Fig. 20.6 (The Japan society for Neuro-Oncology groups (2019))). In patients who have been pretreated with corticosteroids, a second biopsy is recommended when serial MRIs show clear tumor progression, if the biopsy is inconclusive. In case of leptomeningeal or ocular involvement, it is rarely possible to detect lymphoma cells in cerebrospinal fluid (CSF) or vitreous aspirate using immunocytological, flow cytometric, or molecular biological techniques. However, the latter does not provide a clear classification of lymphoma according to WHO criteria, and immunohistochemistry is required for confirmation (Louis et al. 2016). Currently, the role of diagnostic biomarkers (proteins, RNA, DNA) in the cerebrospinal fluid is controversial in clinical routine (Royer-Perron et al. 2017).

20.6.2 Chemotherapy and Radiotherapy 20.6.2.1 Chemotherapy Chemotherapy for systemic lymphoma is ineffective for PCNSL because it is difficult to cross the blood–brain barrier (Ott et al. 1991; Schultz et al. 1996). Thus, the first-line treatment for PCNSL is HD-MTX-based chemotherapy. Methotrexate (MTX) is a drug that targets dihydrofolate reductase (DHFR) and thymidylate

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synthase (TS) in folate metabolism resulting in inhibition of DNA synthesis and methylation of DNA (Fig. 20.4). According to the RTOG 9310 trial, the median PFS and OS of 102 investigated patients was 24 and 36.9 months, respectively. Moreover, the survival outcomes were significantly more favorable when HD-MTX-based chemotherapy was combined with WBRT. High-dose methotrexate (HD-MTX; = 3 g/m2 body surface area, 4-h IV infusion) is the most effective and an important component of all combination regimens (Hoang-Xuan et al. 2015) (Fig. 20.7 (Han and Batchlor (2017))). This regimen should be repeated for at least six cycles, along with adequate supportive care (hydration, urine alkalinization, leucovorin rescue, and monitoring of MTX levels) (Hoang-Xuan et al. 2015). In combination with other bacteriostatic agents capable of passing the blood–brain barrier, such as high-dose cytarabine (HD-AraC), thiotepa, and ifosfamide, the overall response rate is improved in patients under 50 years of age (median disease-free survival 40.3 months) (Abrey et al. 1998). However, late treatmentrelated neurotoxicity was observed in nearly onethird of patients, and those more than 60 years of age were at substantially higher risk. The therapeutic effect of HD-MTX/AraC was further enhanced by the addition of the anti-CD20 antibody rituximab, but the effect was only pronounced when thiotepa (MATRix protocol) was added (overall response rate: 53% versus 74% versus 86%). Hematological adverse events occurred more frequently in the intensified treatment group, but there was no significant difference in the incidence of serious infections or treatmentrelatedmortality (Ferreri et al. 2016). However, it should be noted that this study is a 2 X 2 design and is based on the outcome of randomization of induction therapy (Ferreri et al. 2017). Another reported treatment is HD-MTX/rituximab, procarbazine, and vincristine (R-MPV) followed by integrated reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine. Accordingly, when R-MPV was combined with rdWBRT and cytarabine, it resulted in more favorable response rate (median PFS was 3.3 years, and median OS was 6.6 years), longer period of

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disease control, and also lower neurotoxicity (Morris et al. 2013). Temozolomide (TMZ), which passes the blood–brain barrier, like PCZ, is a derivative of 5 [(1Z)-3-methyltriaz-1-en-1-yl]-1H-imidazole-4carboxamide (MTIC) that has a clear antitumor effect but less toxicity than PCZ. In CALGB 50202, the patients who achieved CR by 5 cycles of MT-R (MTX/TMZ-rituximab) received EA (etoposide/Ara-C) consolidation. Accordingly, the CR to MT-R rate was 66%. The patients were followed for a median period of 4.9 years, and the 2-year PFS was 0.57. While the 2-year time to progression was 0.59 in all patients, it was increased to 0.77 when the consolidation was completed. Patients older than 60 years were as well as younger patients, and the most important clinical prognostic factor was delay in treatment (Rubenstein et al. 2013).

20.6.2.2 Steroid Therapy Rapid tumor shrinkage is seen after steroid administration in nearly half of the cases. However, this therapeutic effect is transient and limited, so treatment is poorly curable for the first few years or few months (Pirotte et al. 1997). In the matter of disease onset, a case showing a therapeutic response to steroids had a median survival time of 17.9 months, while the nonresponder had only 5.5 months. This observation suggested that the steroid reactivity at the initial onset may be a favorable prognostic factor (Mathew et al. 2006). 20.6.2.3 Radiotherapy Because of the highly invasive nature of PCNSL, whole-brain radiation therapy (WBRT) is recommended. In the majority of patients, percutaneous fractionated WBRT results in rapid, and usually complete remission, but early relapse occurs. With combined chemoradiotherapy, if CR is achieved by chemotherapy, dose of WBRT can be decreased to avoid the risk of delayed neurotoxicity. Tumor control has been greatly improved, with median survival ranging from 31 to 90 months (Ferreri et al. 2009; Glass et al. 2016; Morris et al. 2013). However, disease control was not significantly improved in higher

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Fig. 20.4 Folate and methionine metabolic pathways associated with MTX. 5, 10-CH2-THF is either directed toward dTMP and nucleotide synthesis or reduced to 5CH3-THF and directed toward methionine synthesis and methylation reactions. MTX enters the cells through RFC1, inhibits enzymes (DHFR and TS) of the folate pathway, and is exported from the cells by ABCC1, 2, 3, 4 and ABCG2. As a result, MTX inhibits DNA synthesis and hypomethylates of the DNA. Abbreviations: RFC1 reduced folate carrier 1; FPGS dihydrofolate reductase; GGS r-glutamyl hydrolase; ABCC ATP binding cassette

subfamily C member; ABCG ATP binding cassette subfamily G member; DHFR dihydrofolate reductase; MTHFR 5, 10-methylenetetrahydrofolate reductase; TS thymidylate synthase; MS methionine synthase; MTRR methionine synthase reductase; THF tetrahydrofolate; DHF dihydrofolate; dUMP deoxyuridine monophosphate; dTMP deoxythymidine monophosphate; MTX methotrexate; MTX-PG methotrexate-polyglutamates; LV leucovorine; HCY homocysteine, SAM S-adenosylmethionine, SAH S-adenosylhomocysteine

doses of WBRT (more than 40 Gy, recurrence rate: 46%, 5-year FFS: 51%), in comparison with lower doses of 30–36 Gy(recurrence rate: 30%; 5-year FFS: 50%; P = 0.26) (Ferreri et al. 2011). Delayed neurotoxicity occurring over a time course of months to years is a very serious problem. Affected patients exhibit marked leukoencephalopathy, leading to cortical/subcortical atrophy, severe cognitive impairment, gait abnormalities, incontinence, and the need for nursing care. The 5-year incidence of manifest neurotoxicity ranges from 12 to 65%, with a mortality rate of 16% to 66%, especially associated with those older than 60 years (Ferreri et al. 2009; Glass et al. 2016; Morris et al. 2013). Delayed neurotoxicity is also observed in patients undergoing intensive chemotherapy (Hoang-Xuan et al. 2003; Thiel et al. 2010);

however, extensive neurocognitive analysis has shown that the adverse effects of intensive chemotherapy on cognitive performance and quality of life are less severe than radiation (Doolittle et al. 2013; Herrlinger et al. 2017). Patients who are poor-responders or noncandidates for chemotherapy can be treated with 35– 45 Gy and 40–50 Gy (1.5 to 1.8 Gy/fraction) of whole-brain irradiation, respectively (Yahalom et al. 2015).

20.6.2.4 Management in the Elderly Treatment of the elderly is limited by increased risk of comorbidities and treatment-related side effects; polychemotherapy with HD-MTX can be quite effective when renal function is taken into account (reduce the dose if creatinine clearance is less than 100 mL/min). Moreover, the OS or PFS

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was not remarkably different when either oral alkylating agent (PCV or TMZ) or additional intravenous chemotherapy based on HD-MTX was administered. Additional irradiation prolonged PFS and OS for patients with KPS < 70%, but the risk of delayed neurotoxicity was increased (Jahnke et al. 2005). In the only phase III study, G-PCNSL-SG-1, the rates of CR and PR for polychemotherapy with HD-MTX were also 44% in the elderly (> 70 years) and 57% in the young (P = 0.016). Toxicity was independent of age, except for a higher rate of grade III/IV leukopenia in older patients (34% versus 21%, P = 0.007). Mortality during treatment was 18% versus 11%, P = 0.027. Also, the elderly had less favorable survival outcomes including progression-free survival (PFS) (4.0 versus 7.7 months, P = 0.014) and overall survival (12.5 versus 26.2 months, p < 0.001). In the absence of tumor recurrence, delayed neurotoxicity side effects including progressive cognitive impairment may rapidly deteriorate the QOL of patients. HD-MTX therapy with oral alkylating agent without irradiation may be a concern in the elderly, as Grade 3/4 adverse events are less than 10% (Jahnke et al. 2005).

20.6.2.5 Recurrence About one-third of patients with PCNSL are primarily refractory to treatment, and at least, half of those who show an initial response to treatment relapse (Jahnke et al. 2006; LangnerLemercier et al. 2016). There is no established standard care for this situation; there are few prospective clinical trials with high levels of evidence (Grommes and DeAngelis 2017). Thus, treatment of this situation has largely been based on the experience gathered in numerous small retrospective studies. In refractory patients who have received multiple prior therapies, some other drugs could be administered such as temsirolimus (Korfel et al. 2016), lenalidomide (Rubenstein et al. 2018), the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Lionakis et al. 2017) that affect the growth and survival of lymphoma cells by interfering with B cell receptor’s signaling, and so-called checkpoint inhibitors that modulate the

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T-cell-mediated immune response (Nayak et al. 2017), which are effective but associated with significant toxicity in some patients (Fig. 20.5). The efficacy of ibrutinib is remarkable, with high response rates and promising PFS. Interestingly, the response to ibrutinib observed in the brain is significantly higher (Grommes and DeAngelis 2017) than in patients with systemic DLBCL (Wilson et al. 2015) (Figs. 20.6 and 20.7). If the efficacy and tolerability of the drug is confirmed in the trials currently recruiting, it may provide a new treatment option for patients with PCNSL. Temozolomide (TMZ) could be considered an alternative treatment in case of HD-MTX contraindication, which has demonstrated overall response rate and overall survival of 47% and 21 months, respectively (Kurzwelly et al. 2010). New agents targeting this unusual pathway are being introduced into clinical trials for patients with relapsed or refractory PCNSL. Drugs such as ibrutinib, a BTK inhibitor, and immunomodulators (IMiD) such as pomalidomide and lenalidomide have shown promising high response rates in the salvage setting (Grommes et al. 2019). Due to the high risk of neurotoxic adverse events, WBRT should only be used when other treatment alternatives are not available or have been exhausted (Hoang-Xuan et al. 2015).

20.6.3 New Therapeutic Modalities Lymphoma cells remaining in the CNS are treated with myeloablative high-dose consolidation chemotherapy combined with autologous stem cell transplantation (HD-ASCT), which results in very high drug concentrations in the CNS. There are various HDC therapies, and the HDC based on thiotepa studies showed better results (overall response 80–96%, median overall survival 64–104 months) (Illerhaus et al. 2016; Omuro et al. 2015). More recent data indicate that HD-ASCT provides equal efficacy to consolidation WBRT, but is associated with less delayed neurotoxicity such as memory and cognitive impairment (Ferreri et al. 2017). Despite the fact that these reports show relatively good survival rates, they do not target elderly

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Fig. 20.5 Tumor aberrant activation pathways and new therapeutic agents of PCNSL. Activation of TLR4/MYD88 and the BCR complex may contribute to prosurvival signaling via NF-jB. Enhanced production of IL-4/10 contributes to survival signaling as well as the JAK/STAT pathway. Amplification of 9p24 and consequent gene expression increases the dose of PD-L1/2 and contributes to immune escape of PCNSL cells. New therapeutic agents affect tumor pathways and also influence the tumor microenvironment, DNA transcription, translation of antiapoptotic factors, and immune modulation of tumor cells. Abbreviations: BCR B cell receptor; IL-4 Interleukin-4; IL-10 Interleukin-10; TLR Toll-like receptor; NF-kB Nuclear factor-kB; JAK Janus kinase; STAT Signal transducer and activator of

symptoms MRI, CT Check up systemic involvement (PET-CT) including ophthalmic lesion

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transcription; PD-L1 Programmed death-ligand 1; PD-1 Programmed cell death-protein 1; SYK Spleen associated tyrosine kinase; BTK Bruton tyrosine kinase; PKC Protein kinase C; MALT1 MALT1 paracaspase; CARD11 Caspase recruitment domain family member 11; IRK4 Potassium inwardly rectifying channel subfamily J member 14; IRK1 Potassium inwardly rectifying channel subfamily J member 2; TRAF6 TNF receptor associated factor 6; PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase; AKT AKT serine/threonine kinase; mTOR Mechanistic target of rapamycin kinase; MYC MYC proto-oncogene; RGS13 Regulator of G protein signaling 13; MGMT O-6methylguanine-DNA methyltransferase; DAPK Death associated protein kinase; CDKN2A cyclin-dependent kinase inhibitor 2A

patients > 70 years, who account for more than half of PCNSLs. Moreover, it should be noted that 10% of treatment-related deaths have been reported. Thus, HD-ASCT should be carefully chosen.

If possible, steroid treatment should be avoided Surgical intervention (biopsy)

Histologically proven PCNSL

Fig. 20.6 Algorithm diagram for diagnosis of PCNSL

20.7

Follow-Up and Prognosis

The prognosis of PCNSL has improved markedly over the last decades (median survival improved from 2.5 to 26 months) (Mendez et al. 2018). With symptomatic treatment alone, the median survival time is a few weeks to a few months,

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no

Age 70 or an equivalent ECOG score of < 1 is generally considered for resection in patients with brain metastasis (Stark et al. 2005). More recently, evidence suggested open surgical resection for patients with multiple brain metastases and patients with tumor recurrence. Surgery in these cases has been found to improve neurologic performance and prolong overall survival. Furthermore, studies also report quality of life benefit in patients with multiple lesions despite no effect on overall survival. Surgical resection of brain lesions may also be indicated in patients with previously treated metastatic brain cancer where there is evidence of disease progression or recurrence despite prior radiosurgery. Resection of brain metastases has demonstrated significantly reduced local recurrence rates (Yoo et al. 2009). In some patients, life-threatening neurological symptoms can be caused by mass effect, cerebral edema, or in the presence of hemorrhagic lesions. In such cases, cerebral edema and herniation syndromes result in irreversible neurologic damage and/or death. Surgical intervention in these cases is warranted, and the use of steroids such as dexamethasone can dramatically reduce cerebral edema. Advancements in surgical approaches and techniques aiming at disease control and safe maximal resection include intraoperative neuronavigation, use of fluorescent dyes, cortical mapping, and laser interstitial thermal therapy. As described above, 2–14% of patients with intracranial metastasis do not have a known primary cancer. In these patients, surgical intervention in the form of biopsy or surgical resection is the only means of obtaining a histological diagnosis that may guide further treatment. Biopsies are considered in patients with

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lesions in eloquent locations or in cases where the goal is to obtain a pathologic diagnosis only. Patients who are considered for operative surgical resection, undergo pre-operative imaging with MR imaging and/or CT imaging. Contrast is an important consideration in pre-operative imaging and allows for improved visualization and operative planning. Imaging can also be used for frameless stereotaxis and aids in the localization and safe resection of metastatic brain lesions. Surgical intervention and resection of spine metastases are dependent on the location of the spinal lesions. Important considerations in the resection of spinal metastasis are similar to clinical considerations for brain metastases and involve the systemic disease burden, the location of the lesions, the functional status of the patients. Similar score systems to those used to characterize brain metastases patients have also been used to classify the overall functional status of patients with spinal metastases (Conti et al. 2019). Additional studies have also proposed prognostic classification scoring systems for patients with osseous spinal disease that takes into account the performance status of the patient, the number of extra spinal bone metastases, the number of metastases to the vertebral body, disease within other organ systems, the primary cancer, and the degree of spinal cord palsy (Tokuhashi et al. 2005). This prognostic classification scheme has been used to stratify patients into different treatment groups and includes conservative treatment, palliative surgery, and excisional surgery (Tokuhashi et al. 2005). Generally, management depends on the number of levels involved and the overall structural integrity of the spine and includes special consideration of the presence of pathologic fractures, the type of tumor and special tumor characteristics such as the vascularity of the tumor, and the presence of spinal cord compression or neurologic deficit. Surgical interventions for intradural and extramedullary and intramedullary lesions are rare and only typically considered in patients with high pre-operative functional status, surgically resectable tumors,

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and patients with well-controlled systemic disease as well as pathological type. Post-operative dysfunction is a major consideration in patients who undergo surgical resection of intramedullary tumors. Surgical resection includes intraoperative monitoring techniques that measure the motor evoked potentials and somatosensory evoked potentials during surgical resection in an attempt to minimize post-operative deficits. Complete resection of tumor is the goal and has to be balanced with incurring unwanted post-operative neurologic dysfunction (Rashad et al. 2018).

21.6.2 Chemotherapy and Radiotherapy 21.6.2.1 Radiotherapy Radiation therapy for the treatment of metastatic brain lesions can be in the form of whole brain radiation (WBRT) or stereotactic radiosurgery (SRS). Whole brain radiation therapy involved radiation to the entire brain and it typically delivered in a dose of 30 Gy in 10 fractions (Tsao et al. 2018), although a shorter course of 20 Gy in 5 fractions is considered in patients who may have additional oncologic or prognostic factors (Suh et al. 2020). In general, WBRT is considered in patients where surgical resection is not possible and/or SRS is not a consideration. This occurs in cases of leptomeningeal disease, in patients with numerous metastatic lesions, and in patients with poor prognostic factors. In studies, surgical resection followed by WBRT demonstrated greater control rates in patients as compared to patients who did not receive WBRT or in patients who received WBRT without surgery (Noordijk et al. 1994; Patchell et al. 1990). WBRT for brain metastases also carries the risk of neurocognitive deficits which includes memory loss, confusion, and encephalopathy. Thus, the side effects of WBRT should be considered in conjunction with the potential therapeutic benefits. Other toxic sequelae from WBRT include generalized fatigue, altered taste and smell, skin irritation, and alopecia. The toxicities associated with WBRT combined with improvement in cranial imaging

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techniques have propelled SRS as the standard of care in treatment of patients with cranial metastases and high functional cognitive status. Stereotactic radiosurgery delivers precise treatment of cranial lesions with minimization of collateral damage to normal brain parenchyma. SRS can be delivered via multiple modern systems, such as linear accelerator (LINAC)-based systems, like CyberKnife (Accuray Inc, Sunnyvale, CA) or Gamma Knife (Elekta AB, Stockholm, Sweden) (Fig. 21.1). Improvements in SRS now allow for sharp dose curves that deliver highly conformal radiation to brain metastases in 1–5 fractions. SRS is an outpatient procedure that is generally well tolerated, and studies have demonstrated lower cognitive impairment when compared to WBRT. Consequently, SRS is currently recommended by the American Society of Radiation Oncology and the International Stereotactic Radiosurgery Society for treatment of patients with 1–4 brain metastases (Chao et al. 2018; Tsao et al. 2012). Subsequent studies have investigated the treatment of more than four brain metastases, and efficacy in treating patients with increased number of brain metastases has been illustrated. Importantly, these studies also demonstrate overall safety in treating patients with numerous brain metastases (Bhatnagar et al. 2006; Kim et al. 2008; Nath et al. 2010). Post-operative radiation has prior been described with WBRT, and treatment can limit the development of local tumor recurrence within the surgical cavity as well as distant recurrence within the brain. To minimize the development of local and distant metastatic disease after surgical resection, WBRT and SRS therapy have been combined and results illustrated the safety and efficacy of combining these modalities (Roberge et al. 2009). As described previously, WBRT is associated with significant morbidity and decreased neurocognitive function. Given this, SRS to the resection cavity is now considered to be an alternative to WBRT for postoperative local disease control (Mahajan et al. 2017). Retrospective studies have found local disease control rates between 70 and 100% (Iorio-Morin et al. 2014; Soltys et al. 2008) at 1 year, and prospective studies have

T. H. Ung et al.

demonstrated a control rate as high as 85% (Brennan et al. 2014). Overall local recurrence in post-operative SRS patients has been linked to patients with larger tumor sizes, especially tumors that are greater than 3 cm (Jagannathan et al. 2009). Additional factors that may be linked to decreased efficacy and local tumor progression include time to treatment and the overall conformality of the SRS. Treatment with less conformality and the additional irradiation of an area 2 mm beyond the tumor margin have been associated with decreased rates of local tumor recurrence (Choi et al. 2012; Soltys et al. 2008). Timing for SRS after surgical resection has also been associated with local recurrence: SRS treatment delivered more than 3 weeks after surgery correlates with increased local recurrence rates. Current recommendations are to deliver SRS to the resection cavity within 2–3 weeks after surgical resection (Iorio-Morin et al. 2014; Marchan et al. 2018). Post-treatment radiation necrosis is a known complication after SRS. It can be difficult to distinguish between true tumor progression and tumor pseudoprogression/radiation necrosis. Although the rate of tumor necrosis is slightly less than SRS to intact untreated lesions (up to 24%) (Minniti et al. 2011), radiation-induced necrosis can be seen in 1.5– 18.5% of lesions treated with post-operative SRS (Marchan et al. 2018). The treatment of spine metastases with SRS has become more common, and the use of newer image-guided technologies and advanced treatment planning algorithms allows for highly conformal dose distributions. This facilitates steep dose gradients at lesional targets and decreased adjacent exposure to critical structures (Fig. 21.2). Large retrospective studies demonstrated the efficacy of spinal SRS with improved local disease control (Gibbs et al. 2007). SRS has also been found to be effective and is used as the definitive treatment, post-operative, and preoperative treatment of bony spinal metastases. Furthermore, patients with epidural extension of osseous metastatic disease may have neurologic compromise, and studies have shown that decompression of the spinal cord and nerve roots

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Fig. 21.1 Stereotactic radiosurgery treatment with cyberknife targeting a left temporal lesion

improves overall neurologic function (Ryu et al. 2010). Challenges with spinal stereotactic radiation are the lack of anatomical borders within the vertebral elements leading to known local treatment failures. Given this, treatment of spinal lesions will include both consideration of the gross tumor volume as well as the clinical treatment volume (Fig. 21.2). Consortium consensus guidelines also exist as a guide for target volumes in spinal metastases and will take into account the overall tumor volume as well as the known patterns of local tumor progression (Cox et al. 2012) (Figs. 21.3 and 21.4).

21.6.2.2 Chemotherapy Although chemotherapy is used to treat patients with systemic cancer, this is typically not used in patients with brain metastases and is reserved to patients where surgical resection and radiosurgery are not an option. Brain metastases that develop from chemosensitive tumors generally have the same chemoresponsiveness as the primary tumor (Bertolini et al. 2015). However, the effectiveness of chemotherapy agents may be

limited by their ability to reach the brain and spinal cord due to the blood–brain barrier. The anatomical and physiological composition of the astrocytic foot processes and surrounding vasculature prevents passage of chemotherapy, and minimal amounts of drugs are able to cross the blood–brain barrier (Walbert and Gilbert 2009). Also, as described earlier in this chapter (see Sect. 21.2), temporal and spatial mutations can also exist within tumors and be resistant to systemic chemotherapies. Several trials have looked at systemic agents to be used in patients with metastatic brain cancer and have failed to show meaningful response rates. This includes commonly used therapies such as cisplatin, pemetrexed, temozolomide, and cisplatin combined with vinorelbine, paclitaxel, pemetrexed, and cisplatin (Suh et al. 2020).

21.6.3 New Therapeutic Modalities Immunotherapy inhibits tumor progression by eliciting anti-cancer immune responses. Immune

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Fig. 21.2 Spinal stereotactic radiosurgery using cyberknife for a patient with a metastatic lesion targeted at L3

Fig. 21.3 Therapeutic algorithm for brain metastases

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557

Fig. 21.4 Therapeutic algorithm for spine metastases

checkpoint inhibitors such as programmed cell death receptor (PD-1) and cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) have demonstrated promising results in patients with brain metastases (Galldiks et al. 2020). Small molecule-targeted therapy used in brain metastases has shown promise and utilizes known genetic alterations in common cancers. Epidermal growth factor, human epidermal growth factor receptor mutations, and BRAF V600E mutations are commonly known mutations that can be targeted with small molecule agents (Galldiks et al. 2020). Combining radiosurgery and immunotherapeutic techniques has resulted in a synergistic effect on brain and spine metastases. Radiation treatment of metastasis may induce anti-tumor factors that may induce immune-related responses and the inflammatory cascade. The addition of immunotherapy may increase this immune response (Galldiks et al. 2020), and studies have also suggested possible related effect on distant development of metastatic disease (Walle et al. 2018). Studies in malignant melanoma have examined the optimal timing of treatment as well as the effects of combined radiation and immunotherapy either in the form of immune checkpoint inhibitors or targeted therapy. Overall optimal timing in

melanoma patients has been found to be within 4 weeks between treatment with systemic immunotherapy and stereotactic radiosurgery (Galldiks et al. 2020; Rulli et al. 2019). There exist numerous studies looking at the effect of newer small molecule inhibitors and immune checkpoint therapies in patients with brain metastases, and an attempt to cover all these trials and studies is beyond the scope of this chapter (Table 21.2). Critically, it is important to recognize changes that are occurring in the treatment of brain metastases as additional therapies become available and recognize the importance of furthering overall understanding of specific tumor characteristic.

21.7

Follow-Up and Prognosis

Overall prognosis of patients with brain metastases is historically poor and median survival of patients is between 3 and 6 months. The overall survival of patients who develop brain metastases is dependent on different factors including overall systemic disease burden, number of cranial metastases, overall functional status, cancer type, and available treatment modalities. Continued treatment advancements in systemic

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Table 21.2 Current clinical trials investigating immune checkpoint and small molecule inhibitors in brain metastases Type

ID number

Study title

Phase

Status

Immune checkpoint

NCT04650490

SRS timing with immune checkpoint inhibition in patients with untreated brain metastases from nonsmall cell lung cancer

Phase 2

Not yet recruiting

Immune checkpoint

NCT04461418

Accelerated checkpoint therapy for any steroid dependent patient with brain metastases

Phase 2

Recruiting

Immune checkpoint

NCT04187872

LITT and pembrolizumab in recurrent brain metastasis

Phase 1

Recruiting

Immune checkpoint

NCT04047602

Radiosurgery dose reduction for brain metastases on immunotherapy (RADREMI): a prospective pilot study

Not applicable

Recruiting

Immune checkpoint

NCT03728465

Evaluation of safety and efficacy of patients with four and more symptomatic brain metastases of melanoma

Phase 2

Terminated

Immune checkpoint

NCT04348747

Dendritic cell vaccines against HER2/HER3, cytokine modulation regimen, and pembrolizumab for the treatment of brain metastasis from triple negative breast cancer or HER2+ breast cancer

Phase 2

Not yet recruiting

Immune checkpoint

NCT03870464

LIFE—lung cancer, immunotherapy, frailty, effect

Immune checkpoint

NCT02460068

A study of fotemustine (FTM) versus FTM and ipilimumab (IPI) or IPI and nivolumab in melanoma brain metastasis

Phase 3

Unknown status

Immune checkpoint

NCT04434560

Neoadjuvant immunotherapy in brain metastases

Phase 2

Terminated

Immune checkpoint

NCT03458455

Improved therapy response assessment in metastatic brain tumors

Immune checkpoint

NCT02097732

Ipilimumab induction in patients with melanoma brain metastases receiving stereotactic radiosurgery

Phase 2

Terminated

Immune checkpoint

NCT03807765

Stereotactic radiation and nivolumab in the management of metastatic breast cancer brain metastases

Phase 1

Active, not recruiting

Immune checkpoint

NCT03903640

Optune device—TT field plus nivolumab and ipilimumab for melanoma with brain metastasis

Phase 2

Recruiting

Immune checkpoint

NCT02621515

Nivo/Ipi combination therapy in symptomatic brain metastases

Phase 2

Terminated

Immune checkpoint

NCT02115139

GEM study: radiation and YERVOY in patients with melanoma and brain metastases

Phase 2

Completed

Immune checkpoint

NCT02662725

Ipilimumab combined with a stereotactic radiosurgery in melanoma patients with brain metastases

Phase 2

Completed

Immune checkpoint

NCT02374242

Anti-PD-1 brain collaboration for patients with melanoma brain metastases

Phase 2

Active, not recruiting

Immune checkpoint

NCT05048212

A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases

Phase 2

Not yet recruiting

Immune checkpoint

NCT02978404

Combining radiosurgery and nivolumab in the treatment of brain metastases

Phase 2

Active, not recruiting (continued)

Recruiting

Active, not recruiting

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Metastatic Lesions of the Brain and Spine

559

Table 21.2 (continued) Type

ID number

Study title

Phase

Status

Immune checkpoint

NCT04021420

Safety and efficacy of SonoCloud device combined with nivolumab in brain metastases from patients with melanoma

Phase 1

Recruiting

Immune checkpoint

NCT04021420

Safety and efficacy of SonoCloud device combined with nivolumab in brain metastases from patients with melanoma

Phase 2

Recruiting

Immune checkpoint

NCT04674683

Study comparing investigational drug HBI-8000 combined with nivolumab versus nivolumab in patients with advanced melanoma

Phase 3

Recruiting

Immune checkpoint

NCT04511013

A study to compare the administration of encorafenib + binimetinib + nivolumab versus ipilimumab + nivolumab in BRAF-V600 mutant melanoma with brain metastases

Phase 2

Recruiting

Immune checkpoint

NCT01703507

Phase I study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma

Phase 1

Completed

Immune checkpoint

NCT02696993

Nivolumab and radiation therapy with or without ipilimumab in treating patients with brain metastases from non-small cell lung cancer

Phase 1

Recruiting

Immune checkpoint

NCT02696993

Nivolumab and radiation therapy with or without ipilimumab in treating patients with brain metastases from non-small cell lung cancer

Phase 2

Recruiting

Immune checkpoint

NCT05012254

Study of nivolumab and ipilimumab plus chemotherapy as a treatment for patients with stage IV lung cancer with brain metastases

Phase 2

Not yet recruiting

Immune checkpoint

NCT03340129

Anti-PD-1 brain collaboration + radiotherapy extension (ABC-X study)

Phase 2

Recruiting

Immune checkpoint

NCT03873818

Low dose ipilimumab with pembrolizumab in treating patients with melanoma that has spread to the brain

Phase 2

Recruiting

Immune checkpoint

NCT04899921

Troriluzole or placebo plus ipi plus nivo in mel brain mets

Phase 2

Recruiting

Immune checkpoint

NCT00623766

Evaluation of tumor response to ipilimumab in the treatment of melanoma with brain metastases

Phase 2

Completed

Immune checkpoint

NCT03563729

Melanoma metastasized to the brain and steroids

Phase 2

Recruiting

Immune checkpoint

NCT03297463

Radiation therapy with combination immunotherapy for relapsed/refractory metastatic melanoma

Phase 1

Withdrawn

Immune checkpoint

NCT03297463

Radiation therapy with combination immunotherapy for relapsed/refractory metastatic melanoma

Phase 2

Withdrawn

Immune checkpoint

NCT02107755

Stereotactic radiation therapy and ipilimumab in treating patients with metastatic melanoma

Phase 2

Unknown status

Immune checkpoint

NCT01950195

SRS (stereotactic radiosurgery) plus ipilimumab

Phase 1

Terminated

Immune checkpoint

NCT02716948

SRS and nivolumab in treating patients with newly diagnosed melanoma metastases in the brain or spine

Phase 1

Recruiting

(continued)

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T. H. Ung et al.

Table 21.2 (continued) Type

ID number

Study title

Phase

Status

Small molecule

NCT01551680

A trial evaluating concurrent whole brain radiotherapy and iniparib in multiple non-operable brain metastases

Phase 1

Terminated

Small molecule

NCT05033691

A study to evaluate the efficacy of osimertinib with early intervention SRS treatment compared to the continuation of osimertinib alone, in patients with EGFR mutated NSCLC and asymptomatic brain metastases

Not applicable

Recruiting

Small molecule

NCT02605746

Pre-operative ceritinib (LDK378) in glioblastoma multiforme and CNS metastasis

Early phase 1

Completed

Small molecule

NCT04923542

Stereotactic radiation and abemaciclib in the management of HR+/HER2breast cancer brain metastases

Phase 1

Recruiting

Small molecule

NCT04923542

Stereotactic radiation and abemaciclib in the management of HR+/HER2breast cancer brain metastases

Phase 2

Recruiting

cancer will increase the incidence of brain metastases over time. As a result, the treatment of patients is variable and differs from patient to patient. In general, patients who have evidence of systemic metastatic disease will undergo surveillance imaging for the development of bony lesions. This is typically done with PET/CT as described above. MRI and CT scans of the brain are done for disease surveillance as well. Once brain or spinal metastases are detected, close interval imaging scans are needed to closely follow patients. Typically, interval scans are done every 3–6 months. Patients who are treated with SRS to brain metastasis with or without adjuvant therapy also undergo close follow-up with imaging. The response to radiation could be difficult to assess and includes complete response, incomplete response, and pseudoprogression. Pseudoprogression can appear very similar to local disease progression and in SRS-treated patients. Given this, the Response Assessment in NeuroOncology Response Criteria (RANO) working group has composed a response criteria based on radiographical and clinical features (Lin et al. 2015). Within these criteria for evaluation, patients are classified into four categories, completer response, partial response, stable disease, and progression.

Similar to patients with brain metastases, overall survival in patients with spine metastases can range from a couple of weeks to years and depends on multiple variables similar to those described above for patients who develop cranial disease. As demonstrated in different studies, prognosis could be associated with various cancer types, serum albumin levels, analgesic use as a marker of pain, and number of visceral metastases (Switlyk et al. 2015). Radiographic surveillance is also warranted in these patients and is typically done in short intervals between 3 and 6 months. In addition to CT, MRI, and PET/ CT imaging, radiographic imaging may be needed to assess the development of structural instability. This can include standing/upright Xrays and is especially critical in patients with evidence of pathologic fractures on CT or MRI.

21.8

Conclusion

Although current prognosis of patients with brain and spine metastases is poor, advancements in immunotherapy and targeted small molecules will continue to increase the prognosis of patients with brain and spine metastases. Follow-up of patients is necessary, and treatment failure is common in patients and can result in a rapid

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Metastatic Lesions of the Brain and Spine

development of new disease. Follow-up of patients is tailored to each patient as treatment algorithms can differ. A comprehensive approach to the management of these patients is necessary, and many centers have a multidisciplinary teambased approach to the management of these patients.

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Paik PK et al (2015) Next-generation sequencing of stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases. Cancer Discov 5:610–621. https://doi.org/10.1158/21598290.CD-14-1129 Patchell RA et al (1990) A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500. https://doi.org/10.1056/ NEJM199002223220802 Pekmezci M, Perry A (2013) Neuropathology of brain metastases. Surg Neurol Int 4:S245-255. https://doi. org/10.4103/2152-7806.111302 Pelletier EM, Shim B, Goodman S, Amonkar MM (2008) Epidemiology and economic burden of brain metastases among patients with primary breast cancer: results from a US claims data analysis. Breast Cancer Res Treat 108:297–305. https://doi.org/10.1007/ s10549-007-9601-0 Posner JB, Chernik NL (1978) Intracranial metastases from systemic cancer. Adv Neurol 19:579–592 Posner JB (1980) Clinical manifestations of brain metastasis. In: Weiss L, Gilbert HA, Posner JB (eds) Brain metastasis. Springer Netherlands, Dordrecht, pp 189– 207. https://doi.org/10.1007/978-94-009-8799-9_11 Proescholdt MA, Schodel P, Doenitz C, Pukrop T, Hohne J, Schmidt NO, Schebesch KM (2021) The management of brain metastases-systematic review of neurosurgical aspects. Cancers (Basel) 13. https://doi. org/10.3390/cancers13071616 Rashad S, Elwany A, Farhoud A (2018) Surgery for spinal intramedullary tumors: technique, outcome and factors affecting resectability. Neurosurg Rev 41:503– 511. https://doi.org/10.1007/s10143-017-0879-z Roberge D, Petrecca K, El Refae M, Souhami L (2009) Whole-brain radiotherapy and tumor bed radiosurgery following resection of solitary brain metastases. J Neurooncol 95:95–99. https://doi.org/10.1007/ s11060-009-9899-z Rulli E, Legramandi L, Salvati L, Mandala M (2019) The impact of targeted therapies and immunotherapy in melanoma brain metastases: a systematic review and meta-analysis. Cancer 125:3776–3789. https://doi.org/ 10.1002/cncr.32375 Ryu S et al (2010) Radiosurgical decompression of metastatic epidural compression. Cancer 116:2250– 2257. https://doi.org/10.1002/cncr.24993 Samlowski WE et al (2017) High frequency of brain metastases after adjuvant therapy for high-risk melanoma. Cancer Med 6:2576–2585. https://doi.org/10. 1002/cam4.1223 Sampson JH, Carter JH Jr, Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 88:11–20. https://doi.org/10.3171/ jns.1998.88.1.0011

563 Schiff D, O’Neill BP (1996) Intramedullary spinal cord metastases: clinical features and treatment outcome. Neurology 47:906–912. https://doi.org/10.1212/wnl. 47.4.906 Shah LM, Salzman KL (2011) Imaging of spinal metastatic disease. Int J Surg Oncol 2011:769753. https://doi.org/10.1155/2011/769753 Soltys SG et al (2008) Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys 70:187–193. https://doi. org/10.1016/j.ijrobp.2007.06.068 Stark AM, Tscheslog H, Buhl R, Held-Feindt J, Mehdorn HM (2005) Surgical treatment for brain metastases: prognostic factors and survival in 177 patients. Neurosurg Rev 28:115–119. https://doi.org/ 10.1007/s10143-004-0364-3 Suh JH, Kotecha R, Chao ST, Ahluwalia MS, Sahgal A, Chang EL (2020) Current approaches to the management of brain metastases. Nat Rev Clin Oncol 17:279– 299. https://doi.org/10.1038/s41571-019-0320-3 Switlyk MD, Kongsgaard U, Skjeldal S, Hald JK, Hole KH, Knutstad K, Zaikova O (2015) Prognostic factors in patients with symptomatic spinal metastases and normal neurological function. Clin Oncol (r Coll Radiol) 27:213–221. https://doi.org/10.1016/j.clon. 2015.01.002 Takei H, Rouah E, Ishida Y (2016) Brain metastasis: clinical characteristics, pathological findings and molecular subtyping for therapeutic implications. Brain Tumor Pathol 33:1–12. https://doi.org/10.1007/ s10014-015-0235-3 Tokuhashi Y, Matsuzaki H, Oda H, Oshima M, Ryu J (2005) A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine (Phila Pa 1976) 30:2186–2191. https://doi.org/10. 1097/01.brs.0000180401.06919.a5 Tsao MN et al (2012) Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American society for radiation oncology evidencebased guideline. Pract Radiat Oncol 2:210–225. https://doi.org/10.1016/j.prro.2011.12.004 Tsao MN et al (2018) Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 1:CD003869. https://doi.org/10.1002/14651858.CD003869.pub4 Villalva C et al (2013) EGFR, KRAS, BRAF, and HER-2 molecular status in brain metastases from 77 NSCLC patients. Cancer Med 2:296–304. https://doi.org/10. 1002/cam4.82 Vogelbaum MA, Suh JH (2006) Resectable brain metastases. J Clin Oncol 24:1289–1294. https://doi.org/10. 1200/JCO.2005.04.6235 Walbert T, Gilbert MR (2009) The role of chemotherapy in the treatment of patients with brain metastases from solid tumors. Int J Clin Oncol 14:299–306. https://doi. org/10.1007/s10147-009-0916-1

564 Walle T, Martinez Monge R, Cerwenka A, Ajona D, Melero I, Lecanda F (2018) Radiation effects on antitumor immune responses: current perspectives and challenges. Ther Adv Med Oncol 10:17588340 https://doi.org/10.1177/175883401774 17742575. 2575 Wang BX, Ou W, Mao XY, Liu Z, Wu HQ, Wang SY (2017) Impacts of EGFR mutation and EGFR-TKIs on incidence of brain metastases in advanced nonsquamous NSCLC. Clin Neurol Neurosurg 160:96– 100. https://doi.org/10.1016/j.clineuro.2017.06.022 Wang H et al (2019) Genes associated with increased brain metastasis risk in non-small cell lung cancer: comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong association study of thoracic oncology 1036). Cancer 125:3535–3544. https://doi.org/10. 1002/cncr.32372

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22

Malignant Spinal Tumors Mohammad Hassan A. Noureldine, Nir Shimony, and George I. Jallo

Abstract

Malignant spinal tumors constitute around 22% of all primary spinal tumors. The most common location of metastases to the spinal region is the extradural compartment. The molecular and genetic characterization of these tumors was the basis for the updated WHO classification of CNS tumors in 2016, where many CNS tumors are now diagnosed according to their genetic profile rather than relying solely on the histopathological appearance. Magnetic resonance imaging (MRI) is

M. H. A. Noureldine Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA e-mail: [email protected]; [email protected] M. H. A. Noureldine . N. Shimony Johns Hopkins University School of Medicine, Institute for Brain Protection Sciences, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA e-mail: [email protected] N. Shimony Geisinger Medical Center, Institute of Neuroscience, Geisinger Commonwealth School of Medicine, Danville, PA, USA

the current gold standard for the initial evaluation and subsequent follow-up on intradural spinal cord tumors, and the imaging sequences must include T2-weighted images (WI), short time inversion recovery (STIR), and pre- and post-contrast T1-WI in the axial, sagittal, and coronal planes. The clinical presentation is highly variable and depends on the tumor size, growth rate, type, infiltrative, necrotic and hemorrhagic potential as well as the exact location within the spinal compartment. Surgical intervention remains the mainstay of management of symptomatic and radiographically enlarging spinal tumors, where the goal is to achieve maximal safe resection. Tumor recurrences are managed with repeat surgical resection (preferred whenever possible and safe), radiotherapy, chemotherapy, or any combination of these therapies. Keywords

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Malignant Spinal cord tumor Intramedullary Intradural extramedullary Extradural Anaplastic Astrocytoma Glioblastoma Ependymoma Embryonal tumors Malignant peripheral nerve sheath tumor

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G. I. Jallo (&) Institute for Brain Protections Sciences, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_22

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Background and Epidemiology

Spinal tumors can be classified according to exact location within the spinal canal (intramedullary, intradural extramedullary, or extradural), aggressiveness (benign or malignant [diffuse local or metastatic]), and/or the inherent genetic and molecular characteristics (Louis et al. 2016). Spinal tumors account for around 15% of all central nervous system (CNS) tumors. The incidence of all spinal tumors ranges between 0.8 and 2.5 per 100,000 persons (Duong et al. 2012; Elia-Pasquet et al. 2004; Kurland 1958; Liigant et al. 2000; Materljan et al. 2004; Schellinger et al. 2008). The lowest incidence rates are noted in the pediatric population (less than 19 years of age) as opposed to the highest rates in patients between 75 and 84 years of age (Chi and Khang 1989; Duong et al. 2012; Liigant et al. 2000; Schellinger et al. 2008). Gender-specific rates reveal a slightly higher incidence among females (0.77–1.09 per 100,000 persons) compared to males (0.7–0.83 per 100,000 persons) (Duong et al. 2012; Schellinger et al. 2008). Around 60% of all spinal tumors are found in the extradural compartment, whereas 40% are intradural. Among all primary intradural spinal tumors, 60–70% originate from the spinal cord, 26–36% from the spinal meninges, and around 4% from the cauda equina (Duong et al. 2012; Schellinger et al. 2008). Malignant spinal tumors account for around 22% of all primary spinal tumors (Duong et al. 2012). Although metastases from tumors outside the CNS to the intramedullary and intradural extramedullary compartments may occur, most of metastatic lesions (> 95%) to the spinal region are extradural.

22.2

presence of a mutation in the IDH1 or IDH2 genes (Louis et al. 2016). Among all anaplastic astrocytoma tumors, IDH-wildtype astrocytoma is much less common (20%) but more clinically aggressive than its IDH-mutant counterpart, sometimes resembling the clinical course of a glioblastoma. Loss in the chromosome arms of 9p and 19q has been documented in IDH-mutant anaplastic astrocytomas (Killela et al. 2014), and most of these tumors harbor TP53 and ATRX genetic abnormalities (Jiao et al. 2012; Yan et al. 2009). The genetic profile of IDH-wildtype glioblastoma includes but is not limited to CDKN2A/CDKN2B homozygous deletions, several types of EGFR gene alterations, 10p and 10q chromosomal loss, as well as TERT promoter, PTEN, PI3K, and TP53 mutations (Ohgaki and Kleihues 2013). Alternatively, IDH mutations with a hypermethylation phenotype define the IDH-mutant glioblastoma (Noushmehr et al. 2010); chromosomal loss of the 10q arm and ATRX and TP53 mutations is commonly seen in these tumors as well (Ohgaki et al. 2014) (Figs. 22.1 and 22.2).

22.2.2 Anaplastic Ependymoma Anaplastic ependymomas rarely occur in the spinal cord. Spinal ependymomas express several homeobox (HOX) family members, which coordinate anteroposterior tissue patterning during development (Taylor et al. 2005). Based on molecular and genetic characteristics, a study by Pajtler and colleagues (2015) classified ependymomas into nine groups. Among the three groups of the spinal compartment, the anaplastic type was found to be associated with the NF2 mutation (Pajtler et al. 2015).

Genetics, Immunology, and Molecular Biology 22.2.3 Embryonal Tumors

22.2.1 Anaplastic Astrocytoma and Glioblastoma Anaplastic astrocytoma and glioblastoma are broadly classified as isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype, depending on the

Medulloblastoma is the most common embryonal tumor type, originates in the posterior fossa, and metastasizes to the spinal cord through cerebrospinal fluid (CSF) seeding. The 2016 WHO classification system defines medulloblastomas

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Fig. 22.1 Anaplastic astrocytoma. Sagittal and axial T2-weighted a and b and post-contrast T1-weighted c and d images of the cervical spine showing a C3–5 lesion

according to genetic characteristics and histopathological features. Genetically defined medulloblastomas are further classified into WNT-activated, SHH-activated (including TP53wildtype and TP53-mutant), and non-WNT/nonSHH (including Groups 3 and 4) subtypes (Louis et al. 2016). Common genetic aberrations in these categories include: TP53 mutation in WNT-activated and SHH-activated–TP53-mutant; CTNNB1 and DDX3X in WNT-activated; TERT promoter, PTCH1, SUFU, and SMO mutations in SHHactivated–TP53-wildtype; PVT1-MYC in nonWNT/non-SHH—Group 3; KDM6A in nonWNT/non-SHH—Group 4; and GFI1/GFI1B structural variants in both latter groups (Northcott et al. 2012a, b, 2014; Rausch et al. 2012; Remke et al. 2013; Robinson et al. 2012). Atypical teratoid/rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes (ETMR), and other very rare types of CNS embryonal tumors may have been anecdotally reported to originate or localize to the spinal cord. Hallmark molecular biomarkers in these tumors include SMARCB1 (INI1) and SMARCA4 (BRG1) loss in AT/RT and LIN28A expression or C19MC amplification in ETMR (Biegel et al. 1999; Li et al. 2009; Schneppenheim et al. 2010; Spence et al. 2014).

22.2.4 Malignant Peripheral Nerve Sheath Tumors One-half of malignant peripheral nerve sheath tumors (MPNSTs) arise from neurofibromas in NF1 patients, whereas the second half occurs sporadically (40%) and post-radiation exposure (10%) (LaFemina et al. 2013). Concurrent genetic inactivation of NF1, PRC2 components SUZ12 and EED, and CDKN2A, as well as TP53 alterations, are the main drivers for MPNSTs’ development (Lee et al. 2014; Zhang et al. 2014).

22.3

Histopathology and Morphology

22.3.1 Anaplastic Astrocytoma and Glioblastoma The histological grading of all anaplastic astrocytoma and glioblastoma subtypes is the WHO grade III and IV, respectively. Anaplastic astrocytomas infiltrate the surrounding spinal cord without apparent tissue destruction. The hallmark histopathological characteristics include increased mitotic activity, cellular atypia, and anaplasia in a diffusely infiltrating mass. The

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Fig. 22.2 Glioblastoma, disseminated. Post-contrast T1weighted images of the brain a and b and spinal cord depicting a glioblastoma that originated from the brain

and disseminated to the cervical, thoracic, and lumbar spinal cord

proliferation index (Ki-67) ranges between 5 and 10%. On immunohistochemistry, the IDH-mutant subtype is positive for GFAP and p53, is negative for nuclear ATRX, and expresses R132H-mutant IDH1. By definition, the absence of all IDH mutations, including IDH1 codon 132 and IDH2 codon 172, distinguishes the IDH-wildtype from the IDH-mutant anaplastic astrocytoma.

Glioblastomas are poorly delineated lesions and can present with variable histopathologic patterns, the hallmark of which is necrosis and hemorrhage within the mass. Prominent microvascular proliferation, necrosis, and/or extensive nuclear atypia and mitotic activity in the context of a highly cellular glioma are the diagnostic features of this tumor. Glioblastomas have

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a heterogenous composition, where multiple cellular morphologies may be seen in the same tumor. However, one morphology may predominate over others; thus, several morphological subtypes have been distinguished: small-cell glioblastoma, glioblastoma with primitive neuronal components, glioblastoma with oligodendroglioma components, gemistocytic astrocytic neoplasms, multinucleated giant cells, granular cell glioblastoma, heavily lipidized glioblastoma, and metaplastic glioblastoma/gliosarcoma. Except for the gemistocytic astrocytic neoplasms that are usually characteristic of IDH-mutant glioblastoma, most of the other morphological subtypes are documented in IDH-wildtype tumors (Figs. 22.1 and 22.2).

22.3.2 Anaplastic Ependymoma Anaplastic ependymoma is considered a WHO grade III tumor, which usually presents as a delineated mass and only rarely infiltrates the adjacent parenchyma. Characteristic histopathological features include uniform small cells with round nuclei, elevated nuclear-to-cytoplasmic ratio, high mitotic activity and count accompanied by diffuse microvascular proliferation and palisading necrosis, and/or the classical pseudorosettes (perivascular anucleate zones) and ependymal rosettes. The Ki-67 index is high. Pseudorosettes are positive for GFAP. Vimentin and S100 protein are expressed; EMA is also expressed along the luminal surface of ependymal rosettes. Cytokeratin shows focal immunoreactivity, and OLIG2 is negative or has a sparse expression in ependymomas.

22.3.3 Embryonal Tumors Medulloblastoma is a WHO grade IV tumor. Drop metastases to the spinal cord appear as separate tumor nodules. Although four general morphological subtypes exist, namely classic medulloblastoma, medulloblastoma with extensive nodularity, desmoplastic/nodular medulloblastoma, and large cell/anaplastic

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medulloblastoma, elevated nuclear-tocytoplasmic ratio and brisk mitotic activity are hallmark features. Immunophenotypic characteristics reveal NeuN, synaptophysin, and class III beta-tubulin positivity, especially in Homer Wright rosettes and nodules of neurocytic differentiation. GFAP is positive in reactive astrocytes (spider-like shape) and near blood vessels within the tumor, and NFPs are rarely expressed. SMARCB1 and SMARCA4 are expressed in all medulloblastoma subtypes. C19MC-altered ETMR is characterized by mitotically active multilayered rosettes, of which the cells near the lumen have a defined apical surface, the nuclei are pushed away from the lumen, the lumen may be empty or filled with eosinophilic debris. Three morphological patterns of ETMR have been described: embryonal tumor with abundant neuropil and true rosettes, medulloepithelioma, and ependymoblastoma. Nestin and vimentin are excessively expressed in ETMR. Neuronal and glial markers are negative, whereas cytokeratins, CD99, and EMA are focally expressed. High immunoreactivity for NFPs, synaptophysin, and NeuN is detected in neuropil-like foci. The Ki-67 index ranges between 20 and 80%. Diffuse nuclear expression of INI1 is characteristic, and diffuse cytoplasmic staining of LIN28A, which is strongly expressed in poorly differentiated small-cell foci and multilayered rosettes, helps to diagnose ETMR. The histologic WHO grade of AT/RT is IV. Morphological features include poorly differentiated rhabdoid cells with well-defined cell borders and eccentric nuclei, vesicular chromatin, prominent eosinophilic nucleoli, large cytoplasm, and globular eosinophilic cytoplasmic inclusions. These cells are arranged in nests and sheets and are the predominant component in only few cases. High mitotic activity, necrosis, and hemorrhage are common. Primitive neuroectodermal, epithelial, and mesenchymal features are dispersed throughout the tumor, and a small-cell embryonal component is seen in most AT/RTs. The Ki-67 index is typically > 50% in pediatric cases, but may be significantly lower in adults. Vimentin, EMA, SMA, GFAP, NFP, cytokeratins, and synaptophysins are usually positive.

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Loss of nuclear expression of SMARCB1 (INI1) is highly sensitive and specific for the diagnosis of AT/RT. In rare cases of retained nuclear INI1 expression, SMARCA4 (BRG1) expression may be lost instead.

22.3.4 Malignant Peripheral Nerve Sheath Tumors (MPNSTs) MPNSTs are not assigned a specific WHO grade due to lack of sufficient evidence in the literature, but most of these tumors (85%) are considered high-grade lesions. Histopathological features include elongated nuclei with tapered ends in tightly packed spindle cells. MPNSTs originate and grow within nerve fascicles, have high mitotic activity and foci of hemorrhage and necrosis, are often covered in a pseudocapsule, and usually invade adjacent tissue and may spread intraneuraly or hematogenously. Most MPNSTs are positive for p53 and negative for CDKN2A and SOX10. Around one-third are positive for EGFR. Most MPNSTs (90%) associated with NF1 are negative for neurofibromin compared to 40–50% of sporadic cases. The Ki67 index is usually more than 20%. Loss of H3K27me3 expression is also a sensitive and highly specific marker for the diagnosis of MPNSTs.

22.4

Imaging and Radiologic Features

Magnetic resonance imaging (MRI) is the most sensitive imaging tool and the current gold standard for the initial evaluation and subsequent follow-up on intradural spinal cord tumors. The imaging sequences must include, but are not limited to, T2-weighted images (WI), short time inversion recovery (STIR), and pre- and postcontrast T1-WI in the axial, sagittal, and coronal planes. Preoperative planning and postoperative follow-up on intramedullary tumors may also

include diffusion tensor imaging (DTI) and tractography (Landi et al. 2016), which are more sensitive than conventional sequences in delineating the relationship between the lesion and adjacent white matter tracts. Further characterization of specific tumors necessitates using tailored imaging methods. For example, hypervascular tumors can be evaluated using digital subtraction angiography (DSA) for potential preoperative embolization (Krings et al. 2007), and spinal positron emission tomography (PET)may help in differentiating high-grade from low-grade intramedullary lesions (Naito et al. 2015). Table 22.1 summarizes the radiologic features of malignant spinal tumors.

22.5

Clinical Manifestations

The clinical presentation of patients with spinal cord tumors is highly variable and depends on the tumor size, growth rate, type, infiltrative, necrotic and hemorrhagic potential as well as the exact location within the spinal compartment. Unremitting, dull pain is the most commonly reported initial symptom. It may be localized, radiating or radicular in nature, which is often worse at night and in recumbent positions, possibly due to the diurnal variation of endogenous cortisol secretion and/or distension of the epidural venous plexus. Coughing, sneezing, and Valsalva may exacerbate the pain due to dural distension or compression by the expanding tumor (Parker et al. 1996). Symptomatic progression usually occurs over an indolent course. Sensory changes, motor weakness, and/or gait abnormalities commonly follow a period of neck or back pain. Children may also present with torticollis and delayed milestones; sphincter dysfunction is less common (Constantini et al. 1996). Careful history taking and detailed physical examination are the most valuable screening tools to roughly estimate the location of the tumor. Neck pain and stiffness and upper

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Table 22.1 Common MRI features of malignant spinal cord tumors Tumor

MRI features

Glioblastoma (Figs. 22.2, 22.3, 22.4 and 22.5)

– Pre-contrast T1-WI: isointense + hypointense central (necrotic) zone – T2-WI: hyperintense – Post-contrast T1-WI: ring-shaped enhancement – Irregular shape – Multilevel cord involvement – Cervical (Fig. 22.3) > thoracic (Fig. 22.5) – Peritumoral cord edema (Fig. 22.5)

Anaplastic astrocytoma (Fig. 22.1)

– – – – – – –

Pre-contrast T1-WI: isointense or hypointense T2-WI: hyperintense Post-contrast T1-WI: diffuse enhancement Fusiform cord expansion Multilevel cord involvement Cervical > thoracic Possible associated cyst(s) or syrinx but no necrosis

Anaplastic ependymoma

– – – – – –

Pre-contrast T1-WI: isointense or hypointense T2-WI: hyperintense Post-contrast T1-WI: variable enhancement Cervical > thoracic Syrinx and/or cyst(s) Possible peritumoral cord edema

Embryonal tumors

– – – – – – – – – – – – – – – – – – –

Medulloblastoma Pre-contrast T1-WI: hypointense T2-WI: hyperintense (mostly) or isointense Post-contrast T1-WI: marked enhancement Peritumoral edema in 50–75% Rare cysts, calcification, or hemorrhage Mostly drop metastasis from a posterior fossa lesion ETMR Pre-contrast T1-WI: hypointense or isointense T2-WI: isointense or hyperintense Post-contrast T1-WI: variable, heterogenous enhancement Possible cysts or calcification Common necrosis or hemorrhage AT/RT Pre-contrast T1-WI: hypointense or isointense T2-WI: isointense or hyperintense Post-contrast T1-WI: variable, heterogenous enhancement Common cysts, necrosis, hemorrhage, or calcification Variable peritumoral cord edema

Malignant peripheral nerve sheath tumor

– – – – –

Pre-contrast T1-WI: isointense or hypointense T2-WI: hyperintense or isointense Post-contrast T1-WI: heterogenous or homogenous enhancement Fusiform, globular, or dumbbell expansion Rapid growth (important to distinguish from benign nerve sheath tumors) – Possible necrosis and/or hemorrhagic zones – Possible bone destruction with extradural lesions – FDG-PET to search for additional lesions in NF1 patients

AT/RT atypical teratoid/rhabdoid tumor; ETMR embryonal tumor with multilayered rosettes; FDG-PET [18F]fluorodeoxyglucose positron emission tomography; MRI magnetic resonance imaging; T1-WI T1-weighted imaging; T2-WI T2-weighted imaging

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Fig. 22.3 Glioblastoma. Sagittal and axial T2-weighted a and b and post-contrast T1-weighted c and d images showing a lesion extending from the cervicomedullary junction to C4 with diffuse expansion of the cord

Fig. 22.4 Glioblastoma. Sagittal T2-weighted a, short tau inversion recovery (STIR) b, and T1-weighted c images revealing a thoracolumbar junction lesion

extremity paresthesia, numbness and/or weakness point toward a cervical lesion. Back pain, with or without lower extremity weakness, proprioceptive deficits, and/or numbness are typical of thoracic tumors. Upon flexion and extension

of the neck, Lhermitte’s sign may be positive in both cervical and upper thoracic tumors. In children, progressive kyphoscoliosis, probably due to asymmetric dysfunction of the anterior horn cells and uneven activation of one side of

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Fig. 22.5 Glioblastoma. Sagittal a, coronal b, and axial c T2-weighted images of a T8-11 glioblastoma with significant edema affecting the cord cranially and caudally.

Axial d and sagittal e post-contrast T1-weighted images showing heterogenous enhancement with necrotic zones at the upper and lower poles of the lesion

the paraspinal muscles, is an early sign of thoracic lesions (Constantini et al. 1996; Jallo et al. 2003). Lumbar, conus medullaris, and cauda equina tumors typically present with low back pain, radiculopathy, lower limb weakness or paraplegia, saddle and lower limb sensory deficits, sphincter dysfunction, and/or neurogenic claudication secondary to spinal stenosis. Unreasonable delay in the diagnosis is frequently due to delayed imaging or imaging of the wrong spinal level (Segal et al. 2012). For example, a potential mistake in an adult patient with degenerative spine disease is to assume that a radiographic lumbar spinal stenosis is causing proprioceptive deficits, positive Babinski, and hyperreflexia in the context of typical neurogenic claudication; cervical and thoracic imaging in this scenario may reveal a spinal tumor. Therefore, it is imperative to carefully evaluate the ascending and descending pathways of the spinal cord for any subtle deficits. Clinical scores such as the McCormick (McCormick et al. 1990), Frankel (Frankel et al. 1969), and Klekamp and Samii (Klekamp and Samii 1993) scores are useful tools to document the neurologic function and compare the preoperative and postoperative

functional status of patients with spinal cord tumors.

22.6

Therapeutic Approaches

22.6.1 Surgical Intervention The goal of surgical intervention in the management of spinal cord tumors is to achieve maximal safe resection. Utilizing available technologies, including but not limited to advanced preoperative imaging, surgical microscope, microsurgical instruments, ultrasonic aspirator, and intraoperative neuromonitoring (IONM), has a cumulative added benefit in achieving this goal, and this has been demonstrated by comparing current to historical morbidity and mortality outcomes. Surgical intervention remains the mainstay of management of symptomatic and radiographically enlarging spinal tumors. A conservative approach is usually adopted and considered more appropriate for clinically silent and radiographically stable lesions. In some cases, however, surgical intervention is recommended for the sole purpose of obtaining a biopsy, especially when

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malignancy is highly suspected; some tumor debulking may be performed concurrently as long as it is deemed safe to do so. In such cases, tissue diagnosis may be necessary to reveal the molecular profile of the tumor and tailor adjuvant therapy accordingly. In patients with high-grade tumors, gross total resection (GTR) is rarely achieved due to the infiltrative nature of these lesions, during which IONM is of paramount role to prevent injury to critical pathways. Since the behavior of malignant tumors may differ, aggressive surgical resection may be more beneficial in some tumor types. For example, radical resection was associated with a trend of increased overall survival in patients with non-disseminated anaplastic astrocytoma, which was not the case for glioblastoma and disseminated anaplastic astrocytoma (McGirt et al. 2008b). Nevertheless, there is no clear answer to whether GTR should be performed in malignant spinal cord lesions, where some studies showed survival benefit (Jallo et al. 2001; McCormick and Stein 1990; McGirt et al. 2008b; Ononiwu et al. 2012; Wong et al. 2013), while others did not (GarcésAmbrossi et al. 2009; Liu et al. 2015; Raco et al. 2005; Sandler et al. 1992). In general, patients with astrocytoma do much better than those with glioblastoma after radical resection (Luksik et al. 2017; McGirt et al. 2008b); the significance of these findings challenges the historical dogma of treating malignant spinal tumors with biopsy, chemotherapy, and radiation therapy only. In the operating room, the patient is positioned prone with the head pinned in a threepoint fixation for cervical/upper thoracic lesions; upper extremities are positioned parallel to the body (pointing downwards) for cervical/upper thoracic lesions or above the head in a ‘superman’ position for mid-lower thoracic/lumbar lesions. This is followed by setting up the IONM connections for motor evoked potentials (MEPs) and somatosensory evoked potentials (SSEPs). Epidural D-wave monitoring is set up during the procedure. MEPs monitor the integrity of the corticospinal tracts, where a train of electrical stimuli is delivered transcranially and the

M. H. A. Noureldine et al.

response is recorded in upper and lower extremity muscles distally; the ‘All or Nothing’ rule is usually adopted when assessing injury using MEPs (Macdonald et al. 2013), although more conservative surgeons might consider a 50– 80% amplitude drop as significant (Langeloo et al. 2003). Fast-conducting corticospinal tract axons are monitored using epidural D-wave potentials, which are delivered proximal and recorded distal to the tumor; a peak-to-peak amplitude drop of 50% or more is considered a red flag (Legatt et al. 2016), and surgical resection should be halted immediately to prevent permanent neurological deficits. Transient deficits may occur with a D-wave amplitude drop of less than 50%, especially with a simultaneous drop in MEP signals. SSEPs monitor fastconducting, large sensory pathways. Upper and lower extremity SSEPs are typically obtained by stimulating the median and posterior tibial nerves, respectively, and the response is recorded at the level of the peripheral nerves, spinal cord, and contralateral sensory cortex. One of the major drawbacks of SSEPs is the several minutes’ delay in obtaining the response since 500– 1500 responses are averaged to obtain optimal data; thus, detection of permanent nerve injury may be delayed intraoperatively (Schwartz et al. 2007). For intradural lesions, the surgery proceeds with a midline skin incision and subperiosteal dissection above the tumor level. Bony exposure should extend just above and below the solid components of the tumor to prevent excessive spinal cord retraction. Osteoplastic laminoplasty is preferred over laminectomy to prevent the development of vertebral column instability and future spinal deformity, as well as decrease the risk of postoperative CSF leak (McGirt et al. 2008a, 2010). Epidural D-wave electrodes are then placed, and intraoperative ultrasound is used to locate the rostro-caudal limits of the tumor before opening the dura. The dura is opened in the midline, extending above and below the tumor margins, and tenting sutures are placed. Resection of posterolateral extramedullary lesions is safer than their anteriorly located counterparts as minimal manipulation is needed;

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the process starts by finding a dissection plane and tumor debulking under the microscope and using microsurgical instruments and/or the ultrasonic aspirator (Jallo 2001; Jallo et al. 2001). Intramedullary spinal cord lesions are typically more challenging to resect. Clues to locate the tumor include spinal cord surface discoloration, bulging, irregularity, and/or rotation. The shortest trajectory to the tumor is pursued, where the myelotomy is performed through the dorsal median sulcus or the dorsolateral sulcus in the majority of cases; the diving surface vessels are used to locate these sulci in case the normal anatomy is distorted. Once the tumor is reached, frozen sections are sent for pathologic examination. The surgeon should keep in mind that malignant tumors, especially anaplastic astrocytoma and glioblastoma, will always lack a true plane of dissection; therefore, tumor resection must proceed with extreme caution and judicious communication with the neurophysiology team to detect signal changes as early as possible. Ependymomas may be easier to resect, however (Jallo et al. 2003). Optimal surgical strategies during spinal cord tumor resection include minimizing the use of bipolar cautery, which may cause thermal injury, dynamic retraction, i.e., constantly changing the working area, as well as gentle tumor manipulation and suction. At the end of resection, hemostasis is achieved, and the dura is closed in a watertight fashion, with or without the use of a fibrin sealant. D-wave electrodes are typically kept in place until dural closure is completed. During laminoplasty, the bone is fixed using small plates, and the muscular fascia is sutured in multiple layers and watertight (Fig. 22.6).

22.6.2 Chemotherapy and Radiotherapy The standard of care for patients with spinal cord tumors starts with attempting GTR or maximally safe resection. Expectedly, malignant tumors are more difficult to completely resect due to their microscopic infiltrative nature, even when GTR is documented on postoperative imaging. The

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cellular remnants may recur shortly after surgery or remain silent and undetectable, necessitating long, and sometimes, indefinite, periods of follow-up. Tumor recurrences are managed with repeat surgical resection (preferred whenever possible and safe), radiotherapy, chemotherapy, or any combination of these therapies. The role of radiotherapy in the management of malignant spinal tumors is debatable. Conventional fractionation doses of 40–45 Gy are usually delivered to tumor remnants after subtotal resection or to tumor relapses when repeat surgery is contraindicated. While some benefit has been documented in certain types of tumors such as astrocytoma (after GTR, subtotal resection, or recurrence) (Guss et al. 2013) and glioblastoma (after GTR as opposed to subtotal resection) (Konar et al. 2017), other tumors such as ependymoma may not respond to radiotherapy, even in patients with subtotal resection (Lin et al. 2015; Sgouros et al. 1996; Tarapore et al. 2013); these patients may be harmed by radiotherapy instead. Children are especially more vulnerable to the risks associated with radiotherapy, including but not limited to radiation-induced myelopathy, vasculopathy, and other parenchymal changes, growth retardation, development of secondary malignancies, impaired spinal growth, and development of spinal deformity (Tobin et al. 2015). Nevertheless, when all other options are depleted, the desperate need for an adjuvant therapy in a progressive malignant tumor may explain exploring the potential benefit of radiotherapy in these patients. Alternatively, stereotactic radiosurgery (SRS) has been shown to be effective in selected cases (Bennett et al. 2017; Hernández-Durán et al. 2016; Marchetti et al. 2013), although treatment-related toxicity (mostly Grades 1 and 2) to adjacent organs may be as high as 25% (Sharma et al. 2017). Chemotherapy has a limited role as an adjuvant therapy for spinal tumors. Potential explanations include the decreased intrathecal concentration of chemotherapeutic agents due to the blood–spinal cord barrier and a more extensive dilution of the agents that crossed the barrier due to stronger CSF pulsations around the cord. Spinal astrocytoma and glioblastoma are often

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Fig. 22.6 Treatment algorithm

treated with adjuvant temozolomide, an DNA alkylating agent, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor; the use of these agents for spinal tumors has been extrapolated from their use for intracranial tumors (Juthani et al. 2015). In adults with spinal cord glioblastoma, a therapeutic strategy consisting of concomitant radiotherapy and temozolomide followed by adjuvant temozolomide had a 5-year long lasting benefit compared to radiotherapy alone, especially in patients with MGMT promoter methylation (Stupp et al. 2009). These positive results were not reproducible in pediatric patients with high-grade gliomas, where the same treatment plan did not improve the event-free survival (Cohen et al. 2011) compared to the results of the Children’s Cancer Group (CCG-945) study. The inherent differences between adult and pediatric gliomas at the molecular level as well as MGMT-

independent pathways of resistance to temozolomide may explain the negative response in children (Gaspar et al. 2010). In a similar manner, this differential response has been observed when bevacizumab was added to the treatment regimen of children with high-grade gliomas, where the response was inferior to adult published data (Narayana et al. 2010; Parekh et al. 2011; Vredenburgh et al. 2007).

22.6.3 New Therapeutic Modalities Even though surgery is associated with better outcomes than chemotherapy and radiation therapy, the diffusely infiltrative nature of malignant spinal tumors in a highly compact and eloquent neural compartment significantly reduces the safety margin of surgical resection. The therapeutic focus, therefore, has shifted toward

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experimental and targeted therapies, especially with the exponential growth of literature about molecular and genetic characteristics of CNS tumors in the last two decades. Although the approach may differ, the common goal is to target the infiltrating tumor cells while sparing the surrounding spinal cord tissue. Rat models exhibiting growth of intramedullary spinal cord tumors were developed to carry out these studies, some models of which demonstrated close resemblance to the infiltrative behavior of highgrade astrocytoma in the cervical cord (Caplan et al. 2006; Hsu et al. 2012; Ren et al. 2010; Ropper et al. 2016). One of the proposed approaches is the stem cell-based gene-directed enzyme prodrug therapy (SC-GDEPT), which exploits the intrinsic tropism and chemotactic migration capabilities of the neural stem cells (NSCs); these cells are genetically engineered to convert a prodrug into an anti-cancer drug and thus used as vehicles for local delivery to the tumor (Aboody et al. 2000; Kim et al. 2005; Ropper et al. 2016; Schmidt et al. 2005; Zeng et al. 2016). Various types of targeted immunotherapy have been studied, the most reported of which are adoptive lymphocytic transfer, immune checkpoint blockade, surface-directed passive immunotherapies, and oncolytic vaccines (Calinescu et al. 2015; Fecci et al. 2014). The basic idea behind the adoptive lymphocytic transfer is to harvest T-cells from the patient, followed by ex vivo expansion and sensitization, with or without genetic alteration, to allow for more efficient activation against the tumor cells (Han et al. 2015; Samaha et al. 2015). Immune checkpoint pathways, the role of which is to promote self-tolerance by desensitizing T-cells to normal host tissue, are often dysfunctional in tumors, limiting the attack by host T-cells (Calinescu et al. 2015; Pardoll 2012; Platten et al. 2016). Inhibition of immune checkpoints in murine models of glioblastoma showed positive outcomes and led to several clinical trials (Agarwalla et al. 2012; Kim et al. 2017; Wainwright et al. 2014). Surface-directed passive immunotherapies work through binding of the targeting molecule to the surface of the tumor

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cell, thereby activating tumoricidal toxins or blocking vital tumor pathways. Some tumors, however, may easily adapt to the targeting molecule or modify the surface molecular expression, in addition to the decreased CSF concentration of these large molecules due to the impermeability of the blood–spinal cord barrier, rendering the effect of these molecules insignificant (Fecci et al. 2014; Furnari et al. 2015; Platten et al. 2016). The concept of oncolytic vaccines is built upon the idea of inducing immune responses, through production of antibodies, against antigens that are highly selectively expressed by specific tumors (Mitchell et al. 2015; Thomas et al. 2009). Further discussion of the basic biology behind these new therapeutic approaches is beyond the scope of this chapter; however, the future of targeted therapies in the treatment of malignant CNS tumors is promising.

22.7

Follow-Up and Prognosis

In general, malignant spinal cord tumors carry a poor prognosis in terms of quality of life and survival. Several factors contribute to the morbidity and mortality rates in patients harboring these lesions including but not limited to tumor type/histopathology, tumor location, time to presentation, time to surgery, extent of resection, surgical complications, surgeon skills/expertise, patient age, patient pre- and postoperative functional status, tumor recurrence, and tumor response to adjuvant and targeted therapies. For example, the difficulty in tackling ventrally located intradural spinal cord lesions and associated higher risk of complications negatively affects the prognosis (Slin’ko and Al-Qashqish 2004); in fact, the highest rate of surgical complications was reported in thoracic-level tumors located anterior to the spinal cord (Mehta et al. 2013). Another example is the longitudinal extension of intramedullary spinal cord tumors, where the neurological status was found to be worse preoperatively, postoperatively, and on follow-up in patients with tumors extending beyond three vertebral levels (Ebner et al. 2010).

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These factors, however, do not alter the decision to pursue surgery due to its potentially beneficial outcomes. As these tumors have a poor prognosis, patients must be followed closely with serial neurological examinations and imaging studies. A multidisciplinary team-based approach is the gold standard for these patients. We routinely image patients every 3–4 months to assess tumor control or progression of disease. The treatment protocol must be balanced against the aggressive nature of the disease. One must consider alternative therapy options if the tumor continues to grow on the present course (Liu et al. 2015; McGirt et al. 2008b).

22.8

Conclusion

The knowledge about the genetic profiles of malignant spinal cord tumor is growing exponentially. Targeting specific molecular pathways is the best hope in future management of these tumors, for which current management strategies have been consistently proven unsuccessful.

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Benign Spinal Tumors Mohammad Hassan A. Noureldine, Nir Shimony, and George I. Jallo

Abstract

Benign spinal intradural tumors are relatively rare and include intramedullary tumors with a favorable histology such as low-grade astrocytomas and ependymomas, as well as intradural extramedullary tumors such as meningiomas and schwannomas. The effect

M. H. A. Noureldine Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA e-mail: [email protected]; [email protected] Institute for Brain Protection Sciences, Johns Hopkins University School of Medicine, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA N. Shimony Institute of Neuroscience, Geisinger Medical Center, Geisinger Commonwealth School of Medicine, Danville, PA, USA e-mail: [email protected] Institute for Brain Protections Sciences, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA G. I. Jallo (&) Institute for Brain Protections Sciences, Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, USA e-mail: [email protected] N. Shimony Department of Surgery, St Jude Children’s Research Hospital, Memphis, USA

on the neural tissue is usually a combination of mass effect and neuronal involvement in cases of infiltrative tumors. The new understanding of molecular profiling of different tumors allowed us to better define central nervous system tumors and tailor treatment accordingly. The mainstay of management of many intradural spinal tumors is maximal safe surgical resection. This goal is more achievable with intradural extramedullary tumors; yet, with a meticulous surgical approach, many of the intramedullary tumors are amenable for safe gross-total or near-total resection. The nature of these tumors is benign; hence, a different way to measure outcome success is pursued and usually depends on functional rather than oncological or survival outcomes. Keywords

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Benign Spinal tumor Intramedullary Extramedullary Intradural Astrocytoma Ependymoma Hemangioblastoma Ganglioglioma Neurofibroma Schwannoma Meningioma

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Abbreviations

CNS CSF DA GTR LGG

Central nervous system Cerebrospinal fluid Diffuse infiltrative astrocytoma Gross-total resection Low-grade glioma

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_23

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MISME MRI OS PFS RT SBRT SEER SRS STR T1WI VHL WHO

23.1

Multiple inherited schwannomas, meningiomas, and ependymomas Magnetic resonance imaging Overall survival Progression-free survival Radiation therapy Stereotactic body radiation therapy Surveillance, Epidemiology, and End Results Stereotactic radiosurgery Sub-total resection T1-weighted images Von Hippel-Lindau World Health Organization

Background and Epidemiology

Tumors of the spine are generally classified as intramedullary, intradural extramedullary, and extradural. While metastases account for the majority of spinal tumors, these lesions are typically localized to the extradural compartment. The scope of this chapter, however, will include only benign primary spinal cord tumors, which are intramedullary tumors by definition, and benign intradural extramedullary tumors; extradural and malignant spinal tumors, including systemic metastases, are discussed elsewhere is this book. Primary spinal tumors constitute a small proportion (75%) cases of hemangioblastomas (Gläsker et al. 2001; Lee et al. 1998; Shankar et al. 2014). In a process referred to as pseudohypoxia, upregulation of hypoxia-responsive genes (erythropoietin and VEGF) occurs due to loss of function of the VHL gene, which usually controls the cell cycle and suppresses the development of tumors (Favier and Gimenez-RoqueAbdullah 2010). These tumors very rarely exhibit any kind of mitotic changes or necrosis and are mainly composed of vascular channels that demonstrate capillary proliferation, as well as thin pathological vessel walls and stromal cells resembling intravascular tumor cells (Hussein 2007). Approximately two-thirds of hemangioblastomas occur spontaneously, and around one-third are found in patients that have VHL disease (Liu et al. 2016).

23.2.1.4 Ganglioglioma Gangliogliomas (WHO I) of the spinal cord are very rare and usually diagnosed in the pediatric population; these tumors account for 1.1% of all spinal cord tumors (Murakami et al. 2013). Chromosomal abnormalities are reported in up to onethird of gangliogliomas, with gain of chromosome 7 being the most common (Hoischen et al. 2008; Squire et al. 2001; Wacker et al. 1992; Yin et al. 2002). Although not specific for gangliogliomas, the literature suggests that BRAF V600E mutation is the most frequent documented genetic aberration in brain gangliogliomas (Chappé et al. 2013; Dougherty et al. 2010; Schindler et al. 2011). The association between BRAF V600E mutation and spinal cord gangliogliomas is unknown, mainly because of the rarity of this pathology in the spinal cord. Recently published series, however, suggests an occurrence of 10–33% (Deora et al. 2019). Other molecular alterations leading to activation of the MAPK pathway in gangliogliomas include BRAF-FXR1, -KIAA1549, and -MACF1 fusions (Zhang et al. 2013). Neurofibromatosis type 2 may be associated with spinal gangliogliomas (Sawin et al. 1999) (Fig. 23.3).

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23.2.2 Intradural Extramedullary 23.2.2.1 Neurofibroma Neurofibroma is a benign (WHO I), slowgrowing, non-capsulated tumor, with the majority of the cases having tumors that are extradural (dorsal spinal nerve root or peripheral nerves), whereas 36–40% of neurofibromas are intradural (Carman et al. 2013). In the context of NF1, neurofibromas typically develop as a consequence of biallelic inactivation of the NF1 gene in chromosome 17q of S100-positive Schwann cells (Maertens et al. 2006; Perry et al. 2001) and less frequently due to chromosomal losses on 19p, 19q, and 22q (Koga et al. 2002). Some perineural cells, which are S100-negative and are possibly dedifferentiated Schwann cells, were also implicated in the occurrence of neurofibromas (Ribeiro et al. 2013). Sporadic neurofibromas are also thought to occur due to NF1 loss (Beert et al. 2012; Storlazzi et al. 2005) and potentially due to chromosomal losses on 19q and 22q (Koga et al. 2002). The AKT/mTOR and RAS/MAPK pathways are subsequently activated, leading to tumorigenesis (Le et al. 2009; Thomas et al. 2012). 23.2.2.2 Schwannoma Schwannomas account for 25% of all spinal tumors and are the most common nerve sheath tumor (Hirano et al. 2012). Inactivating, small frameshift mutations of the NF2 gene result in truncated merlin/schwannomin proteins and are the main driver in the genesis of schwannomas (Bijlsma et al. 1994; Jacoby et al. 1996, 1994; Louis et al. 1995; Rouleau et al. 1993; Seizinger et al. 1986; Trofatter et al. 1993). Whether chromosome 22q is completely lost without any signs of NF2 gene mutations or the remaining wildtype allele on chromosome 22q is lost in the context of NF2, both scenarios have been associated with merlin loss and development of schwannomas (Hitotsumatsu et al. 1997; Huynh et al. 1997; Sainz et al. 1994). Rare genetic mutations have also been reported, including gain of chromosomes 9q34 and 17q and loss of 1p (Leone et al. 1998; Warren et al. 2003) (Fig. 23.4).

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Fig. 23.3 Ganglioglioma—cervical spine. T2-weighted (a), pre- (b), and post-contrast (c) T1-weighted images

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Fig. 23.4 Schwannoma—lumbar spine. T2-weighted (a), pre- (b), and post-contrast (c) T1-weighted images

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Fig. 23.5 Meningioma— thoracic spine. T2-weighted (a) and post-contrast T1weighted (b) images

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23.2.2.3 Meningioma Meningiomas of the spinal canal are the second most common tumors. Most of the spinal meningiomas will be intradural, and almost all are benign (WHO I). Monosomy 22 is a common genetic abnormality in meningiomas (Zang 2001). Up to two-thirds of sporadic meningiomas and the majority of meningiomas in the context of NF2 are associated with NF2 gene aberrations, including nonsense mutations and insertions/ deletions that lead to frameshifts or stop codons, leading to a truncated merlin/schwannomin protein (Lekanne et al. 1994; Louis et al. 1995; Wellenreuther et al. 1995). Other potential alterations inside and outside of chromosome 22 are in the AP1B1, MN1, SMARCB1, LARGE, AKT1, TRAF7, KLF4, SMO, and SMARCE1 genes (Brastianos et al. 2013; Clark et al. 2013; Mawrin and Perry 2010; Reuss et al. 2013; Sahm et al. 2013; Schmitz et al. 2001; Smith 2015) (Fig. 23.5).

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23.3

Histopathology and Morphology

23.3.1 Intramedullary 23.3.1.1 Low-Grade Astrocytoma Congruent to posterior fossa pilocytic astrocytomas that are usually composed of a mural nodule with a peri- or intratumoral cyst, spinal pilocytic astrocytomas can be associated with a multi-segmental syrinx (Minehan et al. 1995). In general, histopathologic examination reveals astrocytic proliferation with variable patterns (biphasic, piloid, lobular), although compact and microcytic features are typically present. Low-tomoderate cellularity is the common rule, but rare pleomorphic/hyperchromatic nuclei, mitotic figures, infarct-like, small and non-palisading necrotic areas, glomeruloid vascular proliferation, and leptomeningeal infiltration might be

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seen in this benign tumor. Compact piloid portions of the tumor contain Rosenthal fibers, which are composed on alpha-B-crystallin (Dinda et al. 1990). Eosinophilic granular bodies may be present and are positive for period acidSchiff, alpha-1-antitrypsin, and alpha-1-antichymotrypsin (Katsetos et al. 1994). Pilomyxoid astrocytoma is a close variant and shows a more distinctive pattern of common perivascular arrangements and bipolar cells in a myxoid background. Pilocytic astrocytomas are highly vascular; however, regressive changes may show significantly hyalinized, potentially ectatic vessels. Other regressive changes may include infarct-like necrosis, lymphocytic infiltrates, and calcifications, but these are not commonly seen in spinal lesions. Cyst walls are usually vascularized, sometimes surrounded by a dense piloid layer. Unlike diffuse gliomas, pilocytic astrocytomas are relatively solid and discrete, without aggressive infiltration of surrounding tissue. Leptomeningeal invasion and involvement of the subarachnoid space are possible and are not a sign of malignancy. Immunohistochemistry reveals strong expression of S100, GFAP and OLIG2, possible weak/partial expression of synaptophysin, weak-to-absent p53 protein staining, absent R123Fi-mutant IDH1 protein reactivity, consistent MAPK phosphorylation, variable mTOR activation, and low Ki-67 proliferation index (Capper et al. 2010; Giannini et al. 1999; Hütt-Cabezas et al. 2013; Jones et al. 2013; Otero et al. 2011) (Fig. 23.1).

23.3.1.2 Ependymoma True ependymal rosettes (i.e., tumor cells arranged around a central lumen or canal) and pseudorosettes (i.e., anucleate regions of fine fibrillary processes around vessels created by radial arrangement of tumor cells) in the context of a well-circumscribed glioma of monomorphic cells with round/oval nuclei and speckled nuclear chromatin are pathognomonic of classic ependymoma. Ependymal rosettes are less frequently seen than pseuodorosettes on histologic examination. Typically, ependymomas have a low number of mitotic figures and bland cytology. Focal areas of microvascular proliferation

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and palisading necrosis may be present. Intratumoral hemorrhage, metaplastic cartilage/bone formation, myxoid degeneration, and dystrophic calcification are possible features as well. Spinal and posterior fossa tumors may show prominent hyalinization of vessels, and lesions are usually well-demarcated, although some parenchymal infiltration may occur. S100 protein and vimentin are typically expressed in all ependymomas (Kimura et al. 1986); GFAP is localized to pseudorosettes; and EMA is noted as dot-like perinuclear or ring-like cytoplasmic formations in most ependymomas and sometimes expressed along the luminal surface of ependymal rosettes (Kawano et al. 2004). Neuronal antigens are rarely (Andreiuolo et al. 2010; Preusser et al. 2006; Rodriguez et al. 2007) and OLIG2 is sparsely (Ishizawa et al. 2008; Otero et al. 2011; Preusser et al. 2007) expressed, whereas cytokeratin may be focally present (Vege et al. 2000) (Fig. 23.2).

23.3.1.3 Hemangioblastoma Hemangioblastomas are usually described as a vascular nodule originating from or attached to the pial surface and surrounded by a cyst, although around 40% are solid vascular tumors without associated cysts (Wanebo et al. 2003). The characteristic histologic pattern is that of an abundancy of vascular cells among a stromal cellular background, the variable morphology of which distinguishes the cellular from the reticular variants of hemangioblastoma. Resembles a clear-cell morphology, the most characteristic histologic element is the presence of abundant lipid-containing vacuoles. Mitotic activity is rare, and intratumoral hemorrhage may be evident due to the presence of many thin-walled and fragile vessels. Rosenthal fibers and astrocytic gliosis are typically present in the syrinx and cyst walls. On immunohistochemistry, stromal cells, which represent the neoplastic component of hemangioblastomas, are positive for NCAM1, S100, neuron-specific enolase, ezrin, vimentin, aquaporin-1, CXCR4, EGFR, carbonic anhydrase isozymes, HIF1A, and HIF2A (Böhling et al. 1996a, b, c; Flamme et al. 1998; Ishizawa et al. 2005; Liang et al. 2007; Longatti et al. 2006;

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Proescholdt et al. 2005; Zagzag et al. 2005, 2000), but are typically negative for GFAP (Wizigmann-Voos and Plate 1996). On the other hand, markers such as CD31, CD34, and von Willebrand factor delineate endothelial cells in this benign tumor (Böhling et al. 1996b; Wizigmann-Voos and Plate 1996).

23.3.1.4 Ganglioglioma A heterogenous, proportionately variable mixture of glial and neuronal cell elements is the striking histopathological feature of gangliogliomas. The glial cells may be similar to those of astrocytomas or oligodendrogliomas, whereas the neuronal elements are usually a dysplastic, cytomegalic cluster of cells that lack cytoarchitectural organization and characterized by perimembranous Nissl substance aggregation. Myxoid degeneration and/or microcystic cavities may be noted in a fibrillary matrix, and white matter rarefaction is a frequent finding. Rosenthal fibers are present, but eosinophilic granular bodies are more commonly seen. Extensive lymphoid infiltrates, dystrophic calcifications, small necrotic areas, rare mitoses, and substantial capillary networks, which may be resemble a malformative angiomatous zone, are other potential features. Immunostaining for synaptophysin, neurofilaments, MAP2, and chromogranin-A highlights the dysplastic neurons, especially for chromogranin-A that is strongly expressed in dysplastic as opposed to normal neuronal cells. CD34 may be another helpful marker to detect neuronal cells in the tumor (Blümcke et al. 1999). Glial tumoral cells are positive for GFAP but not MAP2, which is present in higher grade astrocytic tumors (Blümcke et al. 2004), and typically have a Ki-67 index of 1.1–2.7% (Hirose et al. 1997; Luyken et al. 2004; Prayson et al. 1995; Wolf et al. 1994) (Fig. 23.3).

23.3.2 Intradural Extramedullary 23.3.2.1 Neurofibroma Typical histopathological features of neurofibromas consist of proliferating Schwann cells and fibroblasts in a background of myxoid material

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and collagen fibers. The nuclei of the neoplastic Schwann cells are thin, curved/elongated, and much smaller than those of schwannomas, the cytoplasm is scant, and the cell processes are barely visible on light microscopy. Nerve axons may still be present, and tactile-like structures such as pseudo-Meissner corpuscles are commonly seen in large tumors. Antoni A-like regions, Verocay bodies, and blood vessel hyalinization are typically absent in neurofibromas as opposed to schwannomas. S100 and nuclear SOX10 are positive on immunostaining (Karamchandani et al. 2012), and EMA is positive in the residual perineurial cells, which are also positive for GLUT1 and claudin (Hirose et al. 2003; Pummi et al. 2006). GFAP may be expressed, CD34 staining highlights some stromal cells, and recruited mast cells satin for KIT.

23.3.2.2 Schwannoma Typically, two striking histopathological patterns are seen in schwannomas: Antoni A and Antoni B. In all Schwann cells forming the tumor, the surface basement membranes are seen as a pericellular reticulin pattern, and a moderate amount of eosinophilic cytoplasm can be noted, although cell borders are not easily distinguished. In Antoni A, tumor cells are elongated with normochromic round or spindle-shaped, taperedended, and potentially palisading nuclei, which are referred to as Verocay bodies when many parallel rows are significantly noticeable. The cells are organized in multidirectional fascicles and packed into an obviously compact pattern. The Antoni A pattern is particularly abundant in NF2-related vestibular schwannomas, which also demonstrate whorl formation and a lobular growth pattern, possibly representing the convergence of many smaller schwannomas (Dewan et al. 2015; Sobel and Wang 1993). In Antoni B, nuclei of tumor cells are typically smaller and round-to-ovoid in shape. The cellular pattern is looser with variable lipidization and indistinguishable processes. Both Antoni A and Antoni B may harbor lipid-laden cells. Intratumoral vessels are markedly hyalinized, thick-walled, and sometimes dilated with associated hemorrhage. On immunohistochemistry, laminin and

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collagen IV stains are pericellular and seen extensively in the surface basal lamina of the tumor. Immunoreactivity to p53 is possible but typically low (Casadei et al. 1995), GFAP is focally expressed (Memoli et al. 1984), LEU7, calretinin and SOX10 stains are often seen (Fine et al. 2004; Pekmezci et al. 2015), and the expression pattern of S100 protein is strong and diffuse (Weiss et al. 1983). Variable, mosaic-type expression of SMARCB1 has been reported for different types of schwannomatosis (Patil et al. 2008) (Fig. 23.4).

23.3.2.3 Meningioma Several histological variants of meningiomas have been described. The benign subtypes are the meningothelial, fibrous, transitional, psammomatous, angiomatous, microcytic, secretory, lymphoplasmacyte-rich, and metaplastic, all of which correspond to the WHO grade I. The meningothelial variant epithelioid tumor cells closely resemble normal arachnoid cap cells and have a uniform arrangement, abundant eosinophilic cytoplasm, and ultrastructural processes that are closely interwoven. The nuclei are oval, with variable clear spaces, pseudoinclusions, and delicate chromatin. Psammoma bodies and whorls are less formed and less common than in some other meningioma variants. Tumor cells of the fibrous variant are spindled and aligned in interweaving and parallel fascicles, sometimes resembling those of solitary fibrous tumors. The matrix is rich in collagen, and focal tumor areas may show nuclear features that are similar to nuclei of the meningothelial subtype. A nuclear palisading pattern similar to Verocay bodies is rarely recognized. The differential diagnoses includes solitary fibrous tumor, which is excluded by a negative nuclear expression of STAT6 (Schweizer et al. 2013), and schwannoma, which has more distinctive Verocay bodies and a more diffuse S100 expression. The transitional variant, as the name implies, shows transitional as well as meningothelial and fibrous features, along with prominent psammoma bodies and whorls. When psammoma bodies are much more prevalent than tumor cells,

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the variant name changes to psammomatous; the psammoma bodies occasionally replace almost all tumor cells, with a confluent and irregular pattern of calcification and sometimes bone. The angiomatous variant is also known as vascular meningioma due to the predominance of medium-sized blood vessels over tumor cells, with variable wall thickness and hyalinization. Polysomy in chromosomes 5, 13, and 20 and aneuploidy are frequently detected in the angiomatous variant (Abedalthagafi et al. 2014). This variant is benign despite the frequent presence of degenerative nuclear atypia (Hasselblatt et al. 2004) on histopathology and significant adjacent brain edema on imaging studies (Osawa et al. 2013), both features of which are also seen in the microcystic variant (Paek et al. 2005). The histopathological picture of the microcystic variant constitutes a cobweb-like background formed by microcysts, which are created by cells with thin and long processes, and occasional macrocysts. The most prominent histopathological feature of the secretory variant is the pseudopsammoma bodies; these are PAS-positive eosinophilic secretions (also reactive to CEA antigen) produced by tumor foci with epithelial differentiation, which are also positive for CEA and cytokeratin. Elevated plasma CEA levels may be detected in recurrent tumors (Louis et al. 1991), and peritumoral edema is common (Tirakotai et al. 2006). A combination of mutations in TRAF7 and KLF4 K409Q is pathognomonic (Reuss et al. 2013) (Fig. 23.5). The lymphoplasmacyte-rich (or inflammationrich) variant is a quite rare and characterized by meningothelial hyperplasia in the context of a widespread and chronic inflammatory infiltration (macrophage-predominant) (Lal et al. 2014), sometimes associated with iron-deficiency anemia and hyperglobulinemia (Zhu et al. 2013). Finally, the metaplastic variant is characterized by mesenchymal differentiation (solo or combined components of lipid, cartilage, bone, etc.), which may not be true metaplasia as the variant name depicts (Colnat-Coulbois et al. 2008).

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23.3.2.4 Lipoma The benign histopathology of a lipoma resembles normal adipose tissue, with a lobular pattern, patchy fibrosis, myxoid changes, and calcifications (Budka 1974). Leptomyelolipomas of the lumbosacral region are commonly associated with a tethered cord. These lesions are most likely congenital malformations rather than true tumors and typically include intradural and subcutaneous portions; a fibrolipomatous stalk usually connects the lesion to the filum terminale or the spinal cord (DePowell et al. 2010). Conspicuous capillary networks with scattered fibrin thrombi are seen at the periphery of the angiolipoma variant, with variable proportions of vessels and adipose cells as well as interstitial fibrosis (Pirotte et al. 1998). 23.3.2.5 Teratoma By definition, teratomas consist of somatic tissue from 2 to 3 germ layers and are subclassified as mature or immature types. Mature teratomas are comprised exclusive adult-type tissues, whereas the presence of fetal tissues, even in relatively small proportions compared to mature tissue within the same tumor, changes the classification to immature. Mitotic activity is absent or rare in the mature type, while the immature type may demonstrate mitotes in the undifferentiated elements. In the mature type, fully differentiated ectodermal (epidermis, choroid plexus, CNS tissue), mesodermal (bone, cartilage, muscle, adipose tissue), and endodermal (glands, hepatic/pancreatic tissue) elements are typically encountered. The immature type contains primitive neuroectodermal elements and embryonic mesenchymal tissues.

23.4

Imaging and Radiologic Features

23.4.1 Intramedullary 23.4.1.1 Low-Grade Astrocytoma Low-grade astrocytomas are mostly located in the cervical cord. On magnetic resonance imaging (MRI), LGGs look different according to their grade. Pilocytic astrocytomas usually have a

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cystic portion and a mural nodule, which is the actual tumor, within the cyst walls. The tumor is hypointense on T1-weighted images (T1WI) and hyperintense on T2WI. Cysts are formed in about 60% of the cases (She et al. 2019). For LGGs (WHO II), the tumors are occasionally exophytic, with a portion of the tumor sometimes extending into the intradural extramedullary compartment. Peritumoral edema is present in approximately 40% of cases, intratumoral cysts are present in about 20%, and peritumoral cysts are present in 15% (Seo et al. 2010). In spinal cord astrocytomas, hemorrhage is a feature that can help differentiate it from ependymomas, since it is quite uncommon in the latter. The enhancing pattern has a variable degree of contrast enhancement but is typically patchy (Seo et al. 2010). For diffuse low-grade lesions, the tumor does not have defined margins in most cases, making gross-total resection (GTR) a very challenging-to-impossible surgical goal (Fig. 23.1).

23.4.1.2 Ependymoma Ependymomas are mostly located in the cervical cord and tend to appear isointense to hypointense in T1WI and hyperintense in T2WI. These tumors are usually located close to the central canal ependymal cells from which the tumor grows. There are also other radiographic parameters that may help to differentiate ependymomas from astrocytomas. Compared to astrocytomas, ependymomas are usually well-circumscribed with homogenous contrast enhancement, they are more likely to show signs for either recent or previous hemorrhage (hemosiderin staining with a hypointense rim showing as the ‘cap sign,’ which is seen in up to one-third of the cases (Koeller et al. 2000; Sun et al. 2003)), and they tend to present with cysts. Most of the cystic components are not tumoral but reactive in nature (Koeller et al. 2000; Patel et al. 1998). Ependymomas is also associated with peritumoral edema in most of the cases (Fig. 23.2.) 23.4.1.3 Hemangioblastoma Hemangioblastomas are mostly located in the thoracic cord and can mimic several other tumors of the spinal cord. The tumor is usually

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isointense or slightly hypointense on T1WI (Imagama et al. 2011). On T2WI, these tumors are usually hyperintense with possible flow voids, especially in large tumors, as well as a strong homogenous enhancement (Imagama et al. 2011). In large hemangioblastomas, however, heterogenicity is quite common (e.g., hypointense on T1WI, heterogenous intensity on T2WI, and heterogenous enhancement (Chu et al. 2001)). Hemangioblastomas are usually accompanied by a syrinx or significant cord edema (Chu et al. 2001), features that typically correlate with clinical signs and symptoms. With the advancement in MRI techniques, the use of angiography is less common, although previous studies showed that this tool is more sensitive for visualizing pathologic blood vessels and can help in finding feeding arteries and draining veins (Li et al. 2016).

23.4.1.4 Ganglioglioma Gangliogliomas are mostly located in the cervical cord. Ganglioglioma of the spinal cord tends to expand over several vertebral levels, has an eccentric location, and is associated with tumoral cysts in almost half of the cases (Koeller et al. 2000). The involvement of tumoral cysts is much more common in gangliogliomas than astrocytomas or ependymomas (Patel et al. 1998). On T1WI, mixed intensity as a result of the mixed cellular origin is almost a hallmark of ganglioglioma whenever this feature is visible (Patel et al. 1998). On T2WI, the usual picture is that of a hyperintensity without significant edema, yet again, the majority of the tumor demonstrates a heterogeneous signal. The enhancement pattern is usually patchy and reaches the surface of the cord, but there is no enhancement at all in about 15% of the cases (Patel et al. 1998). Scoliosis is a common finding in patients with large gangliogliomas (Fig. 23.3).

23.4.2 Intradural Extramedullary 23.4.2.1 Neurofibroma Neurofibromas are mostly located in the cervical spine. Neurofibromas can have the shape of

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dumbbell (like schwannomas and meningiomas), thus associated with enlargement of the intervertebral foramen on computed tomography (CT) and X-ray images. This feature is not unique to neurofibromas, however, and may be seen in other tumors too. On MRI, neurofibromas are usually isointense and potentially hypointense on T1WI and hyperintense on T2WI with the ‘target sign’ in some cases (outer rim is more hyperintense than tumor core on T2WI), which may be seen in schwannomas as well (Koeller and Shih 2019). The enhancement pattern tends to be heterogenous. These tumors usually encase rather than displace nerve roots, a feature that helps to differentiate them from schwannomas (Koeller and Shih 2019). In the case of plexiform neurofibromas, the classic description is that of a ‘bag of worms.’

23.4.2.2 Schwannoma Schwannomas usually arise from the dorsal roots, thus expanding the foramen as seen on CT or X-ray images. True involvement of the spinal cord is rare. On MRI, the tumor looks solid and hypointense-to-isointense on T1WI with clear margins, whereas it appears isointense-to-hyperintense on T2WI with homogenous enhancement in small lesions that sometimes become heterogenous in large tumors (Koeller and Shih 2019; Merhemic et al. 2016). The enhancement pattern is thought to correlate with the histological features of the tumor, where heterogeneous enhancement correlates with Antoni B tissue and hyperdense regions on CT correlates with Antoni A tissue (Lubner et al. 2007) (Fig. 23.4). 23.4.2.3 Meningioma The thoracic spine is a common location for spinal meningioma, where most of the tumors originate from the lateral walls of the spinal canal. When the meningioma arises from the ventral wall of the canal, it is usually located in the cervical spine (Koeller and Shih 2019). In few cases (about 5%), calcifications and a dural tail are noted on imaging (Merhemic et al. 2016). On MRI, the spinal meningioma is hypointenseto-isointense on T1WI and isointense-to-hyperintense on T2WI. These tumors typically have a striking enhancement (Fig. 23.5).

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23.4.2.4 Lipoma Intradural lipoma is usually located in the lumbar spine, as part of conus area or filum terminale area. Other locations are rare. Intradural lipomas typically distort the spinal cord and creates signs and symptoms as a consequence of local mass effect and cord compression. On MRI, spinal lipomas are hyperintense both on T1WI and T2WI and show no enhancement. The use of fat suppression sequences is helpful since the lipoma appears hyperintense on T2WI and hypointense on fat suppression images. Spinal cord abnormalities are very common, with almost all the cases (72–94.8%) showing low-lying conus secondary to lipomas involving the conus or filum terminale (Finn and Walker 2007; Warder and Oakes 1994). Other malformation-like arachnoid cysts, meningoceles, and syringomyelia may be found in correlation with the lipoma. 23.4.2.5 Teratoma Teratomas are rare intradural tumors. In about 37.5% of the cases, a congenital anomaly associated with the lesion can be found (anomalous vertebral fusion, spina bifida, congenital scoliosis, or split cord malformation) (Turan et al. 2016). MRI characteristics correlate with the pathology and may include different embryonal germ layers. Therefore, teratomas can be defined by having mixed signals with inhomogeneous intensities on T1WI and T2WI (Monajati et al. 1986; Moon et al. 2010).

23.5

Clinical Manifestations

The clinical presentation of patients with spinal cord tumors is highly variable and depends on the tumor size, growth rate, type, infiltrative, necrotic and hemorrhagic potential as well as the exact location within the spinal compartment. Unremitting, dull pain is the most commonly reported initial symptom. It may be localized, radiating or radicular in nature, which is often worse at night and in recumbent positions, possibly due to the diurnal variation of endogenous cortisol secretion and/or distension of the

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epidural venous plexus. Coughing, sneezing, and Valsalva may exacerbate the pain due to dural distension or compression by the expanding tumor (Parker et al. 1996). For intradural extramedullary tumors, most symptoms result from local mass effect that disturbs spinal cord tracts or adjacent nerve roots (Bydon and Gokaslan 2015). The symptoms may be related to involvement of a specific nerve root (e.g., Schwannoma). Symptomatic progression usually occurs over an indolent course. Sensory changes, motor weakness, and/or gait abnormalities commonly follow a period of neck or back pain. Children may also present with torticollis and delayed milestones; sphincter dysfunction is less common (Constantini et al. 1996). Careful history taking and detailed physical examination are the most valuable screening tools to roughly estimate the location of the tumor. Neck pain and stiffness and upper extremity paresthesia, numbness and/or weakness point toward a cervical lesion. Back pain, with or without lower extremity weakness, proprioceptive deficits, and/or numbness are typical of thoracic tumors. Upon flexion and extension of the neck, Lhermitte’s sign may be positive in both cervical and upper thoracic tumors. In children, progressive kyphoscoliosis, probably due to asymmetric dysfunction of the anterior horn cells and uneven activation of one side of the paraspinal muscles, is an early sign of thoracic lesions (Constantini et al. 1996; Jallo et al. 2003). Lumbar, conus medullaris, and cauda equina tumors typically present with low back pain, radiculopathy, lower limb weakness or paraplegia, saddle and lower limb sensory deficits, sphincter dysfunction, and/or neurogenic claudication secondary to spinal stenosis. In patients with multiple intradural tumors, such as in schwannomatosis or multiple inherited schwannomas, meningiomas, and ependymomas (MISME), it is crucial to take very thorough history and perform a dedicated physical examination, including evaluation of sensory level loss, since clinical findings significantly help the surgeon to decide which one of the tumors is the cause for the new or current symptoms.

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Unreasonable delay in the diagnosis is frequently due to delayed imaging or imaging of the wrong spinal level (Segal et al. 2012). For intradural extramedullary tumors with local mass effect, the delay is very common, where patients with active symptoms tend to wait for 6 months– 3 years before looking for medical advice (Klekamp and Samii 1999; Koeller and Shih 2019; Solero et al. 1989). Therefore, it is imperative to carefully evaluate the ascending and descending pathways of the spinal cord for any subtle deficits and not to assume that an adult with myelopathic signs and symptoms is most likely suffering from ‘only’ canal stenosis. Clinical scores such as the McCormick (McCormick et al. 1990), Frankel (Frankel et al. 1969), and Klekamp and Samii (Klekamp and Samii 1993) scores are useful tools to document the neurologic function and compare the preoperative and postoperative functional status of patients with spinal cord tumors.

23.6

Therapeutic Approaches

23.6.1 Surgical Intervention The ultimate goal of surgical intervention in the management of spinal cord tumors is to achieve maximal safe resection. Utilizing available technologies, including but not limited to advanced preoperative imaging, surgical microscope, microsurgical instruments, ultrasonic aspirator, and intraoperative neuromonitoring (IONM), has a cumulative added benefit in achieving this goal, and this has been demonstrated by comparing current to historical morbidity and mortality outcomes. Surgical intervention remains the mainstay of management of symptomatic and radiographically enlarging spinal tumors. A conservative approach is usually adopted and considered more appropriate for clinically silent and radiographically stable lesions. In some cases, however, surgical intervention is recommended for the sole purpose of obtaining a biopsy, especially when malignancy is highly suspected; some tumor debulking may be performed concurrently as

long as it is deemed safe to do so. In such cases, tissue diagnosis may be necessary to reveal the molecular profile of the tumor and tailor adjuvant therapy accordingly. Surgical intervention goals include obtaining a diagnosis, alleviating the mass effect on spinal cord tissue, and in some cases, decrease the likelihood for malignant transformation or tumor growth, which may further complicate future treatment of the patient. Use of an osteoplastic laminoplasty, which allows for re-affixation of the posterior bony elements following intradural tumor removal, has been shown to decrease the incidence of postoperative spinal fusion, as well as decrease the rate of CSF leak across different age groups (McGirt et al. 2008b, 2010). For intradural tumors that are not malignant, the exact location (intramedullary versus extramedullary) affects the likelihood of GTR. For meningiomas, schwannomas, and neurofibromas, the best treatment is complete resection. For the low-grade intramedullary tumors, several publications reported favorable results with resection (Constantini et al. 2000; Kutluk et al. 2015; McCormick et al. 1990; McGirt et al. 2008a). Spinal cord ependymomas typically demonstrate clear surrounding cleavage planes that can assist in achieving GTR. GTR is also feasible in lowgrade astrocytomas that are capsulated with clear margins. On the other hand, diffuse low-grade astrocytomas tend to have mixed margins of the tumor and normal spinal cord tissue, which renders GTR dangerous. The use of intraoperative monitoring is crucial to aid the surgeon in performing and achieving maximal safe resection. As mentioned earlier, complete surgical resection is the goal of surgery in order to decrease the likelihood of recurrence, and GTR is best accomplished in intradural extramedullary tumors. In cases where the tumor is more ventrally located, however, achieving complete resection can be challenging. Through the posterior approach, releasing the dentate ligament (sometimes in the adjacent levels as well) can provide the essential surgical corridor without causing significant retraction injury to the spinal cord. For dural-based or involved tumors, such as meningiomas, excision of the involved dura can

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be very challenging because of the subsequent need for water-tight dural closure in order to prevent cerebrospinal fluid (CSF) leak. Therefore, GTR may not be attainable in every patient, and serial postoperative monitoring with imaging is necessary. In some cases of intradural lipomas, follow-up and conservative management without surgical intervention are preferred in patients with no relevant symptoms and signs. Whenever a surgical course is chosen, the surgeon must strongly consider the optimal goal of complete removal; this goal, however, is not feasible in many cases because of adipocyte tissue forming significant attachments to the surrounding neural tissue. During development, spinal cord lipomas may even replace normal neuronal tissue instead of just compression and tethering; therefore, aggressive resection has a greater chance of permanent neurologic injury (Meher et al. 2017). For intramedullary tumors, if the goal of surgery is safe maximal resection and not just obtaining a biopsy, the dural opening should include the two poles of the tumor. The use of neuromonitoring, including D-wave, SSEP, and MEP, is essential for achieving safe maximal resection. One should not attempt to dissect the tumor from the normal spinal cord tissue before debulking the core of the tumor. Any significant retraction or manipulation of the cord in order to achieve en bloc resection may lead to permanent deficit. The myelotomy should be on top of the core of the tumor and the area where the tumor is closest to the surface. There is no need to extend the myelotomy over the poles of the tumor (Fig. 23.6).

23.6.2 Chemotherapy and Radiotherapy The use of adjuvant treatment for spinal cord tumors has a debatable efficacy. For intramedullary tumors, radiation therapy is controversial. It is usually recommended for spinal cord ependymomas or low-grade astrocytomas whenever GTR is not feasible and the remnant of the tumor is either growing or the patient

597

becomes symptomatic. Most authors agree that there is no benefit in radiation therapy (RT) after GTR of spinal cord ependymoma (Brotchi and Fischer 1998; Chang et al. 2002; Tarapore et al. 2013). There is a general agreement that for lowgrade ependymomas, there is no role for RT after GTR and a very questionable role after sub-total resection (STR) and the discussion about RT versus possible re-resection ensues (Wostrack et al. 2018); RT was mainly effective for local tumor control (Isaacson 2000). The use of proton beam therapy was shown to have promising results in progression-free survival (PFS) and even overall survival (OS); yet, field expertise and long-term follow-up are still missing (Amsbaugh et al. 2012). The use of chemotherapy is even more questionable for this group of tumors; it is best described as experimental and is often chosen after everything else has failed. The experience of using chemotherapy for ependymoma is scant, and so far, the results are not promising (Chamberlain 2002a, b). For spinal cord low-grade astrocytomas, achieving GTR is quite challenging in many cases; however, the prognosis is usually very good, and the use of adjuvant treatment is again very questionable. In a recent publication, it was found that many patients suffered from significant post-adjuvant treatment morbidity (Carey et al. 2019); thus, taking into consideration the relatively good natural course of these pathologies, the use of either chemotherapy or RT should be very carefully considered and utilized only when other treatment options are not possible. The use of adjuvant radiotherapy or even RT as a sole treatment for spinal cord hemangioblastoma was described in the literature. There is a consensus that the best treatment for this tumor is complete surgical resection (Roonprapunt et al. 2001). Yet, there is a debate regarding the use of stereotactic radiosurgery (SRS) in cases of VHL, where multiple lesions may be present (Bridges et al. 2017; Li et al. 2016). In the past, conventional RT was used for spinal cord hemangioblastoma when surgical extirpation could not be achieved in a safe manner (Park and Chang 2013). In recent years,

598

M. H. A. Noureldine et al.

Fig. 23.6 Treatment algorithm

the use of SRS as an alternative radiation method in these cases is growing rapidly with supportive results (Bridges et al. 2017; Liebenow et al. 2019). For intradural extramedullary spinal tumors, the mainstay of treatment is surgery with the goal of complete removal when feasible. The use adjuvant therapy in these cases was published in the past with use of stereotactic body radiation therapy (SBRT) for meningiomas or schwannomas that are not amenable to surgical resection. In recent years and with the growing interest and supportive findings of SBRT treatment for spinal metastases, there is a much more literature data about the use of SBRT in patients with intradural extramedullary spinal tumors when surgery is not an option. The main benefit of SBRT in these cases is local control (70–100% in different series), with relatively high pain control (around 80%) (Kalash et al. 2018).

23.7

Follow-Up and Prognosis

Most patients have a good prognosis. For intramedullary tumors, patients with ependymomas tend to do well relative to the extent of resection. Recently published data suggest that intramedullary ependymomas have an OS of 98% at 5 years, 87% at 10 years, and 53% at 15 years (Abdullah et al. 2015). There is a clear consensus that surgery is the main treatment for these tumors; thus, achieving GTR was found to be the most important prognostic factor in decreasing the likelihood of recurrence (Brotchi et al. 2006; Constantini et al. 2000; Garcés-Ambrossi et al. 2009; Klekamp 2015; Svoboda et al. 2018). Considering the relatively small amount of supportive data regarding adjuvant therapy in spinal cord ependymomas, it is recommended to consider a redo surgery when needed. For spinal cord

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Benign Spinal Tumors

astrocytomas, there is a significant difference between high-grade and low-grade tumors in terms of prognosis. The 1- and 5-year survival rates for pediatric patients with low-grade spinal cord astrocytomas were reported at 98.3 and 97.2% according to some recent publications (Luksik et al. 2017). For mixed populations, the results are less favorable with a 5-year OS rate of 82 and 70% for grade 1 and grade 2 spinal cord astrocytomas, respectively (Milano et al. 2010). For spinal cord hemangioblastomas, the treatment as mentioned earlier is mainly surgical, while the use of SRS is still relatively rare (Westwick et al. 2016). In a recent Surveillance, Epidemiology, and End Results (SEER) review, it was noted that survival among these patients is very good. The only risk factor associated with mortality was age >75 years, with a general mortality of 9% at 10year follow-up (Westwick et al. 2016). For intradural extramedullary tumors, the survival is usually very good due to the natural history of the tumors. Therefore, a focused discussion that is solely based on oncology or surgical results does not provide a broad perspective about prognosis and outcomes of these pathologies. For spinal meningiomas, it was found that certain parameters, such as surgery involving an anterior/anterolateral location of dural attachment, surgery performed for a recurrent tumor, neurologic deficit on a presentation involving the sphincter function, and bad preoperative functional status, are associated with worse prognosis (Raco et al. 2017). The functional status of the patient after surgery is more significant as a prognostic parameter than the actual oncological status for spinal low-grade meningiomas. Recent literature data show that the recurrence rate varies from 0 to 20%, and functional improvement after resection of spinal meningioma can be found in more than 90% of the cases (Maiti et al. 2016; Roux et al. 1996; Sandalcioglu et al. 2008). Nerve sheath tumors (schwannomas, neurofibromas) have good prognoses and low recurrence rates when GTR is achieved. According to some series, GTR is possible in more than 95% of cases, and the recurrence rate is less than 5% (Fernandes et al. 2014). Intradural lipomas tend to recur when GTR is not achieved. The patients

599

and their family should be counseled that reoperation is a valid course of treatment if the tumor recurs (adipocyte hyperplasia) or to detether the cord (Pang et al. 2013). For intradural teratomas, the main treatment is tumor resection to mitigate the mass effect, with a surgical goal of achieving GTR if possible. Like with other intradural tumors that are not malignant, the likelihood of recurrence is extremely rare after GTR. Yet, the potential of achieving safe GTR is known to be only around 50%, which led many of these cases to be considered for adjuvant therapy (Ak et al. 2006; Nonomura et al. 2002; Turan et al. 2016).

23.8

Conclusion

Spinal intradural benign tumors are rare CNS tumors that usually demand surgical excision with GTR as the primary treatment goal. In cases where safe GTR cannot be achieved, the treatment modality is usually close follow-up or the use of adjuvant treatment such as RT. The clinical results are usually favorable in terms of survival, mainly because of the natural history of these tumors; therefore, the functional outcome should be the main outcome parameter in the management of these tumors.

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Liebenow B, Tatter A, Dezarn W, Isom S, Chan M, Tatter S (2019) Gamma Knife stereotactic radiosurgery favorably changes the clinical course of hemangioblastoma growth in von Hippel-Lindau and sporadic patients. J Neurooncol 142:471–478 Liu A, Jain A, Sankey E, Jallo G, Bettegowda C (2016) Sporadic intramedullary hemangioblastoma of the spine: a single institutional review of 21 cases. Neurol Res 38:205–209 Longatti P, Basaldella L, Orvieto E, Dei Tos AP, Martinuzzi A (2006) Aquaporin 1 expression in cystic hemangioblastomas. Neurosci Lett 392:178–180 Louis D, Hamilton A, Sobel R, Ojemann R (1991) Pseudopsammomatous meningioma with elevated serum carcinoembryonic antigen: a true secretory meningioma. Case Report J Neurosurg 74:129–132 Louis DN, Ramesh V, Gusella JF (1995) Neuropathology and molecular genetics of neurofibromatosis 2 and related tumors. Brain Pathol 5:163–172 Louis D, Ohgaki H, Wiestler O, Cavenee W (2016) WHO Classification of Tumours of the Central Nervous System vol 1. Revised 4th edition edn. International Agency for Research on Cancer (IARC), Lyon, France Lubner M, Perrin R, Lämmle M, Perry A (2007) Neuropathology for the neuroradiologist: Antoni A and Antoni B tissue patterns. AJNR Am J Neuroradiol 28:1633–1638 Luksik A, Garzon-Muvdi T, Yang W, Huang J, Jallo G (2017) Pediatric spinal cord astrocytomas: a retrospective study of 348 patients from the SEER database. J Neurosurg Pediatr 19:711–719 Luyken C, Blümcke I, Fimmers R, Urbach H, Wiestler OD, Schramm J (2004) Supratentorial gangliogliomas: histopathologic grading and tumor recurrence in 184 patients with a median follow-up of 8 years. Cancer Interdisc Int J Am Cancer Soc 101:146–155 Maertens O et al (2006) Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum Mutat 27:1030–1040 Maiti T, Bir S, Patra D, Kalakoti P, Guthikonda B, Nanda A (2016) Spinal meningiomas: clinicoradiological factors predicting recurrence and functional outcome. Neurosurg Focus 41:E6–E6 Mawrin C, Perry A (2010) Pathological classification and molecular genetics of meningiomas. J Neurooncol 99:379–391 McCormick P, Torres R, Post K, Stein B (1990) Intramedullary ependymoma of the spinal cord. J Neurosurg 72:523–532 McGirt M, Chaichana K, Atiba A, Attenello F, Woodworth G, Jallo G (2008a) Neurological outcome after resection of intramedullary spinal cord tumors in children. Childs Nerv Syst 24:93–97 McGirt M, Chaichana K, Atiba A, Bydon A, Witham T, Yao K, Jallo G (2008b) Incidence of spinal deformity after resection of intramedullary spinal cord tumors in

603 children who underwent laminectomy compared with laminoplasty. J Neurosurg Pediatr 1:57–62 McGirt M et al (2010) Short-term progressive spinal deformity following laminoplasty versus laminectomy for resection of intradural spinal tumors: analysis of 238 patients. Neurosurgery 66:1005–1012 Meher S, Tripathy L, Jain H, Basu S (2017) Nondysraphic cervicomedullary intramedullary lipoma. J Craniovertebral Junction Spine 8:271–274 Mehta G, Asthagiri A, Bakhtian K, Auh S, Oldfield E, Lonser R (2010) Functional outcome after resection of spinal cord hemangioblastomas associated with von Hippel-Lindau disease. J Neurosurg Spine 12:233– 242 Memoli VA, Brown EF, Gould VE (1984) Glial FibriUary acidic protein (GFAP) immunoreactivity in peripheral nerve sheath tumors. Ultrastruct Pathol 7:269–275 Merhemic Z, Stosic-Opincal T, Thurnher M (2016) Neuroimaging of spinal tumors. Magn Reson Imaging Clin N Am 24:563–579 Milano M, Johnson M, Sul J, Mohile N, Korones D, Okunieff P, Walter K (2010) Primary spinal cord glioma: a surveillance, epidemiology, and end results database study. J Neurooncol 98:83–92 Minehan KJ, Shaw EG, Scheithauer BW, Davis DL, Onofrio BM (1995) Spinal cord astrocytoma: pathological and treatment considerations. J Neurosurg 83:590–595 Monajati A, Spitzer RM, Wiley J, Heggeness L (1986) MR imaging of a spinal teratoma. J Comput Assist Tomogr 10:307–310 Moon H, Shin B, Kim J, Kwon T, Chung H, Park Y (2010) Adult cervical intramedullary teratoma: first reported immature case. J Neurosurg Spine 13:283– 287 Murakami T et al (2013) Intramedullary spinal cord ganglioglioma presenting as hyperhidrosis: unique symptoms and magnetic resonance imaging findings: case report. J Neurosurg Spine 18:184–188 Nonomura Y, Miyamoto K, Wada E, Hosoe H, Nishimoto H, Ogura H, Shimizu K (2002) Intramedullary teratoma of the spine: report of two adult cases. Spinal Cord 40:40–43 Osawa T, Tosaka M, Nagaishi M, Yoshimoto Y (2013) Factors affecting peritumoral brain edema in meningioma: special histological subtypes with prominently extensive edema. J Neurooncol 111:49–57 Otero JJ, Rowitch D, Vandenberg S (2011) OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms. J Neurooncol 104:423–438 Paek S et al. (2005) Microcystic meningiomas: radiological characteristics of 16 cases. Acta Neurochir (Wien) 147:965–972; discussion 972 Pajtler KW et al (2015) Molecular classification of ependymal tumors across all CNS compartments,

604 histopathological grades, and age groups. Cancer Cell 27:728–743 Pang D, Zovickian J, Wong S, Hou Y, Moes G (2013) Surgical treatment of complex spinal cord lipomas. Childs Nerv Syst 29:1485–1513 Park H, Chang J (2013) Review of stereotactic radiosurgery for intramedullary spinal lesions. Korean J Spine 10:1–6 Parker A, Robinson R, Bullock P (1996) Difficulties in diagnosing intrinsic spinal cord tumours. Arch Dis Child 75:204–207 Patel U, Pinto R, Miller D, Handler M, Rorke L, Epstein F, Kricheff I (1998) MR of spinal cord ganglioglioma. AJNR Am J Neuroradiol 19:879–887 Patil S et al (2008) Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol 18:517–519 Pekmezci M et al (2015) Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas. Mod Pathol 28:187–200 Perry A, Roth KA, Banerjee R, Fuller CE, Gutmann DH (2001) NF1 deletions in S-100 protein-positive and negative cells of sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. Am J Pathol 159:57–61 Pirotte B, Krischek B, Levivier M, Bolyn S, Brucher J, Brotchi J (1998) Diagnostic and microsurgical presentation of intracranial angiolipomas. Case Rep Rev Lit J Neurosurg 88:129–132 Prayson RA, Khajavi K, Comair YG (1995) Cortical architectural abnormalities and MIB1 immunoreactivity in gangliogliomas: a study of 60 patients with intracranial tumors. J Neuropathol Exp Neurol 54:513–520 Preusser M, Laggner U, Haberler C, Heinzl H, Budka H, Hainfellner J (2006) Comparative analysis of NeuN immunoreactivity in primary brain tumours: conclusions for rational use in diagnostic histopathology. Histopathology 48:438–444 Preusser M, Budka H, Rössler K, Hainfellner J (2007) OLIG2 is a useful immunohistochemical marker in differential diagnosis of clear cell primary CNS neoplasms. Histopathology 50:365–370 Proescholdt MA et al (2005) Expression of hypoxiainducible carbonic anhydrases in brain tumors. Neuro Oncol 7:465–475 Pummi KP, Aho HJ, Laato MK, Peltonen JT, Peltonen SA (2006) Tight junction proteins and perineurial cells in neurofibromas. J Histochem Cytochem 54:53–61 Raco A, Pesce A, Toccaceli G, Domenicucci M, Miscusi M, Delfini R (2017) Factors leading to a poor functional outcome in spinal meningioma surgery: remarks on 173 cases. Neurosurgery 80:602–609

M. H. A. Noureldine et al. Reuss DE et al (2013) Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125:351–358 Ribeiro S et al (2013) Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell reports 5:126–136 Rodriguez FJ et al (2007) Ependymomas with neuronal differentiation: a morphologic and immunohistochemical spectrum. Acta Neuropathol 113:313–324 Roonprapunt C, Silvera V, Setton A, Freed D, Epstein F, Jallo G (2001) Surgical management of isolated hemangioblastomas of the spinal cord. Neurosurgery 49:321–327; discussion 327–328 Rouleau GA et al (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515–521 Roux F, Nataf F, Pinaudeau M, Borne G, Devaux B, Meder J (1996) Intraspinal meningiomas: review of 54 cases with discussion of poor prognosis factors and modern therapeutic management. Surg Neurol 46:458–463; discussion 463–454 Sahm F et al (2013) AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry. Acta Neuropathol 126:757–762 Sainz J, Huynh DP, Figueroa K, Ragge NK, Baser ME, Pulst S-M (1994) Mutations of the neurofibromatosis type 2 gene and lack of the gene product in vestibular schwannomas. Hum Mol Genet 3:885–891 Samii M, KleKamp J (2006a) Extramedullary tumors surgery of spinal tumors, first edition, vol 4, New York, Springer, Berlin Heidelberg, pp 144–312 Samii M, KleKamp J (2006b) Intratramedullary tumors surgery of spinal tumors, first edition, vol 3, New York, Springer Berlin Heidelberg, pp 20–131 Sandalcioglu I, Hunold A, Müller O, Bassiouni H, Stolke D, Asgari S (2008) Spinal meningiomas: critical review of 131 surgically treated patients. Eur Spine J 17:1035–1041 Sawin PD, Theodore N, Rekate HL (1999) Spinal cord ganglioglioma in a child with neurofibromatosis Type 2: case report and literature review. J Neurosurg Spine 90:231–233 Schindler G et al (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405 Schmitz U, Mueller W, Weber M, Sevenet N, Delattre O, von Deimling A (2001) INI1 mutations in meningiomas at a potential hotspot in exon 9. Br J Cancer 84:199–201 Schweizer L et al (2013) Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol 125:651–658

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Segal D, Lidar Z, Corn A, Constantini S (2012) Delay in diagnosis of primary intradural spinal cord tumors. Surg Neurol Int 3:52–52 Seizinger BR, Martuza RL, Gusella JF (1986) Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma. Nature 322:644–647 Seo H, Kim J, Lee D, Lee Y, Suh S, Kim S, Na D (2010) Nonenhancing intramedullary astrocytomas and other MR imaging features: a retrospective study and systematic review. AJNR Am J Neuroradiol 31:498– 503 Shankar GM et al (2014) Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun 2:167 She D-J, Lu Y-P, Xiong J, Geng D-Y, Yin B (2019) MR imaging features of spinal pilocytic astrocytoma. BMC Med Imaging 19:5 Shuangshoti S, Panyathanya R (1974) Neural neoplasms in Thailand: a study of 2897 cases. Neurology 24:1127–1134 Smith MJ (2015) Germline and somatic mutations in meningiomas. Cancer Genet 208:107–114 Sobel RA, Wang Y (1993) Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases. J Neuropathol Exp Neurol 52:106– 113 Solero C, Fornari M, Giombini S, Lasio G, Oliveri G, Cimino C, Pluchino F (1989) Spinal meningiomas: review of 174 operated cases. Neurosurgery 25:153– 160 Squire JA et al (2001) Molecular cytogenetic analysis of glial tumors using spectral karyotyping and comparative genomic hybridization. Mol Diagn 6:93–108 Storlazzi CT, Von Steyern FV, Domanski HA, Mandahl N, Mertens F (2005) Biallelic somatic inactivation of the NF1 gene through chromosomal translocations in a sporadic neurofibroma. Int J Cancer 117:1055–1057 Suh Y-L et al (2002) Tumors of the central nervous system in Korea a multicenter study of 3221 cases. J Neurooncol 56:251–259 Sun B, Wang C, Wang J, Liu A (2003) MRI features of intramedullary spinal cord ependymomas. J Neuroimaging 13:346–351 Svoboda N, Bradac O, Benes V (2018) Intramedullary ependymoma: long-term outcome after surgery. Acta Neurochir (wien) 160:439–447 Tarapore P et al (2013) Pathology of spinal ependymomas: an institutional experience over 25 years in 134 patients. Neurosurgery 73:247–255; discussion 255 Thomas L et al (2012) Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas. Eur J Hum Genet 20:411–419 Tirakotai W, Mennel H, Celik I, Hellwig D, Bertalanffy H, Riegel T (2006) Secretory meningioma: immunohistochemical findings and evaluation of mast cell infiltration. Neurosurg Rev 29:41–48 Trofatter JA et al (1993) A novel moesin-, ezrin-, radixinlike gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791–800

605 Turan N, Halani S, Baum G, Neill S, Hadjipanayis C (2016) Adult intramedullary teratoma of the spinal cord: a case report and review of literature. World Neurosurg 87(661):e623-630 Vege KDS, Giannini C, Scheithauer BW (2000) The immunophenotype of ependymomas. Appl Immunohistochem Mol Morphol 8:25–31 Wacker MR, Cogen PH, Etzell JE, Daneshvar L, Davis RL, Prados MD (1992) Diffuse leptomeningeal involvement by a ganglioglioma in a child: case report. J Neurosurg 77:302–306 Wanebo JE, Lonser RR, Glenn GM, Oldfield EH (2003) The natural history of hemangioblastomas of the central nervous system in patients with von Hippel— Lindau disease. J Neurosurg 98:82–94 Warder D, Oakes W (1994) Tethered cord syndrome: the low-lying and normally positioned conus. Neurosurgery 34:597–600; discussion 600 Warren C, James L, Ramsden R, Wallace A, Baser M, Varley J, Evans D (2003) Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridisation. J Med Genet 40:802–806 Weiss S, Langloss J, Enzinger F (1983) Value of S-100 protein in the diagnosis of soft tissue tumors with particular reference to benign and malignant Schwann cell tumors. Lab Invest 49:299–308 Wellenreuther R et al (1995) Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol 146:827–832 Westwick H, Giguère J, Shamji M (2016) Incidence and prognosis of spinal hemangioblastoma: a surveillance epidemiology and end results study. Neuroepidemiology 46:14–23 Wizigmann-Voos S, Plate K (1996) Pathology, genetics and cell biology of hemangioblastomas. Histol Histopathol 11:1049–1061 Wolf HK, Müller MB, Spänle M, Zenther J, Schramm J, Wiestler OD (1994) Ganglioglioma: a detailed histopathological and immunohistochemical analysis of 61 cases. Acta Neuropathol 88:166–173 Wostrack M et al (2018) Spinal ependymoma in adults: a multicenter investigation of surgical outcome and progression-free survival. J Neurosurg Spine 28:654– 662 Yang R et al (2018) Pediatric low-grade gliomas can be molecularly stratified for risk. Acta Neuropathol 136:641–655 Yin XL, Hui ABY, Pang JCS, Poon WS, Ng HK (2002) Genome-wide survey for chromosomal imbalances in ganglioglioma using comparative genomic hybridization. Cancer Genet Cytogenet 134:71–76 Yuh W, Chung C, Park S, Kim K, Lee S, Kim K (2018) Spinal cord subependymoma surgery: a multi-institutional experience. J Korean Neurosurg Soc 61:233– 242 Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL (2000) Expression of hypoxiainducible factor 1α in brain tumors: association with

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Other Less Prevalent Tumors of the Central Nervous System Jody Filippo Capitanio and Pietro Mortini

Abstract

The presented tumors in this chapter are somewhat very rare, and their management is still debated due to the scarcity of information about their cell of origin, behavior, and biology. Treatment options are still limited, but we are confident that in the near future by discovering the genetic and biological mechanisms that drive tumor growth we will be able to offer new target therapies that should be flanked by surgery, radiotherapy, and chemotherapeutic agents actually in use. The purpose of this chapter is to highlight the most important known characteristics of these tumors offering the chance to recognize the disease and then offer the best opportunity for treatment to patients. The 5th WHO Classification Central Nervous System features substantial changes by moving further to advance the role of molecular diagnostics in CNS tumor classification, but remaining rooted in other established approaches to tumor characterization, including histology and immunohistochemistry, and probably, the category of

J. F. Capitanio . P. Mortini (&) Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy e-mail: [email protected] J. F. Capitanio e-mail: capitanio.jodyfi[email protected]

many tumors will change. Here, the most important characteristics of each neoplasm are summarized focusing on genetic mechanisms and molecular pathways, their histopathologic footprints, signs and symptoms, radiologic features, therapeutic approaches, and prognosis as well as follow-up protocols. Schematic classifications are also presented to offer a better understanding of the pathology. Keywords

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Rare CNS tumors Rare diseases Rare entities Rare neoplasm

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24.1

.

Introduction

Approximately, 150 different brain tumors have been described to date; usually, they are divided into 2 main groups defined as primary and metastatic. Primary brain tumors derive from the brain tissues or surrounding environments. Based on their cell of origin, primary brain tumors are classified as glial or non-glial. While the glial tumors are composed of glial cells, non-glial tumors originate from other brain structures including nerves, blood vessels, and glands though many other tumors that belong to progenitor cells are not identified yet (Ostrom et al. 2020). The tumor behavior is the general root for categorizing tumors as benign or malignant. There is a

© Springer Nature Switzerland AG 2023 N. Rezaei and S. Hanaei (eds.), Human Brain and Spinal Cord Tumors: From Bench to Bedside. Volume 2, Advances in Experimental Medicine and Biology 1405, https://doi.org/10.1007/978-3-031-23705-8_24

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high rate of mortality and morbidity caused by brain tumors, as they comprise the 8th most common tumors in adults over 40 years of age. Besides, in male patients between 40 and 59 years, they are the 5th leading cause of cancer-related death and the 3rd most common cancer overall in individuals aged 15–39 years (Hornick and Fletcher 2005). Among adolescents (15–19 years old), brain tumors are the most common form of cancer, accounting for 21% of diagnoses in this age group each year. The incidence rates for brain tumors are highest among individuals older than 85 years old, and lowest among children and adolescents between 0 and 19 years of age (Hornick and Fletcher 2005). Dissimilarly from other types of cancer, primary brain tumors are not staged but are classified according to the WHO Classification of Tumors of the Central Nervous System, which assigns a “grade” of I–IV (now 1– 4), based on their clinical behavior (Louis et al. 2021). The use of Arabic numbers for grading CNS tumors, as well as other systems, has been highly proposed in the 5th edition of WHO CNS tumor classification. Molecular parameters have been added since they add value to histological findings in assigning a grade (Louis et al. 2021). Grade 1 tumors are typically less aggressive and curable though; grade 4 tumors are the highest and most malignant grade of tumors. CNS tumor classification has long been based exclusively on histological findings supported by subsidiary tissue-based tests (immunohistochemical, ultrastructural). Since 2016, molecular biomarkers have gained importance in providing both ancillary and defining diagnostic information. The 5th edition of WHO CNS tumor classification incorporates numerous molecular changes with clinicopathologic utility that are important for the accurate classification of tumors. Unfortunately, all classifications are deficient, reflecting the state of understanding in a field at a particular time as well as the interpretations of that information by limited numbers of experts. No important updates and innovations regarding rare tumors are present except that the term “hemangiopericytoma” has been retired, with the tumor now termed only solitary fibrous tumor (rather than the hybrid term “Solitary fibrous tumor/

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hemangiopericytoma” used in the 2016 CNS classification) (Louis et al. 2021). Among the rare diseases of the CNS, there exists some tumors that are rather characteristic for their localization, symptoms, and radiological appearance. In some of these cases, the family history should help drive the final diagnosis as well. Here, we present a brief overview of some of the most characteristics and rare neoplasms of the CNS.

24.2

Neurenteric Cyst and Bronchogenic Cyst

24.2.1 Background and Epidemiology Neurenteric cysts account for less than 1% of CNS tumors, which could be a result of incomplete resorption of the neurenteric canal. In the 3rd week of gestation, inappropriate splitting of the embryonic notochordal plate and presumptive endoderm may result in the development of these cysts. As these cysts develop, some abnormal structures may be the result including the persistence of the primitive neurenteric canal, notochordal anomalies, or intradural adhesions. Neurenteric cysts are mainly located in the spine and are often associated with vertebral anomalies such as Klippel–Feil syndrome, hemivertebrae, and spina bifida. In the majority of cases, intracranial cysts are infratentorial and located near the midline (Hingwala et al. 2013) (Baek et al. 2018).

24.2.2 Genetics, Immunology, and Molecular Biology It does not appear that neurenteric and bronchogenic cysts share any common pathways with congenital defects of neural tube closure that are among the commonest and most severe disorders of the fetus and newborn. As a matter of fact, these tumors are so rare that no genetic mutation has been described for them yet. Probably, they are embryologic remnants incompletely adsorbed during the embryonal development of the fetus (Mehta et al. 1984; Nunes Dias et al. 2019).

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24.2.3 Histopathology and Morphology Neurenteric cysts are classified according to the characteristics of the cyst wall, including: (1) Type A cysts are surrounded by a single or pseudostratified layer cyst wall which could be covered by either ciliated or non-ciliated cuboidal or columnar epithelium, (2) Type B cysts also have connective tissue components, glands, smooth muscles, lymphoid tissue, or nerve ganglion, and (3) Type C cysts may have glial elements like ependymal cells in the wall. Microscopic examination of the cyst wall could show the presence or absence of ciliated columnar epithelium, columnar cell, goblet cells or squamous epithelium, or mucous glands as well. The diagnostic root of neuroepithelial/neurenteric cysts is based on the location and imaging characteristics of these lesions (Hingwala et al. 2013).

24.2.4 Imaging and Radiologic Features These cysts are always well-defined and extraaxial. They are typically extended from the midline into the posterior fossa in the interpeduncular and prepontine cisterns. Almost all cysts are oblong, well-defined, and have smooth regular margins. Cysts are rarely multilobulated with smooth, scalloped margins. Dimensions range enormously. On MRI sequences, the signal intensity depends on the cyst contents. While neurenteric cysts might be ISO- to mildly hyperintense on T1-weighted images, their proteinaceous contents make them hyperintense on T2-weighted images. On the other hands, the dense and thickened contents appear with hypointense signals on T2WI. On T1 images, these lesions appear as hyperintense oval, multilobulated lesions located at prepontine, or premedullary cites. The cysts are not often calcified and do not enhance with contrast. Also, on the FLAIR image, these lesions demonstrate facilitated diffusion and low suppression. Intracranial neurenteric cysts should be differentiated from

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other intracranial cystic lesions (Hingwala et al. 2013). CSF intensity cysts are arachnoid cysts, epidermoid cysts, and parasitic cysts, while other conditions such as epidermoids, dermoid cysts, lipomas, and other endodermal cysts like Rathkes or colloid cysts should be misled (Baek et al. 2018) (Figs. 24.1, 24.2 and 24.3).

24.2.5 Clinical Manifestations The presenting symptoms are typically headache and neck pain. Other symptoms include quadriparesis, cranial nerves disturbances, and gait instability, exceptionally they present with intracranial hypertension and its collateral symptoms. The most common presentations include increased intracranial pressure and cranial nerves deficits or anterior midbrain and spinal cord disturbances from direct compression (Baek et al. 2018).

24.2.6 Therapeutic Approaches Total resection is curative. Because cyst should be both intra- and extradural, the extradural space should be explored before dura opening since aseptic meningitis could be a complication of cyst puncture. As the cyst wall is often unstable and some of the cells could drop into the cyst, collection of cyst fluid might help in histopathologic diagnosis (Nunes Dias et al. 2019).

24.2.7 Follow-Up and Prognosis Prognosis is almost always favorable since the cyst does not manifest malignant evolution. Once cysts are removed, they do not tend to recur; the risk of recurrence exists just in case of mere cyst fenestration although rarely reported. Long-term follow-up is recommended just in case of simple fenestration or in case aseptic meningitis develops. Non-contrasted MRI is a valid option for those patients that require control through time.

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Fig. 24.1 Axial, coronal and sagittal T1 contrast enhanced Magnetic Resonance Imaging (MRI) of a prepontine neurenteric cyst located the posterior fossa

Fig. 24.2 Coronal and axial T2 images of neurenteric cyst

Fig. 24.3 T1 and FLAIR axial images of a median prepontine neurenteric cyst

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24.3

Lhermitte–Duclos Disease (Dysplastic Gangliocytoma—WHO Grade 1)

24.3.1 Background and Epidemiology Lhermitte–Duclos disease (LDD) or dysplastic gangliocytoma is an extremely rare lesion, often benign, which is comprised of dysplastic ganglion cells in the cerebellum. The first description of this entity dates back to Lhermitte and Duclos in 1920. The exact etiology of this lesion is still debated, whether it is a neoplasm, malformation, or hamartoma. The latest World Health Organization (WHO) classification categorizes Lhermitte–Duclos disease as a neuronal and mixed neuronal-glial tumor (WHO grade I disease). The association of dysplastic gangliocytoma and multiple hamartomas is now recognized as part of an autosomal dominant familial disorder called Cowden syndrome. Cowden syndrome is characterized by mucocutaneous lesions and other systemic hamartomatous lesions associated with increased incidence of genitourinary, breast, and thyroid cancers (Abel et al. 2005).

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24.3.3 Histopathology and Morphology Histologically, this neoplasm resembles a hamartoma with dysplastic cells, which has abnormally enlarged cerebellar folia. Despite these characteristics, WHO has categorized these tumors as grade I. The combination of aberrant migration and hypertrophy of the granular cells is peculiar. Moreover, the outer molecular layer might be hypomyelinated and thicker than usual. There will be a lack of Purkinje cells and loss of white matter, and dysplastic ganglion cells are present with rounded nuclei and abundant mitochondria invading the inner granular layer (Louis et al. 2007) (Nowak and Trost 2002).

24.3.4 Imaging and Radiologic Features Enhancement following Gadolinium-DTPA administration is typically missing. Tiger stripe sign on T2-weighted sequences, which consists of alternating hypo- and hyperintense bands on MRI, is typically seen in adult-onset cases, whereas is rarely reported in pediatric patients. This affects the preoperative diagnosis rate, as it is reported to be around 40% (50% in adult cases, 16.7% in pediatric ones). (Fig. 24.4.)

24.3.2 Genetics, Immunology, Molecular Biology 24.3.5 Clinical Manifestations Hereditary or sporadic PTEN mutations are found in almost all adult-onset Lhermitte– Duclos disease cases, but not in pediatric cases, suggesting the biology of the two is different. Immunohistochemical analysis displayed high concentrations of phospho-AKT and phospho-S6 in the large ganglionic cells forming LDD, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in its pathogenesis. The high frequency and spectrum of germline PTEN mutations in patients with LDD alone confirm that LDD is a crucial feature of CS (Abel et al. 2005).

The most common presentation is in young adult in the third to fourth decade of life displaying signs and symptoms of a progressive posterior fossa mass. Clinical manifestations include headache, cranial nerve palsies, cerebellar dysfunction, ataxia, unsteady gait, and signs of acute or chronic hydrocephalus.

24.3.6 Therapeutic Approaches Not surprisingly, chemotherapy and radiotherapy are not effective against LDD, considering the very

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Fig. 24.4 Complete panel showing in different MRI sequences the characteristics of a cerebellar dysplastic gangliocytoma. Tiger stripe sign on T2-weighted

J. F. Capitanio and P. Mortini

sequences, consisting of alternating hypo- and hyperintense bands on MRI, is shown. Missing enhancement following contrast administration is characteristics

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Other Less Prevalent Tumors of the Central Nervous System

small growth potential of this benign lesion. Surgical resection is considered the first option when intervention is required. Given the benignity and the indistinct margin of this hamartomatous lesion, some opt in favor of subtotal resection or observation; nevertheless, total resection is highly recommended whenever practicable. The characteristic atypical vascularization of the mass is responsible for severe cases of intra-tumoral hemorrhage. No adjuvant postoperative therapy is regularly taken. However, recurrence has been reported. Surgical excision may be considered when there is a significant mass effect, while biopsy is recommended in pediatric patients to rule out medulloblastoma. Shunting is employed for hydrocephalus (Wang et al. 2017).

24.3.7 Follow-Up and Prognosis Despite being a hamartomatous lesion of the posterior fossa, LDD is classified as a grade I tumor with potential for recurrence. Indeed, LDD is associated with favorable prognosis. Malignant transformation of LDD has not yet been reported in the literature. Genetic counseling and testing are suggested with subsequent active surveillance since LDD is believed to be a pathognomonic feature of CS, a multisystem AD hereditary disorder characterized by multiple hamartomas and an elevated risk of benign and malignant neoplasms that must be monitored over the time. Brain and spine-contrasted enhanced MRI is the preferred technique for long-term follow-up (Abel et al. 2005).

24.4

Gangliocytoma/Ganglioglioma

24.4.1 Background and Epidemiology Glioneuronal tumors are a cluster of rare neoplasms characterized by neural and glial components in assorted proportions, commonly showing a non-aggressive WHO Grade I clinical behavior. Tumor subtypes described under the umbrella of glioneuronal tumors are actively

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evolving: three new types of tumors with neuronal components have been added to the 5th WHO classification including diffuse glioneuronal tumors with oligodendroglioma-like features and nuclear clusters (DGONC), myxoid glioneuronal tumor, and multinodular and vacuolating neuronal tumor (Louis et al. 2021; Miller et al. 1993). A gangliocytoma is a welldifferentiated, slow-growing neuroepithelial neoplasm composed of irregular clusters of mostly mature neoplastic ganglion cells. A ganglioglioma differs from the former in the presence of dysplastic ganglion cells in combination with neoplastic glial cells. Both are classified as WHO grade I (Lang et al. 1993). They represent 0.4–1.3% of all brain tumors. They may present between 2 months and 70 years of age, but it occurs primarily in children and young adults with a peak age of occurrence at 11 years. The incidence is quite the same in male and female subjects. It can develop in any part of the CNS (cerebral hemispheres, spinal cord, brainstem, cerebellum, pineal region, thalamus, sellar region, optic nerve, and peripheral nerves) but occurs most frequently in or near the third ventricle, in the hypothalamus, and the temporal or frontal lobe (Blumcke and Wiestler 2002).

24.4.2 Genetics, Immunology, and Molecular Biology Molecular analysis revealed a gain of chromosome 7, loss of chromosome 9q, deletion of CDKN2A, polymorphisms in the TSC2 gene, and even BRAF mutation. Despite the benign nature of DNET, ganglioglioma could acquire malignant characteristics; therefore, their differentiation is highly important, and synaptophysin could be a good tumor marker for detecting neuron or neuronal differentiation (Blumcke and Wiestler 2002; Luyken et al. 2004). Gangliogliomas more commonly express CD34 compared with DNET. As up to half of the glioneural tumors have BRAF V600E mutation, it could be used as a diagnostic and target marker (Chappe et al. 2013; Schindler et al. 2011).

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24.4.3 Histopathology and Morphology The histologic feature of DGONC is provisional (i.e., will likely become a fully recognized type in a future classification but currently awaits further published characterizations). Myxoid glioneuronal tumor is a lesion typically arising in the septal region and involving the lateral ventricle characterized by a proliferation of oligodendrocyte-like tumor cells embedded in a prominent myxoid stroma, frequently including admixed floating neurons, neurocytic rosettes, and/or perivascular neuropil, and by a dinucleotide mutation in the PDGFRA gene. The third entity is multinodular and vacuolating neuronal tumor, which is histologically maiden of monomorphous neuronal elements in discrete and coalescent nodules. Besides, the tumoral cells and neuropils undergo vacuolar changes in this type of tumor. The tumor originates from a mixture of 2 types of neoplastic cells, neuronal (ganglion) and astrocytic (glial) (Louis et al. 2021). Gangliocytoma macroscopically appears as a nodular and sharply demarcated lesion. Proliferation markers are very low. The tumor is comprised of uniform round cells with a neural immunophenotype and low proliferation index (Tan et al. 2018). Microscopically, it is characterized by neoplastic neurons bi- or multinucleated with eosinophilic cytoplasmic vacuolization, neoplastic fibrillary or pilocytic astrocytes, oligodendrocytes, and Blymphocytic infiltrates. Suggested criteria for diagnosis include (1) clusters of large cells potentially representing neurons, (2) no perineural clustering of glial cells around the suspected neoplastic neurons, (3) fibrosis/desmoplasia, and (4) calcification. Immunophenotype is positive for CD34, synaptophysin, neurofilament, calcineurin, GFAP, and thyrosine-hydroxylase.

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associated with cortical dysplasia. In CT scans, calcifications are common, with no or homogeneous enhancement. On MRI studies, it appears hyperintense on T2/FLAIR and hypo-isointense on T1, with none or homogeneous enhancement. Nonetheless, as the nonspecific characteristics of these tumors on imaging, the diagnosis is usually established by histology and immunohistochemistry (Figs. 24.5 and 24.6.).

24.4.5 Clinical Manifestations Clinical manifestations vary according to the lesion site, but the most common presenting symptom is seizure, often difficult to control medically.

24.4.6 Therapeutic Approaches Seizure management and complete surgical resection represent the cornerstones of management. Chemotherapy and RT are unconvincing. Radiosurgery, especially SRS, should be considered for the treatment of residual or recurrent lesions (Duffner et al. 1994).

24.4.7 Follow-Up and Prognosis Ganglioglioma is a benign tumor with good prognosis (94% of cases may have 7.5-year recurrence-free survival). Recurrence occurs after a long-lasting interval and does not necessarily show higher anaplasia. Seizure control is often attained once GTR is achieved. Follow-up is recommended even after complete resection during the patient’s whole life.

24.5 24.4.4 Imaging and Radiologic Features They vary greatly in radiographic appearance and generally appear as well-demarcated lesions with solid and cystic components, often

Central Neurocytomas

24.5.1 Background and Epidemiology It is an uncommon neoplasm firstly described in 1982 by Hassoun et al. (WHO grade II) typically

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Fig. 24.5 T2 axial, coronal, and T1 axial showing a ganglioglioma of the temporo-mesial lobe

Fig. 24.6 T1 axial, sagittal, and coronal contrast enhanced MRI showing a ganglioglioma of the right temporo-mesial lobe

located in the lateral ventricles (50% of cases) or the third ventricle although an extraventricular case report was documented as well (Hassoun et al. 1982). The cell of origin is unknown, but it may derive from neuroglial precursor cells from the subependymal plate of the lateral ventricle or circumventricular organs. It represents 0.25– 0.5% of all intracranial tumors. It occurs equally in male and female patients, and the age of incidence may vary from 8 days to 67 years, with the mean age of 29 years. Variants include (1) extraventricular neurocytoma located in cerebral parenchyma, cerebellum, thalamus, brainstem, pineal region, and spinal cord and (2) cerebellar liponeurocytoma (Schmidt et al. 2004).

24.5.2 Genetics, Immunology, and Molecular Biology Proliferation markers are low, except for atypical neurocytoma in which Ki-67 is expressed in over 2% of cases. Molecular features may include gains on chromosomes 7, 2p, 10q, 18q, and 13q. PTEN was shown to be overexpressed in 60% of patients as well as aberrant gene expression of NMYC, NRG-2, PDGF-D, and IGF2. However, unique molecular signatures that could aid in making a definitive diagnosis still have not been recognized (Kane et al. 2011). Although controversial in CN, loss of heterozygosity at 1p/19q could be found in 50% to 70% of oligodendrogliomas and is associated with a favorable

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prognosis (Kitange et al. 2005; Ohgaki and Kleihues 2005).

24.5.3 Histopathology and Morphology Macroscopically, it presents as a gray and friable mass with common calcifications. Microscopically, it is characterized by uniform round cells with features of neuronal differentiation and fibrillary areas; cells often have a “fried egg” appearance on H&E staining which can mimic oligodendroglioma. Anaplastic features include mitotic activity, microvascular proliferation, and necrosis. The immunophenotype is positive for synaptophysin, NeuN, MAP, and Olig2 and negative for neurofilament, chromogranin A, and IDH1.

24.5.4 Imaging and Radiologic Features Central neurocytoma appears as a well-defined intraventricular mass, typically broad-based to the septum pellucidum. On CT scan, it is iso- to hyperdense with frequent calcifications and heterogeneous contrast enhancement. Obstructive hydrocephalus is commonly caused by compression of the foramina of Monro. On MRI, it is hyperintense on T2 and FLAIR sequences, and iso- to hypointense on T1 sequences, with heterogeneous contrast enhancement (Figs. 24.7 and 24.8.).

24.5.5 Clinical Manifestations The most common presentations are increased intracranial pressure, ventriculomegaly, and or hydrocephalus. Almost all patients complain of headaches with or without visual changes, and one-third of patients experienced nausea and vomiting at presentation. As the tumor causes obstructive hydrocephalus, most of the symptoms manifest as the result of increased intracranial pressure.

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24.5.6 Therapeutic Approaches It should be noted that as the lack of rich literature on this topic, the diagnosis and management of CN remain controversial. Total resection and shunting are often curative. Radiotherapy is not necessary after total resection while stereotactic radiosurgery may be employed after subtotal resection, in particular, if high proliferation markers are found.

24.5.7 Follow-Up and Prognosis Central neurocytoma is a benign tumor whose prognosis depends mainly on the extent of resection. No recurrence usually is expected when gross total removal is achieved. It was reported that recurrence risk after subtotal resection varied with the MIB-1 labeling index: no recurrence was present at 4 years if MIB1 < 4% while recurrence rate was 50% at 2 years and 75% at 4 years if MIB-1 >4%. The most consistent report from Schild et al. indicated a 5-year survival rate of 81% (Schild et al. 1997).

24.6

Rosette-Forming Glioneuronal Tumor (RGNT) of the CNS

24.6.1 Background and Epidemiology It is a rare, slowly growing (WHO grade I) entity composed of two distinct histological components, one containing uniform neurocytes forming rosettes and/or perivascular pseudorosettes, and the other resembling pilocytic astrocytoma. It presents nearly with the same frequency in male and female patients. The age range is 12–59 years (mean 33 years). It may also develop in the midline, brainstem, cerebellum, pineal gland, optic chiasm, septum pellucidum, and spinal cord. The histogenesis of RGNT is still unclear. RGNTs have been postulated to arise from pluripotent cells of thesubependymal plate (periventricular germinal

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Fig. 24.7 T1 contrast enhanced images showing an intraventricular atypical central neurocytoma

Fig. 24.8 Basal T1 and FLAIR axial and coronal images showing intraventricular atypical central neurocytoma

matrix) located in the infratentorial ventricular system. In the 4th edition of the WHO classification system it has been renamed “rosetteforming glioneuronal tumor”. Despite the benign histological grade (WHO I Grade), little is known about the true nature of this recently recognized tumor entity, since no more than 200 cases have been described in the literature so far (Yang et al. 2017).

most common genetic alteration responsible for RGNT. In addition, the other genetic alterations include FGFR1 mutations (accompanied by PIK3CA mutation), IDH1 KIAA1549/BRAF gene fusion, PPP1R1A, and RNF21. No BRAF alteration, fusion, or mutation has been demonstrated so far (Bidinotto et al. 2015; Ellezam et al. 2012; Eye et al. 2017; Gessi et al. 2012; Lin et al. 2016; Sievers et al. 2019; Yamada et al. 2019).

24.6.2 Genetics, Immunology, and Molecular Biology,

24.6.3 Histopathology and Morphology

Various genetic mutations have been found in association with RGNT. Among all investigated genes, the PIK3CA mutation is considered the

Macroscopically, it presents as a soft-gelatinous whitish-brown mass. Microscopically, the RGNT consists of both neurocytic and glial architecture.

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The neurocytic component forms pseudorosettes, sometimes radiating toward vessels (perivascular pseudorosettes). The glial component is composed of astrocytic tumor cells in a loose fibrillary background. The immunophenotype is positive for synaptophysin and MAP2 (neurocytic), NSE, GFAP, and S100 (astrocytic). Proliferation markers are low or absent. Cases with associated NF1 or Chiari I malformation are reported in the literature.

24.6.4 Imaging and Radiologic Features Central neurocytoma appears as a well-defined heterogeneous mass, typically located at the top of the fourth ventricle. On CT scan, it is hypodense with frequent calcifications, hemorrhage, and cysts and with no contrast enhancement. RGNTs may appear in cystic, solid, or mixed cystic-solid patterns (Yang et al. 2017). The vast majority of RGNTs showed hypointensity around 90% on T1-weighted imaging (T1WI) and hyperintensity around 90% on T2-weighted imaging (T2WI). After the administration of the contrast medium, approximately, a quarter of RGNTs did not enhance, and the others showed heterogeneous (50%), rim (12.5%), or focal (12.5%) enhancement, which was associated with the cystic/solid nature of the tumors. On diffusion-weighted imaging (DWI), there was no evidence of restricted diffusion (Yang et al. 2017).

24.6.5 Clinical Manifestations The clinical manifestations are nonspecific and generally localization-related: intracranial hypertension (headache and nausea/vomiting) and cerebellar symptoms are the most common manifestations, while hydrocephalus was present in less than half of all cases (Adachi et al. 2005).

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24.6.6 Therapeutic Approaches In the literature, approximately, 150 cases of RGNTs have been described yet, and these were limited to single-case reports or small case series. Different characteristics of RGNTs are not very clear yet, which have influenced the current treatment approaches and prognosis of the disease. In general, the efficacy of postoperative adjuvant treatments could not be estimated owing to the limited sample size and are not recommended. Surgical resection remains the mainstay of treatment for RGNTs with a favorable prognosis when GTR is possible. Importantly, it should be noted that due to the midline location of the majority of these tumors and intimate relationship with adjacent key neural structures, especially the cerebellum, brain stem, and spinal cord, GTR may not be always achieved (Hsu et al. 2012; Sharma et al. 2011; Thurston et al. 2013; Xiong et al. 2012). Of note, inadequate resection (biopsy or PR) might increase the risk of tumor progression. While there may be no significant difference in progression between GTR and STR, aggressive surgery with the goal of GTR and neurologic damages, may not be crucial (Yang et al. 2017).

24.7

Pheochromocytomas and Paragangliomas (PPGs)

24.7.1 Background and Epidemiology In the 2017 and 2021 World Health Organization (WHO) classifications (Louis et al. 2016, 2021), pheochromocytoma is an adrenal tumor, and paraganglioma is an extra-adrenal tumor; since the two tumor types cannot be differentiated on the basis of histologic findings, anatomical location is used to distinguish between them. It is a slow-growing tumor arising from paraganglion cells. According to the site of origin, it is possible

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to differentiate carotid body tumors (the most common, 5% bilateral), glomus tympanicum (from the auricular branch of the vagus in the middle ear), glomus jugulare (from the superior vagal ganglion), glomus intra-vagal (from the inferior vagal ganglion), and pheochromocytoma (from adrenal medulla and sympathetic chain). It may occur in a familial (50%) or non-familial pattern (5%, may be multicentric and metachronous). Pheochromocytoma may be sporadic or part of a familial syndrome (von Hippel–Lindau disease, MEN2A/B, and neurofibromatosis): genetic testing is always recommended if the age at diagnosis is 400 pg/mL or MN >236 pg/mL in 24 h urine collection, for total catecholamines and metanephrines are used as well. As a reliable screening and diagnostic test, clonidine suppression test is commonly used. Accordingly, the baseline plasma levels of more than 2000 pg/ml for norepinephrine (NE) and epinephrine (E) or failure to suppress to less than 500 pg/ml after oral clonidine have been considered diagnostic of the presence of a pheochromocytoma (Taylor et al. 1986).

24.7.7 Therapeutic Approaches Mere biopsies are not recommended due to the risk of vascular injury. Optimal management for head and neck paragangliomas represents a challenge; thus, a customized approach is essential. Treatment options should include surgery, endovascular embolization, stereotactic radiosurgery or other external radiation therapies, and wait and repeated scan strategies. A multidisciplinary approach is however recommended depending on the organ of origin. Staging before any kind of treatment is essential; dissemination must be ruled out, and catecholamine production should be tested. Genetic counseling must be

Fig. 24.9 Axial, sagittal, and coronal T1W contrast enhanced images of a large right paraganglioma

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Fig. 24.10 Axial, sagittal, and coronal T1W contrast enhanced images–follow up after RT–7 years later

considered as well. Carotid body tumors are most frequently classified with the use of the Shamblin classification (Table 24.1), whereas the Fisch classification (Table 24.2) is used for Jugulotympanic paragangliomas, both of which guide surgical management (Browne et al. 1993; Shamblin et al. 1971) (Tables 24.3 and 24.4). Surgical resection is the only potentially curative treatment option. It should be considered for small-size glomus tumors while for larger lesions must be carefully weighted. In fact, in advanced cervical paragangliomas, (Shamblin class III) stroke risk is as high as 8–20%; while in jugular paragangliomas (Fisch class C and D), lower cranial nerve deficits are frequent after surgery. Patients with these advanced tumors should receive non-surgical treatment options due to lower morbidity and good overall survival. Radiotherapy is currently used as a primary treatment for large tumors or patients in whom surgery is contraindicated. Embolization is generally reserved for large tumors with favorable blood supply; it is correspondingly

admitted preoperatively to reduce vascularity too. Medical therapy is used for palliation or as an adjunctive treatment before surgery and embolization. Alpha blockers reduce blood pressure preventing peripheral vasoconstriction. Beta-blockers reduce catecholamine-induced tachycardia and arrhythmias.

24.7.8 Follow-Up and Prognosis Malignant PPG should be considered when there is evidence of metastasis (e.g., bone, lymph node). Generally, the overall prevalence is 10.0% among different age groups (Buffet et al. 2012; Mannelli et al. 2009; Pereira et al. 2019; Welander et al. 2011). Tumors larger than 4 cm or extra-adrenal location, pediatric age, and SDHB mutations confer a higher risk of malignancy (Ayala-Ramirez et al. 2011; King et al. 2011). The majority of metastatic PPGs are associated with SDHB mutations and less frequently with NF1, SDHA, HIF2A, MAX,

Table 24.1 Glasscock-Jakson classification of glomus tympanicum paraganglioma I

Neoplasm restricted to the promontory

II

Neoplasm filling the middle ear completely

III

Neoplasm filling the middle ear + reaching mastoid process

IV

Neoplasm extending, characteristics of levels I + II + III + reaching the tympanic membrane to plug the external auditory canal and/or extending to the internal carotid artery

Inspired from (Jackson et al. 1982) Jackson CG, Glasscock ME 3rd, Harris PF. Glomus Tumors. Diagnosis, classification, and management of large lesions. Arch Otolaryngol. 1982 Jul;108(7):401–10. https://doi.org/10.1001/ archotol.1982.00790550005002. PMID: 6,284,098

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Table 24.2 Fish’s classification of temporal bone paragangliomas A

Neoplasm enclosed to the middle ear

B

Neoplasm within the tympano-mastoid with no infra-labyrinthine invasion

C

Neoplasm within the infra-labyrinthine zone of the temporal bone with extension to the petrous apex • C1 Neoplasm with partial involvement of the vertical portion of carotid canal • C2 Neoplasm invading the vertical portion of carotid canal • C3 Neoplasm invading the horizontal portion of carotid canal

D

Neoplasm with intracranial involvement • D1 Neoplasm with less than 2 cm in diameter extension • D2 Neoplasm with a greater than 2 cm in diameter extension

Inspired from (Fisch 1982). Infratemporal Fossa Approach for Glomus Tumors of the Temporal Bone. Annals of Otology, Rhinology and Laryngology, 91(5), 474–479. https://doi.org/10.1177/000348948209100502

Table 24.3 Shamblin classification of carotid paragangliomas Type I

Relatively small tumor with minimal attachment to carotid vessels

Type II

Larger tumor with moderate attachment to carotid vessel but resectable with preservation of the carotid vessels

Type III

Tumor encases the carotid vessels requiring vessel sacrifice with reconstruction

Inspired from (Shamblin et al. 1971) Shamblin WR, ReMine WH, Sheps SG, Harrison EG Jr. Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases. Am J Surg. 1971 Dec;122(6):732–9. https://doi.org/10. 1016/0002-9610(71)90436-3. PMID: 5,127,724

Table 24.4 Classification for esthesioneuroblastomas Type A

Neoplasm limited to the nasal space

Type B

Neoplasm concerning nasal space and/or paranasal sinuses

Type C

Neoplasm encompassing cribriform lamina, skull base, orbit with intracranial invasion

Type D

Neoplasm with head and neck metastasis

Inspired from (Kadish et al. 1976) Kadish et al. (1976) reviewed by Morita et al. 1993

and FH mutations (Burnichon et al. 2012; Gimenez-Roqueplo et al. 2003; Walther et al. 1999).

24.8

Dysembryoplastic Neuroepithelial Tumor (DNET)

24.8.1 Background and Epidemiology It is a benign (WHO grade I) glioneural neoplasm typically located in the temporal lobe of children and young adults responsible for earlyonset epilepsy. Among all neuroepithelial tumors, it represents only 1.2% in patients under

20 years and 0.2% above. It may occur between 3 weeks and 38 years, and the first seizure typically presents before the age of 20 in almost all cases. The M:F ratio is 1.5:1. It is located characteristically in the supratentorial cortex with a predilection for the temporal lobe (half of the cases). Additional potential locations involve the lateral ventricle, septum pellucidum, trigonoseptal region, caudate nucleus, midbrain, cerebellum, and rarely brain stem since it usually originates from focal cortical dysplasia or ectopic neurons in white matter (Weis et al. 2019). DNET represents one of the most frequent supratentorial neoplasms in patients affected by seizures at a young age, being the second in frequency after ganglioglioma.

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24.8.2 Genetics, Immunology, and Molecular Biology Several mutations have been described, among the most consistent are concurrent gains at chromosomes 5 and 7, downregulations of microRNAs such as miR-3138, and upregulation and overexpression of miR-1909. In familiar multinodular DNET, a characteristic germline mutation in fibroblast growth factor receptor 1 (FGFR1) p.R661P mutation has been found. From a molecular perspective, DNET pathogenesis is directly correlated to mitogen-activated protein kinase (MAPK) and mTOR signaling pathways, both depending on the activation of the FGFR1. Mutations of the FGFR1 have been detected in approximately 80% of DNETs. Another common oncogenic alteration is BRAF V600E mutations as well as increased copy numbers. These mutations induce FGFR1 autophosphorylation causing an upregulation of the mitogen-activated protein kinase and also mTOR signaling pathways, ultimately (Braoudaki et al. 2016; Eye et al. 2017; Prabowo et al. 2015; Qaddoumi et al. 2016; Rivera et al. 2016).

24.8.3 Histopathology and Morphology Macroscopically, it presents as single or multiple firm nodules of variable size with a viscous consistency. Microscopically, it is characterized by glioneuronal elements formed by bundles of axons lined by small oligodendroglia-like cells; glial components form typical nodules and show diffuse growth patterns. In complex forms, astrocytes, oligodendrocytes, and neurons are also present. Vascular component varies from poor to exuberant. Moreover, “floating neurons” refers to normal neurons which present between these neoplastic lines with a mucoid alcianophil characteristic. No dysplasia of ganglion cells is present in these lesions. Focal cortical dysplasia (type III B), according to the International League mutations, has also been reported. Particularly, the BRAF V600E mutation may be present.

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Cortical dysplasia is present in 80% of cases. The immunophenotype is positive for GFAP; Ki-67 varies from 0 to 8%.

24.8.4 Imaging and Radiologic Features DNET appears as a well-delineated cortical mass without subcortical infiltration. DNET usually does not exert a mass effect over the surrounding brain parenchyma. The absence of mass effect and peritumoral edema is the distinguishing characteristics of these lesions. On CT scan, it is hypodense with possible calcifications and generally without contrast enhancement. On MRI, it is hyperintense on T2, hypo- to isointense with a hyperintense rim along tumor border on FLAIR sequences, and hypointense on T1 sequences, usually with no contrast enhancement (Figs. 24.11 and 24.12).

24.8.5 Clinical Manifestations DNETs normally cause drug-resistant and partial complex seizures with or without secondary generalization; other forms of epilepsy are also possible. Headache, papilledema, and focal deficits, in the form of focal weakness or numbness, can be other manifestations although rarer. Differential diagnosis is with glioneuronal and glial tumors such as ganglioglioma, oligodendroglioma, pilocytic astrocytoma, and pleomorphic xanthoastrocytoma.

24.8.6 Therapeutic Approaches Surgery is the upfront treatment for DNET with the goal of completely removing the tumor. The majority of DNETs should usually be safely and completely removed. In fact, complete tumor excision is associated with a very high cure and a high chance of seizure control. In cases of partial resection, these tumors tend to remain quiescent for years. There is no role for

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Fig. 24.11 Axial T1, T2 and FLAIR of a huge temporal DNET

Fig. 24.12 Axial DWI–T1 contrast enhanced image showing characteristic of huge temporal DNET

chemotherapy or radiation therapy in a typical DNET; specifically, all forms of radiation are associated with worse outcomes (Weis et al. 2019).

been occasionally reported, especially for tumors not located in the temporal lobe (Liao et al. 2018; Moazzam et al. 2014; Ray et al. 2009; Tonetti et al. 2017).

24.8.7 Follow-Up and Prognosis

24.9 Surgery does not affect the overall survival, since DNETs are benign tumors although risk factors for recurrent seizures include a long preoperative history of seizures, residual tumor, and presence of cortical dysplasia adjacent to DNET. In general, MRI surveillance is suggested in cases where a subtotal rather than complete resection is the only possible option. Accordingly, tumor recurrence and malignant transformation have

Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor (EWS/pPNET)

24.9.1 Background and Epidemiology Ewing’s sarcoma/peripheral primitive neuroectodermal tumors (EWS and pPNETs) occur most often in bone and soft tissues of children and

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young adults. The intracranial manifestation of the disease is rare, and when present, is often misdiagnosed with other varieties of primary brain tumors such as meningiomas or analogous tumors (Tsokos et al. 2012). The pathophysiology of EWS and pPNET is very similar in the mattes of genetics, immunophenotype, and ultrastructure. Therefore, WHO has classified them as EWS/pPNET in the family of soft tissue and bone tumors or the Ewing family of tumors. Although uncommon in general with approximately annual occurrence of 300 cases in the US, the EWS/pPNET comprises the 3rd most common primary malignant neoplasm of bone and soft tissues in children, after osteosarcoma and rhabdomyosarcoma, respectively (Tsokos et al. 2012). Tumors present typically in the 2nd decade of life, but infrequent cases are seen in early childhood and older adults. Overall, there is a male predilection. Extraskeletal tumors constitute 20– 40% of all EWS/pPNET and most often are found in the soft tissues of the trunk and extremities, followed in frequency by the head and neck, retroperitoneum, and other sites, especially those associated with skeletal muscle (Tsokos et al. 2012). Occasionally, it can be found in the female genital tract, adrenal gland, and kidneys.

neoplasms. It is typically characterized by the following panel: CD99+ , NSE+/− , CK+/− , CAV + , Fli-1+ (Cerisano et al. 2004; Kovar et al. 1990; Schenkel et al. 2007).

24.9.2 Genetics, Immunology, and Molecular Biology

The most reported tumor location is the temporal region followed by the parietal and frontal regions while the infratentorial region and the cerebellopontine angle are extremely rare. When suspected, a brain and whole-spine magnetic resonance imaging (MRI) scan must be performed on all patients before surgery. A wholebody CT scan to exclude extra-neuraxial locations must be performed as well. Computed tomography scan (CT scan) of the brain typically shows a well-defined, heterogeneous hyperdense, enhancing lesion that frequently destroys and infiltrates the related bone. Tumors may extend also into the scalp, suggesting the possibility of an aggressive meningioma. Calcifications are not typical but could be present. Isodensity and mixed iso-low densities have been also reported. On MRI, the tumor appears classically as solid or cystic-solid. The tumor could be hypointense on

The unified inclusion criterion for Ewing family of tumors is the presence of a non-random translocation, most commonly t(11;22)(q24;q12), which juxtaposes a portion of the EWS gene on chromosome 22q with the FLI-1 gene on 11q. Moreover, some other cytogenetic changes were detected to involve different gene families. A considerable proportion of EWS/pPNET were identified to present MIC2 (CD99) and FLI-1. MIC2, a 32-kDa membrane glycoprotein, is encoded by a pseudo-autosomal gene on the X and Y chromosomes involved in cell adhesion, migration, and apoptosis. The most common technique to make a diagnosis is immunohistochemistry, indeed, to confirm the diagnosis of EWS/pPNET and to exclude the other similar-appearing round cell

24.9.3 Histopathology and Morphology The primitive mesenchymal cells seem to be accountable for the histogenesis of this tumor although it is still ambiguous. Microscopically, the tumor is a small round blue cell of neuroectodermal origin that involves the CNS either as a primary dural neoplasm or by a direct extension from contiguous bone or soft tissue. It is composed of sheets of small and round cells with scant cytoplasm and uniform nuclei; Homer-Wright rosettes are occasionally seen. The immunophenotype is focally positive for synaptophysin and NSE. The tumor must be confirmed at the molecular level by RT-PCR for the presence of EWSR1-FLI-1 or EWSR1-ERG fusion transcript or FISH for EWSR1 gene rearrangement.

24.9.4 Imaging and Radiologic Feature

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Fig. 24.13 Axial FLAIR–T2–T1 of a frontal Ewing sarcoma

Fig. 24.14 Axial–sagittal–coronal T1 contrast enhanced images

T1 and hyperintense on T2 signals or isointense on T1 and T2, isointense on T1 and hyperintense on T2 signals, or isointense on T1 and mixed T2 signals. On the MRI images, the lesions showed homogeneous enhancement in half of the cases described and a heterogeneous enhancement in the other half. The tumor border is relatively welldefined in most cases and poorly defined occasionally. MRI spectroscopy revealed choline and N-acetyl acetate peaks. (Figs. 24.13, and 24.14).

or neurological deficits emerge when nerves and neural structures are involved. Depending on tumor size, intracranial hypertension followed by vomiting could be the first and most serious symptom of presentation. Prominence over the scalp could be observed. Fever may be present, suggestive of an infection characteristically in case of acute osteomyelitis. Radiographic images may demonstrate periosteal activity while the osseous involvement is absent.

24.9.5 Clinical Manifestations

24.9.6 Therapeutic Approaches

Discomfort, soreness, and pain are typical complaints in the cases of bone and soft tissue tumors, while headache, paresthesia, weakness,

Gross total excision is crucial followed by postoperative radiotherapy in order to improve PFS and OS. Those presenting with metastatic disease

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have the worst prognosis. The management of osseous and extraosseous EWS/pPNET after diagnosis is followed by chemotherapy, generally including a regimen with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide depending on tumor location, size, and response to chemotherapy. Radiation therapy is warranted in all cases of incomplete, partial, and subtotal resection. Treatment intensification for high-risk patients may consist of high-dose chemotherapy followed by the stem cell transplant.

24.10

Langerhans Cell Histiocytosis (LCH)—Histiocytosis X

24.10.1 Background and Epidemiology The appellation of this disease has evolved over the years as new evidence has been obtained. Previously known by many different terms, the name “Langerhans cell histiocytosis” was finally introduced. This name was approved to recognize the essential role of the Langerhans cells. A proliferation of Langerhans cells and antigen presenting cells is present in all stratified epithelium, due to the immune dysfunction and aberrant expression of chemokine receptors. There may be also a multifocal uni-system LCH which can present with fever and bone and skin lesions and a multifocal multisystem LCH which is a fulminant malignant lymphoma in infancy presenting with the Hand-Schuller-Christian triad of diabetes insipidus, exophthalmos, and lytic bone lesions. It may cause lysis of craniofacial bones, changes in the hypothalamic-pituitary region and meninges, white matter and gray matter changes, and cerebral atrophy. Its localization may vary from leptomeninges to intracerebral and intraventricular; three types of CNS involvement are reported: hypothalamic-pituitary, space-occupying, and neurodegenerative. Its incidence is 0.5 per 100.000 children (mean age of 12 years), and it equally affects male and female patients.

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24.10.2 Genetics, Immunology, and Molecular Biology In the past years, it was shown that the detection of phenotypic or ultrastructural properties specific to Langerhans cells such as CD1a, CD207, and Birbeck granules explained the difference between LCH and non-LCH. The majority of mutations are in CSF1R, ALK, RET, NTRK, RAS, RAF, MAP2K, or other kinase genes that have been associated with myeloid-specific growth factor receptor-binding and ERK activation. The BRAF mutation encoding the V600E (Val600Glu) variant—a known oncogenic factor—is found in 2010 and allowed the use of targeted therapies against histiocytosis. However, some histiocytosis are driven by mutations in the MAP kinase pathway that affects MAP2K1, a gene which produces the MEK1 kinase just downstream from BRAF. Most mutations in histiocytosis are point mutations or small deletions or insertions, but some gene fusions result in the production of chimeric proteins. More than 90% of cases of LCH and Erdheim–Chester disease (ECD) have the same mutations activating the MAP kinase pathway (Badalian-Very et al. 2010; Chakraborty et al. 2014; Davies et al. 2002; Histiocytosis syndromes in children. Writing Group of the Histiocyte Society 1987; Nelson et al. 2015).

24.10.3 Histopathology and Morphology They present as yellow to white masses with discrete dural nodules and granular parenchymal infiltration. Microscopically, apart from Langerhans cells, macrophages, and lymphocytes, collagen deposits can be also detected. Their immunophenotype is positive for S100, vimentin, langerin, HLA-DR, and b2-microglobulin. Most data suggest that LCH is a diverse disease with a clonal growth of immature Langerhans cells, half of the cases have mutations of BRAF. LCH is not infectious and transmissible.

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24.10.4 Imaging and Radiologic Features CNS MRI is recommended for all patients. All clinical signs of endocrine dysfunction, including diabetes insipidus and anterior pituitary dysfunction, should be evaluated at diagnosis and during follow-up, even for asymptomatic patients (Courtillot et al. 2016; Sagna et al. 2019). A high-resolution CT scan is key to diagnosing pulmonary LCH, showing nodules that are small or cavitated (or both), and the progressive evolution of these nodules to cysts. Pulmonary function tests frequently detect reduced diffusion capacity. In skull X-ray and CT scan, it presents as lytic skull lesions without sclerosis with associated soft tissue extension. On MRI, it may present with hyperintensities on T2 (also for dilated Virchow-Robin spaces) except for dural

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masses which are hypointense; hypointense white matter on T1 sequences with loss of hyperintense neurohypophysis and thickening of the pituitary stalk; after contrast, only, infundibular stalk enhances. Scintigraphy is insensitive for CNS lesions. FDG-PET shows hypometabolism in the cerebellum, basal ganglia, and frontal cortex (Figs. 24.15. and 24.16).

24.10.5 Clinical Manifestations LCH is a multiorgan disorder manifesting with slowly progressive symptoms. Recurrent dental losses and dental cysts are sometimes revelatory of LCH. Micronodules and cysts in the upper lung lobes are somehow characteristics, but pneumothorax as well as dyspnea and dry cough may present as well. The liver should be

Fig. 24.15 Coronal T1 contrast enhanced images showing a homogenous thickening of the pituitary stalk just until to the hypothalamus sparing the pituitary gland

Fig. 24.16 Sagittal T1 contrast enhanced images showing a homogenous contrast of the pituitary stalk and of hypothalamus

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interested in producing a picture similar to sclerosing cholangitis. Other described symptoms are bone pain or fractures, skin papules and diffuse lymphadenopathy. Pituitary involvement can precede other symptoms by several years with diabetes insipidus being the most common symptom. Bone lesions can be similar to lytic metastases or myeloma and should raise suspicion. Cognitive disturbances, behavioral disorders and neuromotor presentations with gait disturbances, dysarthria, dysphagia, and motor spasticity can result in severe psychiatric disorders.

24.10.6 Therapeutic Approaches Patients presenting with single-system involvement might require only counseling on lifestyle behaviors or surveillance, while bisphosphonates can be prescribed for multiple LCH bone lesions. Systemic non-targeted therapy should take advantage of chemotherapeutic regimens based on Cytarabine alone or combined with methotrexate or cladribine/vinblastine together with steroids. LCH bearing BRAF-mutations should be targeted with Vemurafenib. Recently developed, MEK inhibitors are highly active therapies. In case of mass effect due to the brain or spinal involvement, treatment may include surgical removal. Skull biopsy or complete infiltrated bone removal is useful in case of differential diagnosis. Radiotherapy should be considered in case of resistance to chemotherapy or localized relapses (Emile et al. 2021).

24.10.7 Follow-Up and Prognosis Prognosis of LCH in adults is greatly affected by the response to treatments and frequency of relapses. Prognosis can range from an absence of sequelae to a severe organ (liver, lung) dysfunction or neurodegeneration. Survival rates are 88% at 5–15 years and 77% at 20 years. The event-free survival rate at 15 years is 30% (Emile et al. 2021).

24.11

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Solitary Fibrous Tumors (Known Before as Hemangiopericytomas)

24.11.1 Background and Epidemiology The term “hemangiopericytoma” has been lastly retired and replaced with the single term Solitary fibrous tumor (in preference that the hybrid term “Solitary fibrous tumor/hemangiopericytoma” is used in the 2016 CNS classification) in the 2021 WHO CNS classification. This neoplasm now aligns with the soft tissue nomenclature although the newly modified 3-tiered CNS grading scheme remains a site-associated difference. This decision was determined by the known common genetic etiology between the two tumors. SFT is a mesenchymal tumor of the fibroblastic type, often showing a rich branching vascular pattern. The WHO classification for soft tissue tumors distinguishes grades 1 to 3. It represents 1% of all primary CNS tumors. It occurs in adults, typically in the fourth to sixth decades of life (mean age 43 years), with equal frequency in male and female patients. It is frequently located in cranial or spinal dura, less commonly localized in the brain parenchyma and the ventricles.

24.11.2 Genetics, Immunology, and Molecular Biology Molecular analysis may reveal genomic inversion at the 12q13 locus causing NAB2 and STAT6 gene fusion and STAT6 nuclear expression. SFT typically shows gene fusion between NGFI-A binding protein 2 gene (NAB2) and signal transducer and activator of transcription 6 genes (STAT6) (NAB2-STAT6). NAB2-STAT6 fusion results in aberrant accumulation of STAT6 protein in tumors cell nuclei, which can reliably be demonstrated by simple STAT6 immunohistochemistry (Kristensen et al. 2019). Supportive immunostaining markers for SFT diagnosis are CD34, bcl-2, and CD99. The expression of CD34 is strong and diffuse in more than 80% of

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SFT tumors, but its expression can be lost in the most aggressive SFTs (Chmielecki et al. 2013).

24.11.3 Histopathology and Morphology Macroscopically, it appears as a brownish or grayish solid tumor with possible hemorrhages. Microscopically, it may present with a hemangiopericytoma phenotype (highly cellular with closely packed and randomly oriented cells) or solitary fibrous tumor phenotype (spindle cells arranged in fascicles between bands of collagen). The solitary fibrous tumor phenotype appears only in grade I tumors. Anaplastic (grade III) hemangiopericytoma presents increased mitotic activity (at least 5 per 10 HPF) and/or necrosis and at least one between hemorrhage and nuclear atypia. Immunophenotype is positive for STAT6, CD34, CD99, Bcl2, vimentin, b-catenin (Kristensen et al. 2019).

24.11.4 Imaging and Radiologic Features It appears as an extra-axial mass arising from the dura with strong enhancement, well-defined but with lobulated contour. On CT scan, it presents as a heterogeneous iso- to hyperdense mass with a variable grade of bone invasion and calvarium erosion and strong contrast enhancement. On MRI, it is isointense on T2 and T1 sequences, strongly enhanced after contrast. (Fig. 24.17).

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disturbances. Extrameningeal locations include dissemination in the abdominal cavity 31%, limbs 29%, pleura 22%, trunk 11%, and others 7% (the head and neck but not meninges) (Salas et al. 2017). Less than 10%, experience paraneoplastic syndromes named hypertrophic osteoarthropathy (HOA), mainly seen in cases of pleural SFT. HOA syndrome is more frequent than other reported paraneoplastic syndromes such as hypoglycemia which seems to be also an important prognostic factor for OS (Martin-Broto et al. 2021).

24.11.6 Therapeutic Approaches Surgical resection is the treatment of choice for localized SFT or in the case of oligometastatic scenery. Almost all meningeal SFTs are attached to the dura mater, and their most usual location is along the tentorium cerebelli followed by the frontal convexity, cerebellopontine angle, ventricles, falx cerebri, and posterior fossa (Carneiro et al. 1996). In patients with partial or subtotal resection, or in cases of high mitotic rate and or WHO grades of 2 or 3, neoadjuvant RT is recommended even if the OS seems not to be affected (Haas et al. 2020). Therapeutic regimens such as trabectedin accompanied by low-dose RT seem to be active in selected cases (Martin-Broto et al. 2020). It should be noted that a multidisciplinary team should be involved in treatment of these tumors.

24.11.7 Follow-Up and Prognosis 24.11.5 Clinical Manifestations SFT is a tumor with ubiquitous allocation typically affecting adult patients. Similar to meningiomas, symptoms are mostly related to tumor location: most reported signs and symptoms are headache, exophthalmos and diplopia, vertigo, unsteady gait, dizziness, and cerebellar

Due to the benign nature of SFTs, surgical resection could favorably control the disease. As complete surgical resection implies a better prognosis than subtotal resection, thus all efforts should be directed in order to obtain GTR. Indeed, a higher mitotic rate implies a worse prognosis compared to extra-meningeal SFT. In all these cases, adjuvant RT is usually recommended in

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Fig. 24.17 Axial, coronal, and sagittal T1 contrast enhanced images showing diffuse dural localization of hemangiopericytoma growing diffusely

meningeal SFT, offering a better local control if radiation therapy is added in the adjuvant setting. The 5-year local control in 89 patients was 60% versus 90%, p = 0.052, favoring the postoperative radiotherapy (RT) group (Haas et al. 2020). SFT, although benign, demonstrated time-torecurrence between 4 and 40 months, and recurrence is delayed by irradiation (58 months versus 29 months without irradiation). In 20% of cases, extracranial metastases are present in bone, lung, and liver. Mean survival after metastases is 2 years (Martin-Broto et al. 2021).

24.12

Olfactory Neuroblastoma/ Esthesioneuroblastoma (ENB)

24.12.1 Background and Epidemiology It is a rare aggressive nasal neoplasm that develops in the olfactory neural crest cells in the upper nares which are located in the upper parts of the nasal cavity consisting of the superior

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nasal concha, the roof of the nose, and the cribriform plate. The skull base, cranial vault, and orbit can be invaded by these tumoral cells (Thompson 2009). Its incidence is 0.4 per 100,000 people aged 3–90 years. It has a higher risk of occurrence between the second and third decades. 1400 cases of this tumor have been reported in the literature so far.

24.12.2 Genetics, Immunology, and Molecular Biology More than 10 genetic aberrations have been reported so far. Among all the detected genetic abnormalities, chromosome 11 deletions as well as gains of 1p were associated with poor prognosis and higher susceptibility to metastasis. Levels of phosphorylated p-Akt, p-Erk, and pSTAT3 are significantly increased and are potential biomarkers for the diagnosis of ENB (Fiani et al. 2019).

24.12.3 Histopathology and Morphology The nucleus/cytoplasm ratio is often high in ENBs. Homer-Wright rosettes are presented in up to 30% of cases, and Flexner-Wintersteiner rosettes are seen in up to 5%. The ultrastructural characteristics of ENB are dense membrane-bound neurosecretory granules with neurofilaments and microtubules in the cytoplasm and nerve processes. ENB stains positive for neuron-specific enolase, neurofilament protein, synaptophysin, chromogranin, CD56, and LEU-7. Of note, the epithelial markers are rarely present altogether in ENBs, and these tumors might be bare of the characteristic markers of other tumors such as hematolymphoid tumors, melanoma, myogenic, and Ewing sarcoma. Ki-67 shows a high proliferative index between 10 and 50% (Faragalla and Weinreb 2009; Gandhoke et al. 2017; Soler and Smith 2012).

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24.12.4 Imaging and Radiologic Features CT scans frequently show cribriform plate erosion rather than hyperostosis such as in olfactory groove and planum meningiomas. On MRI, it is isointense on T2 and T1 sequences, strongly enhanced after contrast. It helps in distinguishing between extradural tumor, dural invasion, or parenchymal brain invasion. Chest CT scan and PET should be used to rule out metastasis. In a recent study, it has been found a frequent expression of somatostatin receptor 2a in ENB. This distinctive feature justifies radioreceptor diagnosis and therapy with somatostatin analogs (Czapiewski et al. 2018).

24.12.5 Clinical Manifestations Rhinorrhea, nasal obstruction, epistaxis, headache, visual impairment, tearing, proptosis, and neck swelling are the most reported sign and symptoms in order to justify a further evaluation.

24.12.6 Therapeutic Approaches Surgical resection is the current choice of treatment for ENB. The common clinical classification that is used to help in choosing the best medical care is Kadish’s. Utilizing combined RT and CT prior to craniofacial resection is used in some patients. Endoscopic resection with negative margins for Kadish A and B and bifrontal craniotomy with lateral rhinotomy for Kadish C and D and reconstruction of the cranial base to prevent CSF leaking should be considered. It should be noted the adjuvant RT increases the risk of recurrence.

24.12.7 Follow-Up and Prognosis The average time of recurrence of ENB ranges from 2 to 6 years; the median overall survival is 7 years; however, isolated cases reported OS as

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long as 19 years as well. Long-term follow-up and surveillance are vital to ensure the best outcome. Prognostic factors include the magnitude of extension at diagnosis, the extent of resection, positive margin, male gender, lymph node involvement, and age at diagnosis. Intracranial recurrence is typically treated with repeat transcranial resection; however, for higher-grade lesions, perioperative RT and adjuvant chemotherapy must be part of the treatment plan. Among available radiation techniques, stereotactic radiosurgery should be preferred to protect critical neural structures. The recent discovery regarding the frequent expression of somatostatin receptor 2a provides a rationale for radioreceptor diagnosis and treatment with somatostatin analogs (Czapiewski et al. 2018). The treatment plan must be arranged with oncologists, radiotherapists, and surgeons.

24.13

Atypical Teratoid/Rhabdoid Tumor (ATRT)

24.13.1 Background and Epidemiology It is an extremely malignant (WHO grade IV) CNS embryonal tumor composed predominantly of poorly differentiated elements and frequently rhabdoid cells. It represents 1–2% of pediatric tumors (10% of CNS pediatric tumors). It occurs usually under the age of 3 years (mean age 2 years), and it is slightly more frequent in males (M:F = 1.8). It may be frequently located in cerebral hemispheres, ventricular system, suprasellar region, and cerebellum, while other locations such as brain stem and spinal cord are affected infrequently (Pawel 2018).

24.13.2 Genetics, Immunology, and Molecular Biology As a member of SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, the SMARCB1 gene mainly participates in regulation of gene expression through

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epigenetic mechanisms. SMARCB1 is like a tumor suppressor gene, and the loss of function of both alleles gives rise to SMARCB1-deficient tumors. Nearly, all AT/RTs express vimentin, and the majority express EMA and/or broad spectrum cytokeratins. An inconstant expression of neuronspecific enolase (NSE), synaptophysin, glial fibrillary acidic protein (GFAP), and smooth muscle actin has been documented. Desmin and CD34 are rarely present (Pawel 2018).

24.13.3 Histopathology and Morphology Macroscopically, it presents as a red to white soft or firm mass, well-demarcated from surrounding parenchyma, with necrotic foci and hemorrhages. Microscopically, it is characterized by cells with rhabdoid features (abundant cytoplasm with eosinophilic inclusions and eccentric nuclei) with various components such as small embryonal cells, primitive neuroectodermal cells, and mesenchymal or epithelial cells. The immunophenotype is polyphenotypic. Proliferation markers show high mitotic activity with Ki-67 of 50–100%.

24.13.4 Imaging and Radiologic Features It presents as a heterogeneous mass with cysts, calcifications, and necrosis and often causes obstructive hydrocephalus. On CT scan, it appears as a heterogeneous hyperdense mass with contrast enhancement. On MRI, it may present hyperintense on T2 (for the cystic component) and get a strong heterogeneous enhancement on T1 sequences (Fig. 24.18).

24.13.5 Clinical Manifestations AT/RT typically affects the pediatric population, is very aggressive, and is invariably fatal. Due to its rapid growth and large size upon presentation, AT/RT often lead to intracranial hypertension requiring urgent intervention; it frequently

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Fig. 24.18 A rare case of atypical rhabdoid teratoid tumor of the pineal recess with incipient hydrocephalus in 18year-old boy. Tumor encased all deep venous structures

obstructs the hydrocephalus.

ventricular

system

causing

24.13.6 Therapeutic Approaches The treatment of AT/RT mainly stands on surgical resection (as much as possible), together with adjuvant chemo-radiotherapy. Despite surgical ability and radicality, its aggressive behavior, and lack of molecular targets to now, this tumor is considered incurable. Adjuvant radiotherapy is always recommended independently of the magnitude of resection. Multiple studies revealed that progression is proportional to delay in radiotherapy. Multiple studies have demonstrated improved outcomes with earlier timing of radiation (Chen et al. 2006; Lee et al. 2017; Pai Panandiker et al. 2012). Biopsy should be avoided at all costs since there is a high risk of bleeding after the procedure. As reported so far, the chemotherapeutic regimens for AT/RT are similar to sarcomas comprising of high-dose chemotherapy and hematopoietic stem cell rescue (HDSCT) which could be administered with or without intrathecal chemotherapy.

24.13.7 Follow-Up and Prognosis ATRT is an exceptionally aggressive neoplasm with a very poor prognosis; mean survival is esteemed to be 11 months (range 3–24 months).

The largest database reported an OS at 6 months, 1 year, and 5 years, respectively, of 65%, 46.8%, and 28.3% (Ostrom et al. 2014). Assumed the long-term toxicities associated with therapies, protocols should include a broad follow-up with experts in endocrinology, ophthalmology, and neuropsychology, as well as regular evaluations with a physiotherapist. If chemotherapeutic regimens utilizing agents that carry significant cardio- and pulmonary toxicity are utilized, longterm surveillance should be included. There are great expectations for new targeted therapies due to the progress in the ability to treat deregulated molecular pathways (Faragalla and Weinreb 2009).

24.14

Desmoplastic (Infantile) Astrocytoma/Ganglioglioma (DIA/DIG)

24.14.1 Background and Epidemiology It is a benign glioneural tumor that can be considered as WHO grade I. The histopathologic characteristics of these tumoral cells are prominent desmoplastic stroma with a neuroepithelial population restricted either to neoplastic astrocytes (DIA) or astrocytes with a mature neuronal component (DIG). It is a rare childhood tumor, representing 0.3% of all CNS tumors and 1.25% of childhood brain tumors. Age of incidence

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varies from 1 to 24 months; however, noninfantile cases, 5–25 years and older, have been reported as well. The male-to-female ratio is 1.5. It is commonly located in the supratentorial region, particularly in the frontal or parietal lobe. They may derive from embryonal neoplasms or develop from specialized subpial astrocytes (Bianchi et al. 2016).

24.14.2 Genetics, Immunology, and Molecular Biology Genetic alterations involve chromosome 1p, 3p, 3q, 5q, 7q, 9p, 11q, 14q, 21q, and 22q. Gangliogliomas in pediatric patients are known to harbor v-Raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutations, variably reported in 35%, 50%, and >60% of cases. It has been discovered recently a ganglion cell rich DIG with a rare, previously unreported BRAF V600D mutation (amino acid substitution at position 600 in BRAF, from a valine [V] to an aspartic acid [D]) rather than the far more common BRAF V600E (Greer et al. 2017; Hummel et al. 2012).

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with clear or xantochromic fluid. Microscopically, it is possible to distinguish: (1) desmoplastic leptomeningeal components with fibroblast-like spindle-shaped cells and pleomorphic neoplastic neuroepithelial cells, (2) poorly differentiated neuroepithelial components with predominant astrocytic tumors associated with neoplastic tumors, and (3) cortical components. The immunophenotype varies in different tumor components, as fibroblast-like cells are reactive for vimentin, neuroepithelial component for GFAP, and synaptophysin and fibrillar network for collagen type IV (Bianchi et al. 2016).

24.14.4 Imaging and Radiologic Features DIA/DIG appear as large tumors with solid and cystic components (the nodule is cortically located in contact with dura) and cystic components. On CT scans, they present as mixed hypodense and hyperdense components, with nodular contrast enhancement. On MRI, the cystic components appear hyperintense on T2, hypo- to isointense on T1 sequences; the nodular component is always isointense with marked contrast enhancement (Figs. 24.19 and 24.20).

24.14.3 Histopathology and Morphology 24.14.5 Clinical Manifestations Macroscopically, they present as firm, gray/white large masses with an extracerebral solid superficial part involving the leptomeninges and superficial cortex and uni- or multiloculated cysts filled

DIGs and DIAs are supratentorial tumors in the vast majority of cases; most are localized in the frontal and parietal lobes, In infants, typical

Fig. 24.19 T1 contrast enhanced right frontal cystico-nodular desmoplastic astrocytoma

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Fig. 24.20 T2, FLAIR, T1 basal MRI showing right frontal cystico-nodular desmoplastic astrocytoma

symptoms include rapid head growth often associated with a bulging of the anterior fontanel, sunset eye, and bulging of the bone structures over the tumor while in the older children the classic presentation is intracranial hypertension often associated with focal neurological signs. Seizures are not characteristics although are reported in almost 20% of the cases (Duffner et al. 1994; Hummel et al. 2012).

24.14.6 Therapeutic Approaches The treatment is surgical with a potential cure after gross total resection. Slow recurrence has been reported in those cases GTR was not achieved. Gross total resection might be limited by the strict adhesion of the tumor to the cortex and the dura, especially when involving eloquent or deep areas of the brain. In those cases and in the infants, intraoperative blood loss is a limiting factor for surgery. Complementary treatments such as chemo and radiotherapy are primarily not necessary unless recurrence or residual tumor growth has been documented; in such cases, if surgery is not an option, chemotherapy might be considered. Radiotherapy is not a therapeutic option before 5 years and is considered only in case of

inoperability, growth, and recurrence after chemotherapy. Identifying any type of BRAF mutation in a DIA/DIG opens a new chance of treatment and should be assessed (Hummel et al. 2012).

24.14.7 Follow-Up and Prognosis Although normally DIA and DIG are associated with good prognosis and long progression-free survival, an aggressive behavior has been rarely described; a slight difference has been reported in literature among the higher incidence of malignant evolution between DIA and DIG; indeed DIAs have a prevalent astrocytic component which shows an emblematic tendency to malignant transformation concerning tumors of neuronal origins. Typical markers of potential malignancy are not different from the ones seen in other forms of aggressive supratentorial gliomas, including necrosis, mitosis, neovascularization, and the evidence at diagnosis of cerebrospinal metastasis. Complementary treatments are primarily not advocated unless recurrence or residual tumor growth has been documented; in such cases, if surgery is not an option, chemotherapy might be considered (Bianchi et al. 2016).

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24.15

Choroid Plexus Papilloma, Atypical Choroid, and Carcinoma of Plexus (CPPs)

24.15.1 Background and Epidemiology It is a ventricular papillary neoplasm derived from choroid plexus epithelium; a structure made from tufts of villi within the ventricular system that produces cerebrospinal fluid (CSF). It ranges from choroid plexus papillomas (WHO Grade 1), atypical (WHO Grade 2), to choroid plexus carcinomas (WHO Grade 3). Its annual incidence is 0.3 per 1 million population per year, and it represents 0.3–0.6% of all brain tumors. Median age varies with location (1.5 years for tumors in the lateral and third ventricles, 22 years for tumors in the fourth ventricle, and 35 years for tumors in the cerebellopontine angle). So that patients under 1 year of age represent 10–20% of the total and patients under 15 years of age 2– 4%. It is slightly more frequent in males, above all tumors located in the fourth ventricle. It may occur in lateral ventricles (50%), fourth ventricle (40%), third ventricle (5%), and cerebellopontine angle (5%). In 5% of cases, more than one ventricle is involved. In adults, these tumors are usually infratentorial, whereas, in children, they tend to occur supratentorially in the lateral ventricle with a predilection for the left side (Joseph and Das 2021; Louis et al. 2007).

24.15.2 Genetics, Immunology, and Molecular Biology A 2006 study points to the role of a transmembrane receptor protein (NOTCH3) in the pathogenesis of human choroid plexus tumors. The NOTCH pathway has been increasingly documented in human cancers and is expressed in ventricular zone progenitor cells in the fetal brain and functions as an oncogene if activated (Dang et al. 2006). Indeed CPPs seems to be associated especially with the Li-Fraumeni and

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the Aicardi syndromes. Of note, experimental studies have shown that Simian virus (SV) 40 has an association with the occurrence of choroid plexus tumors as well as BK virus and John Cunningham (JC) viruses; however, recent data do not conclude about their causative role in humans (Okamoto et al. 2005; Zhen et al. 1999).

24.15.3 Histopathology and Morphology This tumor is a circumscribed mass that is attached to the ventricular wall and welldelineated from the brain tissue. Microscopically, it has a single layer of epithelial cells with underlying connective tissue. The immunophenotype is positive for cytokeratins, vimentin, transthyretin, S100, and GFAP. A low mitotic activity can be seen in this tumor.

24.15.4 Imaging and Radiologic Features On CT scan, it presents as an iso- to hyperdense lesion with common calcifications. It may cause hydrocephalus. It is characterized by strong contrast enhancement. On MRI, it may present hyperintense on T2 and hypointense on T1 sequences with strong homogeneous enhancement (Figs. 24.21, and 24.22). Flow voids are seen, indicating active blood flow. In newborns and infants, transfontanellar ultrasound demonstrates echogenic mass within the ventricles that with Doppler signal shows bidirectional flow throughout the diastole, indicating blood flow through vessels flows indiscriminately.

24.15.5 Clinical Manifestations It may present with seizures, subarachnoid hemorrhage, or focal neurological deficit such as hemiparesis, sensory deficit, cerebellar signs, or cranial nerve palsies. Hydrocephalus is the most

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Fig. 24.21 Preoperative MRI showing a IV Ventricle Carcinoma of Choroid Plexus (Grade III WHO)

Fig. 24.22. 2-year follow-up MRI showing a completely resected IV Ventricle Carcinoma of Choroid Plexus (Grade III WHO) with no PD

common presentation due to obstruction of CSF outflow or communicating hydrocephalus due to overproduction of CSF. Infants, especially those with a tumor located in the third ventricle, can present with hydrocephalus or macrocephaly, as well as associated increased intracranial pressure (Joseph and Das 2021).

24.15.6 Therapeutic Approaches There are two different viable options, especially in incidentally discovered tumors: elective surgical removal or planning for an active follow-up until the development of hydrocephalus; since after hydrocephalus, it is easier to remove the

tumor as the length of the corridor to the ventricles reduces and space around the tumor increases. The disadvantage of the second strategy is that patients may develop cognitive deficits as well as focal neurological deficits due to mass effects or even seizures, although rare. Gross total resection (GTR) is always recommended if viable, since CPPs are benign neoplasms and complete cure should be obtained with surgery. Postoperative complications include major blood loss that in the pediatric population can be a cause of postoperative death; thus, in selected cases, preoperative embolization should be considered. In adults, subdural collections from persistent ventriculo-subdural fistula have been described. There is no role for

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chemotherapy or radiotherapy for WHO grade I lesions. Gross total resection leads to the best possible result even in the case of 2 and 3-grade CPPs. Radiosurgery should be considered as an accompanying strategy in case of disease residue. Adjuvant chemotherapy increases survival in the treatment of choroid plexus carcinoma and may be indicated for aggressive disease. Anti-VEGF such as bevacizumab has been used in the case of leptomeningeal carcinomatosis with some results. Residual hydrocephalus should be treated depending on its persistence since it often resolves following the removal of the mass (Joseph and Das 2021).

24.15.7 Follow-Up and Prognosis GTR correlates with an increase in both PFS and OS. Recurrences are uncommon. Metastases and craniospinal seeding, though rare, have been reported in grade 3 carcinomas and bear a grim prognosis (Abdulkader et al. 2016; Safaee et al. 2013).

24.16

Conclusion

Tumors presented in this chapter are rather heterogeneous in their behavior but are characterized by peculiar genetic pathways that made them unique. With the renewed ability to collect new insights about the mechanisms that cause tumor growth, new target therapies which could cure these tumors are at the door. The pivotal role of genetic pathways is witnessed by the central role acquired in the new classification of CNS tumors; indeed some tumors received new names or have been identified with their specific mutation to address future specific treatments. We undertook a long and arduous road, but it seems that we are on the good ones.

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Brain and/or Spinal Cord Tumors Accompanied with Other Diseases or Syndromes Jody Filippo Capitanio and Pietro Mortini

Abstract

Several medical conditions that interest both the brain and the spinal cord have been described throughout the history of medicine. Formerly grouped under the term Phacomatosis because lesions of the eye were frequently encountered or genodermatosis when typical skin lesions were present, these terms have been progressively discarded. Although originally reported centuries ago, they still represent a challenge for their complexity of cure. Nowadays, with the introduction of advanced genetics and the consequent opportunity of whole-genome sequencing, new single cancer susceptibility genes have been identified or better characterized; although there is evidence that the predisposition to a few specific tumor syndromes should be accounted to a group of mutations in different genes while certain syndromes appeared to be manifestations of different mutations in the same gene adding supplementary problems in their characterization and establishing the diagnosis. Noteworthy, many syndromes have been genetically

determined and well-characterized, accordingly in the near future, we expect that new targeted therapies will be available for the definitive cure of these syndromes and other gliomas (Pour-Rashidi et al. in World Neurosurgery, 2021). The most common CNS syndromes that will be discussed in this chapter include neurofibromatosis (NF) types 1 and 2, von Hippel-Lindau (VHL) disease, and tuberous sclerosis complex (TSC), as well as syndromes having mostly extra-neural manifestations such as Cowden, Li-Fraumeni, Turcot, and Gorlin syndromes. Keywords

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Neurofibromatosis I Neurofibromatosis II Cavernomatosis cerebri Tuberous sclerosis Gorlin syndrome Turcot syndrome Li-Fraumeni syndrome Cowden syndrome MEN1 Carney complex syndrome McCune-albright syndrome Von Hippel-Lindau Ollier disease Maffucci syndrome Werner syndrome

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25.1 J. F. Capitanio (&) . P. Mortini Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy e-mail: capitanio.jodyfi[email protected] P. Mortini e-mail: [email protected]

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Introduction

Brain and spinal cord tumors have diverse histopathologic, genetic, imaging characteristics, and different prognosis and survival outcomes. Although each of these pathologies were discussed in detail in the previous chapters of this book, it is worthy to note that some of the CNS

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tumors may occur as part of the manifestation of a genetic syndrome. Therefore, the patients may present not only with signs and symptoms of CNS tumors but also with manifestations of other organ involvements. Accordingly, it is necessary to know these syndromes, in order to better understand the extent of diseases in patients as well as take a multidisciplinary approach to treat them. The current chapter has discussed some of these diseases and syndromes which could be accompanied by CNS tumors, including Neurofibromatosis I, Neurofibromatosis II, Cavernomatosis Cerebri, Tuberous Sclerosis, Gorlin Syndrome, Turcot Syndrome, Li-Fraumeni syndrome, Cowden syndrome, MEN1, Carney Complex Syndrome, McCune-Albright syndrome, von Hippel-Lindau, Ollier disease, Maffucci syndrome, and Werner Syndrome.

25.2

Cavernomas of Brain and Spinal Cord

25.2.1 Cavernomatosis Cerebri (CC) 25.2.1.1 Background and Epidemiology Cerebral Cavernous Malformations (CCM), also called cavernous angiomas or cavernomas, are vascular lesions characterized by irregular capillary tangles without intervening functional brain parenchyma. CCMs occur both as sporadic and familial conditions (Toll et al. 2009). CCMs could be located everywhere in the central nervous system. Their prevalence is estimated to be around 0.5% (Salman et al. 2008). 25.2.1.2 Genetics, Immunology, and Molecular Biology Sporadic cavernomas are isolated lesions easily diagnosed with magnetic resonance imaging and do not carry a germline mutation in any of the three CCM genes (CCM 1,2,3), while multiple lesions are commonly observed in familial cases with increasing numbers through the patients’ lifetime. Inherited CCMs are the result of an AD mutation in one of the described genes (CCM

1,2,3) that exhibit an incomplete clinical and neuroradiological penetrance, indeed the number and extension of CCMs are different specifically from one patient to another. The recent identification of the 3 genes implicated in CCM development offered the opportunity to better understand their behavior. It appears that patients with CCM3 mutations are more prone than CCM1 and CCM2 to develop cerebral hemorrhages at a younger age, although this observation still has to be confirmed. Of note, a highly specific association with multiple meningiomas has been also observed in patients with CCM3 mutation. Genetic investigations of familial forms of CCM have demonstrated that affected patients bear a heterozygous loss-of-function germline mutation in one of the three CCM genes. Indeed, CCMs only are developed when a second, somatic mutation affects the wild-type allele within the endothelial cells. Nevertheless, many pathways that contribute to pathology have been implicated by a combination of functional studies, transcriptomics, and pharmacological suppression screens, which suggest novel therapeutic options (Abdelilah-Seyfried et al. 2020).

25.2.1.3 Histopathology and Morphology The histologic features of cavernomas include closely opposed hyalinized vessels/cystic vascular spaces lined by endothelial cells without any intervening neural parenchyma. The vessel walls are typically comprised of fibrous tissue without smooth muscle. Hemorrhage, reactive gliosis, and calcification, as well as intravascular thrombi, should be encountered occasionally. 25.2.1.4 Imaging and Radiologic Features By definition, cavernous malformations were originally described as angiographically occult masses that do not demonstrate arteriovenous shunting. Angiography is not generally recommended, except in the case of differential diagnosis with hemangioblastomas or other vascular lesions. On CT scan, unless large, CCMs are difficult to be detected as they do not enhance. If

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Brain and/or Spinal Cord Tumors Accompanied with Other Diseases or Syndromes

large enough, they appear as mild to moderate hyperdense zones with or without calcifications. Lesions are more conspicuous and may be surrounded by a mantle of edema if they have already bled. On MRI, they look like popcorns or berries with a rim of signal loss due to hemosiderin pad. T1 and T2 images, the signal depends on the age of the blood products, also fluid–fluid levels may be evident in some cases. White matter edema may be present if a recent hemorrhage occurred. GRE T2*/SWI MRI sequence is extremely useful for detecting tiny CCMs that should be otherwise missed by conventional spin-echo sequences. This sequence is particularly useful in patients with a familial history or those with multiple CCMs. Contrast-enhanced T1 generally does show enhancement, although 20–30% of cavernomas show otherwise. Of note, cavernous malformations can be grouped into 4 types based on MRI appearances using the Zabramski classification (Zabramski et al. 1994) that date timing of hemorrhage or state their shape: Type 1 are those with subacute hemorrhage, Type 2 CCMs that look like popcorns, Type 3 those with old signs of hemorrhage, while type 4 CCMs are those that appear in the white matter with multiple punctate micro hemorrhages. Care must be given since these classifications date back to 1994, prior to the development of the GRE T2/SWI sequence, thus, at that time, several punctate microhemorrhage would be confused with other causes, thus several authors pointed out that type 4 CCMs are those that emerge in GRE/SWI sequence.

25.2.1.5 Clinical Manifestation The principal manifestations of CCMs are epileptic seizures and intracerebral hemorrhages, though symptomatology highly depends on the cavernous malformation location (cerebral parenchyma, brainstem, spinal cord, cauda roots). Progressive or acute myelopathy and radiculopathy are the typical symptoms of spinal cord CCMs. Sporadic cases with a solitary lesion could sometimes remain asymptomatic throughout the entire life though, familial counterparts manifest in almost 50–60% of the cases. Usually, the age of onset in symptomatic individuals is

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around 30, but symptoms can start during childhood or very late in elderly people as well. CCM-related epilepsy is defined as seizure in patients with at least one lesion and evidence of seizure referable to the anatomic location of the CA. In 2011, Josephson et al. reported a 5-year risk of first-ever seizures of 6% in symptomatic CAs and 4% in asymptomatic CAs. The intracranial hemorrhage associated to CCM is considered as acute or subacute onset symptoms including headache, epileptic seizure, impaired consciousness, or new/worsened functional neurological deficits along with radiological, pathological, or surgical evidence of recent extralesional or intralesional hemorrhage (Salman et al. 2008). Different studies have been conducted to estimate the annual or 5-year risk of intracerebral hemorrhages and to characterize the natural history of CCM. The annual hemorrhagic risk is estimated between 0.6 and 6.7% per year. Previous hemorrhage and location in the brainstem seem to increase hemorrhagic risk up to 29.5% and 60%, respectively, while for first intracranial hemorrhage, this risk ranges between 0.4% and 2.4%, respectively (Akers et al. 2017).

25.2.1.6 Therapeutic Approaches Of relevance, intraoperative ultrasound (IOUS) recently demonstrated an almost 100% sensitivity in the identification of CCM and is recommended whenever possible (Barzaghi et al. 2018). Moreover, it was extremely valuable to immediately ascertain the total excision of CA at the end of the surgical procedure. Currently, available therapies include symptomatic treatment of epileptic seizures with antiepileptic drugs when surgery is not deemed possible and surgical resection whenever possible. In case of deeply seated lesions being poorly accessible, radiosurgery is sometimes discussed but its indication is not established. In general, the purpose of cavernomas surgery must be to give the chance of recovery of the preoperative functions lost, minimize iatrogenic morbidity, and nullify the hemorrhagic risk rate as well as offer a prolonged rehabilitative period after hospital discharge.

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25.2.2 Spinal Cord Cavernomas CMs in the spinal cord should be located ubiquitously; they frequently are intradural though they have been described outside of it but in the spinal canal. The lesion could be located in the central zone, anterior, posterior, and lateral; they should also be exophytic. They could even be found beneath the conus medullaris. They could manifest with hematomyelia, intralesional hemorrhage, or as a discrete mass exerting compression on neural structures without acute hemorrhage; rather with progressive myelopathy.

25.2.3 Cavernomatosis Cerebri In the case of familiar cavernomatosis cerebri, the physician must take several important considerations to account: family history must be characterized, lineage determined, and progenies screened since as reported before, the anticipation phenomenon is representative. Furthermore, different mutations bear the different risks of hemorrhage as mentioned before. Counseling for future generations should be proposed as well. It is essential to consider that the number, size, exact location, and the progressive enlargement due to previous hemorrhagic episodes may lead to distinction between symptomatic and nonsymptomatic CCMs and this matter should be noted in surgical removals. Post-operative neurological deficits depend largely on the surgical corridor and the technique. Another crucial reflection is that the burden of CCMs during life could progressively increase: CCMs could increase in number and size and become symptomatic.

25.2.4 Brain Cavernomas Recent guidelines stated that surgical removal must be considered in patients with CCM-related epilepsy, given the rate of seizure control of 70– 90% in patients with sporadic seizures or those with a seizure duration