Oncology of CNS Tumors, 2nd Ed

Oncology of CNS Tumors

Jörg-Christian Tonn Manfred Westphal James T. Rutka (Eds.)

Oncology of CNS Tumors Second edition

Jörg-Christian Tonn, MD Universitätsklinikum München Klinikum Großhadern Neurochirurgische Klinik Marchioninistr. 15 81377 München Germany [email protected]

J. T. Rutka, MD The Hospital for Sick Children Division of Neurosurgery 555 University Avenue Suite 1502 Toronto ON M5G 1X8 Canada [email protected] [email protected]

Manfred Westphal, MD Universitätsklinikum Hamburg Krankenhaus Eppendorf Klinik und Poliklinik für Neurochirurgie Neurologie Martinistr. 52 20246 Hamburg Germany [email protected] [email protected]

ISBN: 978-3-642-02873-1

e-ISBN: 978-3-642-02874-8

DOI: 10.1007/978-3-642-02874-8 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009931700 © Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, 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. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudio Calamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface CNS Textbook, 2nd Edition

Sooner than expected, the first edition of this book has sold out. The fact that the book was so well received shows that there is a demand for a comprehensive, practiceoriented textbook of neuro-oncology. This is all the more true today as there have been many more advances in the diagnosis and treatment of patients with brain tumors than in prior decades. A number of these advancements can be attributed to the use of translational medicine for which there is now good scientific rationale. For this reason a comprehensive revision of the first edition had become necessary. We wish to express our thanks to all authors for the timely revision of their chapters. New topics have been included, such as targeted therapy, radiosurgical treatment of spinal tumors, and also an extensive chapter on palliative medicine and palliative care. Medicine today is maintained through constant dialogue and continuous improvements – therefore, we would appreciate your comments and suggestions for amendments, also concerning the second edition. On this occasion we would like to thank in particular Ms. Ilona Anders (University of Munich, LMU) for her excellent assistance in coordinating and editing the book. In the same way the editors thank Springer-Verlag and its team for their superb cooperation and professional support in publishing this second edition. J.-C. Tonn M. Westphal J.T. Rutka

v

Preface to the 1st Edition

Knowledge about the etiology and diagnosis as well as treatment concepts of neurooncologic diseases is rapidly growing. This turnover of knowledge makes it difficult for the physician engaged in the treatment to keep up to date with current therapies. This book sets out to close the gap and pursues several innovative concepts. As a comprehensive text on neuro-oncology, its chapters are interconnected, but at the same time some chapters or subdivisions are so thoroughly assembled that the whole volume gives the impression of several books combined into one. Neuropathology is treated in an extensive and clearly structured section. The interested reader finds for each tumor entity the latest well-referenced consensus regarding histologic and molecular pathology. Through this “book-in-the-book” concept, information on neuropathology is readily at hand in a concise form and without overloading the single chapters. Pediatric neuro-oncology differs in many entities from tumors in adult patients; also, certain tumors of the CNS are typically or mainly found only in the child. Therefore, pediatric neuro-oncology was granted its own, book-like section. Tumor entities that are treated differently in children and adults are included both in the pediatric neuro-oncology section and in the general section. Entities that typically occur only in the child and adolescent are found in the pediatric section in order to avoid redundancies. Chapters in this book are divided according to practical clinical needs. On the one hand, tumor location was selected as the ordering principle for several chapters (i.e., skull base tumors, hypophyseal adenoma, orbital tumors, spinal tumors, or tumors of the peripheral nerves). On the other hand, division according to histology or tumor type was chosen where this appeared clinically appropriate (astrocytic tumors, lymphomas, hemangioblastomas, etc.). A chapter on general care concludes the book. In order to facilitate orientation on the part of the reader, all chapters (with the exception of neuropathology) adhere to a uniform scheme, intended to be pragmatic for the clinician. This should simplify use of the book in everyday clinical practice. All contributions have been written by excellent international professionals, renowned specialists in their field. Medicine today is nurtured by dialogue; therefore, the editors would appreciate constructive critique and suggestions for improvements, as well as positive reactions. We wish the book to become a topical and practical daily reference for all those interested in neuro-oncology. This work could not have been accomplished without the exceptional commitment of many persons. In particular, Ms. Ilona Anders (University of Munich, LMU) and

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Preface

Ms. Meike Stoeck (Springer) were of invaluable assistance in editing and professionally coordinating the book, not to forget the superb cooperation in terms of format and layout of the volume. The editors deeply acknowledge their assistance and all other contributions that helped generate this book. J.-C. Tonn M. Westphal J.T. Rutka S.A. Grossman

Contents

Part I

Cranial Neuro-Oncology

1

Pathology and Classification of Tumors of the Nervous System . . . . . Guido Reifenberger, Ingmar Blümcke, Torsten Pietsch, and Werner Paulus

2

Targeted Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Manfred Westphal and Katrin Lamszus

77

3

Tumors of the Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roland Goldbrunner

87

4

Meningiomas and Meningeal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . Manfred Westphal, Katrin Lamszus, and Jörg-Christian Tonn

95

5

Low-Grade Astrocytomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nader Sanai and Mitchel S. Berger

119

6

Stereotactic Brachytherapy in Low-Grade Gliomas . . . . . . . . . . . . . . Friedrich W. Kreth and Jan H. Mehrkens

135

7

High-Grade Astrocytoma/Glioblastoma . . . . . . . . . . . . . . . . . . . . . . . . Jon D. Weingart, Matthew J. McGirt, and Henry Brem

147

8

Oligodendroglioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Silvia Hofer, Caroline Happold, and Michael Weller

163

9

Ependymomas and Ventricular Tumors . . . . . . . . . . . . . . . . . . . . . . . . Manfred Westphal

171

10

Medulloblastoma-PNET, Craniopharyngioma Adult Tumors of Pediatric Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aurelia Peraud, Jörg-Christian Tonn, and James T. Rutka

11

Glioneuronal Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Matthias Simon, Rudolf A. Kristof, and Johannes Schramm

3

189

195

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Contents

12

Inactive Adenomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John A. Jane Jr, Aaron S. Dumont, Jason P. Sheehan, and Edward R. Laws Jr

211

13

Functioning Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dieter K. Lüdecke, Takumi Abe, Jörg Flitsch, Stephan Petersenn, and Wolfgang Saeger

219

14

Tumors of the Pineal Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yutaka Sawamura, Ivan Radovanovic, and Nicolas de Tribolet

239

15

Tumors of the Cranial Nerves. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Berndt Wowra and Jörg-Christian Tonn

251

16

Hemangioblastoma and Von Hippel–Lindau Disease. . . . . . . . . . . . . . Juha E. Jääskeläinen and Mika Niemelä

269

17

Tumors of the Skull Base. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kadir Erkmen, Ossama Al-Mefty, and Badih Adada

279

18

Orbital Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christoph Hintschich and Geoff Rose

309

19

Primary CNS Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joachim M. Baehring, Uwe Schlegel, and Fred H. Hochberg

331

20

Brain Metastasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zeena Dorai, Raymond Sawaya, and W. K. Alfred Yung

345

Part II

Pediatric Neuro-Oncology

21

Neurocutaneous Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul Kongkham and James T. Rutka

365

22

Supratentorial Hemispheric Low-Grade Gliomas in Children . . . . . . Paul Chumas and Atul Tyagi

385

23

Optic Gliomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ian F. Pollack and Regina I. Jakacki

395

24

Thalamic Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christian Sainte-Rose, Darach W. Crimmins, and Jacques Grill

405

25

Midbrain Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leland Albright and Brandon G. Rocque

419

26

Supratentorial High-Grade Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . Phiroz E. Tarapore, Anu Banerjee, and Nalin Gupta

427

Contents

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27

Ganglioglioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concezio Di Rocco and Gianpiero Tamburrini

435

28

Cerebellar Astrocytomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David F. Bauer and John C. Wellons III

445

29

Diffuse Intrinsic Pontine Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Milind Ronghe, Takaaki Yanagisawa, and Eric Bouffet

453

30

Dorsally Exophytic Brain Stem Gliomas . . . . . . . . . . . . . . . . . . . . . . . . Ian D. Kamaly-Asl and James M. Drake

461

31

Cervicomedullary Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey C. Mai and Richard G. Ellenbogen

467

32

Desmoplastic Infantile Gangliogliomas . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey P. Blount and David F. Bauer

477

33

Pleomorphic Xanthoastrocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jean-Pierre Farmer and Michele Parolin

483

34

Hypothalamic Hamartoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey V. Rosenfeld and A. Simon Harvey

491

35

Ependymomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nicholas Wetjen and Corey Raffel

503

36

Medulloblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shobhan Vachhrajani and Michael D. Taylor

513

37

Supratentorial Primitive Neuroectodermal Tumors. . . . . . . . . . . . . . . Ash Singhal, Shahid Gul, and Paul Steinbok

525

38

Dysembryoplastic Neuroectodermal Tumors . . . . . . . . . . . . . . . . . . . . Aurelia Peraud, Jörg-Christian Tonn, and James T. Rutka

533

39

Meningiomas in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abhaya V. Kulkarni and Patrick J. McDonald

539

40

Pineal Region Tumors in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anna J. Janss and Timothy B. Mapstone

545

41

Pituitary Tumors in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nader Pouratian, Aaron S. Dumont, Jay Jagannathan, and John A. Jane Jr

553

42

Craniopharyngiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rémy van Effenterre and Anne-Laure Boch

559

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Contents

43

Intracranial Germ Cell Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kyu-Chang Wang, Seung-Ki Kim, Sung-Hye Park, In-One Kim, Ji Hoon Phi, and Byung-Kyu Cho

571

44

Choroid Plexus Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul Kongkham and James T. Rutka

587

45

Malignant Rhabdoid Tumors of the CNS . . . . . . . . . . . . . . . . . . . . . . . Michael R. Carter

597

46

Langerhans Cell Histiocytosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Walter J. Hader and Clare Gallagher

607

47

Tumors of the Skull Base in Children . . . . . . . . . . . . . . . . . . . . . . . . . . Eve C. Tsai, Gregory Hawryluk, and James T. Rutka

615

48

Tumors of the Cranial Vault in Children. . . . . . . . . . . . . . . . . . . . . . . . John R. W. Kestle

629

49

Epidural Spinal Tumors in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . Krystal Thorington, Colin Kazina, and Patrick McDonald

637

50

Spinal Column Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joshua J. Chern, Andrew Jea, William E. Whitehead, and Anna Illner

645

51

Pediatric Spinal Intradural Extramedullary Tumors . . . . . . . . . . . . . Peter Dirks

663

52

Intramedullary Spinal Tumors in Children . . . . . . . . . . . . . . . . . . . . . John S. Myseros

667

53

Peripheral Nerve Tumors in Children . . . . . . . . . . . . . . . . . . . . . . . . . . Forrest Hsu and Rajiv Midha

675

Part III

Spinal Neuro-Oncology

54

Intramedullary Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Manfred Westphal

689

55

Intradural Extramedullary Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . Roland Goldbrunner

709

56

Epidural Tumors and Metastases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rory J. Petteys, Wesley Hsu, Carlos A. Bagley, and Ziya L. Gokaslan

719

57

Spinal Robotic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alexander Muacevic, Bernd Wowra, and Jörg-Christian Tonn

739

Contents

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Part IV 58

Peripheral Nerve Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joseph Wiley, Asis Kumar Bhattacharyya, Gelareh Zadeh, Patrick Shannon, and Abhijit Guha

Part V 59

60

Peripheral Nerve Tumors 747

Systemic and General Aspects of Neuro-Oncology

General Care of Patients with Cancer Involving the Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stuart A. Grossman

771

Palliative Care in Neuro-Oncology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. D. Borasio, C. Bausewein, S. Lorenzl, R. Voltz, and M. Wasner

783

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

789

Contributors

B. Adada University of Arkansas, 4301 W. Markham St., Slot 507, 72205-7101, Little Rock, AR, USA A. L. Albright Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA e-mail: [email protected] O. Al-Mefty Department of Neurosurgery, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Slot 507, Little Rock, AR 72205, USA e-mail: [email protected] J. M. Baehring Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, TMP 412, New Haven, CT 06510, USA e-mail: [email protected] C. A. Bagley Department of Neurosurgery, The Johns Hopkins University, 600 North Wolfe Street, Meyer Building 8-161, Baltimore, MD 21287, USA A. Banerjee Department of Neurologic Surgery and Pediatrics, University of California, San Francisco, CA 94143-0112, USA D. F. Bauer Division of Neurosurgery, University of Alabama, Birmingham, AL, USA C. Bausewein Department of Palliative Care, King’s College, London, UK M. S. Berger Department of Neurological Surgery, University of California, at San Francisco, 505 Parnassus Avenue, M-779, P.O. Box 0112, San Francisco, CA 94143, USA e-mail: [email protected] A. K. Bhattacharyya Department of Neurosurgery, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada J. P. Blount Children’s Hospital of Alabama, 1600 7th Avenue S, ACC 400, Birmingham, AL 35233, USA e-mail: [email protected] I. Blümcke Department of Neuropathology, Friedrich-Alexander-University, Krankenhausstrasse 8-10, 91054 Erlangen, Germany e-mail: ingmar.blü[email protected]

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A.-L. Boch Department of Neurosurgery, Group Hospitalier Pitié-Salpêtrière, 91, 105 Boulevard de l’Hôpital, 75013, Paris, France e-mail: [email protected] G. D. Borasio Palliative Medicine, Interdisciplinary Center for Palliative Medicine, Munich University Hospital, Grosshadern, 81366 Munich, Germany e-mail: [email protected], www.izp-muenchen.de E. Bouffet Director, Paediatric Neuro-Oncology Program, Professor of Paediatrics, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada e-mail: [email protected] H. Brem Department of Neurosurgery, The Johns Hopkins Hospital, 600 N Wolfe Street, Baltimore, MD 21287, USA e-mail: [email protected] M. R. Carter Department of Neurosurgery, Frenchay Hospital, Frenchay Park Road, Bristol BS16 1LE, UK e-mail: [email protected] J. J. Chern Division of Pediatric Neurosurgery, Department of Neurosurgery, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA B.-K. Cho Division of Pediatric Neurosurgery, Seoul National University, Children’s Hospital, 28 Yongon-dong, Chongno-gu, 110-744 Seoul, Korea P. Chumas Department of Neurosurgery, Leeds General Infirmary, Leeds LS1 3EX, UK e-mail: [email protected] D. W. Crimmins Department of Neurosurgery, Leeds General Infirmary, Leeds/West Yorkshire, LS1 3EX, UK N. de Tribolet Division of Neurosurgery, University Hospitals of Geneva and University of Geneva, Rue Micheli-du-Crest 24, 1211 Geneva, Switzerland e-mail: [email protected] C. Di Rocco Pediatric Neurosurgery, UCSC, Policlinico Gemelli, Largo Gemelli 8, 00168 Rome, Italy e-mail: [email protected] P. Dirks Division of Neurosurgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada e-mail: [email protected] Z. Dorai Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA J. M. Drake Pediatric Neurosurgery, The Hospital for Sick Children, Toronto, Canada e-mail: [email protected] A. S. Dumont Department of Neurosurgery, University of Virginia Health System, Box 800212, 22903, Charlottesville, VA, USA e-mail: [email protected]

Contributors

Contributors

xvii

R. G. Ellenbogen Department of Neurological Surgery, University of Washington, School of Medicine, 325 Ninth Avenue, Seattle, WA 98104, USA e-mail: [email protected] K. Erkmen University of Arkansas, 4301 W. Markham St., Slot 507, 72205-7101, Little Rock, AR, USA J.-P. Farmer Department of Pediatric Surgery, The Montreal Children’s Hospital, McGill University Health Centre, 2300 Tupper Street, Montreal, QC H3H 1P3, Canada e-mail: [email protected] J. Flitsch Neurochirurgische Klinik, Universitätskrankenhaus, Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany e-mail: [email protected] C. Gallagher University of Calgary, Alberta’s Childrens Hospital, 1820 Richmond Rd. SW, Calgary, Alberta, T2T 5C7, Canada e-mail: [email protected] Z. L. Gokaslan Department of Neurosurgery, The Johns Hopkins University, 600 North Wolfe Street, Meyer Building 8-161, Baltimore, MD 21287, USA e-mail: [email protected] R. Goldbrunner Klinik für Allgemeine Neurochirurgie, Zentrum für Neurochirurgie, Uniklinikum Köln, Kerpener Str. 62, 50937 Köln, Germany e-mail: [email protected] J. Grill Institut Gustave-Roussy, 94805 Villejuif, France e-mail: [email protected] S. A. Grossman Cancer Research Building 2, Suite 1M-16, The Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA e-mail: [email protected] A. Guha Department of Neurosurgery, Western Hospital, University of Toronto, 4W-446-399 Bathurst Street, Toronto, Ontario, M5T-2S8, Canada e-mail: [email protected] S. Gul Department of Surgery, British Columbia’s Children’s Hospital, 4480 Oak Street, Vancouver, B.C., V6H 3V4, Canada N. Gupta UCSF Neurosurgery, 505 Parnassus Avenue, Room M779, San Francisco, CA 94143-0112, USA e-mail: [email protected] W. J. Hader Division of Neurosurgery, Alberta’s Childrens Hospital, University of Calgary, 1820 Richmond Rd SW, Calgary, Alberta T2T 5C7, Canada e-mail: [email protected] C. Happold Universitätsspital Zürich, Neurologische Klinik, Frauenklinikstr. 26, 8091, Zürich, Switzerland e-mail: [email protected] A. S. Harvey Children’s Epilepsy Program, Department of Neurology, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia

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G. Hawryluk Division of Neurosurgery, The University of Toronto, The Hospital for Sick Children, Suite 1504, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada C. Hintschich Augenklinik der Universität München, Mathildenstr. 8, 80336 München, Germany e-mail: [email protected] F. H. Hochberg Massachusetts General Hospital, Brain Tumor/Oncology Center, Yawkey 9010, Boston, MA 02114, USA e-mail: [email protected] S. Hofer Medical Oncology, University Hospital Zürich, Rämistr. 100, 8091 Zürich, Switzerland F. Hsu Division of Neurosurgery, University of Calgary, Foothills Medical Center, Rm C1243-1403, 29th St NW, Calgary, AB T2N 2T9, Canada e-mail: [email protected] W. Hsu Department of Neurosurgery, The Johns Hopkins University, 600 North Wolfe Street, Meyer Building 8-161, Baltimore, MD 21287, USA e-mail: [email protected] A. Illner Division of Pediatric Neuroradiology, Department of Radiology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA J. E. Jääskeläinen Neurosurgery, Kuopio University Hospital, Kuopio, Finland e-mail: [email protected] J. Jagannathan Department of Neurosurgery, University of Virginia Health System, Box 800212, Charlottesville, VA 22908-0711, USA R. I. Jakacki Department of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA e-mail: [email protected] J. A. Jane Jr Department of Neurosurgery, University of Virginia Health, System, P.O. Box 800212, Charlottesville, VA 22908-0711, USA e-mail: [email protected] A. J. Janss Emory University, Aflac Children’s Cancer and Blood Disorders Center, 1405 Clifton Road NE, Atlanta, GA 30322, USA A. Jea Division of Pediatric Neurosurgery, Department of Neurosurgery, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA I. D. Kamaly-Asl North West Deanery Greater Manchester Neuroscience Centre, Salford Royal Hospital, Manchester, M6 8HD, UK e-mail: [email protected] C. Kazina Section of Neurosurgery, University of Manitoba, Winnipeg Children’s Hospital, 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada J. R. W. Kestle Division of Pediatric Neurosurgery, Primary Children’s Medical Center, 100 North Medical Drive, Salt Lake City, UT 84103, USA e-mail: [email protected]

Contributors

Contributors

xix

I.-O. Kim Department of Diagnostic Radiology, Seoul National University, Children’s Hospital, 28 Yongon-dong, Chongno-gu, 110-744 Seoul, Korea S.-K. Kim Division of Pediatric Neurosurgery, Seoul National University, Children’s Hospital, 29 Yongon-dong, Chongno-gu, 110-745 Seoul, Korea P. Kongkham Division of Neurosurgery, University of Toronto, Toronto, ON M5G 1L5, Canada e-mail: [email protected] F. W. Kreth Neurochirurgische Klinik und Poliklinik, Klinikum, Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany e-mail: [email protected] R. A. Kristof Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany e-mail: [email protected] A. V. Kulkarni Division of Neurosurgery, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada e-mail: [email protected] K. Lamszus Neurochirurgische Klinik, Universitätskrankenhaus Eppendorf, Martinistr. 52, 20246, Hamburg, Germany E. R. Laws Jr Stanford University, Stanford, USA e-mail: [email protected] S. Lorenzl Interdisziplinäres Zentrum für Palliativmedizin, Marchioninistrasse 15, 81377 München, Germany e-mail: [email protected] D. K. Lüdecke Neurochirurgische Klinik, Universitätskrankenhaus, Eppendorf, Martinistrasse 52, 20246 Hamburg, and HNOKlinik, Marienkrankenhaus Alfredstrasse 9, 22087 Hamburg, Germany e-mail: [email protected]; [email protected] J. C. Mai School of Life Science and Biotechnology, Shanghai Jiao Tong University, 200240 Shanghai, PR China T. B. Mapstone Department of Neurological Surgery, The University of Oklahoma, Health Sciences Center, Suite 400, 1000 N. Lincoln Blvd, Oklahoma City, OK 73104 e-mail: [email protected] P. J. McDonald Section of Neurosurgery- University of Manitoba, Winnipeg Children’s Hospital, 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada e-mail: [email protected] M. J. McGirt Department of Neurology, The Johns Hopkins University, School of Medicine, 600 N Wolfe St., Meyer 7-113, 21287 Baltimore, MD, USA e-mail: [email protected]

xx

J. H. Mehrkens Neurochirurgische Klinik, Klinikum Großhadern, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany e-mail: [email protected] R. Midha Clinical Neurosciences, Division of Neurosurgery, University of Calgary, Foothills Medical Center, Room C1243–1403, 29th Street NW, Calgary, AB T2N 2T9, Canada e-mail: [email protected] A. Muacevic European Cyberknife Centre Munich, Max-Lebsche Platz 31, 81377 Munich, Germany e-mail: [email protected] J. S. Myseros Division of Pediatric Neurosurgery, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA e-mail: [email protected] M. Niemelä Neurosurgery, Helsinki University Hospital, Topeliuksenkatu 5, 00260 Helsinki, Finland e-mail: [email protected] S.-H. Park Department of Pathology, Seoul National University, Children’s Hospital, 28 Yongon-dong, Chongno-gu, 110-799 Seoul, Korea M. Parolin The Montreal Children’s Hospital, McGill University Health Centre, rue Tupper, Montreal, QC H3H 1P3, Canada W. Paulus Department of Neuropathology, Westfälische-Wilhelms-University, Domagkstrasse 19, 48149 Münster, Germany e-mail: [email protected] A. Peraud Neurochirurgische Klinik, Klinikum Großhadern, Marchioninistrasse 15, 81377 München, Germany e-mail: [email protected] S. Petersenn ENDOC Center for Endocrine Tumors, Altonaer Strasse 59, 20357 Hamburg, Germany e-mail: [email protected] R. J. Petteys Department of Neurosurgery, The Johns Hopkins University, 600 North Wolfe Street, Meyer Building 8-161, Baltimore, MD 21287, USA J. H. Phi Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Republic of Korea T. Pietsch Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany e-mail: [email protected] I. F. Pollack Department of Neurological Surgery, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, USA e-mail: [email protected]; [email protected] N. Pouratian Department of Neurological Surgery, University of Virginia, Box 800212, Charlottesville, VA 22908, USA e-mail: [email protected]

Contributors

Contributors

xxi

I. Radovanovic Division of Neurosurgery, University Hospitals of Geneva and University of Geneva, Rue Micheli-du-Crest 24, 1211 Geneva, Switzerland C. Raffel Pediatric Neurosurgery, Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH 43205, USA e-mail: [email protected] G. Reifenberger Department of Neuropathology, Heinrich Heine University, Moorenstrasse 5, 40225 Düsseldorf, Germany e-mail: [email protected] B. G. Rocque Department of Neurological Surgery, University of Wisconsin, Madison, 53792, Wisconsin, USA M. Ronghe Schiehallion Unit, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK G. Rose Moorfields Eye Hospital, NHS Foundation Trust, 162 City Road, EC1V2PD London, UK e-mail: [email protected] J. V. Rosenfeld Department of Neurosurgery, Alfred Hospital, Monash University, Prahran, Victoria 3181, Australia e-mail: [email protected] J. T. Rutka Division of Neurosurgery, The University of Toronto, The Hospital for Sick Children, Suite 1504, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada e-mail: [email protected] W. Saeger Department of Pathology, Marienkrankenhaus, Alfredstrasse 9, 22087 Hamburg, Germany e-mail: [email protected] C. Sainte-Rose Hopital Necker, Enfants Malades, 149, rue de Sèvres, 75743 Paris, Cedex 15, France e-mail: [email protected] N. Sanai Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Avenue, M-779, Box 0112, San Francisco, CA 94143, USA e-mail: [email protected] Y. Sawamura Department of Neurosurgery, Hokkaido University Hospital, North 15, west-7, Kita-ku, Sapporo 060-8638, Japan e-mail: [email protected] R. Sawaya Department of Neurosurgery, 442, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA e-mail: [email protected] U. Schlegel Knappschaftskrankenhaus, Klinik für Neurologie, In der Schornau 23-25, 44892 Bochum, Germany e-mail: [email protected] J. Schramm Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany e-mail: [email protected]

xxii

P. Shannon Department of Pathology, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada J. P. Sheehan Department of Neurosurgery, University of Virginia Health System, Box 800212, Charlottesville, VA 22903, USA e-mail: [email protected] M. Simon Department of Neurosurgery, University of Bonn Medical Center, Siegmund Freud Str. 25, 53127 Bonn, Germany e-mail: [email protected] A. Singhal Department of Pediatric Neurology, University of British Columbia, Vancouver B.C., V6H3V4, Canada P. Steinbok Department of Surgery, British Columbia’s Children’s Hospital, 4480 Oak Street, Vancouver, B.C. V6H 3V4, Canada e-mail: [email protected] T. Abe Department of Neurosurgery, Showa University, School of Medicine, 1-5-8 Hatanodai, Shinagawa-K, Tokyo 1428666, Japan e-mail: [email protected] G. Tamburrini Ped. Neurosurgery, Catholic University, Rome e-mail: [email protected] P. E. Tarapore Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA M. D. Taylor Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada e-mail: [email protected] K. Thorington Section of Neurosurgery, University of Manitoba, Winnipeg Children’s Hospital, 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada J.-C. Tonn Department of Neurosurgery, Klinikum Großhadern, Marchioninistrasse 15, 81377 Munich, Germany e-mail: [email protected] E. C. Tsai Division of Neurosurgery, The University of Toronto, The Hospital for Sick Children, Suite 1504, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada e-mail: [email protected] A. Tyagi Department of Neurosurgery, Leeds General Infirmary, Leeds LS1 3EX, UK S. Vachhrajani Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada R. van Effenterre Department of Neurosurgery, Groupe Hospitalier Pitié-Salpêtrière 91, 105 Boulevard de l’Hôpital, 75013 Paris, France e-mail: [email protected] R. Voltz Department of Palliative Medicine, Dr. Mildred Scheel Haus, University of Cologne, Kerpener Str. 62, 50937 Köln, Germany e-mail: [email protected]

Contributors

Contributors

xxiii

K.-C. Wang Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, 101 Daehangno, Jongno-gu, Seoul 110-744, Korea e-mail: [email protected] M. Wasner Interdisziplinäres Zentrum für Palliativmedizin, Marchioninistrasse 16, 81377 München, Germany e-mail: [email protected] J. D. Weingart Department of Neurosurgery, The Johns Hopkins University, School of Medicine, 600 N Wolfe St., Meyer 7-113, Baltimore, MD 21287, USA M. Weller Neurologische Klinik, Universitäts-Spital Zürich, Frauenklinikstr. 26, 8091 Zürich, Switzerland e-mail: [email protected] J. C. Wellons III Section of Pediatric Neurosurgery, University of Alabama, Birmingham, Children’s Hospital of Alabama, ACC 400, 1600 7th Ave S., Birmingham, AL 35233, USA e-mail: [email protected] M. Westphal Department of Neurosurgery, UK Eppendorf, Martinistr. 52, 20246 Hamburg, Germany e-mail: [email protected] N. Wetjen Department of Neurological Surgery Go8 S, Mayo Clinic, 200 First St. SW, Rochester, MN 55902, USA e-mail: [email protected] W. E. Whitehead Division of Pediatric Neurosurgery, Department of Neurosurgery, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA e-mail: [email protected] J. Wiley Arthur + Sonia Labatts Brain Tumor Centre, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada B. Wowra CyberKnife Zentrum München, Max-Lebsche-Platz 31, 81377 München, Germany e-mail: [email protected] T. Yanagisawa Department of Neuro-Oncology, Division of Pediatric Neuro-Oncology, Comprehensive Cancer Center, International Medical Center, Saitama Medical, University, Moro-Hongo 38, Moroyama-machi, Iruma-gun, Saitama-ken, 350–0495, Japan W. K. A. Yung Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA G. Zadeh Arthur + Sonia Labatts Brain Tumor Centre, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada

Part Cranial Neuro-Oncology

I

1

Pathology and Classification of Tumors of the Nervous System Guido Reifenberger, Ingmar Blümcke, Torsten Pietsch, and Werner Paulus

Contents 1.1 Introduction ............................................................. 1.1.1 Classification of Tumors of the Nervous System ...... 1.1.2 Immunohistochemistry in Brain Tumor Classification ................................................... 1.1.3 Contribution of Molecular Genetics to Brain Tumor Diagnostics ........................................

1.7

4 4 4 8

1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.2.6

Astrocytic Tumors.................................................... Diffuse Astrocytoma ................................................... Anaplastic Astrocytoma .............................................. Glioblastoma ............................................................... Gliomatosis Cerebri .................................................... Pilocytic Astrocytoma ................................................. Pleomorphic Xanthoastrocytoma................................

9 10 11 12 14 15 16

1.3 1.3.1 1.3.2 1.3.3 1.3.4

Oligodendroglial Tumors and Mixed Gliomas.................................................. Oligodendroglioma ..................................................... Anaplastic Oligodendroglioma ................................... Oligoastrocytoma ........................................................ Anaplastic Oligoastrocytoma ......................................

17 17 18 19 20

1.4 1.4.1 1.4.2 1.4.3 1.4.4

Ependymal Tumors ................................................. Ependymoma .............................................................. Anaplastic Ependymoma ............................................ Myxopapillary Ependymoma ..................................... Subependymoma .........................................................

21 21 22 22 23

1.5 1.5.1 1.5.2 1.5.3

Choroid Plexus Tumors ........................................... Choroid Plexus Papilloma........................................... Atypical Choroid Plexus Papilloma ............................ Choroid Plexus Carcinoma .........................................

23 23 24 24

1.6 1.6.1 1.6.2 1.6.3

Other Neuroepithelial Tumors ............................... Astroblastoma ............................................................. Chordoid Glioma of the Third Ventricle..................... Angiocentric Glioma...................................................

24 25 25 26

1.7.1 1.7.2 1.7.3 1.7.4 1.7.5 1.7.6 1.7.7 1.7.8 1.8 1.8.1 1.8.2 1.8.3 1.8.4 1.9 1.9.1 1.9.2 1.9.3 1.10 1.10.1 1.10.2 1.10.3 1.10.4 1.11 1.11.1 1.11.2 1.11.3

Neuronal and Mixed Neuronal-Glial Tumors ...................................... Gangliocytoma and Ganglioglioma .......................... Desmoplastic Infantile Astrocytoma/ Ganglioglioma ........................................................... Dysembryoplastic Neuroepithelial Tumor................ Central Neurocytoma and Extraventricular Neurocytoma ........................... Cerebellar Liponeurocytoma .................................... Papillary Glioneuronal Tumor .................................. Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle .............................................. Paraganglioma ...........................................................

26 27 28 29 29 30 30 31 31

Tumors of the Pineal Region ............................. Pineocytoma .............................................................. Pineal Parenchymal Tumor of Intermediate Differentiation ................................. Pineoblastoma ........................................................... Papillary Tumor of the Pineal Region.......................

32 32

Embryonal Tumors ............................................ Medulloblastoma....................................................... Central Nervous System Primitive Neuroectodermal Tumors (CNS-PNET) .................. Atypical Teratoid/Rhabdoid Tumor (WHO grade IV) .......................................................

34 34

Tumors of the Cranial and Paraspinal Nerves ....................................... Schwannoma ............................................................. Neurofibroma ............................................................ Perineurioma ............................................................. Malignant Peripheral Nerve Sheath Tumor (MPNST) ........................................... Meningeal Tumors ............................................. Meningiomas ............................................................. Mesenchymal, Non-meningothelial Tumors ............ Melanocytic Lesions .................................................

36 38 38 39 40 41 41 42 42 45 47

1.12 G. Reifenberger () Department of Neuropathology, Heinrich Heine University, Moorenstrasse 5, 40225 Düsseldorf, Germany e-mail: [email protected]

Tumors of the Hematopoietic and Lymphoid System........................................ 1.12.1 Primary Central Nervous System Lymphoma (PCSNL) .................................................................... 1.12.2 Histiocytic Lesions Affecting the CNS and Its Coverings.......................................................

32 33 33

J.-C. Tonn et al. (eds.), Oncology of CNS Tumors, DOI: 10.1007/978-3-642-02874-8_1, © Springer-Verlag Berlin Heidelberg 2010

50 50 57

3

4

G. Reifenberger et al.

1.13

Germ Cell Tumors of the CNS ..........................

59

1.14 1.14.1 1.14.2 1.14.3

Familial Tumor Syndromes ............................... Subependymal Giant Cell Astrocytoma ................... Capillary Hemangioblastoma.................................... Dysplastic Gangliocytoma of the Cerebellum ..........

60 61 61 63

1.15 1.15.1 1.15.2 1.15.3 1.15.4 1.15.5

Tumors of the Sellar Region .............................. Craniopharyngioma (WHO Grade I) ........................ Pituitary Adenoma .................................................... Granular Cell Tumor of the Neurohypophysis ......... Pituicytoma................................................................ Spindle Cell Oncocytoma of the Adenohypophysis............................................

64 64 64 66 66

1.16

66

Metastatic Tumors in the Central Nervous System ..........................

67

References ......................................................................

68

1.1 Introduction 1.1.1 Classification of Tumors of the Nervous System Rudolph Virchow (1821–1902), the founder of cellular pathology, already separated gliomas from “psammomas,” “melanomas,” and other “sarcomas” of the nervous system in 1864/65 [185]. However, it was not until 1926 that Bailey and Cushing developed the first systematic classification scheme for gliomas and introduced the concept of brain tumor grading [4]. The first World Health Organization (WHO) classification of tumors of the nervous system was published in 1979 [196], followed by revisions in 1993 [82], 2000 [83] and 2007 [104]. All WHO classifications, including the latest version in 2007 (Table 1.1), followed the histogenetic principle originally proposed by Bailey and Cushing [4]. Based on morphologic and immunohistochemical features, each tumor entity is classified according to its presumed cell of origin. Although commonly used, this concept is challenged by the fact that the actual cell of origin is unknown for most brain tumors. Furthermore, experimental evidence from mouse models suggests that gliomas, for example, are more likely to arise from glial precursor cells than from terminally differentiated astrocytes or oligodendrocytes, respectively [169]. Nevertheless, histological classification according to the WHO criteria allows for a meaningful separation of biologically and clinically distinct brain tumor entities that is unsurpassed by any other diagnostic approach so far. Thus, the morphologic

classification of brain tumors is and will remain the diagnostic gold standard in neuro-oncology. In addition to tumor typing, the WHO classification comprises a histological grading according to a fourtiered scheme ranging from WHO grade I (benign) to WHO grade IV (malignant) (Table 1.2). The WHO grading is not equivalent to the histological tumor grading commonly used in other fields of surgical pathology, but rather reflects an estimate of a tumor’s malignancy and the prognosis of the patient [84]. In general, WHO grade I lesions include tumors with a minimal proliferative potential and the possibility of cure following surgical resection alone. Typical examples are pilocytic astrocytomas, subependymomas, myxopapillary ependymomas of the cauda equina, a variety of neuronal and mixed neuronal/glial tumors, schwannomas and most meningiomas. Tumors of WHO grade II are those with low mitotic activity, but a tendency for recurrence. Diffuse astrocytomas, oligodendrogliomas, oligoastrocytomas and ependymomas are classic examples of WHO grade II tumors. WHO grade III is reserved for neoplasms with histological evidence of anaplasia, generally in the form of increased mitotic activity, increased cellularity, nuclear pleomorphism and cellular anaplasia. WHO grade IV is assigned to mitotically active and necrosis-prone highly malignant neoplasms that are typically associated with a rapid pre- and postoperative evolution of the disease. These include glioblastoma and the various forms of embryonal tumors. To introduce the pathology and genetics of tumors of the nervous system, this chapter will closely adhere to the current WHO classification of 2007 [104]. This classification scheme is being used around the world and thereby facilitates comparison of clinical and experimental brain tumor studies from different countries. However, neuropathology and molecular neuro-oncology are rapidly evolving, so that updates concerning novel tumor entities as well as recent progress in brain tumor genetics have been incorporated into the chapter where appropriate.

1.1.2 Immunohistochemistry in Brain Tumor Classification Immunohistochemical staining for the expression of specific differentiation markers as well as proliferation-associated antigens has greatly facilitated the morphologic

1

Pathology and Classification of Tumors of the Nervous System

Table 1.1 WHO classification of tumors of the central nervous system [104] Tumors of Neuroepithelial Tissue Astrocytic tumors Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Diffuse astrocytoma Fibrillary astrocytoma Protoplasmic astrocytoma Gemistocytic astrocytoma Anaplastic astrocytoma Glioblastoma Giant cell glioblastoma Gliosarcoma Gliomatosis cerebri Oligodendroglial tumors Oligodendroglioma Anaplastic oligodendroglioma Oligoastrocytic tumors Oligoastrocytoma Anaplastic oligoastrocytoma Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Cellular ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Anaplastic ependymoma Choroid plexus tumors Choroid plexus papilloma Atypical choroid plexus papilloma Choroid plexus carcinoma Other neuroepithelial tumoors Astroblastoma Chordoid glioma of the third ventricle Angiocentric glioma Neuronal and mixed neuronal-glial tumors Dysplastic gangliocytoma of the cerebellum (LhermitteDuclos) Desmoplastic infantile astrocytoma/ganglioglioma Dysembryoplastic neuroepithelial tumor Gangliocytoma Ganglioglioma Anaplastic ganglioglioma Central neurocytoma Extraventricular neurocytoma Cerebellar liponeurocytoma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor of the fourth ventricle Paraganglioma

5

Tumors of the pineal region Pineocytoma Pineal parenchymal tumor of intermediate differentiation Pineoblastoma Papillary tumor of the pineal region Embryonal tumors Medulloblastoma Desmoplastic/nodular medulloblastoma Medulloblastoma with extensive nodularity Anaplastic medulloblastoma Large cell medulloblastoma CNS primitive neuroectodermal tumor CNS neuroblastoma CNS ganglioneuroblastoma Medulloepithelioma Ependymoblastoma Atypical teratoid /rhabdoid tumor Tumors of Cranial and Paraspinal Nerves Schwannoma (Neurinoma, Neurilemmoma) Cellular schwannoma Plexiform schwannoma Melanotic schwannoma Neurofibroma Plexiform neurofibroma Perineurioma Intraneural perineurioma Soft tissue perineurioma Malignant peripheral nerve sheath tumor (MPNST) Epitheloid MPNST MPNST with mesenchymal differentiation Melanotic MPNST MPNST with glandular differentiation Tumors of the Meninges Tumors of meningothelial cells Meningioma Meningothelial meningioma Fibroblastic (fibrous) meningioma Transitional meningioma Psammomatous meningioma Angiomatous meningioma Microcystic meningioma Secretory meningioma Lymphoplasmacyte-rich meningioma Metaplastic meningioma Chordoid meningioma Clear cell meningioma Atypical meningioma Papillary meningioma Rhabdoid meningioma Anaplastic (malignant) meningioma Mesenchymal tumors Lipoma Angiolipoma Hibernoma

(continued)

6 Table 1.1 (continued) Liposarcoma Solitary fibrous tumor Fibrosarcoma Malignant fibrous histiocytoma Leiomyoma Leiomyosarcoma Rhabdomyoma Rhabdomyosarcoma Chondroma Chondrosarcoma Osteoma Osteosarcoma Osteochondroma Hemangioma Epitheloid hemangioendothelioma Hemangiopericytoma Anaplastic hemangiopericytoma Angiosarcoma Kaposi sarcoma Ewing sarcoma - PNET Primary melanocytic lesions Diffuse melanocytosis Melanocytoma Malignant melanoma Meningeal melanomatosis Other neoplasms of the meninges Capillary hemangioblastoma Lymphomas and Hematopoietic Neoplasms Malignant lymphomas Plasmacytoma Granulocytic sarcoma (chloroma) Germ Cell Tumors Germinoma Embryonal carcinoma Yolk sac tumor Choriocarcinoma Teratoma Mature teratoma Immature teratoma Teratoma with malignant transformation Mixed germ cell tumors Tumors of the Sellar Region Craniopharyngioma Adamantinomatous craniopharyngioma Papillary craniopharyngioma Granular cell tumor Pituicytoma Spindle cell oncocytoma of the adenohypophysis Metastatic Tumors

classification of brain tumors. Table 1.3 provides a list of diagnostically helpful antigens that are commonly used

G. Reifenberger et al.

for the differential diagnosis of different tumor entities or the assessment of proliferative activity. In the routine diagnostic setting, immunohistochemistry for these antigens is usually performed on formalin-fixed paraffin sections using peroxidase- or alkaline phosphatase-based detection systems. Thereby, important differential diagnostic problems that are difficult or even impossible to solve by conventional staining can be clarified. For example, the challenging differential diagnosis of malignant small round blue cell tumors can usually be solved by immunohistochemistry. In case of a metastasis of unknown primary, several organ-specific markers are now available that help to identify the organ site and type of the primary tumor. Immunohistochemistry has also been instrumental for the reclassification of certain entities, e.g., the so-called monstrocellular sarcoma [196] as giant cell glioblastoma, and the identification of novel tumor entities, e.g., the chordoid glioma of the third ventricle. However, there are a number of issues that cannot be solved by immunohistochemical staining, such as the differential diagnosis of mixed gliomas (oligoastrocytomas), which still suffers from considerable subjectivity and interobserver variability because specific immunohistochemical markers for neoplastic astrocytes or oligodendrocytes are missing. In addition, most of the available differentiation antigens are expressed in both neoplastic and non-neoplastic cells, i.e., do not allow for a reliable distinction between neoplastic and reactive lesions. For example, GFAP immunoreactivity is found in normal and reactive astrocytes as well as in astrocytic tumor cells. Recently, it has been suggested that immunoreactivity for the Wilms’ tumor gene product WT1 is restricted to neoplastic astrocytes and thus may help to distinguish astrocytic tumor cells from normal and reactive astrocytes [166]. To facilitate the histological assessment of a tumor’s malignancy grade, immunohistochemistry for the proliferation-associated antigen Ki-67 using the MIB1 antibody has become a common practice. Although there is no doubt that the MIB1 index does provide diagnostically useful information in several circumstances, the fact that staining results and evaluation methods are quite variable in different laboratories, together with the considerable overlap of MIB1 positivity in tumors of different WHO grades, have so far precluded the definition of diagnostic cutoff values. Therefore, the WHO classification has not included MIB1 staining as a diagnostic criterion for the classification or grading of most tumor entities, with the meningiomas being a notable exception (see Chap. 12).

1

Pathology and Classification of Tumors of the Nervous System

Table 1.2 WHO grading of tumors of the central nervous system Tumor group Tumor entity Astrocytic tumors

Oligodendroglial tumors Mixed gliomas Ependymal tumors

Choroid plexus tumors

Other neuroepithelial tumors Neuronal and mixed neuronal-glial tumors

Pineal parenchymal tumors

Embryonal tumors

Tumors of peripheral nerves

Tumors of the meninges

Tumors of the sellar region

Pilocytic astrocytoma Pilomyxoid astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Diffuse astrocytoma Anaplastic astrocytoma Glioblastoma Gliomatosis cerebri Oligodendroglioma Anaplastic oligodendroglioma Oligoastrocytoma Anaplastic oligoastrocytoma Myxopapillary ependymoma Subependymoma Ependymoma Anaplastic ependymoma Choroid plexus papilloma Atypical choroid plexus papilloma Choroid plexus carcinoma Angiocentricglioma Chordoid glioma of the 3rd ventricle Gangliocytoma Ganglioglioma Anaplastic ganglioglioma Dysembryopl. neuroepithelial tumor Desmoplastic infantile ganglioglioma Central/extraventricular neurocytoma Cerebellar liponeurocytoma Papillary glioneuronal tumor Rosette-forming glioneuronal tumor of the fourth ventricle Paraganglioma of the filum terminale Pineocytoma Pineal parenchymal tumor of intermediate differentiation Pineoblastoma Papillary tumor of the pineal region Medulloblastoma Medulloepithelioma CNS-PNET Atypical teratoid/rhabdoid tumor Schwannoma Neurofibroma MPNST Perineurioma Meningioma Atypical meningioma Clear cell meningioma Chordoid meningioma Anaplastic meningioma Papillary meningioma Rhabdoid meningioma Capillary hemangioblastoma

7

Grade I

Grade II

Grade III

Grade IV

o o o o o o (o) o

o

o (o)

o o o o o o o o o o o o o o

(o) o

o o o o o o o o o

o

o

o

o o o o o o o o o

o (o)

o (o)

o o o o o o o

Craniopharyngioma Granular cell tumor

o o

Pituicytoma Spindle cell oncocytoma of the adenohypophysis

o o

o

8 Table 1.3 Immunohistochemical markers commonly used in brain tumor classification Neuronal and neuroendocrine markers Synaptophysin, neurofilament proteins, NeuN, chromogranin A

G. Reifenberger et al.

inhibitors [117], such inhibitors showed limited activity in clinical studies of malignant glioma patients, and molecular predictive factors for therapy response are still lacking (for review, see [12]).

Glial markers Glial fibrillary acidic protein (GFAP), S-100 protein, MAP2 Epithelial markers Cytokeratins, epithelial membrane antigen (EMA) Melanocytic markers Melan A, HMB-45 Mesenchymal markers Vimentin, desmin, smooth muscle actin (SMA), myoglobin Blood cell markers CD45 (pan-leukocytes), CD20 (B cells), CD3 (T cells), CD68, HLA-DR (monocytes, macrophages, microglia), CD138 (plasma cells) Germ cell markers ß-HCG, alpha-fetoprotein (AFP), placental alkaline phosphatase (PLAP), human placental lactogen (HPL), OCT4 (germinomas), c-Kit (germinomas), CD30 (embryonal carcinomas) Pituitary hormones Prolactin, ACTH, TSH, FSH, LH, GH Proliferation marker Ki-67 (MIB1) Other useful markers p53, CD34, thyroid transcription factor 1 (TTF1), Cdx2, prostate-specific antigen (PSA), thyreoglobulin, estrogen and progesterone receptors, HER2/Neu, EGFR, INI1

In the future, immunohistochemical analyses will certainly become even more important in brain tumor diagnostics, as novel cell- and/or tumor-type specific markers are being developed. In addition, the advent of targeted therapies directed against certain proteins that are aberrantly activated or overexpressed by tumor cells requires specific immunohistochemical analyses to demonstrate expression of the target proteins before therapy is initiated. Prominent examples from general oncology include the demonstration of Her2/Erbb2 overexpression in breast carcinomas and cKit overexpression in gastrointestinal stromal tumors. In neurooncology, immunohistochemical assessment of such target proteins is likely to become of diagnostic importance as well, e.g., the immunohistochemical demonstration of the epidermal growth factor receptor as a target for the molecular therapy of malignant gliomas [153]. However, while co-expression of the EGFRvIII variant and PTEN in glioblastoma has been reported as an indicator for responsiveness to EGFR kinase

1.1.3 Contribution of Molecular Genetics to Brain Tumor Diagnostics Knowledge of the molecular pathogenesis of primary brain tumors is rapidly advancing, and numerous genetic and epigenetic alterations have been identified in the different tumor types. At present, however, genetic analysis has not yet had a significant impact on the classification, prognostic assessment and therapeutic management of most CNS tumor entities. However, there are notable exceptions (Table 1.4). In anaplastic oligodendroglial tumors, for example, prospective clinical trials have corroborated the importance of allelic losses on chromosome arms 1p and 19q as an independent marker for response to radio- and chemotherapy as well as longer survival [20, 184]. Therefore, molecular testing of anaplastic oligodendroglial tumors for 1p and 19q deletions is now often applied at several centers. Furthermore, in ongoing clinical trials the 1p/19q deletion status is being used as a criterion for the inclusion of patients with anaplastic gliomas of WHO grade III, irrespective of the histological subclassification [112]. Molecular testing for 1p/19q loss and EGFR amplification may also help to solve the histologically difficult differential diagnosis between anaplastic oligodendroglioma and small cell glioblastoma. The MGMT promoter methylation status represents another important example for a molecular test that has gained clinical significance in neuro-oncology. MGMT encodes the DNA repair enzyme O6-methylguanine DNA methyltransferase, also known as O6-alkylguanine DNA alkyltransferase, which removes mutagenic alkyl adducts from the O6 position of guanine and thereby causes resistance to those alkylating drugs that are commonly used for glioma treatment, in particular temozolomide. Epigenetic silencing of MGMT by means of promoter hypermethylation is present in about 40% of primary glioblastomas and even more common in secondary glioblastomas as well as oligodendroglial tumors. Based on a subset of patients from the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada

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Pathology and Classification of Tumors of the Nervous System

Table 1.4 Molecular diagnostic tests in neuro-oncology Genetic variable Tumor type/indication 1p/19q loss

1p/19q loss

1p/19q loss & EGFR amplification MGMT promoter methylation *

INI1 mutation

*

MYCN/MYCC amplification

Anaplastic oligodendroglioma, anaplastic oligoastrocytoma: prediction of response to adjuvant therapy and prognosis Oligodendroglioma, oligoastrocytoma: planning of therapeutic strategy on tumor progression Anaplastic oligodendroglioma/ small cell glioblastoma; Differential diagnosis Glioblastomas: prediction of response to chemotherapy with DNA-alkylating drugs Atypical teratoid/rhabdoid tumor: confirmation of diagnosis Medulloblastoma: indicator of poor prognosis

*

In comparison to the 1p/19q and MGMT tests, these tests have little clinical relevance so far

(NCIC) prospective clinical trial 26981–22981/CE.3 [173], which defined the combination of surgery followed by radiotherapy with concomitant and adjuvant temozolomide as the current standard of care for glioblastoma patients, Hegi et al. [61] reported that those patients whose glioblastomas had a hypermethylated MGMT promoter responded significantly better to the temozolomide treatment and showed significantly longer survival when compared to those patients whose tumors had an unmethylated MGMT promoter. As MGMT promoter methylation can be tested by methylation-specific polymerase chain reaction analysis or other methods, MGMT testing is now increasingly being requested by both physicians and patients. Furthermore, the MGMT promoter status is being used to select glioblastoma patients for different clinical trials, thereby trying to optimize the treatment for both MGMT methylated and unmethylated tumors individually. In addition to 1p/19q deletion and MGMT promoter methylation, several other molecular markers will probably gain clinical significance in the future (Table 1.4). For example, a number of genetic and chromosomal aberrations, including amplification of MYCC or MYCN, losses or gains of chromosome 6, and other aberrations, are linked to outcome in pediatric medulloblastoma. These findings may lead to a novel molecular subclassification of medulloblastomas that will help to better stratify patients into distinct risk groups requiring different treatment protocols.

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Molecular tests also may be valuable to solve clinically important differential diagnostic problems, such as the classification of histologically ambiguous malignant gliomas. In fact, first data suggest that classification of such tumors by microarray-based expression profiling correlates better with clinical outcome than histological classification [128]. In addition, the differential diagnosis between certain other tumor types, such as pilocytic astrocytoma versus diffuse astrocytoma, potentially may be facilitated by the testing for characteristic genetic changes, e.g., BRAF aberrations or IDH1 mutation [6, 74, 140]. Moreover, molecular analyses are of importance to specifically identify aberrant signaling pathways that can be blocked selectively by novel targeted therapies, including small molecule inhibitors and monoclonal antibodies. Finally, highthroughput techniques, such as array-based comparative genomic hybridization, next generation large-scale sequencing, as well as mRNA and protein expression profiling, are currently being used to identify novel molecular parameters and gene signatures that may serve as diagnostic, prognostic or predictive markers in brain tumors. First data already hint at defined expression signatures that are associated with survival in malignant astrocytic gliomas [49, 142]. Nevertheless, despite the impressive technical advances and promising recent findings, molecular analyses certainly will not replace the established morphologic brain tumor classification and grading according to the WHO classification of tumors of the central nervous system.

1.2 Astrocytic Tumors Astrocytic gliomas are the most common primary brain tumors and account for about 60% of all glial neoplasms. They can be divided into two major categories: (1) the more common group of diffusely infiltrating astrocytomas (diffuse astrocytoma, anaplastic astrocytoma, glioblastoma and gliomatosis cerebri) and (2) the less common group of astrocytic neoplasms with a more circumscribed growth (pilocytic astrocytoma, subependymal giant cell astrocytoma and pleomorphic xanthoastrocytoma). Tumors of the latter group preferentially develop in children and young adults, grow slowly, have a limited potential for malignant progression and can be cured by tumor resection. In contrast, the diffusely infiltrating astrocytic tumors predominantly affect adult patients,

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have an inherent tendency for local recurrence and malignant progression, and usually cannot be cured by neurosurgery, radiotherapy and chemotherapy.

1.2.1 Diffuse Astrocytoma Definition. A slow-growing, well-differentiated, diffusely infiltrating astrocytic glioma that preferentially develops supratentorially in young adults and has an intrinsic tendency for malignant progression to anaplastic astrocytoma and eventually secondary glioblastoma. Incidence and age distribution. Diffuse astrocytomas account for approximately 5% of all primary CNS tumors and 10–15% of the astrocytic gliomas. They preferentially develop in young adults (age peak: 30–40 years), but may occur at any age. Macroscopy and localization. Diffuse astrocytomas predominantly grow in the cerebral hemispheres. Other localizations are rare, except for the brain stem in children. Macroscopically, diffuse astrocytomas are ill-defined, gray to yellow, usually soft lesions in the white and/or gray matter. They enlarge preexisting structures and blur normal anatomical boundaries (Fig. 1.6a). Cystic changes are common. The tumors may infiltrate to contralateral structures via the corpus callosum. Histopathology. Microscopy shows a well-differentiated astrocytic tumor of low to moderate cellularity and infiltrative growth into the adjacent brain parenchyma. Microcystic degeneration is a common feature. The mitotic activity is low. Necrosis and microvascular proliferation are absent. Three histological subtypes are distinguished. The fibrillary astrocytoma (Fig. 1.7a) is the most common variant and composed of multipolar neoplastic astrocytes with scant cytoplasm and fine cell processes that build a fiber-rich glial matrix. The less common gemistocytic astrocytoma (Fig. 1.7b) is characterized by gemistocytic astrocytes, i.e., tumor cells with an enlarged eosinophilic cytoplasm, eccentric nuclei and stout processes. To make the diagnosis, at least 20% of the tumor cells should demonstrate the gemistocytic phenotype. The third variant, the protoplasmic astrocytoma, is rare and composed of tumor cells with eosinophilic cytoplasm and a few flaccid processes embedded in a microcystic or mucoid matrix (Fig. 1.7c). The tumor cell processes in protoplasmic astrocytomas contain only small amounts of glial filaments. Rare cases of diffuse or anaplastic astroytoma may contain neuropil-like

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islands that are synaptophysin positive and rimmed in a rosette-like fashion by sometimes quite pleomorphic neurocytic and/or neuronal cells. Such neoplasms were originally reported as rosetted glioneuronal tumors [176]. The WHO classification considers the presence of neuropil-like islands as a rare growth pattern that does not constitute a tumor entity of its own. Rare cases of diffusely infiltrative astrocytoma may contain a prominent component of granular cells, which are large, round cells packed with eosinophilic, PASpositive granules [16]. Occasional tumors may almost entirely consist of such atypical granular cells (granular cell astrocytoma). Lymphocytic infiltrates are often present. Granular cell differentiation may be present in astrocytomas of WHO grade II, III or IV, although most patients show rather poor survival. Molecular genetic investigation showed a high incidence of genetic alterations typically found in high-grade astrocytic tumors, in particular losses on chromosome arms 9p and 10q, but no specific genetic alterations that would distinguish “granular cell astrocytomas” from other diffuse astrocytic gliomas [23]. Thus, these neoplasms represent a distinct growth pattern of diffuse astrocytoma, but do not constitute their own entity. Grading. Diffuse astrocytomas correspond to WHO grade II. However, these tumors have an inherent tendency for recurrence and spontaneous progression to anaplastic astrocytoma or secondary glioblastoma. Histological signs of progression, such as increased cellularity and mitotic activity, may develop focally. Therefore, selection of biopsy site and tissue sampling are important issues. Gemistocytic astrocytomas have been associated with a higher tendency to progression and less favorable prognosis. In contrast, a subset of WHO grade II astrocytomas in patients with longstanding epilepsy has a lower likelihood of recurrence and a more favorable survival [167]. Immunohistochemistry. Diffuse astrocytomas stain positive for glial fibrillary acidic protein (GFAP) and protein S-100. GFAP immunoreactivity is strong in the gemistocytic and fibrillar variants, whereas protoplasmic astrocytomas are only weakly positive. Immunostaining for the p53 tumor suppressor protein shows widespread nuclear immunoreactivity in about 60% of the cases. The Ki-67 (MIB1) labeling index is low (10%), but often shows marked regional heterogeneity. Differential diagnosis. The presence of microvascular proliferation and/or necrosis distinguishes glioblastoma from anaplastic astrocytoma. The differential diagnosis of anaplastic oligodendroglioma and anaplastic oligoastrocytoma is more difficult and associated with

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considerable interobserver variability. Molecular testing may be helpful in certain instances, such as the differential diagnosis between small cell astrocytoma/glioblastoma and anaplastic oligodendroglioma [149, 134]. Molecular pathology (Fig. 1.1). Molecular genetic analyses have shown that the pattern of genetic aberrations differs between primary and secondary glioblastomas [130]. Primary glioblastomas more frequently demonstrate EGFR amplification, homozygous deletion of CDKN2A and p14ARF, CDK4 amplification, MDM2 or MDM4 amplification, RB1 mutation/ homozygous deletion, monosomy 10 and PTEN mutation [147]. TP53 mutations are found in approximately 30% of primary glioblastomas, but more than 60% of secondary glioblastomas. In the latter, TP53 mutations cluster at codons 248 and 273 [129]. EGFR, MDM2 or MDM4 amplification as well as PTEN mutation is rare, and allelic losses on chromosome 10 are frequently confined to markers on 10q. Allelic losses on 19q and 13q, promoter hypermethylation of the RB1 gene and overexpression of PDGFRA are more common in secondary glioblastomas. Furthermore, IDH1 point mutations are common in secondary glioblastomas, but rare in primary glioblastomas [6, 133]. Taken together, primary and secondary glioblastomas carry different genetic alterations. However, the genetic alterations in both glioblastoma types target the same oncogenic pathways, namely the p53, pRb1, Pten/Pi3k/Akt and mitogen-activated protein kinase pathways [147, 177]. Oligodendroglioma-associated combined deletions of 1p and 19q are rare in glioblastomas, even among glioblastomas from long-term survivors [95]. TP53 mutations are detected in up to 80% of giant cell glioblastomas, while PTEN mutations are found at similar frequency (approximately 30%) as in primary glioblastomas. EGFR amplification and homozygous deletions of CDKN2A and p14ARF are rare. Gliosarcomas show similar genetic changes to primary glioblastomas, except for less common EGFR amplification. Gliomatous and sarcomatous areas invariably share common genetic aberrations, which strongly argues for a monoclonal origin of both components [1, 152].

1.2.4 Gliomatosis Cerebri Definition. A diffuse glioma with extensive infiltration of three or more cerebral lobes, usually with bilateral

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hemispheric growth and/or extension into the deep gray matter, brain stem, cerebellum and even spinal cord. Most cases show evidence of astrocytic differentiation, although oligodendroglial and oligoastrocytic tumors occasionally may also present as gliomatosis cerebri. General comment. The WHO classification of 2007 considers gliomatosis cerebri as an astrocytic glioma with a particularly invasive growth pattern rather than an entity of its own. The diagnosis is usually established by the combination of histology (showing a diffusely infiltrating glioma) and radiological features (showing extensive tumor growth with involvement of three or more cerebral lobes). Incidence and age distribution. Gliomatosis cerebri is a rare lesion that may be found in any age group, but preferentially develops in adults (age peak: 40–50 years). Macroscopy and localization. By definition, gliomatosis cerebri is characterized by extensive tumor infiltration of the brain involving three or more cerebral lobes. Bilateral tumor spread via the corpus callosum is common, as is involvement of the basal ganglia. Extension into infratentorial structures and even the spinal cord may occur. Depending on the presence or absence of a circumscribed tumor mass, two types of gliomatosis cerebri may be distinguished. Type I is the classic form with diffuse tumor growth and widespread involvement of large parts of the CNS. Type II is characterized by the presence of a focal mass lesion, usually a high-grade glioma, in addition to the diffusely infiltrating areas of gliomatosis. Type I lesions may develop into type II lesions. Histopathology. Histological specimens show an infiltrating glioma composed of monomorphic, often elongated tumor cells that grow diffusely in the brain parenchyma. In most instances, tumor cells demonstrate astrocytic features, while rare cases of oligodendroglial or oligoastrocytic gliomatosis are documented as well. Tumor cells infiltrating the cortex frequently form secondary structures, such as perineuronal satellitosis as well as perivascular and subpial aggregates. Mitotic activity is variable from case to case. Type I lesions of gliomatosis cerebri often lack marked microvascular proliferation and necrosis. In type II lesions, biopsy specimens from the focal mass show histological features similar to the common types of diffuse gliomas, most frequently anaplastic astrocytoma or even glioblastoma.

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Pathology and Classification of Tumors of the Nervous System

Grading. Grading of gliomatosis cerebri is difficult due to the diffusely infiltrating growth with a sometimes very low density of infiltrating glioma cells. Nevertheless, most cases of gliomatosis cerebri show a malignant behavior and are associated with poor prognosis. Therefore, the overall behavior corresponds to a WHO grade III lesion in most cases of gliomatosis cerebri. Nevertheless, WHO grading is routinely performed on the available biopsy specimens and may range from WHO grade II to WHO grade IV lesions. Stratification of gliomatosis cerebri according to histological grade has been shown to correlate with outcome, albeit tissue sampling may not be representative and the diffusely infiltrating nature of the lesion may lead to undergrading of some cases. Immunohistochemistry. Immunoreactivity for GFAP and S-100 is variable in the tumor cells, while reactive astrocytes are generally stained. About half of the cases show nuclear p53 immunoreactivity. MIB1 levels are highly variable, with some cases showing a low labeling fraction (< 1%), while others are highly proliferative. Differential diagnosis. Gliomatosis cerebri is distinguished from the other more common types of diffusely infiltrative astrocytic gliomas by neuroradiological demonstration of widespread tumor growth involving three or more cerebral lobes. Sometimes, biopsy specimens may be of rather low cellularity, making the differential diagnosis of reactive gliosis difficult. The so-called microgliomatosis, a lesion consisting of diffusely infiltrating rod-shaped microglial cells expressing macrophage markers like CD68 and RCA1, is an extremely rare differential diagnosis. Molecular pathology. TP53 mutations were detected in between 11% (2/18 tumors; [114]) and 43% (3/7 tumors; [63]) of the cases. Individual tumors show PTEN mutation and EGFR amplification [63]. Thus, the genetic alterations detected in gliomatosis cerebri are similar to those typically found in diffuse astrocytic gliomas.

1.2.5 Pilocytic Astrocytoma Definition. A slow-growing, well-circumscribed and frequently cystic astrocytoma of children and young adults. Histological characteristics include a biphasic growth pattern of loose and compact tissue, Rosenthal fibers and eosinophilic granular bodies.

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Incidence and age distribution. Pilocytic astrocytomas account for approximately 6% of all intracranial tumors. Children and young adults are preferentially affected. Pilocytic astrocytomas are the most common primary brain tumors in pediatric patients. Patients with neurofibromatosis type 1 (NF1) have an increased risk of pilocytic astrocytomas, in particular optic nerve gliomas. However, the vast majority of pilocytic astrocytomas are sporadic tumors occurring in patients without an inherited tumor syndrome. Macroscopy and localization. More than 80% of pilocytic astrocytomas are cerebellar tumors. Other typical sites include the optic nerve and optic chiasm (“optic glioma”), hypothalamus, thalamus, basal ganglia, brain stem and spinal cord. Rare cases may originate in the cerebral hemispheres. Macroscopically, pilocytic astrocytomas are soft, gray, frequently cystic lesions that are well circumscribed. However, local involvement of the pia mater is not infrequent. Histopathology. Pilocytic astrocytomas are characterized by low to moderate cellularity and biphasic architecture, consisting of compact areas with bipolar (piloid) tumor cells and microcystic areas with multipolar tumor cells (Fig. 1.7j). An important diagnostic feature, albeit not unique to these tumors, is the presence of Rosenthal fibers and eosinophilic granular bodies (Fig. 1.7k). Capillary proliferation, degenerative cellular pleomorphism, foci of non-palisading necrosis and occasional mitoses are still consistent with this diagnosis. However, high mitotic activity and palisading necrosis indicate that the tumor behaves more aggressively. Such rare cases are classified as anaplastic pilocytic astrocytoma. Pilomyxoid astrocytoma is a novel histological variant of pilocytic astrocytoma that was originally reported in 1999 [180] and has been newly included in the 2007 WHO classification. These tumors are characterized by a monomorphic population of bipolar neoplastic astrocytes in a myxoid matrix. The tumor cells form characteristic pseudorosette-like angiocentric architectures (Fig. 1.7l). In contrast to classic pilocytic astrocytomas, Rosenthal fibers are often missing. Pilomyxoid astrocytomas are predominantly found in the optic chiasm/ hypothalamus region of children, but have also been encountered at other sites, including the spinal cord. Clinically, they are associated with a higher risk of local recurrence and CSF seeding as compared to classic pilocytic astrocytoma [180]. Therefore, the WHO classification recommends the WHO grade II for pilomyxoid astrocytoma.

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Immunohistochemistry. Pilocytic astrocytomas are positive for GFAP and protein S-100. Immunostaining for p53 remains negative or restricted to individual cells. MIB1 labeling is usually low (