Neuro-Oncology Compendium for the

Boards and Clinical Practice

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Mrugala
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i

N EU R O - O N C O LOGY COMPE NDIUM

F O R T H E BOAR D S AND
CL IN IC AL PR ACTICE
ii
iii

NEURO-ONCOLOGY
COMPENDIUM FOR THE BOARDS
AND CLINICAL PRACTICE

EDITED BY

Maciej M. Mrugala, MD, PhD, MPH, FAAN

M AY O C LINIC
P H O E NIX , AZ , USA

Na Tosha N. Gatson, MD, PhD, FAAN

B A NNE R MD AND E R SO N C ANC E R C ENT ER
P H O E NIX , AZ , USA
G E I SINGE R C O MMO NW E ALTH SC HO OL OF MEDICINE
S C R ANTO N, PA, USA

Sylvia C. Kurz, MD, PhD

E B E RHAR D K AR LS UNIVE R SITY
T Ü B INGE N, GE R MANY

Kathryn S. Nevel, MD
I N D IANA UNIVE R SITY SC HO O L O F MEDICINE
I N D IANAP O LIS, IN, USA

Jennifer L. Clarke, MD, MPH

U N I V E R SITY O F C ALIFO R NIA
S A N FR ANC ISC O , C A, USA
iv

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v
DEDICATIONS
The years 2020–2021 were particularly difficult for the med-
ical community due to the global pandemic. Hats off to the
providers who maintained excellent care of their patients
and helped to usher innovations using telemedicine and
distance learning. This book is dedicated to those on the
frontline (physicians, advanced care providers, nurses,
aides, technicians, and others) and those acting behind the
scenes (laboratory medicine, maintenance, housekeeping,
food services, and more). Finally, to all the healthcare
workers who continuously go to great lengths to take the
best care of patients. Together, we elevate and educate in
medicine.
vi
vi

IN MEMORIAM

Gordon A. Watson, MD, PhD, co-author of the Rare Tumors chapter, was a beloved Associate Professor and Vice
Chair for Clinical Affairs for the Department of Radiation Oncology at Indiana University. He was among the most
popular and busiest physicians in the department and the Indiana University Melvin and Bren Simon Comprehensive
Cancer Center. Due to his vast wisdom and well-known desire to help, his input was always sought after for the most
challenging of clinical cases. He was an outstanding physician in every way imaginable, who is dearly missed by his
colleagues, patients, family, and friends.
vi
ix

CONTENTS

Foreword xi 12. MetAstAtIc DIseAse In tHe centRAL neRVoUs

sYsteM 179
Preface xiii
Jessica A. Wilcox and Adrienne A. Boire
Acknowledgments xv
Contributors xvii 13. tUMoRs AFFectInG tHe sPInAL coRD 199
Terrence Verla, Kara L. Curley, Matthew T. Neal,
and Alexander Ropper
PA R T I NE U R O- ON C OLOG Y OV ER V IEW
1. neURoPAtHoLoGY PRIMeR 3
PAR T I I I P ED I AT RI C NEURO- ONCOLOGY
Ibrahim Kulac and Melike Pekmezci
14. ePIDeMIoLoGY AnD GeneRAL oVeRVIeW oF
2. IMAGInG oF centRAL neRVoUs sYsteM tUMoRs 29 PeDIAtRIc centRAL neRVoUs sYsteM tUMoRs 219
Shobhit Kumar Garg and Rajan Jain Scott L. Coven

15. neURosURGIcAL MAnAGeMent oF PeDIAtRIc

PA R T I I A D U LT N EU RO- ON C OLOG Y centRAL neRVoUs sYsteM tUMoRs 228

3. GLIoBLAstoMA 59 Nir Shimony, Mohammad Hassan A. Noureldine,

Cameron Brimley, and George I. Jallo
Rimas V. Lukas
16. PeDIAtRIc eMBRYonAL tUMoRs 240
4. DIFFUse GLIoMAs (WHo GRADe 2–3) 76
Aaron Mochizuki and Sonia Partap
Haroon Ahmad and David Schiff
17. PeDIAtRIc LoW-GRADe GLIoMA 255
5. MenInGIoMA 87
Sheetal Phadnis and Theodore Nicolaides
Thomas J. Kaley
18. PeDIAtRIc HIGH-GRADe GLIoMA 267
6. ePenDYMoMA 97
Sameer Farouk Sait, Morgan Freret,
Iyad Alnahhas, Appaji Rayi, Wayne Slone, and Matthias Karajannis
Peter Kobalka, Shirley Ong, Pierre Giglio, and
Vinay K. Puduvalli
PAR T I V MANAGEMENT OF
7. tUMoRs oF tHe PItUItARY GLAnD 110
NEURO- ONCOLOGI C D I S EAS E
Reginald Fong and Andrew R. Conger
19. neURosURGIcAL MAnAGeMent oF ADULt
8. GeRM ceLL tUMoRs 122 centRAL neRVoUs sYsteM tUMoRs 289
Hirokazu Takami Andrew J. Gogos, Ramin A. Morshed, and
Shawn L. Hervey-Jumper
9. IntRAVentRIcULAR tUMoRs 131
20. RADIotHeRAPY In neURo-oncoLoGY 309
Samanthalee C. S. Obiorah, Richard S. Dowd, and
Steven A. Toms Molly Havard Blau and Lia M. Halasz

10. RARe tUMoRs In ADULts, IncLUDInG 21. PRIncIPLes oF sYsteMIc tHeRAPY

MeDULLoBLAstoMA 143 In neURo-oncoLoGY 324
Kevin Shiue, Logan S. DeWitt, John M. Kindler, Nikolaos Andreatos and David M. Peereboom
and Gordon A. Watson†
22. DeVIce-BAseD tReAtMents In
11. PRIMARY centRAL neRVoUs sYsteM LYMPHoMA neURo-oncoLoGY 341
AnD HeMAtoPoIetIc neoPLAsMs AFFectInG Ekokobe Fonkem, Amir Azadi, and
tHe neRVoUs sYsteM 161 Ramya Tadipatri
Mary Jane Lim-Fat and Lakshmi Nayak
x

PA R T V C O M P LIC ATION S OF SYSTEMIC PAR T VI I S P ECI AL CONS I D ERAT I ONS I N

AND C E NT R A L N ER V OU S SYSTEM NEURO- ONCOLOGY
CA NC E R S 28. DesIGnInG AnD DecIPHeRInG cLInIcAL tRIALs:
MetHoDoLoGIcAL InGReDIents to noURIsH A
23. neURoLoGIc coMPLIcAtIons In
HeALtHY stUDY 441
cAnceR PAtIents 355
Katherine B. Peters Michael Glantz and Alireza Mansouri

29. PRoceDURes AnD WeLL-cARe cLInIcs In

24. PARAneoPLAstIc neURoLoGIcAL sYnDRoMes 370
neURo-oncoLoGY: RoLes FoR ADVAnceD
Cristina Valencia-Sanchez and PRActIce PRoVIDeRs 456
Maciej M. Mrugala
Erika N. Leese, Alyssa Callela, and Na Tosha N. Gatson
25. neURo-oncoLoGIc eMeRGencIes 385
30. neURo-oncoLoGY In tHe eLDeRLY 468
Maya Hrachova, David Gritsch, Simon Gritsch, and
Maciej M. Mrugala Valeria Internò, Roberta Rudà, and Riccardo Soffietti

31. PALLIAtIVe cARe, ReHABILItAtIon, AnD

PA R T VI GE NE TIC S A N D
N EU R O - O NC O L OG IC DISEA SE
26. FAMILIAL sYnDRoMes In neURo-oncoLoGY 407
sUPPoRtIVe cARe In neURo-oncoLoGY 480
Jamal Mohamud and Kathryn S. Nevel
32. tHe neURo-oncoLoGY oF WoMen (noW) 491

Radhika Dhamija, Joseph M. Hoxworth, and Na Tosha N. Gatson, Kerianne R. Taylor,

Ashok R. Asthagiri Maria L. Boccia, and Terri L. Woodard

27. tHe neURoFIBRoMAtoses: neURoFIBRoMAtosIs

1, neURoFIBRoMAtosIs 2, AnD
Test Exam Number One 507
scHWAnnoMAtosIs 421 Test Exam Number Two 518
Kun-Wei Song and Scott R. Plotkin About the Editors 531
Index 535

x | contents
xi
FOREWORD
This slim volume manages to be both comprehensive and
succinct at the same time—a welcome combination. The
editors compiled a list of stellar authors, and employed a
standard structure for each chapter, making this book easy
to read and the information highly accessible. The book fills
a critical need for those seeking rapid and current informa-
tion to care for patients with a neuro-oncologic problem.
The focus is on primary intracranial tumors, but the authors
also cover CNS metastases, and other neuro-oncologic topics
such as paraneoplastic syndromes. They review the core di-
agnostic methods and summarize their clinical relevance;
the vivid images of MRI scans and pathology throughout the
book are especially informative. The latest therapeutic studies
are summarized in a clear fashion along with the potential
benefits and toxicities of each therapeutic modality. For those
seeking information to prepare for an oncology or neuro-
oncology Board certification examination, they will find the
key points of each chapter highlighted throughout the text,
followed by flash cards and multiple-choice questions for fu-
ture referral and test practice. The editors and authors are to
be congratulated on this highly practical compilation of data;
it is a “must have” for anyone who cares for neuro-oncologic
patients.
Lisa M. DeAngelis, MD
Physician-in-Chief and Chief Medical Officer
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Within the growing field of Neuro-Oncology, heavy-volume
textbooks or detailed review articles do not meet the need for
rapidly accessible and up-to-date practice-related informa-
tion. This comprehensive, well-structured and good–to-read
volume allows the newcomer to swiftly achieve an overview
and the more advanced practitioner to recapitulate important
facts, i.e. on recent trials, for which main efficacy outcomes
and unwanted effects are summarized.
The present book by a group of experienced practitioners
from all important subspecialties feeding into Neuro-Oncology
covers many different aspects of modern Neuro-Oncology
with the focus on primary Central Nervous System (CNS)
tumors, CNS metastases, and neurological complications of
cancer. Each chapter is structured in a standard way, allowing
for recapitulating diagnostic challenges, clinical courses, and
standard treatments including clinical trial updates. The book
follows a high educational standard and fosters learning,
self-testing as well as preparation for board certification in
Neuro-Oncology for learners around the globe. The editors
and authors are to be congratulated on this highly scholarly
and useful volume, which certainly will help to inform care for
patients with neuro-oncologic disease.
Wolfgang Wick, MD
Chairman, Neurology Clinic, University of Heidelberg
Neuro-Oncology Program Chair, National Center for Tumor
Diseases, Heidelberg and German Cancer Research Center
Heidelberg, Germany
xi
xi
PREFACE
tHe ne UR o- o nc o L oGY c o MP en D I U M
It is with great joy that we deliver this textbook to our readers.
This work would not have been possible without the tre-
mendous dedication of the contributing authors, the Oxford
University Press staff, and our team of editors. We started this
journey several years ago when the five of us identified gaps
in the neuro-oncology curriculum for test takers and those
who sought an up-to-date clinical reference guide. Our field
changes rapidly, leaving gaps in the neuro-oncology library
for books that would provide a high-yield overview of the var-
ious facets of our sub-specialty. This work is designed to not
only address the board exam requirements but also provide
practical knowledge for those who take care of patient pop-
ulation. We were fortunate that some of the top talents from
across the world were enthusiastic to contribute to this project.
A tremendous thanks is owed to the contributing authors, who
spent countless hours making sure the content of their chapters
was filled with relevant information and laid out to maximize
retention and recall of the information for the boards and daily
clinical practice. We hope this textbook will become a staple
educational offering and will be widely used by all who wish to
enhance their knowledge in neuro-oncology.
On a personal note, working on this book brought us
immense joy, allowed for excellent networking, and solidified
our friendships for the years to come. We are very grateful for
this opportunity! We wish you an enjoyable read, success on
the board exams, and satisfaction in your clinical practices.
We would appreciate your feedback and remain open to new
and continued collaborations for future editions of the Neuro-
Oncology Compendium.
The Editors
Maciej M. Mrugala
Na Tosha N. Gatson
Sylvia C. Kurz
Kathryn S. Nevel
Jennifer L. Clarke
xvi
xv
ACKNOWLEDGMENTS
We would like to acknowledge the patients and their caregivers
who allowed us to share in their care and for their participation
in clinical trials or other research that led to advancements in
our field. Words of gratitude go to scientists and academicians
who led the research projects described in this book. We would
also like to acknowledge donors and funding agencies for their
contribution to the science presented in this book. Finally,
we would like to thank the Society for Neuro-Oncology for
supporting our original idea for this work and Craig Panner
and Oxford University Press team for taking our project on.
xvi
xvi

CONTRIBUTORS

Haroon Ahmad, MD Kara L. Curley, PA-C

University of Maryland, School of Medicine Mayo Clinic
Baltimore, MD, USA Phoenix, AZ, USA
Iyad Alnahhas, MD Logan S. DeWitt, DO
Thomas Jefferson University Indiana University School of Medicine
Philadelphia, PA, USA Indianapolis, IN, USA
Nikolaos Andreatos, MD Radhika Dhamija, MD
Mayo Clinic Mayo Clinic
Rochester, MN, USA Phoenix, AZ, USA
Ashok R. Asthagiri, MD Richard S. Dowd, MD, MS
University of Virginia Tufts Medical Center
Charlottesville, VA, USA Boston, MA, USA
Amir Azadi, MD Reginald Fong, MD
Honor Health Neuroscience Geisinger Health
Scottsdale, AZ, USA Danville, PA, USA
Molly Havard Blau, MD, MS Ekokobe Fonkem, DO
University of Washington Medical College of Wisconsin
Seattle, WA, USA Milwaukee, WC, USA
Maria L. Boccia, PhD, LM Morgan Freret, MD, PhD
Baylor University Robbins College of Health and Human Sciences Memorial Sloan Kettering Cancer Center
Waco, TX, USA New York, NY, USA
Adrienne A. Boire, MD, PhD Shobhit Kumar Garg, MD, FRCR
Memorial Sloan Kettering Cancer Center William Harvey Hospital,
New York, NY, USA East Kent Hospitals University Foundation Trust
Ashford, Kent, UK
Cameron Brimley, MD
Geisinger Health Na Tosha N. Gatson, MD, PhD, FAAN
Danville, PA, USA Banner MD Anderson Cancer Center
Phoenix, AZ, USA
Alyssa Callela, PA-C Geisinger Commonwealth School of Medicine
Geisinger Health Scranton, PA, USA
Danville, PA, USA
Pierre Giglio, MD
Jennifer L. Clarke, MD, MPH The Ohio State University
University of California Columbus, OH, USA
San Francisco, CA, USA
Michael Glantz, MD
Andrew R. Conger, MD, MS Penn State College of Medicine - Milton S. Hershey
Geisinger Health Medical Center
Danville, PA, USA Hershey, PA, USA
Scott L. Coven, DO, MPH
Riley Hospital for Children at IU Health
Indianapolis, IN, USA
xvi

Andrew J. Gogos, MBBS, FRACS Erika N. Leese, PA-C

St Vincents Hospital Melbourne Geisinger Health
Fitzroy, AU Danville, PA, USA
David Gritsch, MD Mary Jane Lim-Fat, MD, MSc
Mass General Brigham Sunnybrook Health Sciences
Boston, MA, USA Toronto, ON, Canada
Simon Gritsch, MD, PhD Rimas V. Lukas, MD
Mass General Brigham Northwestern University
Boston, MA, USA Chicago, IL, USA
Lia M. Halasz, MD Alireza Mansouri, MD, MSc, FRCSC
University of Washington Penn State Health
Seattle, WA, USA Hershey, PA, USA
Shawn L. Hervey-Jumper, MD Aaron Mochizuki, DO
University of California San Francisco Cincinnati Children’s Hospital Medical Center
San Francisco, CA, USA Cincinnati, OH, USA
Joseph M. Hoxworth, MD Jamal Mohamud, DO
Mayo Clinic Indiana University School of Medicine
Phoenix, AZ, USA Indianapolis, IN, USA
Maya Hrachova, DO Ramin A. Morshed, MD
University of Oklahoma University of California San Francisco
Oklahoma City, OK, USA San Francisco, CA, USA
Valeria Internò, MD Maciej M. Mrugala, MD, PhD, MPH, FAAN
University of Bari Mayo Clinic
Bari, Italy Phoenix, AZ, USA
Rajan Jain, MD Lakshmi Nayak, MD
New York University Grossman School of Medicine Dana-Farber Cancer Institute, Harvard Medical School
New York, NY, USA Boston, MA, USA
George I. Jallo, MD Matthew T. Neal, MD, MBA
Johns Hopkins All Children’s Hospital Mayo Clinic
St. Petersburg, FL, USA Phoenix, AZ, USA
Thomas J. Kaley, MD Kathryn S. Nevel, MD
Memorial Sloan Kettering Cancer Center Indiana University School of Medicine
New York, NY, USA Indianapolis, IN, USA
Matthias Karajannis, MD, MS Theodore Nicolaides, MD
Memorial Sloan Kettering Cancer Center Caris Life Sciences
New York, NY, USA New York, NY, USA
John M. Kindler, MD Mohammad Hassan A. Noureldine, MD, MSc
Indiana University School of Medicine University of South Florida
Indianapolis, IN, USA Tampa, FL, USA
Peter Kobalka, MD Samanthalee C. S. Obiorah, BSc
Ohio State University Warren Alpert Medical School of Brown University
Columbus, OH, USA Providence, RI, USA
Ibrahim Kulac, MD Shirley Ong, MD
Koç University School of Medicine The Ohio State University Wexner Medical Center
Istanbul, Turkey Columbus, OH, USA
Sylvia C. Kurz, MD, PhD Sonia Partap, MD
Eberhard Karls University Stanford University & Lucile Packard
Tübingen, Germany Children’s Hospital
Palo Alto, CA, USA

xviii | c o n t R I B U t o R s
xi

David M. Peereboom, MD Wayne Slone, MD

Cleveland Clinic Ohio State University
Cleveland, OH, US Columbus, OH, USA
Melike Pekmezci, MD Riccardo Soffietti, MD, PhD
University of California University Hospital of Turin
San Francisco, CA, USA Turin, Italy
Katherine B. Peters, MD, PhD, FAAN Kun-Wei Song, MD
Duke University School of Medicine Massachusetts General Hospital / Dana-Farber Cancer Institute
Durham, NC, USA Boston, MA, USA
Sheetal Phadnis, MD Ramya Tadipatri, MD
University of Alabama Banner MD Anderson Cancer Center
Birmingham, AL, USA Gilbert, AZ, USA
Scott R. Plotkin, MD, PhD Hirokazu Takami, MD, PhD
Massachusetts General Hospital University of Tokyo
Boston, MA, USA Tokyo, Japan
Vinay K. Puduvalli, MD Kerianne R. Taylor, RN
UT MD Anderson Cancer Center Banner MD Anderson Cancer Center
Houston, TX, USA Phoenix, AZ, USA
Appaji Rayi, MD Steven A. Toms, MD, MPH
Charleston Area Medical Center Health System Brown University / Lifespan Health System
Charleston, WV, USA Providence, RI, USA
Alexander Ropper, MD Cristina Valencia-Sanchez, MD, PhD
Baylor College of Medicine Mayo Clinic
Houston, TX, USA Scottsdale, AZ, USA
Roberta Rudà, MD Terrence Verla, MD
University of Turin Baylor College of Medicine
Turin, Italy Houston, TX, USA
Sameer Farouk Sait, MBBS Gordon A. Watson†, MD, PhD
Memorial Sloan Kettering Cancer Center Indiana University School of Medicine
New York, NY, USA Indianapolis, IN, USA
David Schiff, MD Jessica A. Wilcox, MD
University of Virginia Health System Memorial Sloan Kettering Cancer Center
Charlottesville, VA, USA New York, NY, USA
Nir Shimony, MD Terri L. Woodard, MD, MPH
St. Jude Children’s Hospital Baylor University College of Medicine
Memphis, TN, USA Houston, TX, USA
Johns Hopkins University SoM UT MD Anderson Cancer Center
Baltimore, MD, USA Houston, TX, USA
Kevin Shiue, MD
Indiana University School of Medicine
Indianapolis, IN, USA

†
Deceased
x
1

PA RT I. | neURo- oncoLoGY oVeRVIeW

2
3
1 | NEUROPATHOLOGY PRIMER
IBRAHIM KULAC AND MELIKE PEKMEZCI
I n tR oDUc tIo n
Tumors of the central nervous system (CNS) have been tra-
ditionally classified based on their histomorphologic features
and by presumed cell of origin. Histologic grading has been
across tumor entities, and each tumor is assigned to a grade
as part of the nomenclature. Histologic grading is only one of
the prognostic criteria, and a tumor with low histologic grade
may behave aggressively depending on the location, patient’s
performance status, radiographic features, proliferation index,
and, more recently, genetic changes.
The revised fourth edition (2016) of the World Health
Organization (WHO) classification introduced a combined
histologic and molecular classification (integrated diag-
nosis), which dramatically changed the nomenclature.2
But this updated classification and grading scheme has al-
ready become insufficient, given our rapidly growing un-
derstanding of molecular features and numerous new
techniques including methylation profiling. For this pur-
pose, a group of experts gathered to create cIMPACT-NOW
(Consortium to Inform Molecular and Practical Approaches
to CNS Tumor Taxonomy—Not Official WHO), which has
already published multiple update reports, and many of these
updates are expected to be incorporated into the imminent
fifth edition of the WHO classification (2021).3 Important
changes in the upcoming classification include designation
of WHO grade using Arabic numerals, rather than Roman
numerals (which practice we have adopted for this volume)
and reserving the term “glioblastoma” for isocitrate dehy-
drogenase (IDH)-wildtype diffuse astrocytomas with histo-
logic or molecular features of grade 4, while all IDH-mutant
astrocytomas will be diagnosed as such with accompanying
histologic grade (2–4). In this chapter we cover the most
common CNS tumors in a fairly detailed manner and briefly
touch base with the relatively rare ones using the current
diagnostic criteria and terminology, some of which may
change in the near future.
Editors’ Note: This book is being published just as the new 2021 World Health
Organization (WHO) classification of CNS tumors is being released.1 While this
chapter is largely based on the 2016 classification, significant impending changes
are noted where appropriate. 4 For the most up-to date information, please see:
WHO Classification of Tumours; 5th Edition. Central Nervous System Tumours.
Edited by the WHO Classification of Tumours Editorial Board. International
Agency for Research on Cancer 2021.
G L I AL t U M o R s
CNS glial tumors are a diverse group of neoplasms originating
from the supportive cellular elements of CNS. Glial tumors
can be classified as diffuse (infiltrative) or solid glial tumors by
their growth pattern.
Glial tumors can be classified as diffuse (infiltrative) or solid
by their growth pattern.
DIFFUSE GLIAL TUMORS
The mainstay of the classification of adult diffuse gliomas is
the presence of IDH1/IDH2 mutations, which is associated
with concerted CpG island methylation at many gene loci
(G-CIMP phenotype) and with better outcome.
Diffuse gliomas (Chapter 4) have an infiltrative growth pattern,
in which neoplastic glial cells diffusely infiltrate into the existing
neuropil structures of the gray and white matter without a sharp
border between the tumor and the adjacent parenchyma. Earlier
classifications of diffuse gliomas relied only on the morphologic
features; however, the 2016 WHO classification of diffuse glial
tumors has had a major update, including the addition of cer-
tain genetic alterations to the diagnostic criteria, thus providing
an integrated diagnosis.2 Currently, the mainstay of the classifi-
cation is the presence of IDH1/IDH2 mutations, which is asso-
ciated with concerted CpG island methylation at many gene loci
(G-CIMP phenotype) and with better outcome. Furthermore, re-
gardless of the morphologic features, tumors with IDH mutation
and 1p/19q co-deletion are categorized as oligodendroglioma,
while the rest are diagnosed as astrocytoma. While this clas-
sification addresses many important issues and provides an
increased level of objectivity, its application to pediatric diffuse
gliomas has been somewhat limited. Pediatric-type diffuse
gliomas rarely harbor IDH mutations, and their molecular
features overlap significantly with solid glial and glioneuronal
tumors. Those with oligodendroglial morphology often harbor
FGFR1 alterations, and astrocytomas often show MYB/MYBL1
rearrangements.5 And, unlike adult counterparts, pediatric
high-grade gliomas frequently harbor H3 G34 mutations, and
infantile gliomas are frequently associated with NTRK, ALK, or
ROS fusions.6–8 The upcoming WHO classification will incor-
porate molecular alterations of pediatric-type diffuse gliomas
4

and address the role of molecular alterations in grading of
diffuse gliomas.
Pediatric type diffuse gliomas rarely harbor IDH mutations,
and their molecular features overlap significantly with solid
glial and glioneuronal tumors.
D I F F U S E A S T R O C Y T O M A , I D H - M U TA N T ,
WHO GRADE 2
Diffuse astrocytomas are composed of moderately pleomor-
phic cells with hyperchromatic, oval to round nuclei with ir-
regular nuclear contours interspersed in the parenchyma
where neurons or axonal fibers are visible between tumor cells
(see Figure 1.1A). Cellularity may vary but often it is moder-
ately increased compared to normal parenchyma. Mitoses are
absent or rare. Necrosis or microvascular proliferation is not
seen. By definition, these tumors have a mutation in either
IDH1 or IDH2, and the most common mutation is the R132H
mutation in IDH1.9 Concurrent mutations in ATRX and TP53
are typical features of IDH-mutant diffuse astrocytomas.10
Immunohistochemistry (IHC) is almost always very helpful
for diagnosis. Antibody against IDH1 R132H mutant protein
shows diffuse cytoplasmic positivity in majority of the tumors,
as seen in Figure 1.1B, although it is negative in tumors with
non-canonical IDH mutations. Therefore, sequencing for
other IDH1 and IDH2 mutations may be necessary. Loss of
nuclear ATRX expression by IHC suggests presence of an
ATRX mutation and can be used to strongly argue against
an oligodendroglioma. While strong and diffuse p53 nuclear
staining is suggestive of a TP53 mutation, the sensitivity and
specificity as well as the ideal cutoff value of p53 staining are still
debated. Tumor cells are variably positive with GFAP, OLIG2,
SOX10, and MAP2, none of which is specific for the diagnosis.
Neurofilament protein is useful to identify the entrapped ax-
onal fibers, confirming the infiltrative growth pattern.
A N A P L A S T I C A S T R O C Y T O M A , I D H - M U TA N T ,
WHO GRADE 3
Anaplastic astrocytomas either arise from a grade 2 diffuse
astrocytoma or, more frequently, are diagnosed de novo.
Histomorphological features are somewhat similar to diffuse
astrocytoma, IDH-mutant, WHO grade 2, but they tend to
have more prominent cytologic atypia, increased cellularity,
and elevated mitotic activity. Necrosis and microvascular pro-
liferation are not seen. Increased number of mitoses is the key
characteristic feature of anaplastic astrocytoma, IDH-mutant,
WHO grade 3; however, no strict cutoff is set for the number
of mitosis for the diagnosis, and mitotic activity should be
assessed in the context of specimen size. Molecular character-
istics of these tumors are also similar to their grade 2 coun-
terpart, including mutations in IDH1 or IDH2, ATRX, and
TP53 genes, but with more frequent copy number alterations.
There is ongoing debate about the utility of the current grading
system since some studies showed no significant difference in
prognosis between histologic grade 2 and 3 astrocytomas while
others did so.11–13 Future studies may refine mitotic thresholds
and may identify additional genetic alterations associated with
more aggressive clinical behavior to establish better grading
criteria.

(A) (B) (C)

(D) (E) (F)

Figure 1.1 Infiltrating glial tumors. (A) Diffuse astrocytoma, WHO grade 2: Note atypical tumor cells with irregular nuclear borders (>) diffusely infiltrating
to background cortex evidenced by entrapped cortical neurons (>>), Hematoxylin & eosin (H&E). (B) Immunohistochemistry for isocitrate dehydrogenase
(IDH)-1 R132H mutant protein. (C) Glioblastoma, WHO grade 4: Note multilayered endothelial cells referred to as microvascular proliferation (>), H&E.
(D) Oligodendroglioma, IDH-mutant and 1p/19q-co-deleted, WHO grade 2: Note fine, chicken-wire vasculature and perinuclear halos giving cells a fried-egg
appearance, H&E. (E) Diffuse midline glioma, H3 K27M-mutant, WHO grade 4: Note that the absence of microvascular proliferation or necrosis does not preclude
the designation of WHO grade 4, H&E. (F) Immunohistochemistry for H3 K27M mutant protein in diffuse midline glioma.

4 | PA R t I : n e U R o - o n c o L o G Y o V e R V I e W
5
G L I O B L A S T O M A , I D H - M U TA N T , W H O G R A D E 4
IDH mutant glioblastoma comprises approximately 10% of all
glioblastomas and either arises from a preexisting low-grade
astrocytoma or develops de novo. These tumors are composed of
pleomorphic cells with increased mitotic activity and contain mi-
crovascular proliferation and/or areas of necrosis, often palisading
necrosis (see Figure 1.1C). Presence of an IDH mutation can be
demonstrated by IDH1 R132H IHC in most cases.14 ATRX loss
and p53 positivity are also common findings similar to other
IDH-mutant astrocytomas. IDH1 and IDH2 sequencing should
be performed for IDH1 R132H IHC-negative glioblastomas if
there is a history of a lower grade glioma or if a patient is younger
than 55 years at the time of diagnosis and additional IHC studies
suggest strong association with an IDH mutation (i.e., ATRX loss).
While the morphologic features of IDH-mutant and
IDH-wildtype glioblastomas are essentially identical, their
molecular features and clinical outcomes are significantly
different.15,16 Recent studies demonstrated that homozy-
gous deletion of CDKN2A/B in IDH-mutant diffuse gliomas
without microvascular proliferation or necrosis is associated
with a disease course at least as adverse as a histologically de-
fined IDH-mutant glioblastoma.17 Based on a recent consensus
paper, there is a consideration to change the grading scheme
of IDH-mutant diffuse gliomas, including assigning grade 4 to
tumors with CDKN2A/B loss regardless of presence of micro-
vascular proliferation or necrosis, and limiting the term “glio-
blastoma” to IDH-wildtype tumors,18 so that these tumors will
instead be named astrocytoma, IDH-mutant, WHO grade 4.
GLIOBLASTOMA, IDH-WILDTYPE, WHO GRADE 4
The vast majority of high-grade gliomas in older adults are IDH-
wildtype glioblastomas (Chapter 3). They are characterized by
highly atypical, pleomorphic cells with frequent mitoses, ne-
crosis, and/or microvascular proliferation, similar to their IDH-
mutant counterparts (see Figure 1.1C). Chromosome 7p gain in
combination with 10q loss is the most frequent chromosomal
alteration in glioblastoma. Frequent molecular alterations in-
clude TERT promoter mutation, CDKN2A/B homozygous de-
letion, EGFR amplification, PTEN truncating mutations, and
other alterations in p53/MDM2, CDKN2A/RB1, and receptor
tyrosine kinase pathways.19 MGMT (O6-methylguanine-DNA
methyltransferase) promoter methylation, which is predictive
of response to alkylating agents such as temozolomide, is seen
in a subset of glioblastomas; however, it is more common in
IDH-mutant glioblastomas that have a G-CIMP phenotype.20
IDH-wildtype glioblastomas are characterized by highly
atypical, pleomorphic cells with frequent mitoses, necrosis,
and/or microvascular proliferation.
There are a number of histomorphologic variants, some
of which are associated with unique molecular alterations
or clinical behavior. Giant cell glioblastoma is predominantly
composed of highly atypical, multinucleated or mononu-
clear giant cells and harbors frequent TP53 mutations. Small
cell glioblastoma is relatively monomorphic, with bland mor-
phology mimicking a low-grade glioma but harbors frequent
EGFR amplification and other genetic features of glioblastoma.
Epithelioid glioblastoma has a dominant population of closely
packed epithelioid, sometimes rhabdoid cells; shows signifi-
cant morphologic and molecular overlap with anaplastic ple-
omorphic xanthoastrocytoma (PXA); and nearly half of them
harbor BRAF V600E mutation. Gliosarcoma is another well-
recognized morphological variant that has areas resembling
various sarcomas, most often undifferentiated sarcoma, pre-
viously referred as fibrosarcoma. Similar to IDH-mutant gli-
oblastoma, tumor cells are positive for glial markers (GFAP,
OLIG2, SOX10). IHC for IDH1 R132H is negative. Nuclear
ATRX expression is retained. Ki67 proliferation index is high.
Gliosarcoma is another well-recognized morphological var-
iant that has areas resembling various sarcomas, most often
undifferentiated sarcoma, previously referred as fibrosarcoma.
O L I G O D E N D R O G L I O M A , I D H - M U TA N T , 1 P / 1 9 Q
CO-DELETED, WHO GRADE 2
The classic morphologic features of oligodendroglioma
includes an infiltrative tumor composed of cells with round
nuclei with a crisp, fine chromatin structure on a background
of delicate, chicken-wire vasculature. Due to the processing
steps in routine histopathology, the cytoplasm looks clear,
which gives the cells a classic fried egg appearance on hema-
toxylin and eosin (H&E)-stained sections, as seen in Figure
1.1D. So-called secondary structures represent accentuation of
the tumor cells around neurons (perineuronal satellitosis) and
blood vessels and in subpial regions. Microcalcifications and
myxoid degeneration is common. Tumor cells with eccentric,
eosinophilic cytoplasm are referred to as minigemistocytes,
which can be quite numerous. Occasional mitoses can be seen,
but the tumors do not show a brisk mitotic activity.
The classic morphologic features of oligodendroglioma
includes an infiltrative tumor composed of cells with round
nuclei with a crisp, fine chromatin structure on a back-
ground of delicate, chicken-wire vasculature.
By definition, all oligodendrogliomas are IDH-mutant;
therefore, IDH1 R132H stain is positive in almost all cases.
Cases with histomorphologic features of an oligodendroglioma
but negative IDH1 R132H stain should be further tested for
non-canonical IDH mutations by sequencing. Similarly, all
oligodendrogliomas harbor co-deletion of entire chromosome
arms of 1p and 19q, which can be shown by fluorescence in-situ
hybridization (FISH), array comparative genomic hybridiza-
tion (aCGH) or next-generation sequencing, although sensi-
tivity and specificity may vary.2 Frequent alterations include
mutations in FUBP1 and CIC genes, located on chromosomes
1p and 19q, respectively. Oligodendrogliomas frequently
harbor TERT promoter mutations and are ATRX-wildtype;
therefore, they show retained ATRX nuclear staining by IHC.10
Likewise, diffuse strong p53 staining is not expected as TP53
mutations are not common in oligodendrogliomas. Tumor
cells are usually positive with OLIG2, SOX10, and MAP2,
6
none of which is specific for the diagnosis. GFAP staining is
usually limited and more often seen in minigemistocytes or
occasional tumors with astrocytic morphology.
A N A P L A S T I C O L I G O D E N D R O G L I O M A , I D H - M U TA N T ,
1P/19Q CO-DELETED, WHO GRADE 3
Anaplastic oligodendroglioma arises either de novo or by
progression of a grade 2 oligodendroglioma. Anaplastic
oligodendroglioma can be defined as a tumor with high cellularity,
brisk mitotic activity (>6 mitosis per 10 high-power field [HPF}),
and/or microvascular proliferation and/or necrosis that shows
the classic molecular oligodendroglioma signature (IDH mu-
tation and 1p/19q co-deletion). Anaplastic oligodendrogliomas
are prominently more cellular than grade 2 oligodendrogliomas
but may still show classic oligodendroglioma morphology with
round nuclei, perinuclear halos, and chicken-wire vasculature.
The highest grade assigned for a tumor of oligodendroglial lin-
eage is grade 3, per WHO 2016.2 Molecular features of anaplastic
oligodendroglioma are similar to grade 2 oligodendroglioma,
with increased copy number alterations and more frequent
CDKN2A loss. In addition to defining molecular alterations (IDH
mutation and 1p/19q codeletion), anaplastic oligodendrogliomas
also typically harbor TERT promoter mutations.
D I F F U S E M I D L I N E G L I O M A , H 3 K 2 7 M - M U TA N T ,
WHO GRADE 4
As the name specifies, diffuse midline glioma, H3 K27M-
mutant (Chapter 18), is an infiltrative glioma, typically of astro-
cytic morphology, involving midline structures such as thalamus,
basal ganglia, and spinal cord, which harbors a K27M mutation
involving histone H3.3 (H3F3A) or H3.1 (HIST1H3B/C) genes.
Tumors often consist of monomorphic, small glial cells and fre-
quently exhibit features of high-grade glioma, as seen in Figure
1.1E.21 However, paucicellular tumors without mitoses, necrosis,
or microvascular proliferation are not uncommon. Regardless of
the histologic features, these tumors are assigned WHO grade
4. Additional molecular alterations include frequent mutations in
TP53, PTEN, ATM, PPM1D, and CHEK2.22,23 ACVR1 mutations
and FRGR1 rearrangements seem to correlate with the type of
histone mutation and tumor location.24 These tumors are dif-
fusely positive for H3K27M antibody that reacts with both mu-
tant protein products of either H3.1 or H3.3 genes, as seen in
Figure 1.1F.25 Mutation leads to inhibition of PRC2 complex,
resulting decreased levels of trimethylation at the lysine 27 mark
of histone 3 (H3K27me3), which can also be detected by IHC.
Regardless of the histologic features, diffuse midline glioma,
H3 K27M mutant, is assigned WHO grade 4.
D I F F U S E H E M I S P H E R I C G L I O M A , H 3 G 3 4 - M U TA N T
H3 G34-mutant gliomas (Chapter 18) are defined by their mo-
lecular alteration but show variable histology.26,27 It is not yet
accepted as a distinct entity by the WHO 2016 classification,
but it is often seen in cerebral hemispheres of young adults.
Most commonly, they have a biphasic appearance, with a
glial component characterized by a fibrillary background and
atypical, pleomorphic cells, and areas of embryonal features
6 | PA R t I : n e U R o - o n c o L o G Y o V e R V I e W
which sometimes may be the dominant feature. Because of the
embryonal features, in the past, these tumors were diagnosed
as glioblastoma, with primitive neuronal features, or as a CNS
embryonal tumor. They are almost always high grade and often
have morphological hallmarks of a high-grade glial tumor
such as microvascular proliferation and/or palisading ne-
crosis which is very helpful for the correct diagnosis. A GFAP-
positive, OLIG2-negative hemispheric tumor with loss of
nuclear ATRX staining and diffuse p53 staining in the absence
of IDH mutations is highly suggestive of a H3 G34 mutation.
DIFFUSE ASTROCYTIC GLIOMA, IDH-WILDTYPE
Although diffuse astrocytoma, IDH-wildtype, WHO grade 2 and
anaplastic astrocytoma, IDH-wildtype, WHO grade 3 have been
included in the 2016 WHO classification, they have been referred to
as “provisional entities.” It is well-documented that IDH-wildtype
astrocytomas have significantly worse outcome than IDH-mutant
astrocytomas, and some tumors show a disease course similar
to IDH-wildtype glioblastomas. Multiple studies showed that
this group may include diffuse gliomas with distinct molecular
alterations other than IDH mutations, such as H3 K27M or H3
G34R mutations, and these tumors should now be diagnosed as
such. Recent cIMPACT-NOW updates have recommended ad-
ditional molecular testing to identify these tumors, which are ex-
pected to behave aggressively, and the group uses the terminology
“diffuse astrocytic glioma, IDH-wildtype with molecular features
of glioblastoma WHO grade 4.”19 Molecular features suggesting
aggressive behavior in this setting includes EGFR amplification,
TERT promoter mutation, and gain of chromosome 7q with con-
current loss of chromosome 10p.
Molecular features suggesting aggressive behavior in IDH-
wildtype astrocytoma include EGFR amplification, TERT
promoter mutation, and gain of chromosome 7q with con-
current loss of chromosome 10p.
ASTROCYTOMA, NOT OTHERWISE SPECIFIED (NOS)
AND OLIGODENDROGLIOMA, NOS
These tumors have the morphological features of an
astrocytoma or an oligodendroglioma but the molecular
workup needed for definitive integrated diagnosis cannot
be completed. In this setting, the WHO 2016 classification
recommends that pathologists use these diagnostic categories.
Although the diagnostic categories for oligoastrocytoma and
anaplastic oligoastrocytoma, NOS, still exist in the WHO
guidelines, these categories should only be used when fur-
ther testing will not or cannot be completed.28 Histologic
features, corresponding molecular alterations and integrated
diagnosis pathways in diffuse adult and pediatric gliomas are
summarized in Figures 1.2 and 1.3.
SOLID GLIAL TUMORS
PILOCYTIC ASTROCYTOMA, WHO GRADE 1
Pilocytic astrocytoma is the most common glioma in chil-
dren but can also be seen in adults of all ages. Although clin-
ical and radiological features of pilocytic astrocytomas are
7

Diffuse glioma (adult type)

Histologic features oligodendroglioma Astrocytoma

IDH1/IDHZ status IDH-mutant IDH-wildtype

1p/19q status 1p/19q-codeleted 1p/19q-Intact 1p/19q-Intact

CIC and/or FUBP1 mutation ATRX-mutant

Frequent alterations
TERT promoter mutation TP53-mutant

Histologic grade Grades 2 and 3 Grades 2 and 3 Grade 4 Grade 4 Grades 2 and 3

No CDKN2A/B CDKN2A/B TERT promoter mutation None

Alterations associated
homozygous homozygous EGFR amplification
with molecular grading
deletion deletion Polysomy 7/Monosomy 10

(Anaplastic)
Oligodendroglioma, (Anaplastic) Astrocytoma, Astrocytoma, Glioblastoma, (Anaplastic) Astrocytoma,
DIAGNOSIS IDH-mutant and IDH-mutant, IDH-mutant, IDH-wildtype, IDH-wildtype,
1p/19q-codeleted, WHO grade 2 (or 3) WHO grade 4* WHO grade 4 WHO grade 2 (or 3)
WHO grade 2 (or 3)

Other diagnoses to Pediatric-type gliomas,

especially in younger adults Non-infiltrating gliomas
consider and rule out

Figure 1.2 Summary of classification of adult type diffuse gliomas.

often pathognomonic for the diagnosis, histomorphology of bipolar glial cells with long, hair-like (piloid) processes and
can be challenging since they have a wide range of tissue loosely arranged microcystic areas composed of bland, glial
patterns. Most commonly pilocytic astrocytomas have a bi- cells with small nuclei and short, cobweb-like processes in a
phasic growth pattern with relatively compact areas composed variably myxoid background (see Figure 1.4A). Rosenthal

Diffuse glioma (pediatric type)

Location Midline Hemispheric

H3 K27M status H3 K27M-mutant H3 K27M-wildtype

Age group ANY Child/adolescent Infant

H3 G34 status H3 G34-wildtype H3 G34-mutuant

ANY Usually Usually

Histologic grade High-grade Low-grade
high-grade high-grade

ACVR1
ATRX
Additional mutations FGFR1/NF1
TP53
TP53, ATRX

TP53, SETD2, PDGFRA, MYB, Other MAPK NTRK, ROS,

Other alterations FGFR3-TACC3
PIK3CA, NF1, CDKN2A MYBL1 Pathway MET, ALK

Diffuse low- Diffuse

Diffuse midline Diffuse high-grade Diffuse Infantile high-
Angiocentric grade glioma, hemispheric
gioma, pediatric-type astrocytoma, grade glioma,
DIAGNOSIS glioma MAPK glioma,
H3 K27M-mutant, glioma, H3 wildtype MYB-or MYBL1- H3 wildtype,
pathway- H3 G34-mutant,
WHO grade 4 altered PLNTY WHO grade 4
altered WHO grade 4

- Li-Fraumeni syndrome (TP53) - IDH mutant glioma,

Other diagnoses to rule out
-Lynch syndrome (MSH2) especially in adolescents
and syndromic associations
- Biallelic mismatch repair deficiency (PMS2) - Non-infiltrating gliomas

Figure 1.3 Summary of classification of pediatric type diffuse gliomas.

8

(A) (B) (C)

(D) (E) (F)

Figure 1.4 Solid glial, glioneuronal, and ependymal tumors. (All except panel E are hematoxylin & eosin [H&E] stained sections.) (A) Pilocytic astrocytoma, WHO
grade 1: Note bland bipolar cells, microcystic background, and Rosenthal fibers (>). (B) Pleomorphic xanthoastrocytoma, WHO grade 2: Note mixture of spindle
cells, large atypical cells with smudgy irregular nuclei (>), and large cells with foamy (xanthomatous) cytoplasm (>>). (C) Ganglioglioma, WHO grade 1: Note large,
dysmorphic ganglion cells (>) in the background of bland spindled glial cells and numerous eosinophilic granular bodies (>>). (D) Ependymoma, WHO grade
2: Note perivascular fibrillary anucleate zones, referred to as perivascular pseudorosettes (>). (E) Epithelial membrane antigen (EMA) immunohistochemical stain
shows dot-like paranuclear staining in ependymomas. (F) Myxopapillary ependymoma, WHO grade 1: Note papillary structures containing a central vessel with
mucoid degeneration surrounded by small ependymal cells (>) in the myxoid background.

fibers (intracytoplasmic, thick, and long eosinophilic fibers)
are often seen in compact areas, and eosinophilic granular
bodies (EGBs) are prominent in microcystic areas. Atypical
cells with naked nuclei can be seen, especially at the periphery
of the lesion, raising the differential diagnosis of a diffuse
astrocytoma. Oligodendroglioma-like cytomorphology can
be prominent in other cases. Tumors may show degenerative
atypia as well as multinucleated cells.
Most commonly pilocytic astrocytomas have a biphasic
growth pattern with relatively compact areas composed of
bipolar glial cells with long, hair-like (piloid) processes and
loosely arranged microcystic areas composed of bland, glial
cells with small nuclei and short, cobweb-like processes in a
variably myxoid background.
Pilocytic astrocytomas are highly vascular and may show
complex glomeruloid vascular structures, especially lining
the tumoral cyst walls. Necrosis can be focal or extensive
and is usually an infarct type as opposed to a palisading
type; therefore, this should not be interpreted as an alarming
finding. Likewise, mitosis can be seen and may be quite fre-
quent. While the clinical significance is not fully established,
mitotic counts in excess of 4 mitoses per 10 HPFs associated
with palisading necrosis may indicate a potential for more
aggressive behavior, and these tumors are referred to as
anaplastic pilocytic astrocytoma, without an officially desig-
nated WHO grade.
Pilocytic astrocytomas typically harbor alterations
activating the mitogen-activated protein (MAP) kinase
pathway, most frequent of which is a tandem duplication
of BRAF resulting KIAA1549-BRAF fusion.29 Other typical
alterations include BRAF V600E, KRAS, and NF1 mutations,
and FGFR1 and RAF1 fusions. Presence of additional
alterations such as CDKN2A/B homozygous deletion, ATRX
mutation, or TERT promoter mutation seems to be associated
with more aggressive behavior.30
Tumor cells are positive for GFAP, OLIG2, S100, and
SOX10. Synaptophysin often shows weak cytoplasmic staining,
and this should not be interpreted as infiltrative growth pattern
or evidence for a neuronal component. Neurofilament is useful
to demonstrate well-demarcated, solid growth pattern with
scarce entrapped axons at the periphery. However, it should be
kept in mind that rare examples, especially in cerebellum, may
show an extensive infiltrative pattern. Because these tumors do
not harbor IDH mutations, IDH1 R132H stain is expected to
be negative. Although Ki67 proliferation index is typically low
(<5%), some cases may reveal a quite high index.
P ILOMYXOID ASTROCYTOMA
Pilomyxoid astrocytoma (PMA) is considered a variant of
pilocytic astrocytoma, with additional, somewhat character-
istic features. These tumors tend to localize in the thalamic or
hypothalamic region and are seen in earlier ages compared to
pilocytic astrocytomas.31,32 PMAs are solid tumors composed
of monomorphous, bipolar cells with fusiform nuclei and long
glial processes in a homogenous myxoid background. Tumor

8 | PA R t I : n e U R o - o n c o L o G Y o V e R V I e W
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