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WHO Classification of Tumours of

the Central Nervous System


David N. Louis, Hiroko Ohgaki, Otmar D. Wiestier, Webster K. Cavenee, David W. Ellison,
Dominique Figarella-Branger, Arie Perry, Guido Reifenberger, Andreas von Deimling

WHO
World Health Organization Classification of Tumours

WHO OMS

International Agency for Research on Cancer (IARC)

Revised 4th Edition

WHO Classification of Tumours of


the Central Nervous System

Edited by

David N. Louis Hiroko


Ohgaki Otmar D.

Wiestler Webster K.

Cavenee

International Agency for Research on Cancer


Lyon, 2016
World Health Organization Classification of Tumours

Series Editors Fred T. Bosman, MD PhD


Elaine S. Jaffe, MD Sunil R.
Lakhani, MD FRCPath Hiroko
Ohgaki, PhD

WHO Classification of Tumours of the Central Nervous System


Revised 4th Edition

Editors David N. Louis, MD Hiroko Ohgaki, PhD


Otmar D. Wiestler, MD Webster K.
Cavenee, PhD

Senior Advisors David W. Ellison, MD PhD, Dominique


Figarella-Branger, MD Arie Perry, MD
Guido Reifenberger, MD Andreas von
Deimling, MD

Project Coordinator Paul Kleihues, MD

Project Assistant Asiedua Asante

Technical Editor Jessica Cox

Database Kees Kleihues-van Tol

Layout Stefanie Brottrager

Printed by Maestro
38330 Saint-lsmier, France

Publisher International Agency for Research on


Cancer (IARC) 69372 Lyon Cedex 08,
France
This volume was produced with support from and in collaboration with the

German Cancer Research Center

The WHO Classification of Tumours of the Central Nervous System presented in this
book reflects the views of a Working Group that convened for Consensus and
Editorial Meeting at the German Cancer Research Center,
Heidelberg, 21-24 June 2015.

Members of the Working Group are indicated in


the list of contributors on pages 342-348.
Published by the International Agency for Research on Cancer (IARC)

150 Cours Albert Thomas, 69372 Lyon Cedex 08, France

International Agency for Research on Cancer, 2016

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The authors alone are responsible for the views expressed In this publication.

The copyright of figures and charts remains with the authors.


(See Sources of figures and tables, pages 351-355.)

First print run (10 000 copies)

Format for bibliographic citations;


David N. Louis, Hiroko Ohgaki, Otmar D. Wiestler, Webster K. Cavenee (Eds):
WHO Classification of Tumours of the Central Nervous System (Revised 4th edition).
IARC; Lyon 2016.

IARC Library Cataloguing in Publication Data


WHO classification of tumours of the central nervous system / edited by David N. Louis, Hiroko Ohgaki, Otmar D. Wiestler,
Webster K. Cavenee. - Revised 4th edition.
(World Health Organization classification of tumours)

1. Central Nervous System Neoplasms - genetics


2. Central Nervous System Neoplasms - pathology I. Louis David N

ISBN 978-92-832-4492-9 (NLM Classification: WJ 160)


Contents
WHO classification 10 Anaplastic ganglioglioma 141
Introduction: WHO classification and grading of tumours Dysplastic cerebellar gangliocytoma
of the central nervous system 12 (Lhermitte-Duclos disease) 142
Desmoplastic infantile astrocytoma and ganglioglioma 144
1 Diffuse astrocytic and oligodendroglial tumours 15 Papillary glioneuronal tumour 147
Introduction 16 Rosette-forming glioneuronal tumour 150
Diffuse astrocytoma, IDH-mutant 18 Diffuse leptomeningeal glioneuronal tumour 152
Gemistocytic astrocytoma, IDH-mutant 22 Central neurocytoma 156
Diffuse astrocytoma, IDH-wildtype 23 Extraventricular neurocytoma 159
Diffuse astrocytoma, NOS 23 Cerebellar liponeurocytoma 161
Anaplastic astrocytoma, IDH-mutant 24 Paraganglioma 164
Anaplastic astrocytoma, IDH-wildtype 27
Anaplastic astrocytoma, NOS 27 7 Tumours of the pineal region 169
Glioblastoma, IDH-wildtype 28 Pineocytoma 170
Giant cell glioblastoma 46 Pineal parenchymal tumour of intermediate differentiation 173
Gliosarcoma 48 Pineoblastoma 176
Epithelioid glioblastoma 50 Papillary tumour of the pineal region 180
Glioblastoma, IDH-mutant 52
Glioblastoma, NOS 56 8 Embryonal tumours 183
Diffuse midline glioma, H3 K27M-mutant 57 Medulloblastoma 184
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted 60 Medulloblastoma, NOS 186
Oligodendroglioma, NOS 69 Medulloblastomas, genetically defined 188
Anaplastic oligodendroglioma, IDH-mutant and Medulloblastoma, WNT-activated 188
1p/19q-codeleted 70 Medulloblastoma, SHH-activated and TP53-mutant 190
Anaplastic oligodendroglioma, NOS 74 Medulloblastoma, SHH-activated and TP53-wildtype 190
Oligoastrocytoma, NOS 75 Medulloblastoma, non-WNT/non-SHH 193
Anaplastic oligoastrocytoma, NOS 76 Medulloblastomas, histologically defined 194
Medulloblastoma, classic 194
2 Other astrocytic tumours 79 Desmoplastic/nodular medulloblastoma 195
Pilocytic astrocytoma 80 Medulloblastoma with extensive nodularity 198
Pilomyxoid astrocytoma 88 Large cell / anaplastic medulloblastoma
200
Subependymal giant cell astrocytoma 90 Embryonal tumour with multilayered rosettes,
Pleomorphic xanthoastrocytoma 94 C19MC-altered 201
Anaplastic pleomorphic xanthoastrocytoma 98 Embryonal tumour with multilayered rosettes, NOS 205
Other CNS embryonal tumours 206
3 Ependymal tumours 101 Medulloepithelioma 207
Subependymoma 102 CNS neuroblastoma 207
Myxopapillary ependymoma 104 CNS ganglioneuroblastoma 207
Ependymoma 106 CNS embryonal tumour, NOS 208
Papillary ependymoma 111 Atypical teratoid/rhabdoid tumour 209
Clear cell ependymoma 111 CNS embryonal tumour with rhabdoid features 212
Tanycytic ependymoma 111
Ependymoma, RELA fusion-positive 112 9 Tumours of the cranial and paraspinal nerves 213
Anaplastic ependymoma 113 Schwannoma 214
Cellular schwannoma 216
4 Other gliomas 115 Plexiform schwannoma 217
Chordoid glioma of the third ventricle 116 Melanotic schwannoma 218
Angiocentric glioma 119 Neurofibroma 219
Astroblastoma 121 Atypical neurofibroma 220
Plexiform neurofibroma 220
5 Choroid plexus tumours 123 Perineurioma 222
Choroid plexus papilloma 124 Hybrid nerve sheath tumours 224
Atypical choroid plexus papilloma 126 Malignant peripheral nerve sheath tumour (MPNST) 226
Choroid plexus carcinoma 128 MPNST with divergent differentiation 227
Epithelioid MPNST 228
6 Neuronal and mixed neuronal-glial tumours 131 MPNST with perineurial differentiation 228
Dysembryoplastic neuroepithelial tumour 132
Gangliocytoma 136 10 Meningiomas 231
Ganglioglioma 138 Meningioma 232
Meningioma variants 237 Intravascular large B-cell lymphoma 276
Meningothelial meningioma 237 Miscellaneous rare lymphomas in the CNS 276
Fibrous meningioma 237 Low-grade B-cell lymphomas 276
Transitional meningioma 238 T-cell and NK/T-cell lymphomas 276
Psammomatous meningioma 238 Anaplastic large cell lymphoma (ALK+/ALK-) 277
Angiomatous meningioma 238 MALT lymphoma of the dura 277
Microcystic meningioma 239
14 Histiocytic tumours 279
Secretory meningioma 239
Lymphoplasmacyte-rich meningioma 240 Langerhans cell histiocytosis 280
Metaplastic meningioma 240 Erdheim-Chester disease 281
Chordoid meningioma 240 Rosai-Dorfman disease 282
Clear cell meningioma 241 Juvenile xanthogranuloma 282
Atypical meningioma 241 Histiocytic sarcoma 283
Papillary meningioma 242
15 Germ cell tumours 285
Rhabdoid meningioma 243
Anaplastic (malignant) meningioma 244 Germinoma 288
Embryonal carcinoma 289
11 Mesenchymal, non-meningothelial tumours 247 Yolk sac tumour 290
Solitary fibrous tumour / haemangiopericytoma 249 Choriocarcinoma 290
Haemangioblastoma 254 Teratoma 291
Haemangioma 258 Mature teratoma 291
Epithelioid haemangioendothelioma 258 Immature teratoma 291
Angiosarcoma 259 Teratoma with malignant transformation 291
Kaposi sarcoma 259 Mixed germ cell tumour 291
Ewing sarcoma / peripheral primitive 16 Familial tumour syndromes 293
neuroectodermal tumour 259
Lipoma 260 Neurofibromatosis type 1 294
Angiolipoma 260 Neurofibromatosis type 2 297
Hibernoma 260 Schwannomatosis 301
Liposarcoma 260 Von Hippel-Lindau disease 304
Desmoid-type fibromatosis 260 Tuberous sclerosis 306
Myofibroblastoma 260 Li-Fraumeni syndrome 310
Inflammatory myofibroblastic tumour 261 Cowden syndrome 314
Benign fibrous histiocytoma 261 Turcot syndrome 317
Fibrosarcoma 261 Mismatch repair cancer syndrome 317
Undifferentiated pleomorphic sarcoma / malignant Familial adenomatous polyposis 318
fibrous histiocytoma 261 Naevoid basal cell carcinoma syndrome 319
Leiomyoma 262 Rhabdoid tumour predisposition syndrome 321
Leiomyosarcoma 262 17 Tumours of the sellar region 323
Rhabdomyoma 262
Rhabdomyosarcoma 262 Craniopharyngioma 324
Chondroma 262 Adamantinomatous craniopharyngioma 327
Chondrosarcoma 263 Papillary craniopharyngioma 328
Osteoma 264 Granular cell tumour of the sellar region 329
Osteochondroma 264 Pituicytoma 332
Osteosarcoma 264 Spindle cell oncocytoma 334

18 Metastatic tumours 337


12 Melanocytic tumours 265
Meningeal melanocytosis 267
Contributors 342
Meningeal melanomatosis 267
Meningeal melanocytoma 268 Declaration of interest statements 349
Meningeal melanoma 269 IARC/WHO Committee for ICD-0 350
Sources of figures and tables 351
13 Lymphomas 271 References 356
Diffuse large B-cell lymphoma of the CNS 272 Subject index 402
Corticoid-mitigated lymphoma 275 Lisit of abbreviations 408
Sentinel lesions 275
Immunodeficiency-associated CNS lymphomas 275
AIDS-related diffuse large B-cell lymphoma 275
EBV+ diffuse large B-cell lymphoma, NOS 276
Lymphomatoid granulomatosis 276
WHO classification of tumours of the central nervous system
Diffuse astrocytic and oligodendroglial Neuronal and mixed neuronal-glial tumours
tumours
Diffuse astrocytoma, IDH-mutant 9400/3 Dysembryoplastic neuroepithelial tumour 9413/0
Gemistocytic astrocytoma, IDH-mutant 9411/3 Gangliocytoma 9492/0
Diffuse astrocytoma, IDH-wildtype 9400/3 Ganglioglioma 9505/1
Diffuse astrocytoma, NOS 9400/3 Anaplastic ganglioglioma 9505/3
Dysplastic cerebellar gangliocytoma
Anaplastic astrocytoma, IDH-mutant 9401/3 (Lhermitte-Duclos disease) 9493/0
Anaplastic astrocytoma, IDH-wildtype 9401/3 Desmoplastic infantile astrocytoma and
Anaplastic astrocytoma, NOS 9401/3 ganglioglioma 9412/1
Papillary glioneuronal tumour 9509/1
Glioblastoma, IDH-wildtype 9440/3 Rosette-forming glioneuronal tumour 9509/1
Giant cell glioblastoma 9441/3 Diffuse leptomeningeal glioneuronal tumour
Gliosarcoma 9442/3 Central neurocytoma 9506/1
Epithelioid glioblastoma 9440/3 Extraventricular neurocytoma 9506/1
Glioblastoma, IDH-mutant 9445/3* Cerebellar liponeurocytoma 9506/1
Glioblastoma, NOS 9440/3 Paraganglioma 8693/1
Diffuse midline glioma, H3 K27M-mutant 9385/3* Tumours of the pineal region
Pineocytoma 9361/1
Oligodendroglioma, IDH-mutant and Pineal parenchymal tumour of intermediate
1p/19q-codeleted 9450/3 differentiation 9362/3
Oligodendroglioma, NOS 9450/3 Pineoblastoma 9362/3
Papillary tumour of the pineal region 9395/3
Anaplastic oligodendroglioma, IDH-mutant
and 1p/19q-codeleted 9451/3 Embryonal tumours
Anaplastic oligodendroglioma, NOS 9451/3 Medulloblastomas, genetically defined
Medulloblastoma, WNT-activated 9475/3*
Oligoastrocytoma, NOS 9382/3 Medulloblastoma, SHH-activated and
Anaplastic oligoastrocytoma, NOS 9382/3 TP53-mutant 9476/3*
Medulloblastoma, SHH-activated and
Other astrocytic tumours TP53- wildtype 9471/3
Pilocytic astrocytoma 9421/1 Medulloblastoma, non-WNT/non-SHH 9477/3*
Pilomyxoid astrocytoma 9425/3 Medulloblastoma, group 3
Subependymal giant cell astrocytoma 9384/1 Medulloblastoma, group 4
Pleomorphic xanthoastrocytoma 9424/3 Medulloblastomas, histologically defined
Anaplastic pleomorphic xanthoastrocytoma 9424/3 Medulloblastoma, classic 9470/3
Medulloblastoma, desmoplastic/nodular 9471/3
Ependymal tumours Medulloblastoma with extensive nodularity 9471/3
Subependymoma 9383/1 Medulloblastoma, large cell / anaplastic 9474/3
Myxopapillary ependymoma 9394/1 Medulloblastoma, NOS 9470/3
Ependymoma 9391/3
Papillary ependymoma 9393/3 Embryonal tumour with multilayered rosettes,
Clear cell ependymoma 9391/3 C19MC-altered 9478/3*
Tanycytic ependymoma 9391/3 Embryonal tumour with multilayered
Ependymoma, RELA fusion-positive 9396/3* rosettes, NOS 9478/3
Anaplastic ependymoma 9392/3 Medulloepithelioma 9501/3
CNS neuroblastoma 9500/3
Other gliomas CNS ganglioneuroblastoma 9490/3
Chordoid glioma of the third ventricle 9444/1 CNS embryonal tumour, NOS 9473/3
Angiocentric glioma 9431/1 Atypical teratoid/rhabdoid tumour 9508/3
Astroblastoma 9430/3 CNS embryonal tumour with rhabdoid features 9508/3
Choroid plexus tumours Tumours of the cranial and paraspinal nerves
Choroid plexus papilloma 9390/0 Schwannoma 9560/0
Atypical choroid plexus papilloma 9390/1 Cellular schwannoma 9560/0
Choroid plexus carcinoma 9390/3 Plexiform schwannoma 9560/0

10 WHO classification of tumours of the central nervous system


Melanotic schwannoma 9560/1 Osteochondroma 9210/0
Neurofibroma 9540/0 Osteosarcoma 9180/3
Atypical neurofibroma 9540/0
Melanocytic tumours
Plexiform neurofibroma 9550/0
Perineurioma 9571/0 Meningeal melanocytosis 8728/0
Hybrid nerve sheath tumours 9540/3 Meningeal melanocytoma 8728/1
Malignant peripheral nerve sheath tumour Meningeal melanoma 8720/3
Epithelioid MPNST 9540/3 Meningeal melanomatosis 8728/3
MPNST with perineurial differentiation 9540/3 Lymphomas
Meningiomas 9530/0
Diffuse large B-cell lymphoma of the CNS 9680/3
Meningioma Immunodeficiency-associated CNS lymphomas
Meningothelial meningioma 9531/0 AIDS-related diffuse large B-cell lymphoma
Fibrous meningioma 9532/0 EBV-positive diffuse large B-cell lymphoma,
Transitional meningioma 9537/0 NOS
Psammomatous meningioma 9533/0 Lymphomatoid granulomatosis 9766/1
Angiomatous meningioma 9534/0 Intravascular large B-cell lymphoma 9712/3
Microcystic meningioma 9530/0 Low-grade B-cell lymphomas of the CNS T-cell 9714/3
Secretory meningioma 9530/0 and NK/T-cell lymphomas of the CNS Anaplastic
Lymphoplasmacyte-rich meningioma 9530/0 large cell lymphoma, ALK-positive
Metaplastic meningioma 9530/0 Anaplastic large cell lymphoma, ALK-negative 9702/3
Chordoid meningioma 9538/1 MALT lymphoma of the dura 9699/3
Clear cell meningioma 9538/1 Histiocytic tumours
Atypical meningioma 9539/1
Langerhans cell histiocytosis 9751/3
Papillary meningioma 9538/3
Erdheim-Chester disease 9750/1
Rhabdoid meningioma 9538/3
Rosai-Dorfman disease 9755/3
Anaplastic (malignant) meningioma 9530/3
Juvenile xanthogranuloma
Mesenchymal, non-meningothelial tumours 8815/0 Histiocytic sarcoma
Solitary fibrous tumour / haemangiopericytoma**
Grade 1 Germ cell tumours
Grade 2 8815/1 Germinoma 9064/3
Grade 3 8815/3 Embryonal carcinoma 9070/3
Haemangioblastoma 9161/1 Yolk sac tumour 9071/3
Haemangioma 9120/0 Choriocarcinoma 9100/3
Epithelioid haemangioendothelioma 9133/3 Teratoma 9080/1
Angiosarcoma 9120/3 Mature teratoma 9080/0
Kaposi sarcoma 9140/3 Immature teratoma 9080/3
Ewing sarcoma / PNET 9364/3 Teratoma with malignant transformation 9084/3
Lipoma 8850/0 Mixed germ cell tumour 9085/3
Angiolipoma 8861/0 Tumours of the sellar region
Hibernoma 8880/0
Liposarcoma 8850/3 Craniopharyngioma 9350/1
Desmoid-type fibromatosis 8821/1 Adamantinomatous craniopharyngioma 9351/1
Myofibroblastoma 8825/0 Papillary craniopharyngioma 9352/1
Inflammatory myofibroblastic tumour 8825/1 Granular cell tumour of the sellar region 9582/0
Benign fibrous histiocytoma 8830/0 Pituicytoma 9432/1
Fibrosarcoma 8810/3 Spindle cell oncocytoma 8290/0
Undifferentiated pleomorphic sarcoma / malignant8802/3
fibrous histiocytoma Metastatic tumours
Leiomyoma 8890/0 The morphology codes are from the International Classification of Diseases for
Leiomyosarcoma 8890/3 Oncology (ICD-O) {742A}. Behaviour is coded / 0 for benign tumours;
/1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and
Rhabdomyoma 8900/0 grade III intraepithelial neoplasia; and /3 for malignant tumours. The classification
Rhabdomyosarcoma 8900/3 is modified from the previous WHO classification, taking into account changes in
Chondroma 9220/0 our understanding of these lesions.
'These new codes were approved by the IARC/WHO Committee for ICD-O. Italics:
Chondrosarcoma 9220/3 Provisional tumour entities. "Grading according to the 2013 WHO Classification of
Osteoma 9180/0 Tumours of Soft Tissue and Bone.

WHO classification of tumours of the central nervous system 11


WHO classification and grading of Louis D.N.

tumours of the central nervous system

Combined histological-molecular molecular genetic alterations suggest a genetic finding is present, leaving that
classification that such challenges will be readily over- to individual practitioners and institutions,
For nearly a century, the classification of come in the near future {2105}. Many of but the commentary sections do clarify
brain tumours has been based on con- the genetic parameters included in the the implication of certain genetic features;
cepts of histogenesis, hinging on the idea 2016 WHO classification can be as- for example, in what situations IDH status
that tumours can be classified according sessed using immunohistochemistry can be designated as wildtype.
to their microscopic similarities with puta- or FISH, but it is recognized that some
tive cells of origin and their developmental Histological grading
centres may not have the ability to carry
differentiation states. These histological Histological grading is a means of pre-
out molecular analyses and that some
similarities have been characterized pri- dicting the biological behaviour of a
molecular results may not be conclusive.
marily on the basis of the light microscop- neoplasm. In the clinical setting, tumour
With this in mind, an NOS diagnostic des-
ic appearance of H&E-stained sections, grade is a key factor influencing the
ignation has been included in the 2016
the immunohistochemical expression of choice of therapies. Since its first pub-
WHO classification wherever such issues
proteins, and the electron microscopic lication in 1979, the WHO classification
may apply. The NOS designation indi-
assessment of ultrastructural features. of tumours of the central nervous system
cates that there is insufficient informa-
The 2000 and 2007 WHO classifications has included a grading scheme that es-
tion to assign a more specific code. In
considered histological features along sentially constitutes a malignancy scale
this context, the NOS category includes
with the rapidly increasing knowledge (ranging across a wide variety of neo-
both tumours that have not been tested
of the genetic changes that underlie the plasms) rather than a strict histological
for the genetic parameter(s) and tumours
tumorigenesis of CNS tumours. Many grading system {1290,1291,2878}. WHO
that have been tested but did not show
of the canonical genetic alterations had grading is widely used, and it has incor-
the diagnostic genetic alterations. In
been identified by the time the 2007 porated or largely replaced other previ-
other words, the NOS designation does
WHO classification was published, but at ously published grading systems for
not refer to a specific entity; instead, it
the time the consensus opinion was that brain tumours. Although grading is not
designates the lesions that cannot be
such changes could not yet be used to a requirement for the application of the
classified into any of the more precisely
define neoplasms; instead, genetic sta- WHO classification for some tumours,
defined groups.
tus served as supplementary information including gliomas and meningiomas,
within the framework of diagnostic cat- Definitions, disease summaries, and numerical WHO grades are useful addi-
egories established by standard, histolo- commentaries tions to the diagnoses. The WHO Work-
gy-based means. In contrast, the present Each entity-specific section in the 2016 ing Group responsible for this update of
update (the 2016 classification) breaks WHO classification begins with a short the 4th edition has expanded the classifi-
with this nearly century-old tradition and disease definition that describes the es- cation to include additional entities; how-
incorporates well-established molecular sential diagnostic criteria. This initial ever, since the number of cases of some
parameters into the classification of dif- definition is followed by a description of of these newly defined entities is limited,
fuse gliomas. characteristic associated findings; for the assignment of grades to such entities
Changing the classification to include example, although a delicate branching is still provisional, pending publication of
diagnostic categories that depend on vasculature and calcospherites are not additional data and long-term follow-up.
genotype may create certain challenges essential for the diagnosis of oligoden-
Histological grading across tumour
with respect to testing and reporting. droglioma, they are highly characteristic.
entities
These challenges include the availability The diagnostic criteria and characteris-
Grade I lesions are generally tumours
and choice of genotyping and surrogate tic features are then followed by the rest
with low proliferative potential and the
genotyping assays, the approaches that of the disease summary, in which other
possibility of cure after surgical resec-
may need to be taken by centres without notable clinical, pathological, and mo-
tion alone. Grade II lesions are usually
genotyping (or surrogate genotyping) ca- lecular findings are described. Finally,
infiltrative in nature and often recur, de-
pabilities, and the actual formats used to for some entities, there is also additional
spite having low levels of proliferative
report these integrated diagnoses {1535}. commentary that provides information on
activity. Some grade II entities tend to
However, an important consideration for classification, clarifying the nature of the
progress to higher grades of malignancy;
the 2016 WHO classification was that the genetic parameters to be evaluated and
for example, grade II diffuse astrocytoma
implementation of combined phenotyp- providing genotyping information on pos-
tends to transform to grade III anaplas-
ic-genotypic diagnostics in some large sibly overlapping histological entities. The
tic astrocytoma and glioblastoma. The
centres and the increasing availability classification does not specify the type
grade III designation is applied to lesions
of immunohistochemical surrogates for of testing required to establish whether

12 WHO classification and grading


with clear histological evidence of ma- which is the more common practice in implications. For each tumour entity, the
lignancy, including nuclear atypia and non-nervous system tumours. Specifi- combination of these parameters contrib-
sometimes brisk mitotic activity. In most cally, this principle is applied to solitary fi- utes to an overall estimate of prognosis.
settings, patients with grade III tumours brous tumour / haemangiopericytoma, for Patients with WHO grade II tumours typi-
receive radiation and/or chemotherapy. which three different grades can be as- cally survive for > 5 years, and those with
The grade IV designation is applied to signed within the same tumour designa- grade III tumours survive for 2-3 years.
cytologically malignant, mitotically ac- tion. It is anticipated that the greater flex- For patients with WHO grade IV tumours,
tive, necrosis-prone neoplasms that are ibility afforded by grading within tumour prognosis depends heavily on whether
often associated with rapid pre- and entities may be an advantage for future effective treatment regimens are avail-
postoperative disease evolution and WHO classifications of brain tumours. able. Most glioblastoma patients, and in
fatal outcome. Glioblastoma and most particular elderly patients, succumb to
Tumour grade as a prognostic factor
embryonal neoplasms are examples of the disease within a year. For those with
WHO grade is based on histological
grade IV lesions. Widespread infiltration other grade IV neoplasms, the outlook
features and is one component of a set
of surrounding tissue and a propensity may be considerably better. For exam-
of criteria used to predict response to
for craniospinal dissemination character- ple, grade IV cerebellar medulloblasto-
therapy and outcome {1535}. Other cri-
ize many grade IV neoplasms, although mas and germ cell tumours such as ger-
teria include clinical findings (e.g. patient
these features are not essential. minomas are rapidly fatal if left untreated,
age, performance status, and tumour
but state-of-the-art radiation and chemo-
Histological grading within tumour location), radiological features (e.g. con-
therapy result in 5-year survival rates ex-
entities trast enhancement), extent of surgical
ceeding 60% and 80%, respectively. For
To date, the WHO classifications of CNS resection, proliferation index values,
some tumour types, the presence of cer-
tumours have assigned grades as de- and genetic alterations. Genetic profile
tain genetic alterations can shift prognos-
scribed above (i.e. across tumour enti- has become increasingly important be-
tic estimates markedly within the same
ties). For the first time, the 2016 WHO cause some genetic changes (e.g. IDH
grade, in some cases outweighing the
classification has also adopted the prin- mutation in diffuse gliomas) have been
prognostic strength of grade itself {952,
ciple of grading within a tumour entity, found to have important prognostic
1535,2105}.

WHO grades of select CNS tumours Desmoplastic infantile astrocytoma and ganglioglioma I
Papillary glioneuronal tumour I
Diffuse astrocytic and oligodendroglial tumours Rosette-forming glioneuronal tumour I
Diffuse astrocytoma, IDH-mutant II Central neurocytoma II
Anaplastic astrocytoma, IDH-mutant III Extraventricular neurocytoma II
Glioblastoma, IDH-wildtype IV Cerebellar liponeurocytoma II
Glioblastoma, IDH-mutant IV Tumours of the pineal region I
Diffuse midline glioma, H3 K27M-mutant IV Pineocytoma II or III
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted II Pineal parenchymal tumour of intermediate differentiation
Anaplastic oligodendroglioma, IDH-mutant and Pineoblastoma IV
1p/19q-codeleted III Papillary tumour of the pineal region II or III
Other astrocytic tumours Embryonal tumours
Pilocytic astrocytoma I Medulloblastoma (all subtypes) IV
Subependymal giant cell astrocytoma I Embryonal tumour with multilayered rosettes, C19MC- IV
Pleomorphic xanthoastrocytoma II altered
Anaplastic pleomorphic xanthoastrocytoma III Medulloepithelioma IV
Ependymal tumours CNS embryonal tumour, NOS IV
Subependymoma I Atypical teratoid/rhabdoid tumour IV
Myxopapillary ependymoma I CNS embryonal tumour with rhabdoid features IV
Ependymoma II Tumours of the cranial and paraspinal nerves
Ependymoma, RELA fusion-positive II or III Schwannoma I
Anaplastic ependymoma III Neurofibroma I
Perineurioma I
Other gliomas
Malignant peripheral nerve sheath tumour (MPNST) I I, III or IV
Angiocentric glioma I
Chordoid glioma of third ventricle II Meningiomas
Meningioma I
Choroid plexus tumours
Atypical meningioma II
Choroid plexus papilloma I
Anaplastic (malignant) meningioma III
Atypical choroid plexus papilloma II
Choroid plexus carcinoma III Mesenchymal, non-meningothelial tumours
Neuronal and mixed neuronal-glial tumours Solitary fibrous tumour / haemangiopericytoma I, II or III
Haemangioblastoma I
Dysembryoplastic neuroepithelial tumour I
Gangliocytoma I Tumours of the sellar region I
Ganglioglioma I Craniopharyngioma I
Granular cell tumour I
Anaplastic ganglioglioma III
Pituicytoma I
Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos) I
Spindle cell oncocytoma I

WHO classification and grading of tumours of the central nervous system 13


Louis D.N.
Diffuse astrocytic and von Deimling A.
oligodendroglial tumours - Introduction Cavenee W.K.

This 2016 update of the 2007 WHO clas-


sification incorporates well-established
molecular parameters into the classifica-
tion of diffuse gliomas, and this nosologi-
cal shift has impacted the classification
in several ways. Most notably, whereas
all astrocytic tumours were previously
grouped together, now all diffuse gliomas
(whether astrocytic or not) are grouped
together, on the basis of not only their
growth pattern and behaviours, but more
pointedly of their shared IDH1 and IDH2
genetic status. From a pathogenetic
point of view, this provides a dynamic
classification based on both phenotype
and genotype; from a prognostic point of
view, it groups tumours that share similar
prognostic markers; and from the even-
tual therapeutic point of view, it will pre-
sumably guide the treatment of biologi- Fig. 1.01 Diffuse gliomas: from histology, IDH status, and other genetic parameters to W HO diagnosis.
cally similar entities.
In this new classification, the diffuse glio- a reasonably narrowly defined group placed into categories biologically com-
ma category includes the WHO grade II of tumours characterized by K27M mu- patible with either astrocytoma or oligo-
and III astrocytic tumours, the grade II tations in histone H3 genes, a diffuse dendroglioma {2220,2751}, with only rare
and III oligodendrogliomas, the rare growth pattern, and midline location: the cases having histological and molecular
grade II and III oligoastrocytomas, the newly defined H3 K27M-mutant diffuse features of both {1067,2754}. As a result,
grade IV glioblastomas, and the related midline glioma. the more common diagnoses of astrocy-
diffuse gliomas (e.g. those of childhood). The use of integrated phenotypic and toma and oligodendroglioma both be-
This approach more sharply separates genotypic parameters in the 2016 WHO come more homogeneously defined, as
astrocytomas that have a more circum- classification provides an increased does the very uncommon diagnosis of
scribed growth pattern, lack IDH gene level of objectivity. This will presumably oligoastrocytoma.
alterations, and sometimes have BRAF yield more homogeneous and narrowly The above example of classifying as-
mutations (i.e. pilocytic astrocytoma, defined diagnostic entities than in prior trocytomas, oligodendrogliomas, and
pleomorphic xanthoastrocytoma, and classifications, which in turn should lead oligoastrocytomas raises the question of
subependymal giant cell astrocytoma) to better correlations with prognosis and whether classification can proceed on
from diffuse gliomas. In other words, dif- treatment response. It will also result in the basis of genotype alone, i.e. without
fuse astrocytoma and oligodendroglioma potentially larger groups of tumours that histology. At this point in time, it is not
are now nosologically more similar than do not fit into any of the more narrowly possible; in the classification process, a
are diffuse astrocytoma and pilocytic defined entities - groups that themselves diagnosis of diffuse glioma (rather than
astrocytoma; the family trees have been will be more homogeneous and therefore some other tumour type) must first be
redrawn. more amenable to subsequent study and established histologically in order for the
Similarly, paediatric diffuse gliomas were improved classification. nosological and clinical significance of
previously grouped together with their One compelling example of this im- specific genetic changes to be under-
overall (generally adult) counterparts, de- proved objectivity relates to the diagno- stood in the appropriate context. Another
spite known differences in behaviour be- sis of oligoastrocytoma - a difficult-to- reason phenotype remains essential is
tween paediatric and adult gliomas with define category of tumours that has been that some individual tumours do not meet
similar histological appearances. More subject to high interobserver variability in the more narrowly defined genotypic cri-
recent information on the distinct under- diagnosis, with some centres diagnosing teria; for example, a phenotypically clas-
lying genetic abnormalities in paediatric these lesions frequently and others only sic diffuse astrocytoma that lacks the
diffuse gliomas has since prompted the rarely. The use of both genotype and signature genetic characteristics of IDH1/
separation of some of these entities from phenotype in diagnosing these tumours IDH2 and ATRX mutation. However, it is
histologically similar adult tumours - with results in essentially all of them being possible that future WHO classifications

16 Diffuse gliomas
of diffuse gliomas, in the setting of deep-
er and broader genomic capabilities, will
require less histological evaluation - per-
haps only an initial diagnosis of diffuse
glioma. For the time being, the current
WHO classification is predicated on the
concept of combined phenotypic and
genotypic classification, and on the gen-
eration of so-called integrated diagnoses
{1535}.
It is important to acknowledge that
changing the classification to include
diagnostic categories that depend on
genotype may create certain challenges
with respect to testing and reporting,
which have been discussed elsewhere
{1535}. These challenges include the Fig. 1.02 IDH1 and IDH2 mutations in human gliomas, histologically diagnosed according to the 2007 WHO classi-
availability and choice of genotyping and fication. Reprinted from Yan H et al. {2810}.
surrogate genotyping assays, the ap-
proaches that may need to be taken by prognostic information in addition to that or morphology. The finding of a solitary
centres without genotyping (or surrogate provided by histological grade. Never- mitosis in an ample specimen is not suf-
genotyping) capabilities, and the actual theless, in the 2016 WHO classification, ficient proof of WHO grade III behaviour,
formats used to report these integrated diffuse astrocytomas are graded using but the separation of grade II tumours
diagnoses {1535}. However, the imple- a three-tiered system similar to the Ring- from grade III tumours may be facilitated
mentation of combined phenotypic-gen- ertz system {2130}, the St. Anne-Mayo by determination of the Ki-67 proliferation
otypic diagnostics in some large centres system {533}, and the previously pub- index {1056}. Microvascular proliferation
{2105} and the increasing availability of lished WHO schemes {1293,1534}. Ac- is defined as apparent multilayering of
immunohistochemical surrogates for mo- cording to the WHOs current histological endothelium (rather than simple hyper-
lecular genetic alterations suggest that definition, tumours with cytological atypia vascularity) or glomeruloid vasculature.
such challenges will be readily overcome alone (i.e. diffuse astrocytomas) are con- Necrosis may be of any type; perinecrotic
in the near future {2510A). sidered grade II, those that also show an- palisading need not be present. Simple
aplasia and mitotic activity (i.e. anaplas- apposition of cellular zones with interven-
Histological grading of diffuse
tic astrocytomas) are considered WHO ing pallor suggestive of incipient necrosis
astrocytic tumours
grade III, and tumours that additionally is insufficient. The aforementioned crite-
In neuro-oncology, histological grading
show microvascular proliferation and/or ria make their appearance in a predict-
has been most systematically evaluated
necrosis are grade IV. Atypia is defined able sequence: atypia is followed in turn
and successfully applied to diffusely in-
as variation in nuclear shape or size with by mitotic activity, then increased cellu-
filtrative astrocytic tumours, although
accompanying hyperchromasia. Mitoses larity, and finally microvascular prolifera-
recent studies suggest that molecu-
must be unequivocal, but no special sig- tion and/or necrosis.
lar parameters may provide powerful
nificance is accorded to their number

Diffuse astrocytic and oligodendroglial tumours - Introduction 17


von Deimling A. Berger M.S.
Diffuse astrocytoma, IDH-mutant Huse J.T. Weller M.
Yan H. Nakazato Y.
Brat D.J. Burger P.C.
Reifenberger G. Ellison D.W.
Ohgaki H. Louis D.N.
Kleihues P.

Definition Epidemiology those for IDH-mutant anaplastic astrocy-


A diffusely infiltrating astrocytoma with a toma {2103}.
mutation in either the IDH1 or IDH2 gene. Incidence
IDH-mutant diffuse astrocytoma typically Tumour registries have not distinguished Localization
features moderately pleomorphic cells diffuse astrocytomas on the basis of IDH IDH-mutant diffuse astrocytomas can
and is characterized by a high degree of mutation status. However, because most be located in any region of the CNS, but
cellular differentiation and slow growth. cases carry an IDH mutation, the avail- most commonly develop supratentorially
The diagnosis is supported by the pres- able data reflect this genetically defined in the frontal lobes {2428}. This is similar
ence of ATRX and TP53 mutation. The tumour entity to some extent. Diffuse to the preferential localization of IDH-
presence of a component morphologi- astrocytomas account for approximately mutant and 1p/19q-codeleted oligoden-
cally resembling oligodendroglioma is 11-15% of all astrocytic brain tumours droglioma {1418,2871} and supports the
compatible with this diagnosis in the ab- {1862,1863}. Annual incidence rates have hypothesis that these gliomas develop
sence of 1p/19q codeletion. This tumour been estimated at 0.55 and 0.75 new from a distinct population of precursor
most commonly affects young adults and cases per 100 000 population {1862, cells {1830}.
occurs throughout the CNS, but is prefer- 1863,2797}.
entially located in the frontal lobes {2428}. Some reports suggest that the incidence Clinical features
Diffuse astrocytomas have an intrinsic of astrocytomas in children has slightly Seizures are a common presenting symp-
capacity for malignant progression to increased in recent decades in several tom; however, subtle abnormalities such
IDH-mutant anaplastic astrocytoma and Scandinavian countries and North Amer- as speech difficulties, changes in sen-
eventually to IDH-mutant glioblastoma. ica {989,1015,2471}. There is a male pre- sation or vision, and some form of motor
dominance, with a male-to-female ratio of change may be present earlier. Symptom
ICD-0 code 9400/3 1.3:1 {1863}. onset is rarely abrupt, and some tumours
Grading Age distribution are diagnosed incidentally {2390,2511}.
Diffuse astrocytoma corresponds histo- The median and mean ages of patients With frontal lobe tumours, changes in
logically to WHO grade II. with IDH-mutant diffuse astrocytoma are behaviour or personality may be the pre-
in the mid-30s. According to one study senting feature. Such changes may be
Synonyms present for months before diagnosis.
Low-grade astrocytoma (discouraged); of adult patients only, the median age of
fibrillary astrocytoma (no longer patients with IDH-mutant diffuse astro-
cytoma is 36 years, and the mean age Imaging
recommended) Like clinical features, the results of neu-
is 38 years. These values are similar to
roimaging studies can be extremely vari-
able. On CT, diffuse astrocytomas most
often present as poorly defined, homo-
geneous masses of low density, without
contrast enhancement. However, calcifi-
cation and cystic change may be present
early in the evolution of the tumour. MRI
studies usually show T1-hypodensity and
T2-hyperintensity, with enlargement of
the areas involved early in the evolution
of the tumour. Gadolinium enhancement
is not common in low-grade diffuse as-
trocytomas, but tends to appear during
tumour progression.
Macroscopy
Because of their infiltrative nature, these
tumours usually show blurring of the gross
Fig. 1.03 Cumulative age distribution of astrocytomas at diagnosis, both sexes. Based on 613 cases of IDH-mutant diffuse anatomical boundaries. There is enlarge-
astrocytoma (All) and 674 cases of IDH-mutant anaplastic astrocytoma (AIII). Note that in this aggregate of patients, ment and distortion (but not destruction)
despite the difference in grade, the age distribution is similar, with a mean age of 35 years for All and 37 years for AIII. This of the invaded anatomical structures (e.g.
corresponds to similar data published by Reuss DE et al. {2103}, showing that IDH-mutant All and AIII astrocytomas differ
the cortex and the compact myelinated
little with respect to age at diagnosis and survival in adult patients. Includes data from Reuss DE et al. {2103}.

18 Diffuse gliomas
pathways). Local mass lesions may
be present in either grey or white mat-
ter, but they have indistinct boundaries,
and changes such as smaller or larger
cysts, granular areas, and zones of firm-
ness or softening may be seen. Cystic
change most commonly presents as a
focal spongy area, with multiple cysts of
various sizes. Extensive microcyst forma-
tion may cause a gelatinous appearance.
Occasionally, a single large cyst filled Fig. 1.04 A Large diffuse astrocytoma occupying the left temporal lobe, with extension to the Sylvian fissure. Note the
with clear fluid is present. Tumours with homogeneous surface and the enlargement of local anatomical structures. B Large diffuse astrocytoma originating
prominent gemistocytes sometimes have from the pericallosal cortex of the right hemisphere. The tumour extends into the interhemispheric fissure and shifts the
single, large, smooth-walled cysts. Focal midline towards the left hemisphere. Macroscopically, this lesion is well delineated and still shows structures resembling
cortical architecture.
calcification may also be present, and a
more diffuse grittiness may be observed.
Extension into contralateral structures, filaments. The pattern may vary markedly for R132H-mutant IDH1 (sometimes in
particularly in the frontal lobes, is rarely in different regions of the neoplasm. His- combination with p53 immunohistochem-
observed. tological recognition of neoplastic astro- istry and rarely with assessment for tri-
cytes using H&E staining on sectioned somy 7) is a powerful means to distinguish
Microscopy
material depends mainly on nuclear neoplastic from reactive astrocytes {347}.
Diffuse astrocytoma is composed of
characteristics. The normal astrocytic nu- In other situations, however, the differen-
well-differentiated fibrillary astrocytes in
cleus is oval to elongated, but on section- tial diagnosis can be challenging and may
a background of a loosely structured, of-
ing, occasional round cross-sections are rely on standard histological differences.
ten microcystic tumour matrix. Fibrillary
seen. The nucleus is typically vesicular, Diffuse astrocytoma contains astrocytes
astrocytoma is the classic type of diffuse
with intermediate-sized masses of chro- that are increased in number and usually
astrocytoma and is no longer listed as a
matin and often with a distinct nucleolus. in size, but are otherwise difficult to distin-
variant {1533}.
Normal human astrocytes show no H&E- guish on an individual basis from normal
The cellularity is moderately increased
stainable cytoplasm that is distinct from or reactive cells. In minor degrees of ana-
compared with that of normal brain, and
the background neuropil. Reactive as- plasia, it is the number of astrocytes and
nuclear atypia is a characteristic feature.
trocytes are defined by enlarged nuclei (most commonly) the uniformity of their
Mitotic activity is generally absent, but a
and the presence of stainable, defined morphology that is most helpful in recog-
single mitosis does not justify the diagno-
cytoplasm, culminating in the gemisto- nizing their neoplastic nature. Reactive
sis of anaplastic astrocytoma unless ob-
cyte, which has a mass of eosinophilic astrocytes are rarely all in the same stage
served in a small biopsy or in the setting
cytoplasm, often an eccentric nucleus, of reactivity at the same time, so reac-
of obvious nuclear anaplasia. The pres-
and cytoplasm that extends into fine tions reveal mixtures of astrocytes; some
ence of necrosis or microvascular prolif-
processes. with enlarged nuclei, others with varying
eration is incompatible with the diagnosis
amounts of cytoplasm, most often on a
of diffuse astrocytoma. Phenotypically, Differential diagnosis
somewhat rarefied background. In diffuse
neoplastic astrocytes may vary consider- The major entity in the differential diagno-
astrocytoma, almost all of the nuclei look
ably with respect to their size, the promi- sis is reactive astrocytosis. Because most
identical, and the background is of at least
nence and disposition of cell processes, IDH-mutant diffuse astrocytomas have
normal density or shows increased num-
and the abundance of cytoplasmic glial R132H mutations, immunohistochemistry
bers of cellular processes. Microcystic

Fig. 1.05 Diffuse astrocytoma. A Moderately cellular tumour composed of uniform neoplastic fibrillary astrocytic cells. B Extensive microcyst formation.

Diffuse astrocytoma, IDH-mutant 19


reveals identical TP53 mutations in both
gemistocytes and non-gemistocytic tu-
mour cells {2094}. Although it has been
reported that the gemistocytic variant
may be particularly prone to progression
to anaplastic astrocytoma and glioblas-
toma {1377,2204,2273}, this does not jus-
tify a general classification as anaplastic
astrocytoma {320,2273}, nor is this im-
pression based on current molecular
Fig. 1.06 Diffuse astrocytoma. Low cellularity and
characterization, in particular knowledge Fig. 1.07 Diffuse astrocytoma with extensive mucoid
nuclear atypia.
of IDH mutation status. degeneration and cobweb-like architecture. This pattern
was previously designated protoplasmic astrocytoma.
Immunophenotype
change may be present, but most cells Diffuse astrocytomas reliably express
look like one another, without the admix- distinction of true neoplasia from reac-
GFAP, although to various degrees and
ture of gemistocytes more often seen in tive gliosis {347,359}. Strong nuclear p53
not in all tumour cells. In particular, small
reactions to injury. Pre-existing cell types expression is also frequently observed,
round cells with scanty cytoplasm and
(e.g. neurons) are often entrapped. consistent with the high incidence of
processes tend not to label avidly for
TP53 mutations in diffuse astrocytoma
Intraoperative diagnosis GFAP. In these cases, immunopositiv-
{915}. However, the use of p53 immuno-
ity may be restricted to a small perinu-
The smear/squash technique is often positivity to reflect TP53 mutation is not
clear rim and to admixed neoplastic cell
used during stereotaxic biopsies and entirely sensitive or specific {1530,1771}.
processes in the fibrillary tumour back-
yields similar findings, although this In contrast, ATRX expression is almost
ground {1292}. Vimentin is typically im-
method is highly unreliable for estimating invariably lost in the setting of ATRX mu-
munopositive as well, with a labelling pat-
cellularity. Many histological features are tations, which also feature prominently in
tern approximating that of GFAP {995}.
exaggerated and amplified (e.g. nuclear diffuse astrocytoma (see Genetic profile)
The signature molecular characteristics
folds, abnormal chromatin pattern, and {361,1160,1215,2105}. ATRX typically,
of diffuse astrocytoma (see Genetic pro-
astrocytic processes). The presence of demonstrates strong nuclear expression
file) can often be demonstrated immuno-
many round to oval nuclei with smooth in normal, unmutated tissue; therefore,
histochemically. For example, expression
chromatin can indicate the presence of retention of immunolabelling in non-
of R132H-mutant IDH1 (the IDH1 R132H
an apparent oligodendroglial component neoplastic vasculature and admixed
mutation accounts for about 90% of all
or (if the nuclei are less prominent) back- neuronal, glial, and microglial elements
glioma-associated IDH mutations) can
ground white matter. Histologically, there serves as a necessary internal control for
be detected using a mutation-specific
may be significant variation between tu- the accurate interpretation of a negative
antibody {360}. In mutant tumours, all
mours and within the same lesion. ATRX immunostaining pattern. Finally,
neoplastic cells typically exhibit some
consistent with its inapparent mitotic ac-
Growthfraction degree of cytoplasmic (stronger) and
tivity, diffuse astrocytoma nearly always
The growth fraction as determined by the nuclear (weaker) labelling, provided the
has a Ki-67 proliferation index of < 4%
Ki-67 proliferation index is usually < 4%. staining preparation used is technically
{492,1137,1223,2059}.
The gemistocytic neoplastic astrocytes adequate {359}. For this reason, R132H-
show a significantly lower rate of prolif- mutant IDH1 immunohistochemistry has Cell of origin
eration than does the intermingled small- become an invaluable diagnostic ad- The available evidence suggests that
cell component {1046,1372,1377,1847, junct, not only in the molecular stratifi- IDH-mutant and 1p/19q-codeleted oli-
2706,2812}. However, microdissection cation of diffuse glioma, but also in the godendrogliomas, IDH-mutant diffuse

Fig. 1.08 Diffuse astrocytoma. A Cytoplasm and cell processes show a variable extent of GFAP immunoreactivity. B The Ki-67 proliferation index is low.

20 Diffuse gliomas
astrocytomas, IDH-mutant anaplastic protein, and its deficiency has been as- which also predisposes patients to chon-
astrocytomas, and IDH-mutant glioblas- sociated with epigenomic dysregulation drosarcoma {734,1027}.
tomas develop from a distinct population and telomere dysfunction {473}. In par-
Prognosis and predictive factors
of precursor cells that differ from the pre- ticular, ATRX mutations seem to induce
cursor cells of IDH-wildtype glioblastoma an abnormal telomere maintenance Clinical prognostic factors
{870,1830}. mechanism known as alternative length-
ening of telomeres {977}. ATRX mutations In the pre-IDH era, the median survival
Genetic profile time was reported to be in the range of
and alternative lengthening of telomeres
Diffuse gliomas of WHO grades II and 6-8 years, with marked individual vari-
are mutually exclusive with activating mu-
III, including diffuse astrocytoma, are ation. The total length of disease is in-
tations in the TERT gene, which encodes
nearly all characterized by mutations in fluenced mainly by the dynamics of
the catalytic component of telomerase.
IDH genes: either IDH1 or /DH2{118,953, malignant progression, which had been
Interestingly, TERT mutations are found
1895,2810}. Diffuse gliomas that occur in in the vast majority of oligodendroglio- reported to occur after a median time
adults and that do not harbour IDH muta- of 4-5 years {254,1826,1834}. The Eu-
mas and most IDH-wildtype glioblasto-
tion, regardless of their WHO grade, tend ropean Organisation for Research and
mas {349,622,1270}. Distinct telomere
to exhibit more aggressive clinical behav- Treatment of Cancer (EORTC) trials
maintenance mechanisms, mediated by
iour {870,2238}. 22844 and 22845 showed that patient
either activated telomerase or alternative
Glioma-associated IDH1 and IDH2 muta- age > 40 years, astrocytoma histology,
lengthening of telomeres, seem to be re-
tions impart a gain-of-function phenotype quired for the pathogenesis of all diffuse largest tumour diameter > 6 cm, tumour
to the respective metabolic enzymes crossing the midline, and neurological
gliomas.
IDH1 and IDH2, which overproduce deficits prior to surgery were associated
ATRX deficiency has also been associ-
the oncometabolite 2-hydroxyglutarate with inferior outcome {1975}. However,
ated with generalized genomic instability,
{523}. The physiological consequences these prognostic estimates must be re-
which can induce p53-dependent cell
of 2-hydroxyglutarate overproduction are evaluated in the context of IDH mutation
death in some contexts {488}. Therefore,
widespread, including profound effects TP53 mutations in diffuse astrocytoma status; one study that included 683 IDH-
on cellular epigenomic states and gene mutant diffuse astrocytoma cases from
may enable tumour cell survival in the
regulation. Specifically, IDH mutations in- three series showed a median survival of
setting of ATRX loss. The genomic insta-
duce G-CIMP, by which widespread hy- 10.9 years {2103}.
bility of IDH-mutant diffuse astrocytomas
permethylation in gene promoter regions
is reflected in characteristic DNA copy Proliferation
silences the expression of several impor-
number abnormalities, which include Low to absent proliferation rates as esti-
tant cellular differentiation factors {1540, low-level amplification events involv-
2589}. In this way, IDH mutation and mated by mitotic count or the Ki-67 prolif-
ing the oncogenes MYC and CCND2 in eration index have traditionally been con-
G-CIMP are thought to maintain glioma
mutually exclusive subsets {349}. Copy sidered a diagnostic criterion for grading
cells of origin in stem cell-like physiologi-
number events typically associated with a diffuse astrocytoma as WHO grade II.
cal states inherently more prone to self-
IDH-wildtype glioblastoma, such as Among histologically diagnosed diffuse
renewal and tumorigenesis. In particular,
EGFR amplification and homozygous astrocytomas, the level of proliferation
it appears that IDH mutations promote CDKN2A deletion, are rarely encoun-
glioma formation by disrupting chromo- has not been associated with outcome.
tered, emphasizing the biological differ-
somal topology and allowing aberrant Histopathological factors
ences between IDH-mutant and IDH-
chromosomal regulatory interactions that Gemistocytic astrocytoma has been
wildtype astrocytomas {349,622,870}.
induce oncogene expression, including associated with early progression and
On the basis of expression profiling,
glioma oncogenes such as PDGFRA inferior outcome {1834}, but data on
multiple diffuse astrocytoma subclasses
{713A}. Consistent with this concept, IDH have been designated, stratified by IDH larger contemporary patient cohorts with
mutations seem to be among the first ge- known IDH mutation status are lacking.
mutation status as well as neuroglial lin-
netic alterations that occur in WHO grade Other histological factors associated with
eage markers {349,870}. The transcrip-
II diffuse glioma {2709}. MGMT promoter outcome have not yet been identified.
tional profiles of diffuse astrocytomas
methylation was reported in about 50%
indicate distinct cells of origin in addition Genetic alterations
of diffuse astrocytomas in the pre-IDH
to specific genomic features. IDH1/2 mutations distinguish astrocyto-
era, but this proportion may be higher
among IDH-mutant diffuse astrocytomas Genetic susceptibility mas with a more favourable course from
and does not correlate consistently with Diffuse astrocytoma can occur in pa- IDH-wildtype tumours, which have a less
G-CIMP {1753,2589}. tients with inherited TP53 germline mu- favourable course {951}. Among IDH-
The vast majority of IDH-mutant dif- tations / Li-Fraumeni syndrome (see wildtype tumours, a genotype of 7q gain
fuse astrocytomas, as well as the WHO Li-Fraumeni syndrome, p. 310), although and 10q loss is associated with a par-
grade III anaplastic astrocytomas and affected family members more frequently ticularly poor outcome {2731}. However,
grade IV glioblastomas that evolve from develop anaplastic astrocytoma and glio- as noted earlier (see Clinical prognostic
them, also harbour class-defining loss- blastoma. Lower-grade astrocytoma has factors), a study that included 683 IDH-
of-function mutations in TP53 and ATRX been diagnosed in patients with inherited mutant diffuse astrocytomas from three
{1160,1215,1834,2092,2704}. ATRX en- Ollier-type multiple enchondromatosis, series reported a median survival of
codes an essential chromatin-binding

Diffuse astrocytoma, IDH-mutant 21


Fig. 1.09 Gemistocytic astrocytoma. A Tumour cells have abundant eosinophilic cytoplasm, with nuclei displaced to the periphery. B Perivascular lymphocytic infiltrates are common.

10.9 years. IDH mutations may be use- For a diagnosis of gemistocytic astro- Localization
ful as a predictive biomarker when IDH- cytoma, gemistocytes should constitute Gemistocytic astrocytomas can develop
targeted therapies such as small-mole- more than approximately 20% of all tu- in any region of the CNS, but they most
cule inhibitors {2685} or vaccines {2301} mour cells. The presence of occasional commonly develop in the frontal and tem-
become available. Comprehensive gen- gemistocytes in a diffuse astrocytoma poral lobes.
otyping studies have shown correlations does not justify the diagnosis {1533}. Re-
Macroscopy
between IDH mutation status and other ports have suggested that gemistocytic
Macroscopically, gemistocytic astrocy-
molecular parameters; in particular, there astrocytoma may progress more rapidly
tomas are not substantially different from
are strong associations between IDH mu- than standard diffuse astrocytoma to
other low-grade diffuse gliomas. They
tation and TP53 mutation (present in 94% anaplastic astrocytoma and secondary
are often characterized by expansion of
of cases) and ATRX inactivation (present glioblastoma, but these reports are from
the infiltrated brain areas without clear
in 86% of cases) {349}. the pre-IDH era and it remains unclear
delineation of the neoplasm. The involved
whether IDH-mutant gemistocytic astro-
Mutant IDH catalyses the formation of areas may show greyish discolouration,
cytomas have an increased tendency for
2-hydroxyglutarate, which could poten- granularity, firmer or softer consistency,
anaplastic progression {319,1533}.
tially be monitored by MR spectroscopy and microcystic change {1533}.
{449} or in body fluids {358}. However, ICD-0 code 9411/3
Microscopy
the clinical value of these approaches
Grading The histopathological hallmark of gemis-
has yet to be validated.
IDH-mutant gemistocytic astrocytoma cor- tocytic astrocytoma is the presence of a
responds histologically to WHO grade II. conspicuous proportion of gemistocytic
Gemistocytic astrocytoma, neoplastic astrocytes. Gemistocytes
Epidemiology
IDH-mutant should account for more than approxi-
Gemistocytic astrocytomas account for
mately 20% of all tumour cells; the pres-
Definition approximately 10% of all WHO grade II
ence of occasional gemistocytes in a
A variant of IDH-mutant diffuse astrocy- diffuse astrocytomas {981}. The mean
diffuse astrocytoma does not justify the di-
toma characterized by the presence of reported patient age at diagnosis is
agnosis of gemistocytic astrocytoma. The
a conspicuous (though variable) propor- 40 years {2703}, the median age is
mean proportion of gemistocytes is ap-
tion of gemistocytic neoplastic astrocytes 42 years {1377}, and the male-to-female
proximately 35% {2703}. The cut-off point
(gemistocytes). ratio is 2:1 {2703}.
of 20% is somewhat arbitrary, but a useful

Fig. 1.10 Gemistocytic astrocytoma. A Tumour cells have enlarged, glassy, eosinophilic cytoplasm and eccentric nuclei. B Immunostaining shows a marked and consistent
accumulation of GFAP in the cytoplasm of neoplastic gemistocytes. Interspersed are small tumour cells with little cytoplasm; proliferation is largely restricted to this inconspicuous cell
population. C p53 accumulation is present in nuclei of small and gemistocytic tumour cells.

22 Diffuse gliomas
Paediatric diffuse astrocytoma Genetic aspects remains to be determined whether the
Although the histopathology of paedi- Diffuse astrocytomas in children and prognosis of IDH-mutant gemistocytic
atric diffuse astrocytoma resembles adults have distinct genetic profiles. astrocytoma differs significantly from that
that of adult diffuse astrocytoma, there However, diffuse astrocytomas with ge- of IDH-mutant diffuse astrocytoma.
are many important distinctions be- netically defined so-called adult-type
tween the disease in children and in disease can present in adolescents,
adults. and so-called paediatric-type disease
can present in young adults. Paediatric Diffuse astrocytoma,
Clinicopathological aspects diffuse astrocytomas are characterized
The annual incidence of paediatric dif- IDH-wildtype
mainly by alterations in MYB and BRAF. Definition
fuse astrocytoma (defined by patient
Amplification or rearrangements of MYB A diffusely infiltrating astrocytoma without
age < 20 years at diagnosis) is 0.27 cas-
are detected in approximately 25% of mutations in the IDH genes.
es per 100 000 population; lower than paediatric diffuse astrocytomas {2518,
that of adult diffuse astrocytoma, which IDH-wildtype diffuse astrocytoma is rare.
2855}. Rearrangements of MYBL1 have Most gliomas with a histological appear-
is 0.58 per 100 000 {1863}. Most pae-
also been described {2068}. Other pae- ance resembling that of diffuse astrocy-
diatric diffuse astrocytomas are located
diatric diffuse astrocytomas harbour toma but without IDH mutation can be re-
in the cerebral hemispheres, but a sig-
BRAF V600E mutations, FGFR1 altera- classified in adults as other tumours with
nificant proportion present in the thala-
tions, or KRAS mutations {2855}. Rare additional genetic analyses. Tumours
mus, which is an unusual site for adult paediatric diffuse astrocytomas contain
diffuse astrocytoma. Anaplastic pro- that conform to this diagnosis most likely
the H3 K27M mutation usually found in constitute a variety of entities, and can
gression occurs in approximately 75%
paediatric high-grade gliomas {2855}. therefore follow a broad range of clini-
of adult lesions, but is rare in paediatric
The mutations in IDH1, IDH2, TP53, cal courses. Thus, IDH-wildtype diffuse
tumours {284}.
and ATRX that are frequently found in astrocytoma is considered a provisional
adult diffuse astrocytomas are not entity.
present in the paediatric tumours
{2443}. Gliomatosis cerebri growth pattern
Like other diffuse gliomas, diffuse astro-
criterion in borderline cases {1377,2556}. displacement of nuclei to the periphery of cytoma can manifest at initial clinical pre-
The gemistocytes are characterized by the cell body. Expression of p53 protein sentation with a gliomatosis cerebri pat-
plump, glassy, eosinophilic cell bodies of is also frequently seen in gemistocytes tern of extensive involvement of the CNS,
angular shape. Stout, randomly oriented {2706}. with the affected area ranging from most
processes form a coarse fibrillary of one cerebral hemisphere (three lobes
Genetic profile or more) to both cerebral hemispheres
network. These processes are often
Gemistocytic astrocytoma is a variant of with additional involvement of the deep
useful in distinguishing the tumour cells
IDH-mutant diffuse astrocytoma. Reports grey matter structures, brain stem, cer-
from the mini-gemistocytes found in
have noted that gemistocytic astrocyto- ebellum, and spinal cord. See Anaplastic
oligodendroglioma. Gemistocytic neo-
mas are characterized by a particularly astrocytoma, IDH-wildtype (p. 27) for ad-
plastic astrocytes consistently express
high frequency of TP53 mutations, which ditional detail.
GFAP in their perikarya and cell
are present in > 80% of all cases {1834,
processes. The nuclei are usually
2703}, and likely in nearly all cases of
eccentric, with small, distinct nucleoli and
IDH-mutant gemistocytic astrocytoma.
densely clumped chromatin. Perivascular
The fact that TP53 mutations are present
lymphocyte cuffing is frequent {322}.
in both gemistocytes and non-gemis-
Electron microscopy confirms the
tocytic tumour cells indicates that the
Diffuse astrocytoma, NOS
presence of abundant, compact glial
gemistocytes are neoplastic and not re- Definition
filaments in the cytoplasm and in cell
active in nature {2094}. This interpretation A tumour with morphological features of
processes. Enlarged mitochondria have
is also supported by Immunoreactivity to diffuse astrocytoma, but in which IDH
also been noted {609}.
mutant IDH1 protein {359}. mutation status has not been not fully
Proliferation assessed.
Prognosis and predictive factors
The gemistocytic neoplastic astrocytes Full assessment of IDH mutation status in
Gemistocytic astrocytomas have been
show a significantly lower rate of diffuse astrocytomas involves sequence
reported to undergo progression to
proliferation than in the intermingled analysis for IDH1 codon 132 and IDH2
anaplastic (gemistocytic) astrocytoma
smallcell component {1046,1372,1377, codon 172 mutations in cases that are
and IDH-mutant glioblastoma more com-
2706}. However, microdissection has immunohistochemically negative for the
monly than do other diffuse astrocytomas
revealed identical TP53 mutations in both IDH1 R132H mutation.
{1377,1834,1929,1930}. However, these
gemistocytes and non-gemistocytic
data pertain to histologically diagnosed ICD-O code 9400/3
tumour cells {2094}.
gemistocytic astrocytomas irrespective
Immunophenotype of the presence of an IDH mutation. It
The cytoplasm of neoplastic gemisto-
cytes is filled with GFAP, causing

Diffuse astrocytoma, IDH-wildtype 23


von Deimling A. Berger M.S. Paulus W.
Anaplastic astrocytoma, Huse J.T. Weller M. Wesseling P.
Yan H. Burger P.C. Aldape K.D.
IDH-mutant Brat D.J. Ellison D.W. Louis D.N.
Ohgaki H. Rosenblum M.K.
Kleihues P. Reifenberger G.

Definition Synonym diffuse astrocytomas, and IDH-mutant


A diffusely Infiltrating astrocytoma with glioblastomas), are preferentially located
focal or dispersed anaplasia, significant High-grade astrocytoma (discouraged) in the frontal lobe.
proliferative activity, and a mutation in ei-
ther the IDH1 or IDH2 gene. Epidemiology Clinical features
Anaplastic astrocytomas can arise from The peak incidence of IDH-mutant ana- The symptoms are similar to those of
lower-grade diffuse astrocytomas, but plastic astrocytoma occurs at a mean WHO grade II diffuse astrocytoma. In
are more commonly diagnosed without patient age of 38 years {2103}. However, some patients with a history of a diffuse
indication of a less-malignant precursor until the discovery of IDH mutation as a WHO grade II astrocytoma, there are in-
lesion. The presence of a component molecular marker, the diagnosis of ana- creasing neurological deficits, seizures,
morphologically resembling oligodendro- plastic astrocytoma was based only on and signs of intracranial pressure (de-
glioma is compatible with this diagnosis histological evidence {1823,1827}. Hospi- pending on the location of the tumour,
in the absence of 1p/19q codeletion. tal-based data from the University of Zu- the degree of oedema, and the mass
Anaplastic astrocytomas have an intrin- rich in the pre-IDH era showed a mean effect surrounding the lesion). Patients
sic tendency for malignant progression to patient age at diagnosis of approximately with anaplastic astrocytoma commonly
IDH-mutant glioblastoma. 45 years, with a male-to-female ratio of present after a history of a few months,
1.6:1. In one population-based study, the with no evidence of a preceding WHO
ICD-0 code 9401/3 mean patient age at biopsy was 46 years grade II astrocytoma.
{1826}. Population-based registry data Imaging
Grading
from the USA for the period 2007-2011 IDH-mutant anaplastic astrocytoma pre-
IDH-mutant anaplastic astrocytoma
show an annual incidence of 0.37 cas- sents as a poorly defined mass of low
corresponds histologically to WHO
es per 100 000 population, a male-to- density. Unlike in WHO grade II diffuse
grade III. Some retrospective studies
female ratio of 1.39:1, and median patient astrocytomas, partial contrast enhance-
have shown that, in the setting of cur-
age at diagnosis of 53 years {1863}. In ment is usually observed, but the central
rent therapy, IDH-mutant anaplastic as-
a study that incorporated IDH mutation necrosis with ring enhancement typical
trocytomas may follow clinical courses
data and included 562 IDH-mutant ana- of glioblastomas is absent. More rapid
only somewhat worse than those of IDH-
plastic astrocytomas, the median patient tumour growth with development of peri-
mutant diffuse astrocytomas (WHO
age at presentation was 36 years and tumoural oedema can lead to mass shifts
grade II) {870,2103,2464}, but this was
the mean age 38 years, similar to that for and increased intracranial pressure.
not found in other studies {1268}. Al-
IDH-mutant WHO grade II diffuse astro-
though IDH-mutant anaplastic astro- Spread
cytoma {2103}.
cytoma is assigned a WHO grade of III Like other diffuse gliomas, anaplastic as-
based on histological appearance, grad- Localization trocytomas are generally characterized
ing algorithms for distinguishing between IDH-mutant anaplastic astrocytomas can by diffuse infiltrative growth in the brain
IDH-mutant anaplastic astrocytoma and develop in any region of the CNS but {463}. Occasionally, leptomeningeal
IDH-mutant diffuse astrocytoma may most frequently occur in the cerebrum. spread is evident {1059}.
need to be refined. Thesetumours, like other IDH-mutant
diffusegliomas (including oligodendro-
gliomas,

Fig. 1.11A Anaplastic astrocytoma in the right frontotemporal region. Note the ill-defined borders with the adjacent brain structures and focal cysts. B Frontotemporal anaplastic
astrocytoma containing a large cyst but no macroscopically discernible necrosis. C Anaplastic astrocytoma with diffuse, bilateral infiltration of the corpus callosum, the caudate
nucleus, and the fornices. The fornices are grossly enlarged and show petechial haemorrhages.

24 Diffuse gliomas
Macroscopy astrocytomas (i.e. gliomas that lack IDH
Like WHO grade II diffuse astrocytoma, mutations) {953}.
anaplastic astrocytomas tend to infiltrate
Genetic profile
the surrounding brain without causing
The molecular features of anaplastic as-
frank tissue destruction. This often leads
trocytoma largely recapitulate those of
to a marked enlargement of invaded
WHO grade II IDH-mutant diffuse astro-
structures, such as adjacent gyri and
cytoma. By definition, mutations in IDH1
basal ganglia. On cut surface, the higher
or IDH2 are present in all tumours, and
cellularity of the anaplastic astrocytoma
TP53 and ATRX alterations are found in
results in a discernible tumour mass,
the majority of tumours {118,953,1160,
which in some cases is distinguished Fig. 1.12 Anaplastic astrocytoma. Smear preparations 1215,1834,1895,2092,2704,2810}.
more clearly from the surrounding brain show various degrees of nuclear atypia.
Robust molecular correlates of anaplastic
structures than is seen in WHO grade II
progression within diffuse astrocytoma
diffuse astrocytomas. Macroscopic cysts astrocytoma at one end of the range and
lineages have yet to be established, be-
are uncommon, but there are often areas with glioblastoma at the other {492,1137,
cause the biological distinctions between
of granularity, opacity, and soft consist- 1223,2059}. The index may vary con-
IDH-mutant and IDH-wildtype tumours
ency. It is often difficult to grossly dis- siderably, however, even within a single
have emerged only recently. However,
tinguish between a WHO grade III ana- tumour.
compared with WHO grade II IDH-mutant
plastic astrocytoma and a WHO grade II
Immunophenotype astrocytomas, WHO grade III tumours
diffuse astrocytoma.
In general, the immunohistochemical have higher frequencies of chromosome
Microscopy features of anaplastic astrocytoma re- arm 9p and 19q losses {349,1269}.
The principal histopathological features capitulate those of WHO grade II diffuse
astrocytoma, consistent with their shared Prognosis and predictive factors
are those of a diffusely infiltrating astro-
cytoma with increased mitotic activity histogenetic and molecular foundations. Clinical prognostic factors
compared with the WHO grade II equiva- IDH-mutant anaplastic astrocytomas are
lent, usually accompanied by distinct nu- typically positive for GFAP and frequently Historically, median survival has been in
clear atypia and high cellularity. Mitotic exhibit strong and diffuse nuclear expres- the range of 3-5 years, but with marked
activity should be evaluated in the con- sion of p53. The majority express R132H- differences in cases with older patient
text of sample size. In small specimens, mutant IDH1 (reflecting their underlying age and low performance status, both
such as those obtained at stereotactic IDH mutation status) and display nega- of which are associated with inferior
biopsy, a single mitosis suggests signifi- tive immunostaining for nuclear ATRX. outcome {2740}. In the era of subtyping
cant proliferative activity; in such cases, anaplastic astrocytomas by IDH mutation
Cell of origin status, survival estimates now vary more
Ki-67 labelling may be helpful. In large
The cell of origin is unknown. The fact widely (see Genetic alterations). The ex-
resection specimens, a few mitoses are
that diffuse WHO grade II and III astro- tent of surgical resection at diagnosis
not sufficient for WHO grade III designa-
cytomas, IDH-mutant glioblastomas, also seems to impact outcome {2740}.
tion {826}. Regional or diffuse hypercellu-
and oligodendrogliomas all carry an IDH
larity is an important diagnostic criterion; Proliferation
mutation suggests that they may share a
but even in the setting of low cellularity, Proliferative activity, as estimated by
cell of origin different from those of IDH-
the diagnosis is still appropriate if there mitotic count or the Ki-67 proliferation
wildtype glioblastomas and pilocytic
is significant mitotic activity. With pro- index, is not prognostic for anaplastic
gressive anaplasia, nuclear morphology astrocytomas.
becomes more atypical, with increasing
variation in nuclear size, shape, coarse- Histopathological factors
ness, and dispersion of chromatin and Histological factors are not associated
increasing nucleolar prominence and with outcome of anaplastic astrocytoma,
quantity. Additional signs of anaplasia but they have not yet been carefully eval-
include multinucleated tumour cells and uated within the context of IDH-mutant
abnormal mitoses, but these are not ob- anaplastic astrocytoma.
ligatory for WHO grade III. By definition,
Genetic alterations
microvascular proliferation (multilayered IDH1/2 mutations are associated with
vessels) and necrosis are absent. better outcome, whereas IDH-wildtype
Proliferation anaplastic astrocytoma has an outcome
Unlike WHO grade II diffuse astrocy- similar to that of IDH-wildtype glioblasto-
toma, anaplastic astrocytoma displays ma {952}. A study that included 562 IDH-
mitotic activity. The growth fraction as de- mutant anaplastic astrocytomas from
termined by the Ki-67 proliferation index three series showed a median survival
is usually in the range of 5-10%, but can of 9.3 years {2103}. EGFR amplification
overlap with values for low-grade diffuse Fig. 1.13 Anaplastic astrocytoma. Moderate cellularity,
marked nuclear atypia, and mitoses.

Anaplastic astrocytoma, IDH-mutant 25


Fig. 1.14 Anaplastic astrocytoma. A Marked nuclear pleomorphism. Note the atypical mitosis in the centre. B Hypercellularity and hyperchromatic, irregular, so-called naked nuclei
appearing within a fibrillary background. Two mitotic figures are present.

Fig. 1.15 IDH-mutant anaplastic astrocytoma. A Well-delineated focus with higher cellularity, mitotic activity, and a lack of GFAP expression (left). Such foci are encountered in
anaplastic astrocytomas and glioblastomas and may represent new clones resulting from the acquisition of additional genetic alterations, indicating progression to a higher grade of
dedifferentiation and malignancy {750}. B GFAP Immunoreactivity. C Immunoreactivity for the proliferation marker MIB1, including a cell in mitosis.

and a genotype of 7q gain and 10q loss


have been associated with worse out-
come. IDH mutations may be useful as a
predictive biomarker when IDH-targeted
therapies such as small-molecule inhibi-
tors {2685} or vaccines {2301} become
available.
Mutant IDH catalyses the formation of
2-hydroxyglutarate, which could poten-
tially be monitored by MR spectroscopy
{449} or in body fluids {358}. However,
the clinical value of these approaches
has yet to be validated.

Fraction of Samples with Specific Alteration in Gene

Fig. 1.16 Mutations in lower-grade (i.e. WHO grade II and III) gliomas (LGGs), detected in The Cancer Genome
Atlas (TCGA) series {349}. Note that the mutational pattern in LGG with wildtype IDH is similar to that of glioblastoma
(GBM) with wildtype IDH. LGGs with IDH mutation are divided into oligodendroglial tumours with 1p/19q codeletion and
astrocytic tumours with frequent TP53 and ATRX mutations but no 1p/19q codeletion. SNV, single nucleotide variant;
SV, structural variant. Reprinted from: Brat DJ et al., Cancer Genome Atlas Research Network {349}.

26 Diffuse gliomas
Anaplastic astrocytoma, Gliomatosis cerebri growth pattern Anaplastic astrocytoma, NOS
IDH-wildtype Like other diffuse gliomas, anaplastic
astrocytoma can manifest at initial clini- Definition
Definition
cal presentation with a gliomatosis cer- A tumour with morphological features
A diffusely infiltrating astrocytoma with
ebri pattern of extensive involvement of of anaplastic astrocytoma, but in which
focal or dispersed anaplasia and signif-
the CNS, with the affected area ranging IDH mutation status has not been fully
icant proliferative activity but without mu-
from most of one cerebral hemisphere assessed.
tations in the IDH genes.
(three lobes or more) to both cerebral Full assessment of IDH mutation status
IDH-wildtype anaplastic astrocytoma is
hemispheres with additional involvement in anaplastic astrocytomas involves se-
uncommon and accounts for about 20%
of the deep grey matter structures, brain quence analysis for IDH1 codon 132 and
of all anaplastic astrocytomas. Nonethe-
stem, cerebellum, and spinal cord. A IDH2 codon 172 mutations in cases that
less, histologically defined anaplastic
similar extensive, diffuse involvement of are immunohistochemically negative for
astrocytomas have the highest incidence
the deep grey matter structures (i.e. ba- the IDH1 R132H mutation.
of wildtype IDH1 and IDH2 among the
WHO grade II and III diffuse glioma vari- sal ganglia and thalamus), brain stem,
ICD-0 code 9401/3
ants {1269,2810}. Most gliomas with a cerebellum, and spinal cord can also be
histological appearance resembling that seen in the absence of cerebral corti- Grading
of anaplastic astrocytoma but without cal involvement. Gliomatosis was once Anaplastic astrocytoma, NOS, corre-
IDH mutation share molecular features thought to be a distinct nosological en- sponds histologically to WHO grade III.
with IDH-wildtype glioblastoma, and tity, but is now considered to be a pat-
sometimes with H3 K27M-mutant glio- tern of exceptionally widespread involve-
mas if located preferentially in midline ment of the neuraxis. It can be seen in
locations. Tumours in this category are any of the diffuse glioma subtypes, but
more clinically aggressive than are IDH- is most common in anaplastic astrocy-
mutant anaplastic astrocytomas and may toma. There are no unique molecular
follow a clinical course more similar to signatures that distinguish gliomatosis
that of glioblastoma. from the well-characterized subtypes of
diffuse glioma, but IDH mutations seem
Grading to be restricted to tumours with distinct
IDH-wildtype anaplastic astrocytoma solid tumour components {2313}.
corresponds histologically to WHO
grade III.

Anaplastic astrocytoma, IDH-wildtype 27


Glioblastoma, IDH-wildtype Louis D.N.
Suva M.L.
Brat D.J.
Biernat W.
Ohgaki H.
Cavenee W.K.
Stupp R.
Hawkins C.
Burger P.C. Bigner D.D. Wick W. Verhaak R.G.W.
Perry A. Nakazato Y. Barnholtz-Sloan J. Ellison D.W.
Kleihues P. Plate K.H. Rosenblum M.K. von Deimling A.
Aldape K.D. Giangaspero F. Hegi M.

Definition Genetic parameters H3 K27M mutation has also been ex-


A high-grade glioma with predominantly The genetic alterations typical of IDH- cluded) and with no history of a pre-
astrocytic differentiation; featuring nucle- wildtype glioblastoma include TERT existing lower-grade glioma. Although
ar atypia, cellular pleomorphism (in most promoter mutations (present in ~80% it is not possible to establish an exact
cases), mitotic activity, and typically a dif- of cases), homozygous deletion of patient age cut-off point, one algorithm
fuse growth pattern, as well as microvas- CDKN2AICDKN2B (~60%), loss of has suggested that, in the setting of
cular proliferation and/or necrosis; and chromosomes 10p (~50%) and 10q negative R132H-mutant IDH1 immuno-
which lacks mutations in the IDH genes. (~70%), EGFR alterations (i.e. mutation, histochemistry in a glioblastoma from a
IDH-wildtype glioblastoma is the most rearrangement, altered splicing, and/ patient without prior lower-grade glio-
common and most malignant astrocytic or amplification; ~55%), PTEN muta- ma, the probability of an alternative IDH
glioma, accounting for about 90% of all tions/deletion (~40%), TP53 mutations mutation is < 6% in a 50-year-old pa-
glioblastomas and typically affecting {25-30%), and PI3K mutations (~25%) tient and decreases to < 1% in patients
adults, with a mean patient age at diag- {277,1830}. aged > 54 years {425}. The designation
nosis of 62 years and a male-to-female The prognosis of IDH-wildtype glio- IDH-wildtype can therefore be safely
ratio of about 1.35:1. As the synonymous blastoma with current therapies is poor. applied in this setting, even in the ab-
designation IDH-wildtype primary glio- Determining MGMT promoter methyla- sence of IDH sequencing. However, in
blastoma indicates, this glioblastoma tion status provides information in these younger patients, certain findings more
typically arises de novo, with no recog- tumours on response to alkylating and strongly suggest the need for IDH se-
nizable lower-grade precursor lesion. methylating chemotherapies. quencing before designating a tumour
A preferentially supratentorial location Ideally, the designation IDH-wildtype as IDH-wildtype. These include a his-
is characteristic. The tumour diffusely should be applied to a glioblastoma tory of a lower-grade glioma and the
infiltrates adjacent and distant brain when both R132H-mutant IDH1 im- absence of nuclear ATRX expression
structures. munohistochemistry and subsequent (particularly if p53 immunohistochem-
IDH1/2 sequencing reveal wildtype se- istry shows strong and diffuse nuclear
ICD-0 code 9440/3 quences at IDH1 codon 132 and IDH2 positivity and in the absence of stain-
codon 172. However, in some situations ing for K27M-mutant H3.3). In such a
Grading it may, for practical purposes, be suffi- setting, if IDH sequencing cannot be
cient to rely on negative R132H-mutant performed, a diagnosis of glioblastoma,
Glioblastoma and its variants correspond NOS, should be rendered, with a note
IDH1 immunohistochemistry alone,
histologically to WHO grade IV. However, stating that R132H-mutant IDH1 immu-
most notably in older patients with a
in the setting of current therapy, IDH- histologically classic glioblastoma that nohistochemistry was negative.
mutant glioblastomas may follow a clini-
is not in a midline location (unless an
cal course that is less aggressive than is
typical of WHO grade IV tumours.
Synonym

Primary glioblastoma, IDH-wildtype

Epidemiology
Incidence
Glioblastoma is the most frequent malig-
nant brain tumour in adults, accounting
for approximately 15% of all intracranial
neoplasms and approximately 45-50%
of all primary malignant brain tumours
{1826,1863}. In most European and North
American countries and in Australia, the
annual incidence is about 3-4 cases per
100 000 population {1863}, whereas the
Age at diagnosis Female Male
incidence is relatively low in eastern Asia,
with 0.59 cases per 100 000 population Fig. 1.17 Cumulative age distribution of patients with IDH-wildtype glioblastoma. There is a tendency for an earlier
per year in the Republic of Korea, for manifestation in women. Based on 371 cases from Nobusawa S et al. {1797}.

28 Diffuse gliomas
example {1861}. The annual incidence A series of environmental and genetic rostral lateral ventricles {1417}. In general,
of glioblastoma in the USA, adjusted to factors have been studied as potential tumour infiltration extends into the adja-
the United States Standard Population, causes of glioblastoma. To date, these cent cortex and through the corpus cal-
is 3.19 cases per 100 000 population investigations have yielded inconclusive losum into the contralateral hemisphere.
{1863}. The corresponding rate in a popu or negative results, including results on Glioblastoma of the basal ganglia and
lation-based study in Switzerland (adjust- the potential influence of non-ionizing ra- thalamus is common, especially in chil-
ed to the European Standard Population) diation (e.g. from mobile phones) and oc- dren. Glioblastoma of the brain stem
was 3.55 cases per 100 000 population cupational exposures. The only validated is uncommon and most often affects
{1826}. Significantly lower rates have risk factor associations are an increased children {595} (see also Diffuse midline
been reported in Asian and African coun- risk after ionizing radiation to the head glioma, H3 K27M-mutant, p. 57). The
tries, but this may be due in large part to and neck and a decreased risk among cerebellum and spinal cord are rare sites.
underascertainment. individuals with a history of allergies and/
or atopic disease(s) {1861}. Genome- Clinical features
Age and sex distribution Glioblastomas develop rapidly. The
wide association studies have identified
symptoms depend largely on the tumour
Glioblastoma can manifest in patients some specific heritable risk variants as-
location, primarily manifesting as focal
of any age, but preferentially affects sociated with glioblastoma (see Genetic
neurological deficits (e.g. hemiparesis
older adults, with peak incidence occur- susceptibility, p. 42). As our understand-
and aphasia) and tumour-associated
ring in patients aged 55-85 years. Glio- ing of the heterogeneity of glioblastoma
increases with the use of genomic tech- oedema with increase in intracranial
blastoma is the second most common
pressure. As many as half of all patients
type of intracranial neoplasm in adults nologies, our ability to discover and vali-
are diagnosed after an inaugural seizure.
aged > 55 years {1863}. Glioblastomas date glioblastoma subtype-specific risk
Other common symptoms are behaviour-
are rare in individuals aged < 40 years. factors will probably improve.
al and neurocognitive changes, nausea
In the USA, the median age of patients
Localization and vomiting, and occasionally severe
with glioblastoma is 64.0 years, and the
Glioblastoma is most often centred in pulsating headaches {557,2640,2733}. In
annual incidence rate in the 0-19 years
the subcortical white matter and deeper a study of 677 patients with IDH-wildtype
age group, adjusted to the United States
grey matter of the cerebral hemispheres. glioblastoma, the time from first symp-
Standard Population, is 0.14 new cases
In a series of 987 glioblastomas from toms to diagnosis was < 3 months in 68%
per 100 000 population. The median
the University Hospital Zurich, the most of cases and < 6 months in 84% {1827}.
patient age at diagnosis of IDH-wildtype
frequently affected sites were the tem- In patients with a significantly longer
glioblastomas is 62 years. The male-to-
poral lobe (affected in 31% of cases), duration of symptoms, the possibility of
female ratio for glioblastoma is 1.60:1 in
the parietal lobe (in 24%), the frontal an IDH-mutant glioblastoma that has
the USA {1863} and 1.28:1 in Switzerland
lobe (in 23%), and the occipital lobe (in evolved from a lower-grade astrocytoma
{1825}.
16%). Similar location trends are seen in should be considered.
Etiology the USA {1863}. Whereas primary, IDH-
Imaging
A very small proportion of glioblastomas wildtype glioblastomas have a wide-
Glioblastomas are irregularly shaped and
are inherited as part of specific Mende- spread anatomical distribution, second-
have a ring-shaped zone of contrast en-
lian syndromes (see Genetic suscep- ary, IDH-mutant glioblastomas have a
hancement around a dark, central area
tibility, p. 42) {1861}, but the etiology of striking predilection for the frontal lobe,
of necrosis. They may extend widely
most glioblastomas remains unknown. particularly in the region surrounding the

Fig. 1.18 IDH-wildtype glioblastoma. A This tumour appears multifocal on postcontrast T1-weighted MRI. B The corresponding FLAIR image of this multifocal glioma shows an
abnormal signal connecting the seemingly separate foci of contrast enhancement. C This postcontrast T1 -weighted image shows the typical features of a butterfly glioblastoma with
extensive involvement of the corpus callosum leading to bihemispheric spread.

Glioblastoma, IDH-wildtype 29
treated with antiangiogenic therapies,
presumably due to vascular normaliza-
tion {542}.
Gliomatosis cerebri growthpattern
Like other diffuse gliomas, glioblastoma
can manifest at initial clinical presenta-
tion with a gliomatosis cerebri pattern of
extensive involvement of the CNS, with
the affected area ranging from most of
one cerebral hemisphere (three lobes
or more) to both cerebral hemispheres
with additional involvement of the deep
grey matter structures, brain stem, cer-
ebellum, and spinal cord. See Anaplastic
astrocytoma, IDH-wildtype (p. 27) for ad-
ditional detail.
Fig. 1.19 Rare case in which the rapid development of a primary glioblastoma, IDH-wildtype, could be followed by Metastasis
neuroimaging. After a seizure, the 79-year-old man was hospitalized and MRI showed a small cortical lesion of 1 cm Despite its rapid, infiltrative growth, glio-
in diameter. Only 2 months later, the patient presented with a full-blown glioblastoma with ring enhancement, central blastoma does not commonly extend
necrosis, and perifocal oedema {1533,1822}. into the subarachnoid space or spread
through the cerebrospinal fluid, although
into adjacent lobes, the opposite hemi- Other infiltrative patterns give rise to
this may be more frequent in children {90,
sphere, and the brain stem. In the set- secondary structures of Scherer, includ-
880} Similarly, penetration of the dura,
ting of a ring-enhancing mass, biopsies ing perineuronal satellitosis, perivascular
venous sinus, and bone is exceptional
showing high-grade astrocytoma but not aggregation, and subpial spread {2838}.
{812,2002}. Although extension within
demonstrating frank histological features Infiltrative cells are located both inside
and along perivascular spaces is typi-
of glioblastoma should be suspected to and outside of the contrast-enhancing
cal, invasion of the vessel lumen is not a
have been inadequately sampled. rim of glioblastoma and generally create
frequent histological finding. Extracranial
a gradient of decreasing cell density with
Spread metastasis of glioblastoma is uncommon
increasing distance from the tumour cen-
Infiltrative spread is a defining feature of in patients without previous surgical in-
tre. Individual infiltrating tumour cells can
all diffuse gliomas, but glioblastoma is tervention, but has been documented in
be histologically identified several centi-
particularly notorious for its rapid invasion patients who have undergone interstitial
metres from the tumour epicentre, both in
of neighbouring brain structures {316}. therapies and in patients with ventricular
regions that are T2-hyperintense on MRI
Infiltration occurs most readily along shunts {935,1546,2676}. More recently,
and in regions that appear uninvolved.
white matter tracts, but can also involve circulating tumour cells have been found
These infiltrating cells are the most likely
cortical and deep grey structures. When in the blood of some patients with glio-
source of local recurrence after initial
infiltration extends through the corpus blastoma, suggesting that immune mech-
therapy, because they escape surgi-
callosum, with subsequent growth in the anisms or inhospitable environments of
cal resection, do not receive the highest
contralateral hemisphere, the result can distant organs suppress metastatic im-
dose of radiotherapy, and involve regions
be a bilateral, symmetrical lesion (so- plantation and growth {2454}. The find-
with an intact blood-brain barrier (which
called butterfly glioma). Similarly, rapid ing that immunosuppressed recipients of
diminishes chemotherapeutic bioavail-
spread is observed along white matter organ transplants from donors with glio-
ability) {834}. Interestingly, a pattern of
tracts of the internal capsule, fornix, an- blastoma have developed glioblastoma
increased infiltration has been observed
terior commissure, and optic radiation. in their transplanted organ suggests that
in a subset of patients with glioblastoma
the immune system normally suppresses
the metastatic potential of circulating tu-
mour cells {1161}.
Mechanisms of invasion
Mechanisms that promote the invasive
properties of glioblastoma cells include
those involved with cell motility, cell-ma-
trix and cell-cell interactions, and remod-
elling of the extracellular matrix, as well
as microenvironmental influences {160,
573}. Tumour cells produce migration-
enhancing extracellular matrix compo-
Fig. 1.20 A Glioblastoma with bilateral, symmetrical invasion of the corpus callosum and adjacent white matter of the nents and secrete proteolytic enzymes
cerebral hemispheres (butterfly glioblastoma). B Unusual case of a glioblastoma with focal infiltration of the cerebral
cortex and the adjacent subarachnoid space, macroscopically presenting as greyish thickening of the meninges.

30 Diffuse gliomas
tumours and that in approximately 3%
of these, the tumour foci differ in histo-
logical appearance {128}. True multifocal
glioblastomas are most likely polyclonal if
they occur infratentorially and supratento-
rially (i.e. outside easily accessible routes
such as the cerebrospinal fluid pathways
or the median commissures) {2228}. By
definition, multiple independently arising
gliomas must be of polyclonal origin, and
their existence can only be proven by ap-
plication of molecular markers, which in
informative cases enable the distinction
between tumours of common or inde-
pendent origin {175,197,1359}.
Macroscopy
Despite the short duration of symptoms
in many cases, glioblastomas are often
surprisingly large at the time of presenta-
tion, and can occupy much of a lobe. The
lesions are usually unilateral, but those in
Fig. 1.21 A Glioblastoma of the right frontotemporal region with infiltration of the basal ganglia, compression of the the brain stem and corpus callosum can
right lateral ventricle, and midline shift towards the contralateral (left) cerebral hemisphere. B Large, diffusely infiltrating be bilaterally symmetrical. Supratentorial
glioblastoma of the left frontal lobe with typical coloration: whitish-grey tumour tissue in the periphery, yellow areas bilateral extension occurs as a result of
of necrosis, and extensive haemorrhage. Note the extension through the corpus callosum into the right hemisphere.
growth along myelinated structures, in
C Symmetrical glioblastoma infiltrating the lateral ventricles and adjacent brain structures. D Large glioblastoma of
particular across the corpus callosum
the brain stem (pons), causing compression of the fourth ventricle. This location is typical of H3 K27M-mutant diffuse
and the commissures. Most glioblas-
midline gliomas.
tomas of the cerebral hemispheres are
clearly intraparenchymal with an epicen-
that permit invasion, including the matrix angiogenic mechanisms and direct ef- tre in the white matter. Infrequently, they
metalloproteinases MMP2 and MMP9, fects that enhance glioma cell migra- are largely superficial and in contact with
uPA and its receptor uPAR, and cath- tion {1239,2840}. Hypoxic tumour cells the leptomeninges and dura and may
epsins. Gliomas also express a variety display elevated expression of extracel- be interpreted by the neuroradiologist or
of integrin receptors that mediate interac- lular matrix components and intracellu- surgeon as metastatic carcinoma, or as
tions with molecules in the extracellular lar proteins associated with cell motility an extra-axial lesion such as meningi-
space and lead to alterations of the cel- {264,2170}. Activation of a pro-migration oma. Cortical infiltration may produce a
lular cytoskeleton and activation of intra- transcriptional programme seems to be preserved gyriform rim of thickened grey
cellular signalling networks such as the associated with a decrease in prolifera- cortex overlying a necrotic zone in the
AKT, mTOR, and MAPK pathways. Many tion, which may have therapeutic conse- white matter.
growth factors expressed in glioblasto- quences {834,835}. Glioblastomas are poorly delineated;
ma, such as hepatocyte growth factor, fi- the cut surface is variable in colour, with
Multifocal glioblastoma peripheral greyish tumour masses and
broblast growth factor, epidermal growth
Although multifocality is not unusual when central areas of yellowish necrosis from
factor, and VEGF, also stimulate migra-
defined radiologically, the incidence of myelin breakdown. The peripheral hyper-
tion by activation of corresponding re-
truly multiple, independent gliomas oc- cellular zone presents macroscopically
ceptor tyrosine kinases and downstream
curring outside the setting of inherited
mediators that more directly promote mi-
neoplastic syndromes is unknown. Even
gration, including FAK and the Rho fam-
careful postmortem studies on whole-
ily GTPases Rac, RhoA, and CDC42. In
brain sections do not always reveal a
EGFR-amplified glioblastomas, cells with
connection between apparently multifo-
amplification are preferentially located at
cal gliomas, because the cells infiltrat-
the infiltrating edges, suggesting a role in
ing along myelinated pathways are often
peripheral expansion {2385}. The overall
small, polar, and largely undifferentiated.
mass migration of glioblastoma is radially
One careful histological analysis {143}
outward, away from central necrosis and
concluded that 2.4% of glioblastomas
associated severe hypoxia, with rates
are truly multiple independent tumours,
substantially greater than those of pre-
a value similar to that reported by others
necrotic gliomas {2170,2467}. Hypoxia
{2.3%) {2204}. A postmortem study found
promotes invasion through the activa- Fig. 1.22 IDH-wildtype glioblastoma. This intraoperative
that 7.5% of gliomas (including oligoden-
tion of HIF1 and other hypoxia-inducible smear preparation shows small, elongated bipolar cells,
drogliomas) are multiple independent
transcription factors, due to both pro- a characteristic component of glioblastomas {1956}.

Glioblastoma, IDH-wildtype 31
The presence of highly anaplastic glial
cells, mitotic activity, and microvascular
proliferation and/or necrosis is required.
The distribution of these key features
within the tumour is variable, but large
necrotic areas usually occupy the tumour
centre, whereas viable tumour cells tend
to accumulate in the periphery. The cir-
cumferential region of high cellularity
and abnormal vessels corresponds to
the contrast-enhancing ring seen radio-
logically, and is an appropriate target for
needle biopsy. Microvascular prolifera-
tion is seen throughout the lesion, but is
usually most marked around necrotic foci
and in the peripheral zone of infiltration.
Cellular composition and histological
patterns
Few human neoplasms are as heteroge-
neous in composition as glioblastoma.
Fig. 1.23 Diagnostic hallmarks of IDH-wildtype glioblastoma. A focus of ischaemic necrosis (NE) is surrounded by Poorly differentiated, fusiform, round, or
palisading tumour cells and hyalinized vascular proliferation (VP). pleomorphic cells may prevail, but bet-
ter-differentiated neoplastic astrocytes
are usually discernible, at least focally
{317}. This is particularly true of glioblas-
tomas resulting from the progression of
WHO grade II diffuse astrocytomas, but
these are typically IDH-mutant glioblas-
tomas. The transition between areas that
still have recognizable astrocytic differ-
entiation and highly anaplastic cells may
be either continuous or abrupt. In the
case of gemistocytic lesions, anaplas-
Fig. 1.24 Glioblastoma, IDH-wildtype. A Microvascular proliferation in glioblastomas often have a glomeruloid tic tumour cells may be diffusely mixed
appearance. B Palisading necrosis is characterized by irregular zones of necrosis surrounded by dense accumulations
with the differentiated gemistocytes. An
of tumour cells.
abrupt change in morphology may reflect
the emergence of a new tumour clone
as a soft, grey to pink rim or a grey band tumour cells with nuclear atypia and brisk
through the acquisition of one or more
of tumour tissue. However, necrotic tissue mitotic activity. Prominent microvascular
additional genetic alterations (see Primi-
may also border adjacent brain structures proliferation and/or necrosis is an essen-
tive neuronal cells and glioblastoma with
without an intermediate zone of macro- tial diagnostic feature.
a primitive neuronal component, below)
scopically detectable tumour tissue. The As the outdated term glioblastoma mul-
{750}. Cellular pleomorphism includes
central necrosis can occupy as much as tiforme suggests, the histopathology of
the formation of small, undifferentiated,
80% of the total tumour mass. Glioblas- this tumour is extremely variable. Some
lipidized, granular, and giant cells. There
tomas are typically stippled with red and lesions show a high degree of cellular
are also often areas where bipolar, fusi-
brown foci of recent and remote haem- and nuclear polymorphism with numer-
form cells form intersecting bundles,
orrhage. Extensive haemorrhages can ous multinucleated giant cells; others
and fascicles prevail. The accumulation
occur and cause stroke-like symptoms, are highly cellular but relatively mono-
of highly polymorphic tumour cells with
which are sometimes the first clinical sign morphic. The astrocytic nature of the
well-delineated plasma membranes and
of the tumour. Macroscopic cysts, when neoplasms is easily identifiable (at least
a lack of cell processes may mimic meta-
present, contain a turbid fluid and con- focally) in some tumours, but difficult to
static carcinoma or melanoma.
stitute liquefied necrotic tumour tissue, in recognize in tumours that are poorly dif-
Several cellular morphologies appear
contrast to the well-delineated retention ferentiated. The regional heterogeneity
commonly in glioblastomas. Some glio-
cysts present in WHO grade II diffuse of glioblastoma is remarkable, making
blastomas have well-recognized pat-
astrocytomas. histopathological diagnosis difficult on
terns that are characterized by a great
specimens obtained by stereotaxic nee-
Microscopy predominance of a particular cell type.
dle biopsies {317}.
Glioblastoma is typically a highly cellu- These morphologies are discussed in
The diagnosis of glioblastoma is often
lar glioma, usually composed of poorly the following subsections, along with the
based on the identification of the tissue
differentiated, sometimes pleomorphic corresponding glioblastoma patterns that
pattern rather than of specific cell types.

32 Diffuse gliomas
Fig. 1.25 Small cell glioblastoma. A Central portion of an EGFR-amplified, IDH-wildtype, 1p/19q-intact small cell glioblastoma showing a highly cellular monomorphic population
of small tumour cells with frequent mitoses despite only mild nuclear atypia. B Delicate processes are evident on a GFAP immunostain. C The Ki-67 labelling index is very high.

can be established if a particular cellu- mitotic activity. In the zone of infiltration, IDH mutations are absent {1183,1937}.
lar morphology predominates. Because tumour cells can be difficult to identify In one series, mutations of TP53 were
most of these glioblastoma patterns are as neoplastic, given their small size and found to be slightly less common in this
found in IDH-wildtype glioblastomas, bland cytology. GFAP immunoreactivity subtype, but the difference did not reach
they are discussed here, but it is recog- variably highlights delicate processes, statistical significance {1031}. The clini-
nized that some of these variants (e.g. and the Ki-67 proliferation index is typi- cal behaviour of the small-cell subtype is
gemistocytic astrocytomas progressing cally high. Due to their nuclear regular- similar to that of other primary glioblas-
to glioblastoma) are more characteristic ity, clear haloes, microcalcifications, tomas in general, with a median survival
of IDH-mutant glioblastoma. and chicken wire-like microvasculature, time of 11 months in one series {1937}.
these tumours overlap with anaplastic In the same series, about a third of the
Small cells and small cell glioblastoma oligodendroglioma {1937}. But unlike cases presented as non-enhancing or
This subtype features a predominance oligodendrogliomas, small cell glioblas- minimally enhancing masses with no
of highly monomorphic small, round to tomas frequently have EGFR amplifi- evidence of microvascular proliferation or
slightly elongated, hyperchromatic nu- cation (present in -70% of cases) and necrosis on histology. However, follow-up
clei with minimal discernible cytoplasm, chromosome 10 losses (in > 95%). As in imaging 2-3 months later often showed
little nuclear atypia, and (often) brisk other primary glioblastomas in general, ring enhancement, and survival times
were shorter for these cases (median:
6 months), suggesting that these cases
constitute early presentations of WHO
grade IV glioblastoma rather than WHO
grade III anaplastic astrocytoma {1937}.
Primitive neuronal cells and glioblastoma
with a primitive neuronal component
This subtype constitutes an otherwise
classic diffuse glioma with one or more
solid-looking primitive nodules showing
neuronal differentiation. The glioma com-
ponent is typically astrocytic, although
rare primitive neuronal foci have also
been reported in oligodendrogliomas
{1946}. The primitive foci are sharply
demarcated from the adjacent glioma and
display markedly increased cellularity and
a high nuclear-to-cytoplasmic ratio and
mitosis-karyorrhexis index. More variable
features include Homer Wright rosettes,
cell wrapping, and anaplastic cytol-
ogy similar to that of medulloblastoma or
other CNS embryonal neoplasms. Addi-
tional primitive neuronal features include
immunoreactivity for neuronal markers
such as synaptophysin, reduction or loss
of GFAP expression, and a markedly ele-
Fig. 1.26 Glioblastoma with a primitive neuronal component. A Diffuse astrocytoma component on the right and
vated Ki-67 proliferation index compared
primitive neuronal component on the left. B Homer Wright rosettes within the primitive neuronal component of a
with adjacent foci of glioma. This subtype
glioblastoma. C Strong synaptophysin positivity in the primitive cells.

Glioblastoma, IDH-wildtype 33
they may have a better prognosis than
standard glioblastoma {975,1031,1360}.
More recent studies suggest that this is
a heterogeneous tumour group, and that
some cases are IDH1- or /DH2-mutant
glioblastomas. The current WHO classi-
fication does not consider glioblastoma
with an oligodendroglioma component
to be a distinct diagnostic entity; with
genetic analysis, it should be possible to
classify such tumours as IDH-wildtype
glioblastoma (in particular the small-cell
variant, given the morphological overlap
with oligodendroglial cells), IDH-mutant
glioblastoma, or IDH-mutant and 1p/19q-
codeleted anaplastic oligodendroglioma.

Gemistocytesand gemistocytic
astrocytic neoplasms
Gemistocytes are cells with copious,
Fig. 1.27 Granular cell glioblastoma. A Eosinophilic cytoplasm reminiscent of a granular cell tumour of the pituitary, but glassy, non-fibrillary cytoplasm that dis-
with cytologically more atypical cells. B GFAP Immunoreactivity. C The strong nuclear 0LIG2 Immunoreactivity helps places the dark, angulated nucleus to
to establish its glial lineage. D In contrast to most glioblastomas, the granular cell variant often shows immunoreactivity the periphery of the cell. Processes ra-
for EMA.
diate from the cytoplasm, but are stubby
and not long-reaching. GFAP staining is
presents either de novo or during pro- patients, the typically strong and exten-
largely confined to the periphery of the
gression from a known diffuse glioma. In sive tumoural p53 immunoreactivity, and
cell, with the central hyaline organelle-
both settings, the survival time and ge- the presence of IDH1 R132H mutations in
rich zone remaining largely unstained.
netic background are similar to those of 15-20% of cases {1183,2394}.
Perivascular lymphocytes frequently
glioblastoma in general {1946}. However,
Oligodendroglioma components populate gemistocytic regions, but of-
this subtype is distinctive in its high rate
Occasional glioblastomas contain foci ten avoid other regions in the same neo-
(30-40%) of cerebrospinal fluid dissemi-
that resemble oligodendroglioma. These plasm. When present in large numbers,
nation and frequency (~40%) of MYCN
areas are variable in size and frequency, particularly in a patient known to have a
or MYC gene amplification. MYC ampli-
and individual pathologists thresholds pre-existing glioma (e.g. an IDH-mutant
fication is found only in the primitive-ap-
for identifying oligodendroglioma fea- gemistocytic astrocytoma), these cells
pearing nodules, and it is likely that such
tures vary. Two large studies of malignant may constitute a lower-grade precursor
alterations drive the primitive-appearing
gliomas suggest that necrosis is associ- lesion within a secondary IDH-mutant
clonal transformation at least in part,
ated with a significantly worse prognosis glioblastoma. Better-differentiated areas
given that a similar phenotype has been
in the setting of anaplastic glioma with can sometimes be identified radiologi-
observed in N-myc-driven murine fore-
both oligodendroglial and astrocytic cally as non-contrast-enhancing periph-
brain tumours {2468}. In some cases, ei-
components {1667,2617}; patients whose eral regions, and in whole-brain sections,
ther new 10q losses or expanded regions
tumours had necrosis had a substantially as WHO grade II to III astrocytomas
of 10q loss are also found in the primi-
shorter median overall survival than did clearly distinct from foci of glioblastoma
tive neuronal focus {750}. Evidence that
patients whose tumours did not. Such tu- {317,2266}. Immunohistochemical stud-
some examples of this subtype are sec-
mours were classified as glioblastomas ies have emphasized the low proliferation
ondary glioblastomas includes the his-
with an oligodendroglial component, and rate of the neoplastic gemistocyte itself,
tory of a lower-grade precursor in some
despite the reported tendency of WHO
grade II or III gemistocytic astrocytoma
lesions to progress more rapidly to glio-
blastoma than non-gemistocytic coun-
terparts of the same grade {2706}. The
proliferating component presents as a
population of cells with larger hyperchro-
matic nuclei and scant cytoplasm {2706}.
Multinucleated giant cells
Large, multinucleated tumour cells are
often considered a hallmark of glio-
Fig. 1.28 Glioblastoma, IDH-wildtype. A High degree of anaplasia with multinucleated giant cells. B Focal blastomas and occur with a spectrum
oligodendroglioma-like component. of increasing size and pleomorphism.

34 Diffuse gliomas
Fig. 1.29 Glioblastoma with epithelial metaplasia. A In addition to adenoid cytology, this glioblastoma features occasional squamous morules, indicative of true epithelial metaplasia.
B Loss of GFAP expression within foci of epithelial metaplasia. C Focal squamous cell metaplasia characterized by marked cytokeratin expression.

Although common, the presence of multi- lesion such as demyelinating disease. 2506}. The lipidized cells may be grossly
nucleated giant cells is neither an obliga- Given their lysosomal content, granular enlarged {811}. If such a lesion is super-
tory feature nor associated with a more tumour cells may be immunoreactive for ficially located in a young patient, the
aggressive clinical course {315}. Despite macrophage markers such CD68, but diagnosis of pleomorphic xanthoastrocy-
their appearance, these cells are con- not for specific markers such as CD163. toma should be considered, particularly
sidered a type of regressive change. If Occasional cells may have peripheral im- if the xanthomatous cells are surrounded
multinucleated giant cells dominate the munopositivity for GFAP, but most cells by basement membranes staining posi-
histopathological picture, the designation are negative {271,793}. Some diffuse as- tively for reticulin and accompanied by
of giant cell glioblastoma is justified (see trocytic tumours feature extensive granu- eosinophilic granular bodies {1248}.
Giant cell glioblastoma, p. 46). lar cell change and have been termed Other lipid-rich lesions have epithelioid
granular cell astrocytoma" or granular cytological features {2180}. Lobules of
Granular cells and granular cell
cell glioblastoma. These lesions have a juxtaposed fully lipidized (i.e. not foamy)
astrocytoma/glioblastoma cells can simulate adipose tissue.
distinct histological appearance and are
Large cells with a granular, periodic acid-
typically characterized by aggressive
Schiff-positive cytoplasm may be scat- Metaplasia and gliosarcoma
glioblastoma-like clinical behaviour {271},
tered within glioblastoma. In rare cases, In general, metaplasia refers to the ac-
even when the histology otherwise sug-
they dominate and create the impression quisition by a differentiated cell of mor-
gests only a WHO grade II or III desig-
of a morphologically similar but unrelated phological features typical of another dif-
nation; one review of 59 reported cases
granular cell tumour of the pituitary stalk ferentiated cell type. However, the term is
found median survival times of 11 months
{569,948}. In the cerebral hemispheres, also used to designate aberrant differen-
for WHO grade II cases and 9 months for
transitional forms between granular cells tiation in neoplasms. In glioblastoma, this
WHO grade lll-IV cases {2283}.
and neoplastic astrocytes can be identi- is exemplified by foci displaying features
fied in some cases, but in others it is dif- Lipidized cells and heavily lipidized of squamous epithelial cells (i.e. epithelial
ficult to identify any conventional astro- glioblastoma whorls with keratin pearls and cytokeratin
cytoma component. Although larger and Cells with foamy cytoplasm are another expression) {320,1734}.
more coarsely granular, the tumour cells feature occasionally observed in glio- Occasionally, glioblastomas contain foci
also resemble macrophages. Especially blastoma. The rare lesions in which they with glandular and ribbon-like epithelial
in the context of perivascular chronic predominate have been designated structures {2180}. These elements have
inflammation, the tumour cells may be malignant gliomas with heavily lipidized a large oval nucleus, prominent nucleo-
misinterpreted as a macrophage-rich (foamy) tumour cells {1247,1253,2180, lus, and round well-defined cytoplasm.

Fig. 1.30 Adenoid glioblastoma. A Adenocarcinoma-like cytology with small epithelioid cells arranged in nests and rows set within a mucin-rich stroma. B Despite the Carcinoma-Iike
appearance, the glial histogenesis of this adenoid glioblastoma is supported by strong nuclear expression of OLIG2.

Glioblastoma, IDH-wildtype 35
for the formation of bone and cartilage,
which predominates in gliosarcoma and
in a variety of childhood CNS neoplasms
{1608}.
Secondary structures
The migratory capacity of glioblastoma
cells within the CNS becomes readily
apparent when they reach a border that
constitutes a barrier: tumour cells line up
and accumulate in the subpial zone of
Fig. 1.31 IDH-wildtype glioblastoma. GFAP immunohisto- the cortex, in the subependymal region, Fig. 1.32 Subpial, perivascular, and perineuronal
chemistry typically labels only some cells in glioblastoma, accumulation of glioblastoma cells. Asterisk indicates
and around neurons (so-called satellito-
highlighting the tumour cell bodies and processes. uninvolved subarachnoid space.
sis) and blood vessels. These patterns,
called secondary structures {2267}, re-
They are also referred to as adenoid One feature of many glioblastomas, es-
sult from the interaction of glioma cells
glioblastomas. Expression of GFAP in pecially the small-cell variant, is exten-
with host brain structures, and are highly
these areas may be diminished, and re- sive involvement of the cerebral cortex.
diagnostic of an infiltrating glioma. Sec-
placed by expression of epithelial mark- Secondary structures and most of the
ondary structures may also be present
ers. Small cells with even more epithelial apparently multifocal glioblastomas arise
in other highly infiltrative gliomas, such
features and cohesiveness are less com- essentially as a result of the pathways
as oligodendroglioma {2266,2267}. This
mon {1250}. When there is an extensive of migration of glioma cells in the CNS
concept also extends to the adaptation
mesenchymal component, in particular {1440}. The subependymal region may
of tumour cells to myelinated pathways,
a spindle cell sarcoma-like component, also be diffusely infiltrated, especially in
which often acquire a fusiform, polar
a diagnosis of gliosarcoma should be the terminal stages of disease.
shape as a result. Identifying neoplas-
considered. A mucinous background
tic astrocytes in the perifocal zone of Proliferation
and a mesenchymal component (gliosar-
oedema and at more distant sites can Proliferative activity is usually prominent,
coma) are not uncommon in metaplastic
be challenging for pathologists, in par- with detectable mitoses in nearly every
glioblastomas. Adenoid and squamous
ticular when dealing with stereotaxic case. Atypical mitoses are frequently
epithelial metaplasia are more common
biopsies {535}. Small cell glioblastomas present. However, there is great intertu-
in gliosarcoma than in ordinary glioblas-
pose a particular problem in this regard. moural and intratumoural variation in mi-
toma {1250,1734}. This is similarly true
totic activity. The growth fraction as de-
termined by the Ki-67 proliferation index
can thus show great regional variation.
Typical values are 15-20%, but some
tumours have a proliferation index of
> 50% focally. Rare tumours have a low
proliferation index despite other histo-
logical features of malignancy. Tumours
with small, undifferentiated, fusiform cells
often show marked proliferative activ-
ity, in contrast to tumours composed of
neoplastic gemistocytes, which typically
have a lesser degree of proliferation
{2706}. Despite the wide range in the pro-
liferation index observed in glioblastoma,
an association between proliferation in-
dex and clinical outcome has not been
demonstrated {1715}.
Microvascular proliferation and
angiogenesis
The presence of microvascular prolif-
eration is a histopathological hallmark
Fig. 1.33 Intravascular thrombosis in glioblastoma (GBM). A A central vessel within a GBM is occluded by intravascular of glioblastoma. On light microscopy,
thrombus (arrow). The vessel is dilated proximal to the occlusion and surrounded by delicate fibrillarity and scattered microvascular proliferation typically pre-
apoptotic cells, most likely representing the initial stages of palisade formation (arrowhead). B As the palisading front
sents as so-called glomeruloid tufts of
of tumour cells (arrowhead) enlarges around a central thrombosed vessel (arrow), perivascular necrosis becomes
multilayered mitotically active endothelial
more prominent. C H&E staining of a GBM demonstrates intravascular thrombosis occluding and distending a vessel
cells together with smooth muscle cells /
(arrow) within the centre of a palisade (arrowhead). D Immunohistochemistry for HIF1A of a serial tissue section shows
increased nuclear staining in palisades, indicating an adaptive response to hypoxia (arrowhead). Reprinted from Rong Y
pericytes {920,1741,2734}. Another (less
et al. {2170}.

36 Diffuse gliomas
pericytes (which are negative for CD31 of VEGFA by monoclonal antibodies,
and CD34, positive for SMA, and positive used for the treatment of recurrent glio-
for PDGFRB) {2264}. Morphologically blastoma {1998}, seems to target pri-
inconspicuous vessels have a Ki-67 pro- marily small, immature vessels and lead
liferation index of 2-4%, whereas prolif- to vascular normalization accompanied
erating tumour vessels have an index of by improved perfusion and oxygenation
> 10% {2702}. {2398}. Other signalling pathways impor-
Glioblastomas are among the most vascu- tant for glioblastoma angiogenesis in-
larized of all human tumours. Vasculariza- clude angiopoietin/Tie2 receptor signal-
tion occurs through several mechanisms, ling, IL8/IL8R signalling, platelet-derived
including vessel cooption (adoption of growth factor (PDGF) / PDGF receptor
pre-existing vessels by migrating tumour signalling, WNT/beta-catenin signalling,
cells {708,1559}), classic angiogenesis Eph/ephrin signalling, and transforming
(sprouting of capillaries from pre-existing growth factor beta signalling. Pericytes /
vessels by endothelial cell proliferation/ smooth muscle cells and perivascular
migration), and vasculogenesis (homing bone marrow-derived cells (in addition
of bone marrow-derived cells that sup- to endothelial cells) also participate in the
port vessel growth in a paracrine man- vascular remodelling processes typically
ner {6,708,1559}). Intussusception and observed in glioblastoma.
Fig. 1.34 Potential mechanism of palisade formation.
cancer stem cell-derived vasculogen- Necrosis
A Endothelial injury and the expression of procoagulant
factors result in intravascular thrombosis and increasing
esis have also been described {944,1127, Tumour necrosis is a fundamental feature
perivascular hypoxia (light blue). Tumour cells begin
1989}. Hypoxia is a major driving force of glioblastoma, and its presence is one
to migrate away, creating a peripherally moving of glioblastoma angiogenesis {6} and of the strongest predictors of aggres-
wave of palisading cells. B The zone of hypoxia and leads to intracellular stabilization of the sive behaviour among diffuse astrocytic
central necrosis expands. Hypoxic tumour cells of master regulator HIF1A. HIF1A accumu- tumours {315,1031,2079}. Presenting on
palisades secrete proangiogenic factors (VEGF, IL8). lation leads to transcriptional activation of neuroimaging as a hypodense core within
C Microvascular proliferation in regions adjacent to > 100 hypoxia-regulated genes encod- a contrast-enhancing rim, necrosis con-
central hypoxia causes an accelerated outward migration ing proteins that control angiogenesis stitutes areas of non-viable tumour tissue
of tumour cells towards a new vasculature. Illustration
(e.g. VEGFA, angiopoietins, erythropoi- that can range from extremely small to
2005 Mica Duran. Adapted from Rong Y et al. {2170}.
etin, and IL8), cellular metabolism (e.g. accounting for > 80% of the total tumour
common) form is hypertrophic proliferat- carbonic anhydrase and lactate dehydro- mass. Higher proportions of necrosis on
ing endothelial cells within medium-sized genase), survival/apoptosis (e.g. BNIP), MRI have been associated with shorter
vessels. Microvascular proliferation of and migration (e.g. hepatocyte growth survival, and the extent of necrosis is also
the glomeruloid type is most commonly factor receptor, CXCR4, and ACKR3). related to the tumours transcriptional
located in the vicinity of necrosis and is VEGFA seems to be the most important profile {904,1969}. Grossly, necrosis pre-
directionally oriented to it, reflecting the mediator of glioma-associated vascu- sents as a yellow or white granular co-
response to vasostimulatory factors re- lar functions; it is primarily produced by agulum. Microscopically, glioma cells in
leased from the ischaemic tumour cells. perinecrotic palisading cells as a conse- various stages of degeneration are seen
Vascular thrombosis is common and quence of cellular stress such as hypoxia within necrobiotic debris, together with
may be apparent to the neurosurgeon and hypoglycaemia {1239,1988,2357}. faded contours of large, dilated necrotic
as so-called black veins. It may play a VEGFA is regulated by transcription fac- tumour vessels. Occasionally, preserved
role in the pathogenesis of ischaemic tu- tors, oncogenes, tumour suppressor tumour vessels with a corona of viable tu-
mour necrosis {2170}. The hyperplastic genes, cytokines, and certain hormones. mour cells can be seen within extensive
endothelial cells (which are positive for VEGFA induces tumour angiogenesis, in- areas of necrosis.
CD31 and CD34, negative for SMA, and creases vascular permeability (oedema), A second form of necrosis that is a his-
positive for VEGFR2) are surrounded by and regulates homing of bone marrow- tological hallmark of glioblastoma is the
basal lamina and an incomplete layer of derived cells {6}. Therapeutic blocking

Fig. 1.35 Extensive coagulative ischaemic necrosis Fig. 1.36 A Longitudinal cut of perinecrotic palisades, presenting as long, serpiginous pattern. B Reticulin stain of a
(right). Note several large thrombosed tumour vessels. perinecrotic garland of proliferated tumour vessels.

Glioblastoma, IDH-wildtype 37
palisading form (historically called the the release of mitochondrial factors glioblastomas. In poorly differentiated
pseudopalisading form), which consists or by death receptor ligation by mem- tumours, the expression of OLIG2 may
of multiple, small, irregularly shaped bers of the tumour necrosis factor fam- be of diagnostic utility, being strongly
band-like or serpiginous foci surround- ily, including TNFSF10/TNFRSF10B and positive far more commonly in astrocy-
ed by radially oriented, densely packed TNFSF6/TNFRSF6 {943,1872}. The high- tomas and oligodendrogliomas than in
glioma cells {2170}. The outdated term er levels of apoptosis seen in palisading ependymomas and non-glial tumours
pseudopalisading" implied that the tu- cells surrounding necrosis may be due {1101,1865}. The expression of cytokerat-
mour cells did not truly aggregate around to increased expression or ligation of ins is determined by the class of these
necrosis, but only created this impres- death receptors {264,2485}. TNFSF10 intermediate filaments and antibodies
sion, because they were believed to be induces apoptosis in glioblastoma by used, some of which may indicate cross-
a rim of hypercellular tumour cells that binding to TNFRSF10B and ultimately reactivity with GFAP; keratin positivity is
remained after central degeneration of a activating caspase-8 {943}. Levels of most often detected with the keratin anti-
highly proliferative clone. However, this both TNFRSF6 and TNFSF6 are higher body cocktail AE1/AE3, in contrast to the
is likely not actually the case, given that in astrocytomas than in normal brain lack of positivity for many other keratins
the palisading cells have lower rates of and correlate with tumour grade {2485, {2535}. Nestin is frequently expressed in
proliferation than adjacent glioma cells 2563}. MostTNFRSF6 expression in glio- glioblastoma and can be diagnostically
and the central area of smaller palisading blastoma is within palisading cells; physi- useful to distinguish glioblastoma from
structures often consists of a fine fibrillary cal interactions between tumour cells other high-grade gliomas {88}.
network without viable or necrotic glioma expressing TNFRSF6 and TNFSF6 may Glioblastomas with missense TP53 mu-
cells {264,1847,2170[. Palisading cells promote apoptosis. In malignant gliomas, tations show strong and diffuse immu-
are hypoxic and strongly express HIF1A the overall levels of cell death due to apo- nohistochemical overexpression of p53
and other hypoxia-inducible transcription ptosis are low (compared with coagula- {2496}, with such overexpression evident
factors {2841,2861}. Downstream hypox- tive necrosis), and apoptotic rates do not in 21-53% of cases {276,1443,2007,
ic upregulation of VEGF, IL8, and other correlate with prognosis {1663,2272}. 2455}. This may facilitate discrimina-
proangiogenic factors is responsible for tion between neoplastic astrocytes and
Inflammation
the microvascular proliferation that oc- those in reactive gliosis in treated cases
The number of inflammatory cells in glio-
curs immediately adjacent to palisading of glioblastoma {268}. Detection of WT1
blastomas varies. Notable perivascular
cells, providing a biological link between expression, which is sometimes pres-
lymphocyte cuffing occurs in a minority
the histological hallmarks of necrosis and ent in both low-grade and high-grade
of glioblastomas, most typically in areas
microvascular hyperplasia in glioblasto- gliomas, may serve a similar purpose
with a homogeneous gemistocytic com-
ma {1989,2170}. The initiating necrogenic {2281}. EGFR expression occurs in about
ponent. Inflammatory cells are scant if
events have yet to be firmly established, 40-98% of glioblastomas and correlates
present at all in small cell glioblastomas.
but vascular cooption by neoplastic (to some extent) with the presence of
The inflammatory cells have been char-
cells has been hypothesized to induce gene amplification {198,678,1023,1443}.
acterized primarily as CD8+ T lympho-
vascular regression through endothelial EGFRvlll expression is less common (oc-
cytes, with CD4+ lymphocytes present
angiopoetin-2 expression {708,1030}. It curring in 27-33% of cases) {198,678}.
in smaller numbers {227,2184} and with
has been speculated that microscopic Tumours harbouring H3 K27M mutations
B lymphocytes detectable in < 10% of
vaso-occlusion and intravascular throm- (see Diffuse midline glioma, H3 K27M-
cases {2184}. Extensive CD8+ T-cell
bosis may initiate or propagate the devel- mutant, p. 57) can be detected using an
infiltrates may be more common in the
opment of hypoxia and necrosis, given antibody specific for K27M-mutant H3,
tumours of long-term glioblastoma sur-
that thrombi are present near regions of which can be useful in distinguishing
vivors {2813}. Microglia and histiocytes
necrosis in nearly all glioblastomas (but these neoplasms from other astrocytic
are also present in glioblastomas {1494,
not in lower-grade, non-necrotic astro- tumours {2644}. Some glioblastomas
2162}, although lipid-laden histiocytes are
cytomas) and are often observed within (i.e. IDH-mutant glioblastomas) express
uncommon in untreated glioblastomas.
or emerging from palisades {264,2529}. R132H-mutant IDH1, but the presence
In this proposed sequence, hypoxia- Immunophenotype of R132H-mutant IDH1 expression is
induced cell migration away from cen- Glioblastomas often express GFAP, but not compatible with a diagnosis of IDH-
tral hypoxia establishes the palisading the degree of reactivity differs markedly wildtype glioblastoma.
structures, which subsequently develop between cases; for example, gemisto-
Cell of origin
into increasingly larger regions of central cytic areas are frequently strongly posi-
The cellular origin of glioblastoma re-
necrosis and continue to expand radially tive, whereas primitive cellular compo-
mains unknown. The expression of mark-
outward {2170}. nents are often negative. The gliomatous
ers of differentiated astrocytes by glio-
component of gliosarcoma may show
Apoptosis blastoma cells has long been considered
expression of GFAP, as opposed to ab-
Apoptosis, the programmed death of to indicate the dedifferentiation of the
sent or meagre focal expression in the
individual cells, is a cell-intrinsic process cells after transformation. More recently,
sarcomatous component, which may
characterized by nuclear fragmentation the cellular, biochemical, and genetic
express alpha-1-antitrypsin, alpha-1-an-
and condensation, with packaging of heterogeneity that typify glioblastoma, to-
tichymotrypsin, actin, and EMA. S100
apoptotic bodies within an intact mem- gether with the distinct clinical responses
protein is also typically expressed in
brane. The process is initiated through of histologically similar tumours, has led

38 Diffuse gliomas
to the hypothesis that the tumours arise Table 1.01 Genetic profile of IDH-wildtype glioblastomas
from the malignant transformation of ei- Gene Change % of tumours References
ther a bipotential precursor cell {1794} or TERT Mutation 72-90% {622,1268,1270}
an even more primordial cell: the neural
EGFR Amplification 35-45% {350,1823,1895}
stem cell {1616}. This interpretation is
supported by the coincident anatomical CDKN2A Deletion 35-50% {350,1823,1895}

position in the subventricular zone of the TP53 Mutation 28-35% {350,1823,1895}


brain of dividing cells with stem cell-like PTEN Mutation 25-35% {350,1823,1895}
properties and the development of glio-
NFKB1A Deletion 25% {273A}
blastoma. Moreover, cells with stem cell-
like properties have been isolated from NF1 Mutation 15-18% {350,1895}

glioblastoma tumours and cell lines and PIC3CA Mutation 5-15% {350,1288A, 1895}
can be produced by the expression of a PDGFRA Amplification 13% {350}
set of developmental transcription factors
PTPRD Mutation 12% {350}
in glioblastoma cells {2461}. These cells,
called brain tumour stem cells, are only RB1 Mutation 8-12% {350}

a minor subpopulation, but they have the PIK3R1 Mutation 8% {1895}


capacity of self-renewal, express mark- MDM2 Mutation 5-15% {350.2848A}
ers of developmental regulation, and
MDM4 Amplification 7% {350}
are tumorigenic in animals. Therefore,
brain tumour stem cells may be the de- MET Amplification 4% {350}
scendants of neural stem cells that had IDH1 Mutation 0% {1797}
unrepaired DNA damage leading to
IDH2 Mutation 0% {2810}
mutations in cancer genes or that were
subject to an environmental carcinogenic
insult {1112,1756,2230,2365,2650}. Ei- Chromosome 7p gain in combination with Various truncations of EGFR can occur
ther of these initiating events could seed 10q loss is the most frequent genetic al- within the same tumour {732,1906}.
a tumour, given the unlimited growth po- teration in glioblastoma {1079,2072}. This
Receptor tyrosine kinase / PI3K / PTEN /
tential of the neoplastic cells. combination is associated with EGFR
AKT/mTOR pathway
amplification. Allelic loss of the chromo-
Genetic profile Alterations in receptor tyrosine kinase
somal region containing the PTEN gene
signalling pathways occur in nearly 90%
occurs in 75-95% of glioblastomas,
Genetics of glioblastomas {350}. In addition to
whereas PTEN mutations are present in
Malignant transformation of neuroepithe- EGFR alterations, alternate routes to me-
30-44% of cases. Not only is loss of 10q
lial cells is a multistep process driven by diate aberrant receptor tyrosine kinase
the most frequent genetic alteration, but
the sequential acquisition of genetic and signalling include PDGFRA amplification
it also typically co-presents with any of
epigenetic alterations. Of the astrocytic (present in 15% of cases), MET ampli-
the other genetic alterations. Another le-
neoplasms, glioblastoma contains the fication (in 5%) and (in rare cases) the
sion frequently observed in glioblastoma
greatest number of genetic changes. The fusion protein FGFR1-TACC1 or FGFR3-
is the combined gain of 19 and 20 {277}.
following sections focus on so-called pri- TACC3 {2364,2645}. Amplification of the
mary IDH-wildtype glioblastoma, which Epidermal growth factor receptor PDGFRA gene is often associated with
differs in its genetic profile from so-called EGFR is the most frequently amplified gene truncations, the most common of
secondary IDH-mutant glioblastoma (see gene in glioblastomas {764} and is as- which is an in-frame deletion of exons
Glioblastoma, IDH-mutant, p. 52). Many sociated with overexpression; 70-90% 8 and 9 (PDGFRAA8,9) {1869}. EGFR,
of the genetic alterations that are char- of glioblastomas with EGFR overexpres- PDGFRA, and MET amplifications and
acteristic of IDH-wildtype glioblastomas sion show EGFR amplification {198, truncations can occur in different cells
are also present in the majority of WHO 2562}. EGFR amplification occurs in in the same tumour, which could pose
grade II and III IDH-wildtype gliomas, approximately 40% of primary glioblas- a problem for targeted therapies {2385}.
suggesting that these various grades tomas {277,627,1823,2780} but rarely in Mutations and amplifications in PI3K
of IDH-wildtype tumours constitute a secondary glioblastomas {1823,2705}. genes (e.g. PIK3CA and PIK3R1) are in-
continuum of disease and further re- Amplification of the EGFR gene is often frequent in glioblastomas (occurring in
inforcing the necessity of distinguishing associated with gene truncations, most < 10% of cases) {350,1309,1692,1720}.
IDH-wildtype from IDH-mutant diffuse commonly truncation of the gene encod- The PTEN gene is involved in cell prolifer-
gliomas {349}. ing EGFRvlll {2753}, which is present in ation, tumour cell migration, and tumour
20-50% of glioblastomas with EGFR am- cell invasion, and is mutated in 15-40%
Cytogenetics and numerical
plification {198,277,2306,2446}. The pro- of glioblastomas, almost exclusively in
chromosome alterations
tein is structurally and functionally similar primary glioblastomas {277,2562}. The
The most common chromosomal imbal-
to v-erbB and is constitutively activated mutation pattern suggests that PTEN
ances are gain of 7 and loss of 9, 10, and
in a ligand-independent manner {458}. truncation at any site and PTEN missense
13 [http://www.progenetix.net/l94403].

Glioblastoma, IDH-wildtype 39
mutations in the region homologous to rare {993}, and gene promoter methyla- Genetic parameters (p. 28) for discus-
tensin/auxilin and dual-specificity phos- tion correlated with loss of RB1 expres- sion of the steps necessary to designate
phatases are associated with a malignant sion is more common in secondary glio- a glioblastoma as IDH-wildtype.
phenotype. Mutations in the NF1 gene blastomas (occurring in 43% of cases)
Chromatin-related genes
are present in approximately 20% of glio- than in primary glioblastomas (occurring
Mutations in chromatin-remodelling
blastomas {350}. in 14% of cases) {1755}.
genes are common in glioblastomas.
p53/MDM2/p14ARF pathway TERT promoter mutations Paediatric high-grade gliomas also bear
Alterations in the p53 pathway occur in The promoter region of TERT contains signature mutations directly affecting the
nearly 90% of glioblastomas {350}. TP53 two hotspots for point mutations, with histone gene H3F3A and less commonly
mutations are more often genetic hall- most glioblastomas (-80% in one study) HIST1H3B/C. These histone genes have
marks of clinicopathologically defined carrying these mutations {1270}. Within two mutation hotspots, in codons K27
secondary glioblastomas and, in almost IDH-wildtype adult diffuse gliomas, TERT and G34, with K27 mutations more often
all cases, are already present in precur- promoter mutations are inversely corre- found in midline, i.e. brain stem, thala-
sor lower-grade or anaplastic astrocyto- lated with TP53 mutations {1801}. They mus, and spinal cord tumours (see Dif-
mas {2705}. They are significantly less are frequent in IDH1-wildtype glioblasto- fuse midline glioma, H3 K27M-mutant,
common in clinicopathologically defined mas but rare in secondary (IDH1-mutant) p. 57) and G34 alterations in hemispheric
primary glioblastomas (present in -25% glioblastomas and astrocytomas. TERT lesions {1263,2444}. In paediatric high-
of cases) {1823}. G:C>A:T transitions at mutations are also frequent in oligoden- grade gliomas, H3 mutations are asso-
CpG sites are most common {1823}. drogliomas. TERT promoter mutations ciated with mutations in its chaperone
Amplification of MDM2or overexpression lead to the recruitment of multimeric GA- ATRX and are inversely related to IDH
of MDM2 is an alternative mechanism for binding protein (GABP) transcription fac- mutations. ATRX mutations also occur
escaping p53-regulated control of cell tor specifically to the mutant promoter, in adult astrocytomas and glioblastomas
proliferation. Amplification is observed in leading to aberrant TERT expression {277}, particularly in those with IDH muta-
< 10% of glioblastomas without TP53 mu- {159A}. In IDH1-mutant glioblastomas tions {1160,2304,2792}.
tations {2084}. Overexpression of MDM2 and astrocytomas, telomere mainte-
Epigenetics, chromatin, and promoter
has been observed in > 50% of primary nance preferentially uses the alternative
methylation
but only 11% of secondary glioblastomas lengthening of telomeres pathway, which
The interplay between epigenetic regu-
{199}. is activated by mutations in the ATRX
lation and gliomagenesis has several
The CDKN2A locus gives rise to several gene (see Epigenetics, chromatin, and
modalities. Epigenetic modifiers can be
splice variants encoding distinct proteins promoter methylation).
bona fide oncogenes or tumour sup-
(CDKN2A and p14ARF) with tumour-
IDH mutations pressors that are directly affected by
suppressing function. The p14ARF pro-
Mutations of the IDH1 and IDH2 genes, gain- or loss-of-function genetic muta-
tein binds directly to MDM2 and inhibits
which encode IDH1 and IDH2 {1895}, tions, resulting in the disruption of epige-
MDM2-mediated p53 degradation. Loss
are frequent in diffuse astrocytomas, netic regulatory processes by affecting
of p14ARF expression is frequent in glio-
anaplastic astrocytomas, oligodendro- histone modifications, DNA methylation,
blastomas (occurring in 76% of cases),
gliomas, anaplastic oligodendroglio- and chromatin remodelling {2462}. In
and correlates with homozygous deletion
mas, oligoastrocytomas, and anaplastic one study, nearly half of the 291 IDH-
or promoter methylation of the CDKN2A
oligoastrocytomas (occurring in > 70% wildtype glioblastoma samples sub-
gene {1752}.
of cases) {2810}. These mutations are jected to whole-exome sequencing har-
CDKN2A / CDK4 / retinoblastoma present in nearly all glioblastomas that boured one or more non-synonymous
protein pathway have progressed from astrocytomas (i.e. mutations affecting chromatin organiza-
Alterations in the retinoblastoma pro- clinicopathologically defined secondary tion {277}. Even in the absence of direct
tein pathway occur in nearly 80% of all glioblastomas), but they are exceptional genetic alterations, epigenetic modifiers
glioblastomas {350}. In glioblastomas, in primary glioblastomas and absent in can modulate gene expression to directly
CDKN2A deletion and RB1 altera- pilocytic astrocytomas {118,277,2709, regulate glioma-relevant processes such
tions are mutually exclusive {2594}. The 2810}. A clinically primary glioblastoma as glioma stem cell programmes, senes-
CDKN2A locus encodes the CDK4 in- with an IDH1 mutation may be misclas- cence, genome stability, and invasion
hibitor CDKN2A as well as the alternate sified and may actually constitute an {2443,2461}.
reading frame protein p14ARF. Inactiva- asymptomatic lower-grade glioma that One of the key functions of chromatin
tion of genes in this pathway is common has progressed and has only become regulation is to maintain inactive portions
in both primary and secondary glioblas- symptomatic as a secondary glioblas- of the genome in repressive chromatin
tomas {200,1752}. The CDK4 gene is am- toma {1797}. Thus, IDH1 mutations con- structures with a compact organization
plified in approximately 15% of all high- stitute a reliable molecular signature of a refractory to regulatory activity. Canoni-
grade gliomas {1789,2086}, particularly separate group of glioblastomas that may cal repressive states include classic het-
in those without CDKN2A homozygous be synonymous with the secondary type erochromatin marked by H3K27me3, a
deletion {1789}. These homozygous de- {1797}. Notably, the presence of IDH1 mark deposited by PRC2 and its catalytic
letions also involve the nearby CDKN2B mutation is incompatible with the diag- subunit, EZH2. EZH2 is overexpressed in
gene on 9p {2397}. RB1 mutations are nosis of IDH-wildtype glioblastoma. See IDH-wildtype glioblastoma and various

40 Diffuse gliomas
other cancer types, presumably con-
tributing to the silencing of key tumour
Active chromatin Repressive chromatin
suppressor genes {556}. Loss of func-
tion of EZH2 can also promote cancer in
a context-dependent manner. Although
loss-of-function mutations of EZH2 in
IDH-wildtype glioblastoma are rare (oc-
curring in < 1% of cases), studies have
strongly implicated an inhibition of its en-
zymatic activity through a mutation of H3
genes in paediatric glioblastoma {277,
2304,2791}. Apparently, a fine-tuning of
PRC2 activity must be maintained, with
both gain and loss of activity linked to
gliomagenesis. Mutations in ATRX, which Fig. 1.37 Pathways of chromatin organization. DNA methylation, histone modifications, and numerous chromatin
encodes a chromatin remodeller that de- regulators determine the global structure of chromatin and are frequently altered in glioblastoma. Active chromatin (left)

posits H3.3 in pericentromeric and sub- is globally accessible for transcriptional regulation. Repressive chromatin (right) sequesters portions of the genome, is
enriched for characteristic histone modifications, and is refractory to regulatory activity. DNMTs, DNA methyltransferases;
telomeric regions, were observed in 13 of
HDMs, histone demethylases; HMTs, histone methyltransferases; MLL, mixed-lineage leukaemia protein; UTX, histone
291 IDH-wildtype glioblastomas {277}.
demethylase UTX (also called KDM6A). Adapted from Suva ML et al. {2462}.
ATRX mutations are observed in about
60-70% of IDH-mutant gliomas and in
about 30% of paediatric glioblastomas promutagenic alkyl groups from the 06 pilocytic astrocytoma {2124}, anaplastic
{1160,2304,2792}. position of guanine in DNA, thereby astrocytoma {765}, and oligodendroglio-
Within chromatin, both genes and regu- blunting the treatment effects of alkylat- ma {765}; primary glioblastoma from sec-
latory elements are associated with ing agents {653,798}. MGMT promoter ondary glioblastoma {2580}; and IDH-
characteristic chromatin modifications. methylation is common in glioblastoma mutant glioma from IDH-wildtype glioma,
Actively transcribed gene bodies are (present in 40-50% of cases) {277,654, across grades and histology {277,870,
marked by H3K36me3, a mark deposit- 982}, with the percentage varying de- 1810,2444}. Unsupervised analysis of
ed by the methyltransferase SETD2. Rare pending on the assay used {2051}. It is expression profiles can be used to clus-
mutations in SETD2 occur in about 2% of predictive of benefit from therapy with ter glioma into groups that correlate with
IDH-wildtype glioblastoma and are more alkylating agents such as temozolomide histology and grade {886,1812} and may
common in paediatric and IDH-mutant in patients with glioblastoma {982,1577, be a better predictor of patient outcome
gliomas {277,722}. Enhancers and pro- 2742}. A higher frequency of MGMT pro- {645}. A commonly used gene expres-
moters are marked by histone acetylation moter methylation (> 75%) is associated sion-based classification of glioblastoma
and H3K4 methylation. The methylation with glioblastomas that have G-CIMP, defines proneural, neural, classic, and
mark is catalysed by complexes that con- which is characteristic of IDH-mutant mesenchymal subtypes, which correlate
tain the mixed-lineage leukaemia (MLL) gliomas {105,277,1830}. Distinct DNA with genomic alterations including TP53
homologues. Missense mutations in methylation subclasses (three of which mutation, EGFR mutation/amplification,
KMT2B, KMT2C, and KMT2D have been are linked with specific mutations) have and NF1 deletion/mutation {2645}. How-
detected in some cases {2-3%) of IDH- been identified, which is suggestive of di- ever, individual cells characteristic of dif-
wildtype glioblastoma. Histone deacety- verse developmental and pathogenetic/ ferent subtypes can be found within the
lases (HDAC2 and HDAC9) and a range pathoepigenetic origins {277,2444}. Mu- same glioblastoma {1906}.
of histone demethylases (e.g. KDM4D, tations in IDH1 have been causally linked
Genotype-phenotype correlations
KDM5A/B/C, and KDM6A/B) are also in- with G-CIMP and longer survival {1810,
Most cases (> 90%) are glioblastomas
frequently mutated in IDH-wildtype glio- 2589}. Two methylation subtypes are re-
that develop rapidly and de novo (so-
blastoma, broadly affecting chromatin lated to hotspot mutations in H3 genes
called primary glioblastoma), with no
activity. Both histone and DNA demethyl- (H3 K27 and H3 G34), which are most
known less-malignant precursor lesion,
ases are inhibited by the IDH mutations, prevalent in paediatric glioblastomas
often in middle-aged or elderly patients
suggesting that different classes of glio- {2105,2444}. H3F3A G34 is associated
(as opposed to the so-called secondary
mas use different modalities to inactivate with a CpG hypomethylator phenotype
glioblastomas that have IDH1 mutations;
key epigenetic regulators {2443}. {2444}. Cancer-relevant pathways (e.g.
see Glioblastoma, IDH-mutant, p. 52).
In addition to chromatin regulation, epi- the WNT pathway) that contribute to
Glioblastomas in which multinucleated
genetic gene silencing by DNA meth- malignant behaviour and resistance to
giant cells constitute > 5% of the tumour
ylation of their promoters is a common therapy are frequently deregulated by
are associated with frequent TP53 muta-
mechanism of inactivating genes or non- aberrant promoter methylation of genes
tions but infrequent EGFR amplification
coding RNAs with tumour suppressing encoding inhibitory factors {914,1425}.
{1931}, whereas small cell glioblastomas
functions {2010}. The MGMT gene is the
often have EGFR amplification {318}. In
most commonly methylated gene across Expression profiles
younger patients, high-grade gliomas
tumour types {462} and encodes a DNA Gene expression patterns can be
(including glioblastomas) of the brain
repair protein. It specifically removes used to distinguish glioblastoma from

Glioblastoma, IDH-wildtype 41
Paediatric high-grade diffuse Clinicopathological aspects are found exclusively in diffuse midline
astrocytic tumours The annual incidence of paediatric gliomas, whereas H3.3 G34R or (rarely)
Paediatric high-grade diffuse astrocytic glioblastoma (defined by patient age G34V mutations are found exclusively
tumours (WHO grade lll/IV) should be < 20 years at diagnosis) is 0.14 cases in tumours of the cerebral hemispheres
considered, for therapeutic purposes, per 100 000 population; lower than that {2443,2792}, which are more frequently
as a single category encompassing of adult glioblastoma, which is approxi- seen in teenagers and young adults. In
both paediatric glioblastoma and pae- mately 4 per 100 000 {282,1863}. Most contrast, hemispheric glioblastomas in
diatric anaplastic astrocytoma. This ap- diffuse WHO grade II astrocytomas pre- infants harbour NTRK fusions in approx-
proach is supported by our understand- senting in adults eventually progress to imately 40% of cases, and histone mu-
ing of these childhood tumours similar high-grade astrocytomas (anaplastic tations have not been reported. Other
genetic profiles and clinical courses. astrocytoma or glioblastoma). In con- commonly altered genes in hemispheric
Although the histopathologies of paedi- trast, nearly all paediatric high-grade high-grade astrocytomas of childhood
atric high-grade astrocytomas overlap diffuse astrocytic tumours arise de novo, are TP53 (present in 30-50% of cas-
with those of their adult counterparts, rarely deriving from a WHO grade II es), ATRX (in -25%), SETD2 (in -15%),
the two groups have distinct genetic al- astrocytoma. CDKN2A (deletion; in -30%), and
terations {2304,2444,2792}. Unlike adult PDGFRA (amplification and/or mutation;
Genetic aspects
glioblastomas, paediatric high-grade in -30%) {2792}. In contrast, IDH muta-
Recurrent mutations in paediatric
diffuse astrocytic tumours frequently tions, TERT promoter mutations, and
high-grade diffuse astrocytic tumours
arise in the midline of the neuraxis, EGFR mutations/amplifications are rare.
involve genes coding for proteins in-
commonly in the pons (as diffuse pon- Several hereditary tumour syndromes
volved in chromatin and transcription
tine glioma) or the thalamus and rarely predispose paediatric patients to diffuse
regulation, or the receptor tyrosine ki-
in the spinal cord or cerebellum. These astrocytic tumours, including Li-Frau-
nase / RAS / MAPK and/or retinoblas-
diffuse midline gliomas share genetic al- meni syndrome (associated with TP53),
toma protein / p53 pathways. Many of
terations and are discussed separately neurofibromatosis type 1, and constitu-
these genes are also mutated in the
(see Diffuse midline glioma, H3 K27M- tional mismatch repair deficiency.
equivalent adult tumours, but some al-
mutant, p. 57). Distinct from these tu-
terations are particularly associated
mours and from their adult counterparts
with paediatric or adult disease. H3
are the cerebral hemispheric high-grade
variant (H3.1/H3.3) K27M mutations
diffuse astrocytic tumours of childhood.

Table 1.02 Frequent genetic alterations in diffuse


astrocytic tumours: paediatric versus adult disease stem and thalamus often harbour muta- neurofibromatosis type 1, as well as less
Gene class Paediatric tions in histone genes, particularly K27M common syndromes such as Ollier-type
Histone protein H3F3A K27M1
mutations in H3.3 and H3.1 {1263,2444} multiple enchondromatosis {734}. In rare
variants H3F3A G34R/V2 (see Diffuse midline glioma, H3 K27M- cases, patients with L-2-hydroxyglutar-
HIST1H3B K27M mutant, p. 57). Rare glioblastomas or low- ic aciduria have developed malignant
Histone modification SETD23 er-grade astrocytic neoplasms have been brain tumours, including glioblastoma
reported with focal losses of SMARCB1 {928}. Five independent genome-wide
Growth factor ACVRf
expression, often with monosomy 22 and association studies have identified eight
BRAF V600E
epithelioid or rhabdoid cytology {1013, specific heritable risk variants in seven
Cell signalling PDGFRA mutation/ 1299}; these can be called SMARCB1- genes (TERT, EGFR, CCDC26,
amplification deficient glioblastoma. Epithelioid glio- CDKN2B, PHLDB1, TP53, and RTEL1)
Gene class Adult
blastomas often have BRAF V600E mu- associated with an increased risk of
Cell signalling EGFR mutation/amplification tations. Overall, glioblastomas in children glioma {1861}.
Telomere TERT promoter mutation have a genetic profile distinct from that Prognosis and predictive factors
maintenance of glioblastomas in adult patients; the dif- Glioblastoma is an almost invariably fatal
Intermediate IDH1 R132H
ferences between adult- and paediatric- disease, with most patients dying within
metabolism type glioblastomas are discussed sepa- 15-18 months after diagnosis, and < 5%
rately (see the box Paediatric high-grade of patients alive after 5 years {596}. Even
Phosphatase PTEN mutation / biallelic
diffuse astrocytic tumours). in clinical trials with somewhat more fa-
deletion
vourable patient selection, the 5-year
Specific chromo- Gain of chromosome 7 and Genetic susceptibility
survival rates do not exceed 10% {2442}.
some copy number loss of chromosome 10 Glioblastomas sometimes occur in more
Younger age (< 50 years) and complete
alteration than one member of a family. This is
macroscopic tumour resection are asso-
1In tumours of midline (mutation in ~80% of diffuse most often the case within the setting
ciated with longer survival; on a molecu-
intrinsic pontine gliomas), thalamus, and spinal cord. of inherited tumour syndromes such as
lar level, tumours associated with longer
2ln tumours of cerebral hemispheres. Turcot syndrome (in particular Turcot
survival often exhibit two favourable
3ln diffuse intrinsic pontine gliomas only (-20%). syndrome type 1, which is character-
4Both
molecular aberrations: MGMT promoter
alternative lengthening of telomeres and ized by non-polyposis colorectal car-
telomerase re-expression reported.
methylation {2088,2442} and/or IDH mu-
cinoma), Li-Fraumeni syndrome, and
tation {950}.

42 Diffuse gliomas
Table 1.03 IDH-wildtype glioblastoma: genetic susceptibility because of partial blood-brain barrier
Syndrome Gene Chromosome OMIM preservation and high interstitial pressure
Li-Fraumeni* TP53 17p13.1 151623 in the tumour tissue; (2) invasive proper-
ties of glioblastoma cells that enable
L-2-hydroxyglutaric aciduria L2HGDH 14q21.3 236792
them to spread distantly within the CNS
Turcot MLH1, PMS2, MSH2, MSH6 3p21.3, 7p22, 2p22-p21,2p16 276300
and remain behind an intact blood-brain
Neurofibromatosis type 1 NF1 7q12 162200 barrier; (3) retention of DNA repair ma-
Ollier/Maffucci PTHR1 3p21-22 166000 chinery that abrogates the effectiveness
of chemotherapy and radiotherapy; (4)
Glioblastomas associated with Li-Fraumeni syndrome are IDH-mutant.
intratumoural heterogeneity and genomic
instability resulting in clonal populations
Age that these uncertainties will be clarified of resistant cells, making it necessary to
A prospective series {2728} and numer- by molecular-based classifications of identify the driving events on an ongoing
ous clinical trials {439,837,838,2442} such tumours. basis; (5) the presence of a population
have shown that younger patients with of tumour-initiating or stem cell-like cells
Genetic alterations and biomarkers
glioblastoma (those aged < 50 years that may harbour resistance mechanisms
MGMT promoter methylation is a strong
at diagnosis) have a substantially bet- distinct from those of the majority of bulk
predictive marker for the efficacy of and
ter prognosis. In one large population- tumour cells and that may contribute to
response to alkylating and methylating
based study, patient age was a signifi- cellular heterogeneity; and (6) secondary
chemotherapy agents in glioblastoma
cant prognostic factor; the correlation oncogenic changes induced by tumour
{982,2729,2741,2742,2480}. More than
persisted through all of the age groups in progression.
90% of long-term surviving patients with
a linear manner {1823}. Because elderly Besides MGMT promoter methylation,
glioblastoma have a methylated MGMT
patients have an inferior prognosis over- there are no predictive biomarkers {2743}
promoter {2442}, versus only 35% of the
all, distinct and de-escalated treatment that facilitate the tailoring of primary {982,
general population of patients with glio-
strategies favouring a short therapeutic 2741,2742} or secondary {2480,2729}
blastoma {2441}. IDH1 and IDH2 muta-
course and the best quality of life pos- therapies, and MGMT promoter methyla-
tions are positive prognostic factors and
sible are commonly proposed to patients tion is only identified in less than half of
are closely associated with secondary
aged > 65-70 years. However, there is all patients using current assays {2441,
glioblastoma {2810} (see Glioblastoma,
no prospectively validated age cut-off 2743}. Cellular responses to DNA dam-
IDH-mutant, p. 52). There is no consist-
for clinical decisions. Although the fre- age involve distinct DNA repair path-
ent correlation between EGFR amplifica-
quency of MGMT promoter methylation ways, such as mismatch repair and base
tion and survival, regardless of patient
(see Genetic alterations and biomarkers) excision repair. Mismatch repair is criti-
age at clinical manifestation {1823}. Allel-
is stable across the various age groups, cal for mediating the cytotoxic effect of
ic loss of 10q was associated with shorter
recent research has identified molecular 6-O-methylguanine. The mismatch repair
survival in one study {1823}; however, the
profiles associated with paediatric glio- pathway consists of several proteins (i.e.
presence of PTEN mutations is not clear-
blastoma, younger patient age, and sec- MLH1, PMS2, MSH2, MSH3, and MSH6)
ly associated with prognosis {1823,2289,
ondary glioblastoma, and these profiles and corrects errors in DNA base pairing
2374,2728}.
may suggest novel therapeutic targets that occur during DNA replication. De-
{2444,2728}. Mechanisms of treatment response and fects in this system arise in the setting
resistance of alkylating chemotherapy and may re-
Histopathology sult in resistance to such therapy {342,
Glioblastoma is highly resistant to thera-
In general, histopathological features do 2826}, potentially by causing tolerance of
py, with only modest survival increases
not confer significant prognostic informa- the mispairing of 6-O-methylguanine with
achieved in a minority of patients, even
tion, but in some studies, giant cell glio- thymine {2244}, but also through chemo-
after aggressive surgical resection, ex-
blastoma (see Giant cell glioblastoma, therapy-induced mutagenesis {1167}. Te-
ternal beam radiation therapy, and maxi-
p. 46) has been noted to have a some- mozolomide treatment of WHO grade II
mum tolerated doses of chemotherapy
what better prognosis than ordinary glio- gliomas induces a hypermutational state
with agents such as temozolomide or ni-
blastoma {1356,1853}. and causes driver mutations in the ret-
trosoureas, including in conjunction with
Greater extent of necrosis is associated inoblastoma protein and AKT/mTOR
blood stem cell transplantation or use
with shorter survival {126,315,1031}. The pathways {2627}. In one small series,
of transgenic haematopoietic stem cells
presence of necrosis in a high-grade 5 of 6 hypermutated tumours showed
{8}. Over the past several decades, hun-
oligoastrocytic neoplasm confers a pro- de novo mutations in mismatch repair
dreds of clinical trials have achieved only
gnosis consistent with a WHO grade IV genes {2627}.
limited therapeutic success; responders
designation {1667}, but whether the Molecular abnormalities in glioblastoma
have been very rare and trial designs
presence of oligodendroglial features also provide specific mechanisms of
have limited the lessons learned from
in a glioblastoma has prognostic value resistance and susceptibility to therapy.
the failed approaches, including those
relative to other glioblastomas remains Some of the signature genetic alterations
of targeted therapies. The therapeutic
uncertain, with some studies showing a in glioblastoma (e.g. mutations in PTEN,
resistance is due to a variety of factors,
positive association {85,1667} and others TP53, EGFR, NF1, RB1, PIK3CA,
including: (1) uncertain drug delivery
having negative results {983}. It is likely PIK3R1, and IDH1) may be related to
resistance
Glioblastoma, IDH-wildtype 43
may be seen (in particular, decreases
in enhancement and oedema). These
changes reflect the effect of the agents
on the tumour vasculature and may ben-
efit patients symptomatically, but antian-
giogenic agents have not clearly been
shown to improve survival {141,1543}. By
normalizing the tumour vasculature to
some extent, antiangiogenic agents may
also facilitate perfusion and oxidation of
tumours.
Cellular immunotherapy / tumour vaccine
approaches were initiated decades ago,
but to date have had little effect on the
survival of patients with glioblastoma.
However, recent vaccine/immunotherapy
treatment of glioblastoma may be more
promising; for example, against targets
such as cytomegalovirus, the poliovirus
receptor, and EGFRvlll. It is also possible
Fig. 1.38 MGMT promoter methylation (meth) and progression-free survival in glioblastoma patients randomized to that combining vaccine approaches with
treatment with radiotherapy (RT) alone or radiotherapy plus temozolomide (TMZ). Reprinted from Hegi ME et al. {982}. the checkpoint inhibitors discussed be-
low could increase efficacy. The glioblas-
{350,1895}. Inactivation of the p53 path- analyses encompassing the full genome, toma microenvironment shows profound
way leads to defects in apoptosis and epigenome, and transcriptome, or even alterations compared with the normal
cell cycle arrest. Mutations of the retino- the proteome and metabolome, possibly brain microenvironment. Blood-brain
blastoma protein pathway in glioblasto- at the single-cell level {1906}, will be nec- barrier leakage, hypoxia, acidosis, accu-
mas result in failure of appropriate cell essary to identify driving changes that mulation of soluble mediators, and attrac-
cycle arrest. Point mutations of the RAS are accessible to targeted therapeutic tion of stromal cells from the peripheral
genes in glioblastoma are rare, but the approaches. circulation markedly alter the immuno-
RAS pathway is secondarily activated Recently, a population of glioma-initi- biology of gliomas {415}. One compel-
through insulin-like growth factor recep- ating, potentially neural stem cell-like ling explanation is that a pool of particu-
tor, EGFR, and PDGF receptor signalling. glioma cells has been identified in glio- larly resistant and slow-proliferating cells
Downstream events such as silencing blastoma {122,780,2365}. These cells called glioma-initiating cells, perhaps lo-
of the NF1 tumour suppressor gene can are highly tumorigenic in immunosup- cated in a perivascular or hypoxic niche,
also activate the RAS pathway, causing pressed mice, inducing intracranial tu- may act as a source for repopulation of
uncontrolled cellular proliferation. Simi- mours with a much smaller cellular inocu- the bulk tumour, thus complicating im-
larly, the PI3K pathway can be activated lum than do non-stem cell-like glioma munotherapeutic approaches. Glioma-
by abnormal IGF1, epidermal growth fac- cells from glioblastomas. The intracranial initiating cells have been investigated
tor, or PDGF signalling, or downstream tumours induced by these stem cell-like with respect to their immunosuppressive
by abnormalities in the PTEN gene {891, glioma cells have the morphological hall- potential and as a potential target for im-
2432}. These redundant signalling path- marks of glioblastoma. They respond to munotherapy, given that they have anti-
way abnormalities suggest that a sin- treatment with bevacizumab (a neutral- genic properties that are different from
gle, specific, small-molecule signalling- izing antibody to VEGF), and the same those of bulk tumour cells {423}. Mo-
pathway inhibitor could only be effective humanized VEGF-neutralizing antibody lecular mechanisms of immunosuppres-
in treating glioblastoma if it targeted a has achieved a 60-65% response rate in sion involve transforming growth factor
downstream and driving factor. Deter- a phase II trial in recurrent glioblastomas beta, STAT3, PDL1 (which is expressed
mining such an effect may be difficult, {2671}. One of the mechanisms of ra- by many cancer cells and binds to its
without orthotopic patient-derived mod- diation resistance, activation of the DNA receptor PD1 to suppress T-cell prolif-
els or clinical data available to develop checkpoint response, may exist preferen- eration and IL2 production {385}), and
tightly constructed controls. For example, tially in the stem cell-like glioma cell pop- CD276 {1469}. In addition, CTLA4, an
the assumption that testing individual ulation {122}. BMP4 causes a significant immunoglobulin similar to the costimula-
glioblastoma biopsies for EGFRvlll and reduction of stem-like precursor cells of tory protein CD28 that is expressed pref-
PTEN {1634} could potentially enable the human glioblastoma and abolishes their erentially on helper T cells, transduces
identification of patients responsive to the tumour-initiating capacities in vivo. inhibitor signals upon engagement of
EGFR kinase inhibitors is complicated Given the marked vascularity of glio- the costimulatory receptors CD80 and
by the fact that this signature character- blastomas, antiangiogenic agents such CD86, which are expressed on antigen-
izes a poor prognostic subgroup that as bevacizumab and cediranib are now presenting cells {2681}. The kynurenine
currently lacks therapeutic implication widely used for the treatment of these pathway may also be involved in altering
{2614}. This suggests that more intensive tumours. On scans, notable responses the immunobiology within gliomas; for

44 Diffuse gliomas
1. Cross-Resistance 2. Tumor Heterogeneity

3. Cancer Stem Cell Resistance 4. Tumor Microenvironment

Fig. 1.39 Malignant glioma and therapeutic resistance. Glioblastomas are adept at evading inhibition of EGFR receptor function through several possible mechanisms. (1) Brain
tumour cells that are intractable to DNA damage-induced apoptosis may also tolerate apoptotic cues driven by TKI-mediated inhibition of EGFR. Combinatorial therapy using
inhibitors of anti-apoptotic activity may overcome this cross-resistance. (2) Intratumoural diversity within glioblastomas may drive resistance to single agent-based anti-EGFR
therapy due to: RTK co-activation, PTEN deletion/mutations, and tumour cell-tumour cell interactions via secreted molecules. PTEN* denotes mutation. (3) Efflux of EGFR TKIs
and increased genetic stability may lead to the maintenance of cancer stem cell populations and tumour relapse. (4) Enhanced immunosuppression mediated by circulating growth
factors, cytokines, and suppressor T cells can antagonize the systemic immune responses generated by anti-EGFR immunotherapies. Additionally, circulating IL6 in the tumour
microenvironment can facilitate resistance intracellularly via activation of the JAK/STAT3/Bcl-xL pathway. Reprinted from Taylor TE et al. {2526A}.

example, tryptophan is catabolized by


key rate-limiting dioxygenases, chiefly in-
doleamine 2,3-dioxygenase, creating an
immunosuppressive milieu due to deple-
tion of tryptophan and accumulation of
immunosuppressive tryptophan catabo-
lites such as kynurenine {11}.

Glioblastoma, IDH-wildtype 45
Giant cell glioblastoma Ohgaki H. Macroscopy
Kleihues P. Due to its high connective tissue content,
Plate K.H. giant cell glioblastoma may have the
Nakazato Y. gross appearance of a firm, well-
Bigner D.D. circumscribed mass, which can be
mistaken for a metastasis or (when
attached to the dura) ameningioma.
Lesions less rich in connective tissue may
Definition have features more typical of
A rare histological variant of IDH-wildtype glioblastoma {1533}.
glioblastoma, histologically characterized
Microscopy
by bizarre, multinucleated giant cells and
Giant cell glioblastoma is histologically
an occasionally abundant reticulin network.
characterized by numerous
Despite the high degree of anaplasia, gi-
multinucleated giant cells, small fusiform
ant cell glioblastoma is often more circum-
syncytial cells, and a reticulin network
scribed and has a somewhat better pro-
{1584}. The giant cells are often
gnosis than ordinary glioblastoma {1356,
extremely bizarre, can be as large as 0.5
1853}. The genetic profile differs from that
mm in diameter, and can contain
of IDH-wildtype glioblastoma in the high Fig. 1.41 Giant cell glioblastoma. The multinucleated
anywhere from a few nuclei to >20.Giant
frequency of TP53 mutations {1932} and in giant cells are easily recognizable in the smear
cells are often angulated, may contain
AURKB expression {2533}, whereas EGFR preparation {1956}.
prominent nucleoli, and on occasion
amplification is rare.
contain cytoplasmic inclusions. Both
cell glioblastoma (n = 592) was 54.5 years
palisading and large ischaemic necroses
ICD-0 code 9441/3 {1853}. The male-to-female ratio is 1.1-
are observed. Atypical mitoses are
15:1 {1356,1533,1853} .
frequent, but the overall proliferation rate
Grading Localization
is similarto that of ordinary glioblastomas.
The localization of giant cell glioblastoma
Giant cell glioblastoma corresponds histo- A typical,(although vari-able) feature is
issimilar to that of IDH-wildtype
logically to WHO grade IV. the perivascular accumulation of tumour
glioblastoma {1356,1853} .
cells with the formation of a
Epidemiology Clinical features
pseudorosette-like pattern {1533}. Occa-
Giant cell glioblastomas account for < 1% Giant cell glioblastomas develop de novo
sionally, perivascular lymph-ocyte cuffing
of all glioblastomas {1853}, but may be after a short preoperative history and
is observed. Microvascular proliferation is
more common in paediatric populations without clinical or radiological evidence of
not common.
{1356}. Giant cell glioblastoma develops in a less-malignant precursor lesion. The
younger patients than does ordinary glio- symptoms are similar to those of IDH- Immunophenotype
blastoma, with an age distribution covering wildtype glioblastoma. GFAP expression is consistently present,
a wider range, including children {1226, but the level of expression is highly vari-
Imaging
1356,1658,1931}. In a study of 16 430 glio- able. TP53 mutation is present in > 80%
Giant cell glioblastomas are distinctive be-
blastomas in the SEER database of the of all cases, and these tumours typically
cause of their circumscription. They are
United States National Cancer Institute, show marked nuclear accumulation of
often located subcortically in the temporal
the mean age of patients with giant cell p53
and parietal lobes. On CT and MRI, they
glioblastoma (n = 171) was 51 years, sig- can mimic a metastasis.
nificantly younger than that of patients with
glioblastoma (62 years) {1356}. Similarly, in
a SEER-based study of 69 935 glioblasto-
mas, the mean age of patients with giant

Fig. 1.40 Giant cell glioblastoma. The cut surface shows


a multinodular lesion with necrosis and haemosiderin
Fig. 1.42 Multinucleated cells in giant cell glioblastoma. The number of nuclei ranges from a few to > 20.
deposits.

46 Diffuse gliomas
protein {1233,1931}. Neuronal markers
are virtually all negative, unlike in
pleomorphic xanthoastrocytoma {1597}.
Genetic profile
Giant cell glioblastomas do not carry IDH
mutations and are therefore considered
variants of IDH-wildtype glioblastoma.
They are further characterized by
frequent mutations in TP53 (occurring in
75-90% of cases) and PTEN (in 33%),
but typically lack EGFR
amplification/overexpression and
homozygous CDKN2A deletion
{1596,1658,1931,1932}.
These attributes indicate that giant cell
glioblastoma has a hybrid profile, shar-
ing with IDH-wildtype glioblastoma a
short clinical history, the absence of a
less-malignant precursor lesion, and fre-
quent PTEN mutations. Like IDH-mutant
glioblastoma, which typically develops Fig. 1.43 Giant cell glioblastoma. A Most of the tumour cells show strong reactivity for nestin. B The expression of
through progression from a lower-grade GFAP is highly variable. In this case, smaller GFAP-expressing tumour cells form a corona around GFAP-negative
astrocytoma, giant cell glioblastoma has multinucleated giant cells. C High Ki-67/MIB1 proliferation index. The proliferation rate of smaller tumour cells is
a high frequency of TP53 mutations particularly high, whereas multinucleated giant cells are often quiescent. D Prominent reticulin fibre deposition.
{1932}. The level of AURKB expression
at the mRNA and protein levels is
is somewhat better than that of ordinary with ordinary glioblastoma {3.4%) {1356}.
significantly higher in giant cell
glioblastoma {323,1060,1356,1820,1853, Similarly, a study of 67 509 glioblastomas
glioblastomas than in ordinary
2347}. A study of 16430 glioblastomas in in the USA National Cancer Data Base
glioblastomas, and ectopic over-
the SEER database found that the medi- found that patients with giant cell glio-
expression of aurora kinase B induces a
an survival time of patients with giant cell blastoma (n = 592) had a median overall
significant increase in the proportion of
glioblastoma was 11 months, significantly survival of 13.5 months, versus 9.8 and
multinucleated giant cells in TP53-mu-
longer than that of patients with ordinary 8.8 months for patients with ordinary glio-
tant U373-MG (but not TP53-wildtype
glioblastoma {8 months) {1356}. The over- blastoma and gliosarcoma, respectively
U87-MG) malignant glioma cells {2533}.
all 5-year survival rate among patients {1853}.
Prognosis and predictive factors with giant cell glioblastoma was > 10%,
Most giant cell glioblastomas have a significantly higher than that of patients
poor prognosis, but the clinical outcome

Table 1.04 Genetic profiles of histologically defined glioblastoma (GBM) variants; adapted from Oh JE et al. {1819}

Primary GBM Secondary GBM


Gliosarcoma Giant cell GBM
(IDH-wildtype) (IDH-mutant)
Age at GBM diagnosis 59 years 56 years 44 years 43 years

Male-to-female ratio 1.4 1.4 1.6 1.0

Length of clinical history 3.9 months 3.0 months 1.6 months 15.2 months

IDH1/2 mutation 0% 0% 5% 100%

PTEN mutation 24% 41% 33% 5%

ATRX expression loss 0% 0% 19% 100%

TERT mutation 72% 83% 25% 26%

TP53 mutation 23% 25% 84% 74%

Loss of 19q 4% 18% 42% 32%

EGFR amplification 42% 5% 6% 4%

Light blue, typical for IDH-wildtype GBMs; yellow, typical for IDH-mutant GBMs. Giant cell GBM shares characteristics with both GBM types.

Giant cell glioblastoma 47


Gliosarcoma Burger P.C. Spread
Giangaspero F. Like in ordinary glioblastoma, the infil-
Ohgaki H. trative growth of this variant is generally
Biernat W. restricted to the brain parenchyma. In-
vasion of the subarachnoid space is un-
common. Haematogenous spread with
extracranial metastases is rare, but has
been reported {148}.
Definition in patients aged 40-60 years (mean age:
Macroscopy
A variant of IDH-wildtype glioblastoma, 52 years). Rare cases occur in children
Due to its high connective tissue con-
characterized by a biphasic tissue pat- {1228}. Males are more frequently affect-
tent, gliosarcoma has the gross appear-
tern with alternating areas displaying glial ed, with a male-to-female ratio of 1.8:1.
ance of a firm, well-circumscribed mass,
and mesenchymal differentiation.
Localization which can be mistaken for a metastasis
Gliosarcoma principally affects adults.
Gliosarcomas are usually located in the or (when attached to the dura) a menin-
The entity was originally defined as a
cerebral hemispheres, involving the tem- gioma. Lesions less rich in connective
glioblastoma in which the sarcomatous
poral, frontal, parietal, and occipital lobes tissue may have features more typical of
component was the consequence of
in decreasing order of frequency. Rarely, glioblastoma.
malignant transformation of proliferating
gliosarcoma occurs in the posterior fossa
tumour vessels {682}, but there is cy- Microscopy
{1774,1793}, lateral ventricles {2243}, or
togenetic and molecular evidence for a A mixture of gliomatous and sarcoma-
spinal cord {370}. Like standard glioblas-
monoclonal origin of both the glial and tous tissues confers to gliosarcoma a
tomas, some gliosarcomas are multifocal
mesenchymal components. Although striking biphasic tissue pattern. The gli-
{1881}.
usually associated with classic (astro- al portion is astrocytic and anaplastic,
cytic) glioblastoma, gliosarcomas can Clinical features mostly showing the typical features of a
also arise in ependymoma (ependymo- The clinical profile of gliosarcoma is the glioblastoma. Epithelial differentiation,
sarcoma) {2153} and oligodendroglioma same as that of IDH-wildtype glioblas- manifesting as carcinomatous features
(oligosarcoma) {2152}. Gliosarcomas can toma, with symptoms of short duration {1871} with gland-like or adenoid forma-
present de novo or appear during the that reflect the location of the tumour and tions and squamous metaplasia {1250,
post-treatment phase of glioblastoma. increased intracranial pressure. Gliosar- 1734}, occurs in the glial portions of
The prognosis is poor. Occasional cases comas can appear at the time of initial some cases. By definition, the sarcoma-
disseminate systemically and/or pen- presentation of glioblastoma, but many tous component shows signs of malig-
etrate the skull. occur during the post-treatment course nant transformation (e.g. nuclear atypia,
of the disease {939}. mitotic activity, and necrosis) and often
ICD-0 code 9442/3 demonstrates the pattern of a spindle
Imaging
cell sarcoma, with densely packed long
In cases with a predominant sarcomatous
Grading bundles of spindle cells surrounded indi-
component, the tumour presents as a
vidually by reticulin fibres. Occasionally,
Gliosarcoma corresponds histologically well-demarcated hyperdense mass with this component has considerably more
to WHO grade IV. homogeneous contrast enhancement, pleomorphism {779,1774}. A subset of
and may mimic meningioma {2166,2466}. cases show additional lines of mesen-
Epidemiology
In cases with a predominant gliomatous
Gliosarcomas account for approximately chymal differentiation, such as the forma-
component, the radiological features are
2% of all glioblastomas {779}, although tion of cartilage {119}, bone {1608}, os-
similar to those of glioblastomas.
higher frequencies (as high as 8%) have teoid-chondroid tissue {520,973,2487},
also been reported {1713,2242}. The age smooth and striated muscle {1262}, and
distribution is similar to that of glioblasto- even lipomatous features {755}. Primitive
ma overall, with preferential manifestation

Fig. 1.44 Gliosarcoma. Spindle cells, often mitotically Fig. 1.45 Gliosarcoma. Biphasic pattern. Serial sections showing an alternating pattern of (A) GFAP-expressing glioma
active, are a typical feature in smear preparations. tissue and (B) sarcomatous areas that contain reticulin fibres but lack GFAP.
Reprinted from Burger PC {312}.

48 Diffuse gliomas
Fig. 1.46 Gliosarcoma. The gliomatous component shows strong GFAP expression and may be (A) geographically separated from or (B) intermingled with the sarcomatous tumour
cells. C Biphasic tissue pattern denoting reticuiin-rich sarcomatous and reticulin-free gliomatous elements.

neuronal components occur rarely a sarcomatous phenotype {1179,1633}. mutations, but infrequent EGFR ampli-
{2349}. Distinction of the two components In a study using FISH, 2 of 3 gliosarco- fication {7,2095}, suggesting that they
is facilitated by combined histochemical mas showed identical numerical aberra- have a distinct profile, similar to that of
and immunohistochemical staining. Col- tions of chromosomes 10 and 17 in the IDH-wildtype glioblastoma (except for
lagen deposition in the mesenchymal glial and mesenchymal components, the infrequent EGFR amplification). Com-
part is well demonstrated by a trichrome whereas in the third case, trisomy X was parative genomic hybridization in 20
stain. Similarly, reticulin staining shows restricted to the chondrosarcomatous gliosarcomas found that several chromo-
abundant connective tissue fibres in the element {1913}. Similar cytogenetic pat- somal imbalances were common: gains
mesenchymal (but not glial) component. terns were observed in both glial and on chromosomes 7 (present in 75% of
The demonstration of a clearly malignant mesenchymal components in another cases), X {20%), 9q {15%), and 20q {15%)
mesenchymal component negative for study, using FISH, comparative genomic and losses on chromosomes 10 {35%),
GFAP is important to distinguish true glio- hybridization, microsatellite allelic imbal- 9p {35%), and 13q {15%) {7} [http://www.
sarcomas from glioblastomas with florid ance analysis, and cytogenetic analysis progenetix.net/progenetix/l94423]. Simi-
fibroblastic proliferation (desmoplasia) {232}. These results suggested that both lar genetic alterations have been found in
elicited by meningeal invasion. components were derived from neoplas- the gliomatous and mesenchymal com-
tic glial cells. This explanation has been ponents, indicating a monoclonal origin.
Immunophenotype further supported by the observation of Expression of SNAI2, TWIST, MMP2, and
The reticulin-free glial component is posi- p53 immunoreactivity in both tumour MMP9 is characteristic of mesenchymal
tive for GFAP. The mesenchymal com- components {39}. Proof of a monoclonal tumour areas, suggesting that the mech-
ponent is largely negative for GFAP, but origin has been demonstrated in 2 cases anisms involved in epithelial-mesenchy-
isolated positive spindle cells are com- of gliosarcoma in which the gliomatous mal transition in epithelial neoplasms
mon. Staining for R132H-mutant IDH1 and sarcomatous components each may also play roles in mesenchymal
is negative in almost all cases {1183}. contained an identical TP53 mutation differentiation in gliosarcomas {1737}.
Immunopositivity for p53, if present, is {197}. In addition, identical PTEN, TP53, Microarray-based comparative genomic
identified in both glial and mesenchymal and TERT mutations were detected in hybridization analysis in glial and mes-
components {197,1038}. the gliomatous and sarcomatous tumour enchymal tumour areas also suggests
Cell of origin components of other gliosarcoma cases that the mesenchymal components may
Originally, gliosarcoma was thought to {2095,2679}. The monoclonality of the be derived from glial cells with additional
be a collision tumour, with a separate two components of the gliosarcomas genetic alterations in a small proportion
astrocytic component and independent was also confirmed by identification of of gliosarcomas {1736}. See Table 1.04
development of the sarcomatous portion CDKN2A deletion and MDM2 and CDK4 on p. 47.
from the proliferating vessels. Several im- coamplification in both tumour areas
Prognosis and predictive factors
munohistochemical studies seemed to {2095}. These studies strongly support
Large clinical trials have failed to reveal
support this assumption, by demonstrat- the hypothesis that the sarcomatous ar-
any significant differences in outcome
ing immunoreactivity for von Willebrand eas are a result of a phenotypic change
between gliosarcoma and classic glio-
factor {2276}, UEA-I {2370}, and mono- in the glioblastoma cells, rather than an
blastoma {779}. However, there have
histiocytic markers {885,1312}. Another indication of the coincidental develop-
been multiple reports of gliosarcomas
hypothesis was that the sarcomatous ment of two separate neoplasms.
with systemic metastases and even inva-
portion resulted from advanced glioma Genetic profile sion of the skull {148,1902,2302}.
dedifferentiation with subsequent loss Gliosarcoma contains PTEN muta-
of GFAP expression and acquisition of tions, CDKN2A deletions, and TP53

Gliosarcoma 49
Epithelioid glioblastoma Ellison D.W. astrocytoma has been identified by bi-
Kleinschmidt-DeMasters B.K. opsy as pre-existent or coexistent with
Park S.-H. the epithelioid tumour {285,1297,1735,
1795,1977}. The fact that anaplastic pro-
gression of a pleomorphic xanthoastro-
cytoma can manifest as an epithelioid
glioblastoma raises the possibility that
the two entities may be related, an asso-
Definition ciation reinforced by their sharing a high
A high-grade diffuse astrocytic tumour frequency of BRAF V600E mutation {48,
variant with a dominant population of 2508}.
closely packed epithelioid cells, some Approximately 50% of epithelioid glio-
rhabdoid cells, mitotic activity, microvas- blastomas harbour a BRAF V600E mu-
cular proliferation, and necrosis. tation, but it is unknown what genetic
Epithelioid glioblastomas occur predomi- mechanism(s) might be responsible for
nantly in young adults and children, are the emergence of epithelioid morphology
preferentially located in the cerebrum or di- in the remainder. One microarray-based
encephalon, and are aggressive tumours comparative genomic hybridization study
with short survival, particularly in children. of a coexistent diffuse astrocytoma and
Compared with other glioblastomas, more epithelioid glioblastoma identified three
epithelioid glioblastomas (-50%) contain a copy number alterations observed only
BRAF V600E mutation. in epithelioid tumour cells: a homozygous
Epithelioid glioblastoma is distinct from gli- deletion in LSAMP and heterozygous de-
Fig. 1.47 Epithelioid glioblastoma. Complex abnormali- letions in TENM3 and LRP1B. This result
omas or glioneuronal tumours with a poor-
ties (including solid and cystic areas and focal
ly differentiated SMARCB1-deficient com- awaits independent validation, but sug-
enhancement) usually characterize the MRI.
ponent (which may contain rhabdoid cells gests that BRAF V600E mutation alone
and exhibit a polyimmunophenotype). It is may be permissive but not sufficient for
also distinct from glioblastoma with epi- development of epithelioid phenotype.
thelial metaplasia, which exhibits glandu- ICD-0 code 9440/3
Localization
lar formations and squamous metaplasia.
Grading Epithelioid glioblastomas have been
The term rhabdoid glioblastoma should
described mainly in the cerebral cortex
be avoided. Tumours previously reported Epithelioid glioblastoma corresponds
and diencephalon. Temporal and frontal
as such are either epithelioid glioblasto- histologically to WHO grade IV.
lobes are common sites, but any lobe
mas without evidence of SMARCB1 or
Epidemiology can be affected {285,331,1297,1699}.
SMARCA4 alteration or rare glioblastomas
Incidence data are not yet available for Rare examples occur in the cerebellum,
with a population of SMARCB1-deficient
this uncommon variant, which has been but none have been reported in the spi-
cells, from which the epithelioid glioblasto-
inconsistently defined in various studies. nal cord {1302}.
ma, with its different genetic profile, should
be distinguished. Epithelioid glioblastoma Etiology Clinical features
may coexist with pleomorphic xanthoas- The etiology and cell of origin of epithe- The clinical manifestation of epithelioid
trocytoma, but the relationship between lioid glioblastoma are unknown, but most glioblastoma parallels that of other glio-
epithelioid glioblastoma and malignant cases arise de novo. In several cases of blastomas; most patients present with
progression in pleomorphic xanthoastro- epithelioid glioblastomas with confirmed symptoms and signs of raised intracranial
cytoma requires further clarification. SMARCB1 expression, a low-grade

Fig. 1.48 Epithelioid glioblastoma. A Foci of necrosis are found in most cases. B Tumours may contain cells with an epithelioid, rhabdoid, or gemistocytic morphology.

50 Diffuse gliomas
Fig. 1.49 Epithelioid glioblastoma. A Most tumours contain plentiful GFAP-immunopositive cells, though these may be sparse in others. B Focal cytokeratin expression. EMA may
also be seen. C BRAF V600E mutations are present in about half of cases, and expression of the mutant gene product can be detected by immunohistochemistry.

pressure, although a minority of patients membrane, eosinophilic cytoplasm, a express melan-A, desmin, myoglobin, or
manifest neurological deficit or epilepsy paucity of cytoplasmic processes, and a smooth muscle antigen. SMARCB1 is re-
{331,1297,1699}. Studies rarely suggest laterally positioned nucleus. There is vari- tained throughout the tumour cell popula-
a precursor lesion, but there have been ation in how often cytoplasmic filamen- tion. In cases where it has been sought,
several reports of transformation from tous-like balls are described or sought expression of SMARCA4 has been dem-
pleomorphic xanthoastrocytoma or WHO by electron microscopy, but some rhab- onstrated {285}. Immunohistochemistry
grade II astrocytoma {1297,2508}. doid cells are found in epithelioid glio- using the VE1 antibody that recognizes
blastoma. Less xanthomatous change V600E-mutant BRAF shows reactivity in
Imaging about 50% of epithelioid glioblastomas, a
is seen in epithelioid glioblastoma than
On MRI, epithelioid glioblastoma char- result concordant with sequencing results
in pleomorphic xanthoastrocytoma, al-
acteristically presents as a gadolinium- {1298}.
though exceptional cases have been
enhancing solid mass, occasionally with
noted to contain giant cells {1298}, lipidi-
cysts {285,1297,2508}. Epithelioid glio- Genetic profile
zation {2151}, a desmoplastic response
blastomas are prone to haemorrhage and A BRAF V600E mutation is detected in
{2151}, or cytoplasmic vacuoles {1795}.
often spread through the leptomeninges. about half of all epithelioid glioblastomas
Rosenthal fibres and eosinophilic granu-
{285,1297}. An H3F3A K27M mutation
Spread lar bodies are not features of epithelioid
has been reported in a single epithe-
Epithelioid glioblastomas demonstrate glioblastoma. By definition, squamous
lioid glioblastoma, but other H3F3A and
a tendency to spread throughout the nests, glandular formation, and adenoid
HIST1H3B mutations have not been re-
neuraxis, showing leptomeningeal dis- features are absent {2151}. Necrosis is
ported {285}. Epithelioid glioblastomas
semination in as many as one third of all present, but is usually of the zonal rather
also lack IDH1 and IDH2 mutations.
patients {976,1299,1699,2755}. One re- than palisading type. Some reports have
Copy number alterations in genes in-
ported paediatric tumour spread to the noted a relative paucity of microvascular
volved in high-grade gliomas are oc-
scalp via a shunt device {285}. proliferation, but others have found no
casionally present; EGFR amplification,
substantial difference in the vasculature
Macroscopy homozygous deletion of CDKN2A, and
patterns of epithelioid glioblastoma and
Epithelioid glioblastomas are typically loss of PTEN have been reported, but
classic glioblastoma {285}.
unifocal lesions, although at least one copy number alterations at the PDGFRA,
case with multifocal distribution has Immunophenotype PTEN, and MET loci are rare {285,1297}.
been reported, and metastatic disease Epithelioid glioblastomas show Immunore-
Genetic susceptibility
may occur {788}. Although no feature activity for vimentin and S100. They also
Epithelioid glioblastomas have not been
is pathognomonic on gross examina- show Immunoreactivity for GFAP, although
reported in association with dysgenetic
tion, haemorrhage and necrosis may be it is often patchy and in a few cases entire-
or hereditary tumour syndromes.
prominent. A superficial location, even ly absent from most areas of the tumour.
with dural attachment, has occasionally Some epithelioid glioblastomas express Prognosis and predictive factors
been noted. Leptomeningeal spread is epithelial markers, cytokeratins, and EMA In both adult and paediatric patients, epi-
relatively common. Cyst formation oc- {285,2151}. Because classic glioblasto- thelioid glioblastoma has a particularly poor
curs, but is not a common feature. mas sometimes express cytokeratin AE1/ prognosis, even for a glioblastoma {285,
AE3 or EMA {965,1818}, an epithelial Im- 426,1299}. It demonstrates early progres-
Microscopy munophenotype should not be consid- sion and a median survival of 6.3 months
Epithelioid glioblastomas are dominated ered diagnostic of the epithelioid variant (range: 0.6-82 months) in adults and
by a relatively uniform population of epi- in isolation, without additional morphologi- 5.6 months (range: 1.5-9.7 months) in chil-
thelioid cells showing focal discohesion, cal evidence. Most authors have noted fo- dren, despite various adjuvant therapies.
scant intervening neuropil, a distinct cell cal immunoreactivity for synaptophysin
or NFP. Epithelioid glioblastomas do not

Epithelioid glioblastoma 51
Ohgaki H.
Glioblastoma, IDH-mutant Kleihues P.
Reifenberger G.
Yan H.
von Deimling A. Weller M.
Louis D.N.

Definition
A high-grade glioma with predominantly
astrocytic differentiation; featuring nucle-
ar atypia, cellular pleomorphism (in most
cases), mitotic activity, and typically a dif-
fuse growth pattern, as well as microvas-
cular proliferation and/or necrosis; with a
mutation in either the IDH1 or IDH2 gene.
IDH-mutant glioblastomas account for
approximately 10% of all glioblastomas.
Glioblastomas that develop through
malignant progression from diffuse as-
trocytoma (WHO grade II) or anaplastic
astrocytoma (WHO grade III) are almost
always associated with IDH mutation and
therefore carry the synonym secondary
glioblastoma, IDH-mutant. IDH-mutant
glioblastoma is morphologically indistin-
guishable from IDH-wildtype glioblas-
toma, except for a lesser extent of necro-
sis. IDH-mutant glioblastomas manifest
in younger patients (with a mean patient
age at diagnosis of 45 years), are pref-
Fig. 1.50 Genetic pathways to IDH-wildtype and IDH-mutant glioblastoma. This chart is based on the hypothesis
erentially located in the frontal lobe, and
that IDH-mutant glioblastomas share common glial progenitor cells not only with diffuse and anaplastic astrocytomas,
carry a significantly better prognosis than but also with oligodendrogliomas and anaplastic oligodendrogliomas. Adapted from Ohgaki H and Kleihues P {1830}.
IDH-wildtype glioblastomas {1797,2810}.

Genetic hallmarks grading reflects the natural course of the glioblastoma had a histologically proven
The defining genetic hallmark is the disease rather than response to therapy. prior low-grade glioma {605}. When IDH1
presence of IDH mutations {1895}, Therefore, because most patients even- mutations were used as a genetic mark-
which are associated with a hyper- tually succumb to high-grade disease, er, secondary glioblastomas accounted
methylation phenotype {1810}. These IDH-mutant glioblastomas are designat- for 9% of all glioblastomas at the popula-
mutations are the earliest detectable ed as WHO grade IV. tion level {1797} and for 6-13% of cases
genetic alteration in precursor low- Synonym in hospital-based studies {118,1078,1417,
grade diffuse astrocytoma, indicating 2810}.
that these tumours are derived from Secondary glioblastoma, IDH-mutant Age distribution
common neural precursor cells that At the population level, secondary glio-
differ from those of IDH-wildtype glio- Epidemiology blastomas develop in patients signifi-
blastoma. Additional typical genetic cantly younger (mean: 45 years) than do
Incidence
alterations are TP53 and ATRX muta- primary glioblastomas (mean: 62 years)
Until the discovery of IDH1 mutation as
tions and loss of chromosome arm {1823,1826}. Correspondingly, the mean
a molecular marker, the diagnosis of
10q {1822,1830}. age of patients with /DHI-mutant glio-
secondary glioblastomas was based on
clinical observations (i.e. neuroimaging blastoma is 48 years, significantly youn-
ICD-0 code 9445/3 and/or histological evidence of a preced- ger than that of patients with glioblasto-
ing low-grade or anaplastic astrocytoma) mas that lack IDH1 mutations {61 years)
Grading {1823,1827}. In a population-based study {1797}. Several hospital-based studies
IDH-mutant glioblastoma corresponds in Switzerland, using clinical criteria and have also shown that patients with IDH-
histologically to WHO grade IV. histopathological evidence, only 5% of all mutant glioblastoma were significantly
The prognosis of IDH-mutant glioblasto- glioblastomas diagnosed were second- younger than those with IDH-wildtype
ma is considerably better than that of IDH- ary {1823,1826}. Similarly, another study glioblastoma {214,1078,2810}.
wildtype glioblastoma; however, WHO showed that 19 of 392 cases {5%) of

52 Diffuse gliomas
Table 1.05 Key characteristics of IDH-wildtype and IDH-mutant glioblastoma in adults
Sex distribution
One population-based study of IDH-mu- IDH-wildtype glioblastoma IDH-mutant glioblastoma References

tant glioblastoma found a male-to-female Primary glioblastoma, Secondary glioblastoma,


Synonym {1830}
ratio {1830} that is significantly lower than IDH-wildtype IDH-mutant
seen in patients with IDH-wildtype glio- Not identifiable; Diffuse astrocytoma
Precursor lesion {1827}
blastoma {1823}. In a multicentre study, develops de novo Anaplastic astrocytoma
49 of 618 glioblastomas {7.9%) carried an
Proportion of glioblastomas -90% -10% {1797}
IDH1 mutation, and the male-to-female
ratio was 0.96:1, versus a ratio of 1.63:1 {214,1078,1797,
Median age at diagnosis -62 years -44 years
2103}
for IDH-wildtype glioblastomas {1417}.
Male-to-female ratio 1.42:1 1.05:1 {214,1417,1797}
Localization
Mean length of clinical history 4 months 15 months {1797}
Whereas IDH-wildtype glioblastomas
Median overall survival
show a widespread anatomical distribu-
Surgery + radiotherapy 9.9 months 24 months {1797}
tion, IDH-mutant glioblastomas have a
Surgery + radiotherapy
striking predominance of frontal lobe in- 15 months 31 months {2810}
+ chemotherapy
volvement, in particular in the region sur-
Location Supratentorial Preferentially frontal {1417}
rounding the rostral extension of the lat-
eral ventricles {1417}. This is similar to the Necrosis Extensive Limited {1417}
preferential localization of WHO grade II TERT promoter mutations 72% 26% {1801,1830}
IDH-mutant diffuse astrocytoma {2428}
TP53 mutations 27% 81% {1797}
and IDH-mutant and 1p/19q-codeleted
ATRX mutations Exceptional 71% {1519}
oligodendroglioma {1418,2871}, support-
ing the hypothesis that these gliomas de- EGFR amplification 35% Exceptional {1797}
velop from a distinct population of com- PTEN mutations 24% Exceptional {1797}
mon precursor cells {158,1830}.

Clinical features glioblastoma, IDH-mutant glioblastoma which are hallmarks of IDH-wildtype glio-
presents more frequently with non-en- blastoma, are usually absent.
Clinical history
hancing tumour components on MRI,
The mean length of the clinical history of
with larger size at diagnosis, with lesser Microscopy
patients with clinically diagnosed second-
extent of oedema, and with increased The histological features of IDH-mutant
ary glioblastoma was 16.8 months, sig-
prevalence of cystic and diffuse compo- glioblastomas are similar to those of
nificantly longer than that of patients with IDH-wildtype glioblastomas. However,
nents {644,1417}.
primary glioblastoma {6.3 months) {1823, morphological studies have revealed
1826,1827}. Correspondingly, patients
Macroscopy two significant differences. Areas of is-
with secondary glioblastoma harbour-
Like all glioblastomas, IDH-mutant glio- chaemic and/or palisading necrosis
ing an IDH1 mutation had a much longer
blastomas diffusely infiltrate the brain have been observed in 50% of IDH-
mean clinical history (15.2 months) than
parenchyma, without clear macroscopic mutant glioblastomas, significantly less
did patients with primary IDH-wildtype frequently than in IDH-wildtype glio-
delineation. However, large yellowish ar-
glioblastomas (3.9 months) {1797}. blastomas (90%) {1797}, whereas focal
eas of central necrosis or haemorrhage,

Symptoms
Because IDH-mutant glioblastomas are
preferentially located in the frontal lobe,
behavioural and neurocognitive changes
are likely to predominate, although focal
neurological deficits (e.g. hemiparesis
and aphasia) also frequently occur. Due
to the slow evolution from diffuse astrocy-
toma or anaplastic astrocytoma, tumour-
associated oedema is less extensive and
symptoms of intracranial pressure may
develop less rapidly than in patients with
primary IDH-wildtype glioblastoma.
Imaging
Unlike in IDH-wildtype glioblastoma, Age at diagnosis
large areas of central necrosis are usu-
Fig. 1.51 Cumulative age distribution of glioblastomas with and without IDH1 mutations. Combined data from
ally absent. Compared with IDH-wildtype
Nobusawa S et al. {1797} and Cancer Genome Atlas Research Network {350}.

Glioblastoma, IDH-mutant 53
diagnosis in 385 of 407 cases {95%)
{1797}. In this regard, IDH mutations are
considered to be a defining diagnostic
molecular marker of glioblastomas de-
rived from IDH-mutant diffuse astrocy-
toma or IDH-mutant anaplastic astrocy-
toma that is more objective than clinical
and/or histopathological criteria.
Timing of IDH mutation
IDH mutations are an early event in glio-
magenesis and persist during progres-
sion to IDH-mutant glioblastoma. Analy-
sis of multiple biopsies from the same
patients revealed no cases in which the
IDH1 mutation occurred after the ac-
Fig. 1.52 These MRIs show the typical progression of a frontotemporal IDH1-mutant diffuse astrocytoma (left) to an
quisition of a TP53 mutation {2709}. An
IDH1-mutant secondary glioblastoma (right) over a period of 5 years {1533}. Note the absence of central necrosis.
exception is IDH1 mutations in patients
with Li-Fraumeni syndrome, caused by a
oligodendroglioma-like components are Cell of origin germline TP53 mutation. In this inherited
more common in IDH-mutant glioblasto- Despite their similar histological fea- tumour syndrome, the TP53 mutation is
mas than in IDH-wildtype glioblastomas tures, IDH-mutant glioblastomas and by definition the initial genetic alteration
{54% vs 20%) {1797}. A larger propor- IDH-wildtype glioblastomas seem to be and significantly affects the subsequent
tion of tumour cells with oligodendroglial derived from different precursor cells. acquisition of the IDH1 mutation. The
morphology has also been reported in Secondary glioblastomas, astrocytomas, R132C (CGT->TGT) mutation, which is
IDH1-mutant glioblastomas, in a large and oligodendrogliomas contain IDH uncommon in sporadic cases, was the
study of 618 cases {1417}. mutations, share a preferential frontal lo- only IDH1 mutation found in diffuse as-
cation, and have been hypothesized to trocytomas, anaplastic astrocytomas,
Immunophenotype originate from precursor cells located in and secondary glioblastomas carrying a
The presence of IDH1 R132H (the most (or migrating to) the frontal lobe. In con- TP53 germline mutation {2710}.
frequent IDH1 mutation in oligodendro- trast, IDH-wildtype glioblastomas have
gliomas, astrocytomas, and IDH-mutant more widespread locations. Additional Types of IDH mutation
glioblastomas) can be detected immuno- All reported IDH1 mutations are located
evidence supporting this hypothesis in-
histochemically using an antibody to the at the first or second base of codon 132
cludes the observation that glioblasto-
gene product, R132H-mutant IDH1 {357}. {118,1895,2709}. The most frequent is
mas that are IDH-mutant and those that
Positivity in a glioblastoma is indicative of the R132H (CGT>CAT) mutation, found
are IDH-wildtype develop in patients of
an IDH-mutant glioblastoma, but negativ- in 83-91% of astrocytic and oligoden-
different ages, have a different sex distri-
ity could be due to the presence of one bution, and have a significantly different droglial gliomas {118,2709,2810}. Other
of the less common types of IDH1 mu- mutations are rare, including R132C
clinical outcome {1830}. Their stem cells
tation or an IDH2 mutation {953}. Lack (CGT>TGT; found in 3.6-4.6% of cases),
may also be different; in one study, the
of immunoreactivity could also indicate R132G (in 0.6-3.8%), R132S (in 0.8-
relative content of CD133-positive cells
the presence of a primary IDH-wildtype 2.5%), and R132L (in 0.5-4.4%) {118,
was significantly higher in primary glio-
glioblastoma. 2709,2810}.
blastomas than in secondary glioblasto-
Mutations in the ATRX gene are typically mas, and CD133 expression was associ- The IDH2 gene encodes the only human
present with IDH1/2 mutations and TP53 protein homologous to IDH1 that uses
ated with neurosphere formation only in
mutations in WHO grade II or III diffuse primary glioblastomas {158}.
astrocytomas and IDH-mutant glioblas-
tomas {1160}. Mutations in ATRX result Genetic profile
in lack of expression, which can be dem-
onstrated immunohistochemically {2750}. IDH mutations
Immunohistochemical overexpression of IDH mutations were first reported in 2008
p53 is frequent, reflecting the high fre- {1895}, and the authors noted that mu-
quency of TP53 mutations (present in the tations in IDH1 occurred in a large pro-
vast majority of cases). Overexpression portion of young patients and in most pa-
of EGFR is unusual; EGFR amplification tients with secondary glioblastomas and
is a hallmark of IDH-wildtype glioblas- were associated with an increase in over-
toma. GFAP expression is consistently all survival. In one study, the presence
present, although the level of expression of IDH1 mutations as a genetic marker of Fig. 1.53 Immunohistochemistry of a glioblastoma using

is variable. secondary but not primary glioblastoma an antibody to R132H-mutant IDH1. Note the strong
corresponded to the respective clinical cytoplasmic expression by tumour cells and the lack of
expression in the vasculature.

54 Diffuse gliomas
NADP+ as an electron acceptor. IDH2 studies found that 3-6% of patients with Genetic alterations typical of IDH-
mutations are all located at residue R172, IDH1-mutant glioblastomas clinically di- wildtype glioblastoma include EGFR
which is the analogue of the R132 resi- agnosed as primary were 13-27 years amplification, PTEN mutation, TERT
due in IDH1 {2805}. It is located in the ac- younger than those with glioblasto- promoter mutation, and complete loss
tive site of the enzyme and forms hydro- mas without IDH1 mutations {118,1829, of chromosome 10 {89,752,1801,1823,
gen bonds with the isocitrate substrate. 2561,2810}. The possibility exists that 1827}. Alterations more common in
IDH2 mutations are rare in IDH-mutant these glioblastomas have rapidly pro- secondary IDH-mutant glioblastomas
glioblastoma and located at codon 172 gressed from precursor astrocytomas include TP53 mutations and 19q loss
{2810}, with the R172K mutation being that escaped clinical diagnosis and {1754,1823,1827}. However, until the iden-
the most frequent. were therefore misclassified as primary tification of IDH mutation as a molecular
glioblastomas. marker of secondary glioblastoma {118,
Secondary glioblastomas without IDH 1797,2709,2810}, the patterns of genetic
mutation ATRX mutations alterations, although different, did not en-
The few clinically diagnosed second- Mutations in the ATRX gene cause loss
able unequivocal diagnosis of these two
ary glioblastomas that lack an IDH mu- of expression. They are typically present
glioblastoma subtypes.
tation have infrequent TP53 mutations, with IDH and TP53 mutations in WHO
and patients have a shorter clinical his- grade II IDH-mutant diffuse astrocytoma, Expression profile
tory and a poor prognosis {1797}. Most WHO grade III IDH-mutant anaplastic More than 90% of IDH-mutant glioblas-
secondary glioblastomas lacking IDH1 astrocytoma, and IDH-mutant glioblasto- tomas have a proneural expression sig-
mutations develop through progression mas {1160,1519}. nature, and approximately 30% of glio-
from a WHO grade III anaplastic astro- blastomas with a proneural signature are
Other genetic alterations
cytoma, whereas the majority of second- IDH-mutant {2645}. These findings sug-
Genetic profiling of primary and second-
ary IDH1-mutant glioblastomas progress gest that IDH-mutant glioblastomas are a
ary glioblastomas has shown that the fre-
from a WHO grade II diffuse astrocytoma relatively homogeneous group of gliomas,
quency of TP53 mutations is significantly
{1797}. Therefore, some tumours diag- characterized by a proneural expression
higher in secondary glioblastomas {67%) pattern. IDH-mutant diffuse astrocytoma
nosed as anaplastic astrocytoma may
than in primary glioblastomas {11%)
actually have been primary glioblasto- and IDH-mutant and 1p/19q-codeleted
{2705}. EGFR overexpression prevails
mas misdiagnosed due to a sampling oligodendroglioma also have the typical
in glioblastomas that are IDH-wildtype
error. proneural signature {496}, further sup-
but is rare in secondary glioblastomas
porting the assumption that these neo-
Primary glioblastomas with IDH mutation {2705}. In one study, only 1 of 49 glio-
plasms share common neural progenitor
In a population-based study, only 14 of blastomas showed both TP53 mutation cells. In contrast, IDH-wildtype glioblas-
4D7 glioblastomas {3.4%) clinically diag- and EGFR overexpression, suggesting
tomas are heterogeneous, with several
nosed as primary carried an IDH1 mu- that these alterations are mutually exclu-
distinct expression profiles.
tation. The patients were approximately sive events that could define two differ-
10 years younger than patients with sec- ent genetic pathways in the evolution of Hypermethylation phenotype
ondary glioblastomas, but the genetic glioblastoma {2705}. Subsequent studies IDH-mutant glioblastomas show con-
profiles of the two tumour groups were provided evidence that primary and sec- certed CpG island methylation at many
similar, including frequent TP53 muta- ondary glioblastomas develop through loci {1810}. A similar hypermethyla-
tions and absence of EGFR amplification distinct genetic pathways. tion phenotype has been observed in
{1797}. Similarly, several hospital-based IDH-mutant diffuse astrocytomas {454}

Fig. 1.54 A Cumulative survival rate of patients with glioblastoma treated with surgery plus radiotherapy. Note that patients carrying an IDH1 mutation had significantly longer overall
survival survival. Reprinted from NobusawaSetal.{1797}. B In a more recent study, the median survival was 31 months for 14 patients with mutated IDH1 or IDH2, versus 15 months for
115 patients with wildtype IDH1 or IDH2. For patients with IDH-mutant glioblastomas, survival was calculated from the date of the secondary diagnosis. Reprinted from Yan H et al. {2810}.

Glioblastoma, IDH-mutant 55
and oligodendrogliomas {454}, as well as neural precursor cells that already carry
in IDH-mutant acute myeloid leukaemia a germline TP53 mutation.
{706}. The introduction of mutant IDH1 Glioblastoma, NOS
Prognosis and predictive factors
into primary human astrocytes alters spe-
In his pioneering work on glioblastomas, Definition
cific histone markers and induces exten-
H-J Scherer {2265} wrote, in 1940: From A high-grade glioma with predominantly
sive DNA hypermethylation, suggesting
a biological and clinical point of view, the astrocytic differentiation; featuring nucle-
that the presence of an IDH1 mutation is
secondary glioblastomas developing in ar atypia, cellular pleomorphism (in most
sufficient to establish a hypermethylation
astrocytomas must be distinguished from cases), mitotic activity, and typically a
phenotype {2589}. Moreover, IDH muta-
primary glioblastomas. They are prob- diffuse growth pattern, as well as micro-
tions disrupt chromosomal topology and
ably responsible for most of the glioblas- vascular proliferation and/or necrosis; in
thus allow aberrant chromosomal regula-
tomas of long clinical duration' mentioned which IDH mutation status has not been
tory interactions that induce oncogene
in the literature." This early observation fully assessed.
expression, including glioma oncogenes
has been repeatedly confirmed. In a Determination of IDH mutation status
such as PDGFRA {713A}.
1980-1994 population-based study, the is important for all glioblastomas; how-
Genetic susceptibility median overall survival of patients with ever, if full testing is not possible (see
Astrocytic gliomas, including diffuse as- clinically diagnosed secondary glioblas- Genetic parameters in Glioblastoma,
trocytomas, anaplastic astrocytomas, toma was 7.8 months, significantly longer IDH-wildtype, p. 28), the diagnosis of
and secondary glioblastomas, are the than that of patients with primary glio- glioblastoma, NOS, can be made, pro-
most frequent brain tumours associated blastoma {4.7 months) {1823}. Similarly, vided that the histological variants giant
with TP53 germline mutations in fami- the analysis of patients who were treated cell glioblastoma, gliosarcoma, and epi-
lies with Li-Fraumeni syndrome {1294, with surgery and radiotherapy showed thelioid glioblastoma can be ruled out.
1841}. In patients from three families that the mean overall survival of patients
with Li-Fraumeni syndrome, IDH1 mu- with IDH-mutant glioblastomas was ICD-O code 9440/3
tations were observed in 5 astrocytic 27.1 months, 2.4 times as long as that of
Grading
gliomas that developed in carriers of a patients with IDH-wildtype glioblastoma
Glioblastoma, NOS, and its variants (e.g.
TP53 germline mutation. All 5 contained {11.3 months) {1797}. In another study,
giant cell glioblastoma that cannot be
the R132C (CGTTGT) mutation {2710}, patients with IDH-mutant glioblastomas
tested for IDH mutation status) corre-
which in sporadic astrocytic tumours ac- treated with radiotherapy/chemotherapy
spond histologically to WHO grade IV.
counts for < 5% of all IDH1 mutations had an overall survival time of 31 months,
overall {118,2709,2810}. This remark- twice as long as that of patients with IDH-
ably selective occurrence suggests wildtype glioblastoma {2810}.
a preference for R132C mutations in

56 Diffuse gliomas
Hawkins C.
Diffuse midline glioma, Ellison D.W.
Sturm D.
H3 K27M-mutant

Definition glioma (DIPG), respectively. Mitotic ac-


An infiltrative midline high-grade glioma tivity is present in most cases, but is not
with predominantly astrocytic differentia- necessary for diagnosis; microvascular
tion and a K27M mutation in either H3F3A proliferation and necrosis may be seen.
/-HIST1H3B/C. Tumour cells diffusely infiltrate adjacent
H3 K27M-mutant diffuse midline glioma and distant brain structures. The progno-
predominates in children but can also be sis is poor, despite current therapies, with
seen in adults, with the most common lo- a 2-year survival rate of < 10%.
cations being brain stem, thalamus, and
ICD-0 code 9385/3
spinal cord. Brain stem and pontine ex- Fig. 1.56 Location of diffuse midline gliomas, H3 K27M-

amples were previously known as brain mutant. Pontine gliomas manifest primarily in children,

stem glioma and diffuse intrinsic pontine whereas spinal cord lesions predominantly affect adults.
Reprinted from Solomon DA et al. {2392A}.

Grading
H3 K27M-mutant diffuse midline glioma
corresponds to WHO grade IV.
Epidemiology
Incidence data on diffuse gliomas specif-
ically arising in midline structures are not
available, because large brain tumour
registries have not yet included these as
a distinct category. The median patient
age at diagnosis of diffuse midline glioma
is 5-11 years, with pontine tumours aris-
ing earlier on average (at ~7 years) than
their thalamic counterparts (at ~11 years).
There is no clear sex predilection {1229,
1358,1863,2700,2776}.
Localization
Diffuse midline gliomas typically arise
in the pons, thalamus, or spinal cord,
with occasional examples involving the
cerebellum.
Clinical features
Most patients with DIPG present with
brain stem dysfunction or cerebrospinal
fluid obstruction, typically developing
over a short period of time {1-2 months).
Classic clinical symptoms include the tri-
ad of multiple cranial neuropathies, long
tract signs, and ataxia {2700}. With tha-
lamic gliomas, common initial symptoms
include signs of increased intracranial
Fig. 1.55 H3 K27M-mutant diffuse midline glioma. A Sagittal T2-weighted MRI showing a diffusely infiltrating
pressure, motor weakness/hemiparesis,
pontine glioma expanding the pons with crowding of the neural structures at the craniocervical junction and tonsillar and gait disturbance {1358}.
herniation to the level of the C1 posterior arch. B Axial FLAIR MRI demonstrates a diffusely infiltrating pontine glioma
Imaging
expanding the pons and encasing the basilar artery. C Axial FLAIR MRI shows an expansile left thalamic glioma and
associated obstructive hydrocephalus, with mild to moderate dilatation of the lateral ventricles, periventricular oedema,
On MRI, diffuse midline gliomas are
and distortion of the third ventricle. D Expansile thalamic glioma showing heterogeneous enhancement on the post-
gadolinium coronal T1 sequence.

Diffuse midline glioma, H3 K27M-mutant 57


usually T1-hypointense and T2-hyperin- synaptophysin immunoreactivity can be
tense. Contrast enhancement, necrosis, focal, but chromogranin-A and NeuN are
and/or haemorrhage may be present. not typically expressed. An H3F3A K27M
DIPG typically presents as a large, ex- mutation can be detected by immuno-
pansile, and often asymmetrical brain histochemistry using a mutation-specific
stem mass occupying more than two antibody. Nuclear p53 immunopositivity
thirds of the pons {2700}. There may be may be present, suggesting an under-
an exophytic component encasing the lying TP53 mutation, which is present in
basilar artery or protruding into the fourth about 50% of cases. In about 10-15% of
ventricle. Infiltration into the cerebellar cases, an ATRX mutation leads to loss of
peduncles, the cerebellar hemispheres, Fig. 1.57 Axial section of H3 K27M-mutant diffuse
nuclear ATRX expression.
the midbrain, and the medulla is fre- midline glioma showing expansion of the pons with areas
Cell of origin
quent. Contrast enhancement rarely in- of haemorrhage and yellowish discolouration suggesting
The common (epi)genetic features of
volves > 25% of the tumour volume {135}. necrosis.
diffuse gliomas arising in midline loca-
Spread areas of necrosis or haemorrhage show tions, especially the pons and the thala-
Two large autopsy-based studies have focal discolouration and softening. mus, suggest a distinct developmental
found that leptomeningeal dissemination Microscopy origin {1175,2443}. Examination of the
of DIPG occurs in about 40% of cases Diffuse midline gliomas infiltrate grey and spatiotemporal distribution of neural pre-
{304,2831}. Diffuse tumour invasion of white matter structures. The tumour cells cursor cells in the human brain stem in-
the brain stem is common among DIPGs, are generally small and monomorphic, dicated a nestin- and OLIG2-expressing
with 25% spreading to involve the upper but can be large and pleomorphic. They neural precursor-like cell population in
cervical cord and thalamus as well {304, typically have an astrocytic morphology, the ventral pons, which has been pro-
362,2831}. Some patients exhibit distal although oligodendroglial morphology is posed as the possible cell of origin of
spread as far as the frontal or (rarely) also a recognized pattern. About 10% of diffuse pontine gliomas {1701}. However,
the occipital lobes, creating some phe- DIPGs lack mitotic figures, microvascu- the exact cell or cells of origin of diffuse
notypic overlap with gliomatosis cerebri. lar proliferation, and necrosis, and thus midline gliomas remain unknown.
No large series of diffuse midline glio- are histologically consistent with WHO
mas centred in the thalamus has been Genetic profile
grade II. The remaining cases are high-
reported, but some cases of gliomatosis grade, with 25% containing mitotic fig- Mutation spectrum
cerebri have been reported to show an ures and the remainder containing mitot- Sequencing studies have identified re-
H3F3A K27M mutation, suggesting that ic figures as well as foci of necrosis and current heterozygous mutations at po-
the thalamic version has a similar tenden- microvascular proliferation. However, for sition K27 in the histone coding genes
cy for diffuse invasion. DIPG, grade does not predict the out- H3F3A, HIST1H3B, and HIST1H3C in
come in genetically classic cases (see high-grade gliomas from the pons (in
Macroscopy
Prognosis and predictive factors). -80% of cases), thalamus (in -50%),
Diffuse infiltration of CNS parenchyma by
and spinal cord (in -60%) {305,721,
tumour cells produces distortion and en- Immunophenotype 2304,2521,2791,2792}. Within the brain,
largement of anatomical structures. Sym- Virtually all tumour cells express NCAM1, these mutations occur exclusively in dif-
metrical or asymmetrical fusiform en- S100, and OLIG2, but immunoreactivity fuse midline gliomas. K27M mutations
largement of the pons is typical in cases for GFAP is variable in these neoplasms. affecting H3.3 (encoded by H3F3A) are
of diffuse pontine glioma. Tumours with MAP2 expression is common, and about three times as prevalent as the

Fig. 1.58 H3 K27M-mutant diffuse midline glioma. A Tumour cells infiltrate and entrap normal brain elements. B High-grade morphological features with focal necrosis.

58 Diffuse gliomas
in TP53, PPM1D, CHEK2, or ATM; occur- Table 1.06 Additional mutations in H3 K27M-mutant

ring in -70% of cases), and to a lesser diffuse midline glioma

extent the retinoblastoma protein path- TP53 mutation 50%

way {305,2521,2792}. Activating muta- PDGFRA amplification 30%


tions or fusions targeting FGFR1 were CDK4/6 or CCND1-3 amplification 20%
specifically identified in a small propor-
ACVR1 mutation 20%
tion of thalamic high-grade gliomas
{10%) {721}. In contrast, recurrent muta- PPM1D mutation 15%

tions in ACVR1, the gene encoding the MYC/PVT1 amplification 15%


BMP receptor ACVR1, were detected in ATRX mutation 15%
Fig. 1.59 Strong nuclear staining for K27M-mutant H3 is
a subset (-20%) of DIPGs, and seem to
CDKN2A/B homozygous deletion <5%
present in tumour cells but not in the vasculature. correlate with H3.1 mutations {305,2521,
2792}.
same mutation in histone variant H3.1
Structuralvariations Genetic susceptibility
(occurring in HIST1H3B or HIST1H3C).
High-level focal amplifications detected Rarely, patients with Li-Fraumeni syn-
The K27M substitution (lysine replaced
in diffuse midline gliomas include ampli- drome or neurofibromatosis type 1 pre-
by methionine at amino acid 27) results in
fication of PDGFRA (in as many as 50% sent with midline infiltrating gliomas, but
a decrease in H3K27me3, thought to be
of DIPGs), MYC/MYCN (in as many as there is no known specific genetic sus-
due to inhibition of PRC2 activity {1480}.
35%), CDK4/6 or CCND1-3(in 20%), ID2 ceptibility for these tumours.
In addition to the specific mutations in
(in 10%), and MET (in 7%), whereas ho-
histone variants H3.3 and H3.1, chro-
mozygous deletion of CDKN2A/B or loss Prognosis and predictive factors
matin regulation is further targeted by
of RB1 or NF1 is detected only very rarely For diffuse midline gliomas in general, the
additional non-recurrent mutations in
(in < 5% of cases). Fusion events involv- finding of an H3 K27M mutation confers
a diverse range of chromatin readers
ing the tyrosine kinase receptor gene a worse prognosis than that of wildtype
and writers, such as members of the
FGFR1 occur in thalamic diffuse gliomas, cases {304,1263}. In diffuse midline glio-
mixed-lineage leukaemia (MLL), lysine-
and a small proportion {4%) of pontine mas arising in the thalamus, high-grade
specific demethylase, and chromodo-
gliomas have been found to carry neu- histology is associated with short overall
main helicase DNA-binding protein fami-
rotrophin receptor (NTRK) fusion genes. survival regardless of histone gene sta-
lies {2792}.
Common broad chromosomal alterations tus. This does not seem to be the case
Other mutations in canonical cancer
include single copy gains of chromo- for tumours with classic clinical and radi-
pathways frequently target the recep-
some 1q and chromosome 2. In addition, ological features arising in the pons, but
tor tyrosine kinase / RAS / PI3K pathway
there may be a subset of pontine gliomas < 10% of these patients survive beyond
(e.g. mutations in PDGFRA, PIK3CA,
(as many as 20%) that harbour few copy 2 years.
PIK3R1, or PTEN; occurring in -50% of
number changes {251,305,2792}.
cases), the p53 pathway (e.g. mutations

Diffuse midline glioma, H3 K27M-mutant 59


Reifenberger G. Cairncross J.G
Oligodendroglioma, IDH-mutant and Collins V.P. Yokoo H.
1p/19q-codeleted Hartmann C.
Hawkins C.
Yip S.
Louis D.N.
Kros J.M.

Genetic classification of analysed with comprehensive molecu-


Definition oligodendroglial tumours lar testing or in which the test results
A diffusely infiltrating, slow-growing gli- In contrast to the 2007 WHO classifica- were inconclusive or uninformative.
oma with IDH1 or IDH2 mutation and tion, the current WHO classification of Rare tumours demonstrate classic oli-
codeletion of chromosomal arms 1p and oligodendrogliomas requires demon- godendroglial histology but lack IDH
19q. stration of IDH1 or IDH2 mutation, typi- mutation and 1p/19q codeletion on
Histologically, IDH-mutant and 1p/19q- cally by immunohistochemistry using molecular testing, a situation most fre-
codeleted oligodendroglioma is com- the mutation-specific antibody against quently encountered in paediatric oligo-
posed of tumour cells morphologically R132H-mutant IDH1 (followed by DNA dendrogliomas. Such tumours should
resembling oligodendrocytes, with iso- genotyping when R132H-mutant IDH1 not be classified as oligodendroglioma,
morphic rounded nuclei and an artefactu- immunostaining is negative), as well as NOS, and must be further evaluated
ally swollen clear cytoplasm on routinely demonstration of 1p/19q codeletion by to exclude histological mimics, such
processed paraffin sections. Microcalci- FISH, chromogenic in situ hybridiza- as dysembryoplastic neuroepithelial
fications and a delicate branching cap- tion, or molecular genetic testing. The tumour, clear cell ependymoma, neu-
illary network are typical. The presence WHO classification does not mandate rocytoma, and pilocytic astrocytoma.
of an astrocytic tumour component is the use of a particular method for mo- Once histological mimics are excluded,
compatible with the diagnosis when mo- lecular testing of these markers, but such tumours can be tentatively clas-
lecular testing reveals the entity-defining recommends that 1p/19q assays be sified as oligodendroglioma lacking
combination of IDH mutation and 1p/19q able to detect whole-arm chromosomal IDH mutation and 1p/19q codeletion
codeletion. The vast majority of IDH- losses. Pathologists should have expe- (paediatric-type oligodendroglioma). In
mutant and 1p/19q-codeleted oligoden- rience with their method of choice and children, most of these tumours seem
drogliomas occur in adult patients, with be aware of potential methodological to belong to a group of paediatric low-
preferential location in the cerebral hemi- and interpretational pitfalls. grade diffuse gliomas that are geneti-
spheres (most frequently in the frontal On the rare occasion that the entity- cally characterized by FGFR1, MYB, or
lobe). defining molecular markers (i.e. IDH MYBL1 alterations (see Oligodendrogli-
mutation and 1p/19q codeletion) can- oma lacking IDH mutation and 1p/19q
ICD-0 code 9450/3 not be fully determined and classic codeletion, p. 68).
histological oligodendroglioma features Tumours demonstrating evidence of
Grading are present, classification of the tumour 1p/19q codeletion but lacking detect-
IDH-mutant and 1p/19q-codeleted oligo- as oligodendroglioma, NOS, is recom- able IDH1 or IDH2 mutations should be
dendroglioma corresponds histologically mended (see Oligodendroglioma, NOS, further evaluated to exclude the possi-
to WHO grade II. p. 69). This diagnosis indicates that the bility of incomplete deletions on 1p and/
Oligodendroglial tumours constitute a tumour is a histologically classic oligo- or 19q. Such alterations may be pres-
continuous spectrum ranging from well- dendroglioma, which will likely exhibit ent in subsets of IDH-wildtype (mostly
differentiated, slow-growing neoplasms a clinical behaviour similar to that of an high-grade) gliomas, including glioblas-
to frankly malignant tumours with rapid IDH-mutant and 1p/19q-codeleted oli- tomas, and have been associated with
growth. The WHO grading system tra- godendroglioma, but that could not be poor outcome.
ditionally distinguished two malignancy
grades for oligodendroglioma: grade II for
well-differentiated tumours and grade III
longer survival of patients with WHO data from a large combined Japanese
for anaplastic tumours. Several studies
grade II versus grade III oligodendro- and The Cancer Genome Atlas (TCGA)
have reported WHO grading as an inde-
glial tumours with concurrent IDH muta- cohort suggest a limited prognostic role
pendent predictor of survival for patients
tion and TERT promoter mutation (with of histological grading in patients with
with oligodendroglial tumours {686,
a median survival of 205.5 months with WHO grade II and III oligodendroglial
830,1446,1826}. However, these studies
grade II tumours versus 127.3 months tumours {2464}. However, interpreta-
did not consider IDH mutation status,
with grade III) {1268}. In contrast, a ret- tion of these retrospective data requires
which is prognostically relevant. A more
rospective analysis of 212 patients with caution, because of the potential bias
recent study confirmed WHO grade II as
IDH-mutant and 1p/19q-codeleted oli- due to lack of inclusion of prognostically
a favourable prognostic factor independ-
godendroglial tumours did not find WHO relevant clinical information (e.g. extent
ent of 1p/19q codeletion in 95 patients
grade to be a significant predictor of of resection) and variable postoperative
with oligodendroglial tumours {2256}.
overall survival {1836}. Similarly, recent treatment of the patients. The current
Other authors have reported significantly
60 Diffuse gliomas
Registry of the United States (CBTRUS), 225 gliomas {2164}. Concurrent HHV6A
the adjusted annual incidence rate of oli- infection and diffuse leptomeningeal oli-
godendroglioma is estimated at 0.26 cas- godendrogliomatosis has been reported
es per 100 000 population {1863}. The in a 2-year-old boy {2445}, and there
incidence rates for anaplastic oligoden- have been reports of isolated cases of
droglioma and oligoastrocytic tumours oligodendroglioma arising in patients
are estimated at 0.11 and 0.21 cases per with immunodeficiency (including pa-
100 000 population, respectively. Oligo- tients with HIV infection) {499} and after
dendroglial tumours account for 1.7% of organ transplantation {2271}. Rare cases
all primary brain tumours (oligodendro- of oligodendroglioma in association with
Fig. 1.60 Cumulative age distribution (both sexes)
gliomas for 1.2% and anaplastic oligo- a demyelinating disease have also been
of 105 cases of IDH-mutant and 1p/19q-codeleted
dendrogliomas for 0.5%) and for 5.9% reported {373}. However, epidemiologi-
oligodendroglioma (mean patient age at diagnosis:
of all gliomas. Oligoastrocytic gliomas cal data do not indicate an increased
44.3 years) and 126 cases of IDH-mutant and 1p/19q-
codeleted anaplastic oligodendroglioma (mean age: 45.7
account for 0.9% of all primary brain tu- incidence of gliomas in patients with au-
years). Combined data from the German Glioma Network
mours and for 3.3% of all gliomas. toimmune disease {990}.
and the University of Heidelberg.
Age and sex distribution Localization
IDH-mutant and 1p/19q-codeleted oligo-
Epidemiological data based on histo-
WHO classification adheres to the prior dendrogliomas arise preferentially in the
logical classification indicate that most of
white matter and cortex of the cerebral
two-tiered histological grading of oligo- these tumours arise in adults, with peak
hemispheres. The frontal lobe is the most
dendroglial tumours, with well-differen- incidence in patients aged 35-44 years
common location (involved in > 50% of
tiated tumours assigned a WHO grade {1826,1863}. Oligodendrogliomas are
all patients) followed in order of decreas-
of II and anaplastic tumours a WHO rare in children, accounting for only 0.8%
ing frequency by the temporal, parietal,
grade of III. Future studies should inves- of all brain tumours in patients aged
tigate whether the traditional histological and occipital lobes. Involvement of more
< 15 years and 1.8% in adolescents
than one cerebral lobe or bilateral tumour
grading criteria should be modified and/ aged 15-19 years {1863}, with paediatric
spread is not uncommon. Rare loca-
or complemented by molecular marker oligodendrogliomas frequently lacking
tions include the posterior fossa, basal
assessments, such as CDKN2A dele- IDH mutation and 1p/19q codeletion (see
ganglia, and brain stem. Leptomenin-
tion or TCF12 mutation, which has been Oligodendroglioma lacking IDH muta-
geal spread is seen in only a minority of
linked to clinically aggressive behaviour tion and 1p/19q codeletion, p. 68). With
in IDH-mutant and 1p/19q-codeleted oli- patients {2163}. There have been rare
rare exceptions, children with 1p/19q-
cases of primary leptomeningeal oligo-
godendroglioma {1407}. codeleted oligodendroglioma are usually
dendrogliomas {1775} or oligodendroglial
older than 15 years at diagnosis {2157}.
Historical annotation gliomatosis cerebri {2489}. Primary oli-
Overall, men are affected more frequently
The first description of an oligodendro- godendrogliomas of the spinal cord are
than women, with a male-to-female ratio
glioma was published by Bailey and rare, accounting for only 1.5% of all oligo-
of 1.3:1 {1863}. In the USA, oligodendro-
Cushing {108} in 1926. This publication dendrogliomas and 2% of all spinal cord
glioma is more common in Whites than
was followed in 1929 by the classic pa- tumours {729}. Rare cases of primary
in Blacks, with an incidence rate ratio of
per by Bailey and Bucy {107}, Oligo- spinal intramedullary oligodendroglioma
2.5:1 {1863}.
dendrogliomas of the brain. The asso- and secondary meningeal dissemination
ciation between 1p/19q codeletion and Etiology have been reported, including a 1p/19q-
oligodendroglial histology was reported Rare cases of oligodendroglial tumours codeleted tumour {898}. Isolated cases
in 1994 {2091} and 1995 {161,1359}, fol- diagnosed after brain irradiation for oth- of oligodendroglioma arising in ovarian
lowed in 2008 {118} and 2009 {2810} by er reasons have been documented {49, teratomas have been reported, although
the first reports on IDH mutation. 600}. Although oligodendrogliomas and there was no assessment of IDH muta-
oligoastrocytomas are among the most tion and 1p/19q codeletion status {2592}.
Epidemiology
frequent types of CNS tumours induced
Note that these and the following para- Clinical features
experimentally in rats by chemical car-
graphs mostly refer to epidemiological Approximately two thirds of patients pres-
cinogens such as ethylnitrosourea and
and clinical data based on histological tu- ent with seizures {1680}. Other common
methylnitrosourea, there is no convincing
mour classification according to the pre- presenting symptoms include headache
evidence of an etiological role for these
vious WHO classification. For the most and other signs of increased intracranial
substances in human gliomas. Similarly,
part, this information can be considered pressure, focal neurological deficits, and
the existence of a viral etiology of oligo-
to be similar for the newly defined entity cognitive or mental changes {1446,1845}.
dendroglioma is uncertain. Polyomavirus
of IDH-mutant and 1p/19q-codeleted oli- In older studies, durations of > 5 years
(SV40, BK virus, and JC virus) genome
godendroglioma, as well as for oligoden- between the onset of symptoms and
sequences and proteins have been de-
droglioma, NOS. diagnosis were common, but modern
tected in oligodendrogliomas {570} and a
neuroimaging has markedly reduced the
Incidence case of oligoastrocytoma {2099}. Howev-
time to diagnosis {1845}.
According to the Central Brain Tumor er, other authors found no frequent poly-
omavirus sequences in a large series of

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted 61


Fig. 1.61 A Recurrent oligodendroglioma with bilateral, diffuse infiltration of the frontal and temporal lobes. B Small Fig. 1.62 Oligodendroglioma (OL) of the temporal lobe
oligodendroglioma of the medial basal ganglia, compressing the right lateral ventricle. Note the homogeneous cut with infiltration of the hippocampus (HC). Note the zone of
surface. calcification (arrowheads) at the periphery of the lesion.

Imaging structures, brain stem, cerebellum, and cellular tumours. Areas of increased cel-
On CT, IDH-mutant and 1p/19q-codelet- spinal cord {2489}. lularity, often in the form of circumscribed
ed oligodendrogliomas usually present nodules, can occur in some otherwise
Macroscopy
as hypodense or isodense well-demar- well-differentiated tumours, so wide sam-
Oligodendroglioma usually presents as a
cated mass lesions, typically located in pling of resection specimens is required.
relatively well-defined, soft, greyish-pink
the cortex and subcortical white matter. However, small biopsies sometimes show
mass. The tumour is typically located in only scattered oligodendroglioma cells
Calcification is common but not diagnos-
the cortex and white matter, leading to
tic. MRI shows a lesion that is T1-hypoin- infiltrating the brain parenchyma, which
blurring of the grey matter-white mat-
tense and T2-hyperintense. The lesion is are identifiable by their characteristic nu-
ter boundary. Local invasion into the
usually well demarcated and shows little clei and (if the most common IDH muta-
overlying leptomeninges may be seen.
perifocal oedema {2678}. Some tumours tion is present) by immunostaining for
Calcification is frequent and may impart
show heterogeneous features due to In- R132H-mutant IDH1 (see Immunophe-
a gritty texture to the tumour. Occasion- notype). Classic oligodendroglioma cells
tratumoural haemorrhages and/or areas
ally, densely calcified areas may present
of cystic degeneration. Gadolinium en- have uniformly round nuclei that are slight-
as intratumoural stones. Zones of cystic
hancement has been detected in < 20% ly larger than those of normal oligodendro-
degeneration, as well as intratumoural
of WHO grade II oligodendrogliomas but cytes and show an increase in chromatin
haemorrhages, are common. Rare cases
in > 70% of WHO grade III anaplastic density or a delicate salt-and-pepper
with extensive mucoid degeneration look
oligodendrogliomas {1260}. Contrast pattern similar to that of neuroendocrine
gelatinous. tumours. A distinct nuclear membrane is
enhancement in low-grade oligodendro-
gliomas has been associated with less Microscopy often apparent. In routinely formalin-fixed
favourable prognosis {2621}. Demonstra- and paraffin-embedded material, there is
tion of elevated 2-hydroxyglutarate lev- Histopathology a tendency for the tumour cells to undergo
els by MR spectroscopy is a promising Oligodendrogliomas are diffusely infil- degeneration by acute swelling, which re-
new means of non-invasive detection of trating gliomas of moderate cellularity sults in an enlarged rounded cell with a
IDH-mutant gliomas (including oligoden- that in classic cases are composed of well-defined cell membrane and clear
drogliomas) {449}. Differences in certain monomorphic cells with uniform round cytoplasm around a central spherical nu-
features between 1p/19q-codeleted and nuclei and variable perinuclear haloes on cleus. This creates the typical honeycomb
1p/19q-intact low-grade gliomas have paraffin sections (a honeycomb or fried- or fried-egg appearance, which although
been reported on MR spectroscopy {292, egg appearance). Additional features in- artefactual is a helpful diagnostic feature
685,2678}, but reliable discrimination by clude microcalcifications, mucoid/cystic when present. However, this artefact is not
neuroimaging is not yet possible. degeneration, and a dense network of seen in smear preparations or frozen sec-
delicate branching capillaries. Mitotic tions, and may also be absent in rapidly
Spread activity is either absent or low. Nuclear fixed tissue and in paraffin sections made
IDH-mutant and 1p/19q-codeleted oligo- atypia and an occasional mitosis are from frozen material.
dendrogliomas characteristically extend compatible with the diagnosis of a WHO Some oligodendrogliomas contain tu-
into adjacent brain in a diffuse manner. grade II tumour, but brisk mitotic activity, mour cells with the appearance of small
Like other diffuse gliomas, oligodendro- prominent microvascular proliferation, gemistocytes with a rounded belly of
glioma can also (although rarely) mani- and spontaneous necrosis are indica- eccentric cytoplasm that is positive for
fest at initial clinical presentation with a tors of anaplasia, corresponding to WHO GFAP. These cells have been referred
gliomatosis cerebri pattern of extensive grade III (see Anaplastic oligodendrogli- to as minigemistocytes or microgemisto-
involvement of the CNS, with the affected oma, IDH-mutant and 1p/19q-codeleted, cytes. Gliofibrillary oligodendrocytes are
area ranging from most of one cerebral p. 70). typical-looking oligodendroglioma cells
hemisphere (three lobes or more) to both on routine stains but show a thin peri-
cerebral hemispheres with additional Cellular composition
Oligodendrogliomas are moderately nuclear rim of positivity for GFAP {994}.
involvement of the deep grey matter
GFAP-negative mucocytes or even sig-
net ring cells are occasionally seen. Rare

62 Diffuse gliomas
Fig. 1.63 IDH-mutant and 1p/19q-codeleted oligodendroglioma. A Typical honeycomb or fried-egg pattern of oligodendrogliomas: the tumour cells show a clear perinuclear halo
and a sharply delineated plasma membrane; although this feature is an artefact that occurs during tissue processing, it is a hallmark of oligodendroglioma. B Perinuclear clearing.
C Delicate chicken-wire network of branching capillaries. Note the moderate nuclear atypia and occasional microcalcification. D Conspicuous network of branching capillaries.

cases of oligodendroglioma consisting astrocytic morphology is also compatible Mineralization and other degenerative
largely of signet ring cells (called sig- with this diagnosis when molecular test- features
net ring cell oligodendroglioma) have ing confirms IDH mutation and 1p/19q A frequent histological feature is the pres-
been described {1373}, and eosinophilic codeletion; in other words, diffuse glio- ence of microcalcifications (sometimes
granular cells are present in some oligo- mas with oligoastrocytoma histology or associated with blood vessels) within the
dendrogliomas {2498}. Rare cases with with ambiguous histological features tumour tissue proper or in the invaded
neurocytic or ganglioglioma-like differ- should be diagnosed as IDH-mutant and brain. Mineralization along blood vessels
entiation have also been reported {1939, 1p/19q-codeleted oligodendroglioma typically takes the form of small, punctate
1948}. The presence of these various when molecular testing reveals this en- calcifications, whereas microcalcifica-
cellular phenotypes does not preclude tity-defining genotype {349,2464,2731}. tions in the brain (called calcospher-
an oligodendroglioma diagnosis if the Reactive astrocytes are typically scat- ites) tend to be larger, with an irregular
tumour is positive for IDH mutation and tered throughout oligodendrogliomas and sometimes laminated appearance.
1p/19q codeletion. The presence of tu- and may be particularly prominent at the However, this feature is not specific for
mour cells with fibrillar or gemistocytic tumour borders. oligodendroglial tumours, and due to

Fig. 1.64 Immunohistochemical features of IDH-mutant and 1p/19q-codeleted oligodendroglioma. A MAP2. B 0LIG2. C GFAP.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted 63


Fig. 1.65 IDH-mutant and 1p/19q-codeleted oligodendroglioma. A Gliofibrillary oligodendrocytes, GFAP stain. B This oligodendroglioma shows an unusually large number of
minigemistocytes - oligodendroglioma cells with a small globular paranuclear area of strongly GFAP-positive cytoplasm.

generally incomplete tumour sampling, an antibody specific for R132H-mutant oligodendrogliomas {1336}. GFAP and
is sometimes not found in the available IDH1 {360}. Positive R132H-mutant IDH1 vimentin immunostaining is often posi-
tissue sections even when clearly dem- staining greatly facilitates the immuno- tive in the astrocytic-appearing tumour
onstrated on CT. Areas characterized histochemical differential diagnosis of components of IDH-mutant and 1p/19q-
by extracellular mucin deposition and/ oligodendroglioma versus other clear codeleted oligodendrogliomas that his-
or microcyst formation are frequent. Rare cell tumours of the CNS and non-neo- tologically resemble oligoastrocytoma.
tumours are characterized by marked plastic and reactive lesions {356,357}. Cytokeratins are absent, although cer-
desmoplasia {1156}. However, a lack of R132H-mutant IDH1 tain antibody cocktails, such as AE1/
immunopositivity does not exclude oli- AE3, may give false-positive staining due
Vasculature
godendroglioma, given the possibility of to cross-reactivity {1773}.
Oligodendrogliomas typically show a
less common IDH1 and IDH2 mutations Several antigens are specifically ex-
dense network of branching capillaries
that cannot be detected with the R132H- pressed by normal oligodendrocytes in
resembling the pattern of chicken wire. In
mutant IDH1 antibody and instead re- vivo or in vitro, including myelin basic
some cases, the capillary stroma tends
quire DNA sequence analysis. Unlike protein; proteolipid protein; myelin-asso-
to subdivide the tumour into lobules.
most IDH-mutant diffuse astrocytomas, ciated glycoprotein; galactolipids, such
There is a tendency for intratumoural
IDH-mutant and 1p/19q-codeleted oli- as galactocerebroside and galactosul-
haemorrhages.
godendrogliomas typically retain nuclear fatide; certain gangliosides; and several
Growthpattern expression of ATRX {1519,2105}. In addi- enzymes, such as carbonic anhydrase C,
Oligodendrogliomas grow diffusely in tion, IDH-mutant and 1p/19q-codeleted CNP, glycerol-3-phosphate dehydroge-
the cortex and white matter. Within the oligodendrogliomas usually lack wide- nase, and lactate dehydrogenase. How-
cortex, tumour cells tend to form sec- spread nuclear p53 staining, a finding ever, none of these antigens has demon-
ondary structures such as perineuronal consistent with the mutual exclusivity of strated significance as a diagnostically
satellitosis, perivascular aggregates, and TP53 mutation and 1p/19q deletion in useful marker for oligodendrogliomas.
subpial accumulations. Circumscribed IDH-mutant gliomas {349,2464}. Some are not expressed in oligodendro-
leptomeningeal infiltration may induce a Oligodendrogliomas are consistently im- glioma cells (e.g. myelin basic protein
desmoplastic reaction. A rare spongio- munopositive for MAP2, S100 protein, {1746}), some are expressed only in a
blastic growth pattern consists of paral- and LEU7 {221,1746,2087}. MAP2 often minority of cases (e.g. myelin-associated
lel rows of tumour cells with somewhat reveals perinuclear cytoplasmic immu- glycoprotein {1746}, galactocerebroside,
elongated nuclei forming rhythmic pali- nostaining without significant process proteolipid protein, and CNP {2457}), and
sades. Occasionally, perivascular pseu- labelling. However, all three markers some have expression that is not restrict-
dorosettes are seen, although some of are also commonly positive in astrocytic ed to oligodendroglial tumour cells (e.g.
these are a result of perivascular neuropil gliomas. Similarly, the oligodendrocyte carbonic anhydrase C {1747}).
formation within foci of neurocytic differ- lineage-associated transcription fac- Synaptophysin immunoreactivity of re-
entiation {1948}. These patterns are gen- tors OLIG1, OLIG2, and SOX10 are ex- sidual neuropil between the tumour cells
erally present only focally. pressed in oligodendrogliomas but also is frequently seen in oligodendroglial tu-
in other gliomas {121,1500}. GFAP is mours and should not be mistaken for
Immunophenotype detectable in intermingled reactive as- evidence of neuronal or neurocytic dif-
To date, no single immunohistochemical trocytes but can also be found in neo- ferentiation. However, IDH-mutant and
marker has been found that is specific for plastic cells such as minigemistocytes 1p/19q-codeleted oligodendroglioma
oligodendroglial tumour cells. The major- and gliofibrillary oligodendrocytes {994, may contain neoplastic cells that express
ity of oligodendrogliomas demonstrate 2087}. Vimentin is infrequently expressed synaptophysin and/or other neuronal
strong and uniform immunoreactivity with in well-differentiated oligodendroglio- markers, such as NeuN and neurofila-
mas but more often found in anaplastic ments {1939,1948}. Immunostaining for

64 Diffuse gliomas
the proneural alpha-internexin protein is are common in IDH-mutant and 1p/19q- diastase-sensitive periodic acid-Schiff
frequent {607} but cannot substitute as codeleted oligodendrogliomas but positivity, Immunoreactivity for EMA and
a reliable surrogate marker for 1p/19q exceptional in IDH-mutant diffuse as- desmoplakin, and lack of IDH mutation.
codeletion {625}. Similarly, NOGO-A trocytomas. The considerable overlap Metastatic clear cell carcinomas dif-
positivity is typical of, but not exclusive between TERT promoter mutation and fer from oligodendrogliomas in that they
to, 1p/19q-codeleted oligodendroglio- 1p/19q codeletion in IDH-mutant gliomas have sharp tumour borders, are immuno-
mas {1600}. suggests that TERT promoter mutation reactive for cytokeratins and EMA, and
may be useful as a surrogate marker for lack R132H-mutant IDH1 immunostain-
Proliferation
1p/19q codeletion. However, minor sub- ing or other IDH mutations.
Mitotic activity is low or absent in WHO
sets of IDH-mutant and 1p/19q-codelet- In adult patients, the differential diagnosis
grade II oligodendrogliomas. Accord-
ed oligodendrogliomas have been re- with pilocytic astrocytoma rarely poses a
ingly, the Ki-67 proliferation index is usu-
ported to lack TERT promoter mutation, major problem, because foci of classic
ally < 5% (see Prognosis and predictive pilocytic features are usually present in
and some IDH-mutant but 1p/19q-intact
factors). On average, the Ki-67 prolifera-
astrocytomas may carry TERT promoter pilocytic astrocytomas, and IDH muta-
tion index is significantly lower in WHO
mutations {89,1314,1408,2464}. There- tion and 1p/19q deletion are absent.
grade II oligodendrogliomas than in ana-
fore, the general use of TERT promoter Neuroradiological features, such as mid-
plastic oligodendrogliomas. However, a
sequencing instead of 1p/19q codeletion line tumour location and mural nodule/
definitive diagnostic cut-off point cannot
testing is not recommended. Immuno- cyst formation, may also provide helpful
be established, due to marked variability ancillary information. Molecular demon-
histochemical features that may further
in staining results between institutions.
support the differential diagnosis include stration of BRAF fusion genes supports
Nevertheless, interobserver agreement
frequent nuclear p53 immunostaining the diagnosis of pilocytic astrocytoma,
on Ki-67 proliferation index scoring as
and loss of nuclear ATRX expression in although BRAF gain and KIAA1549-
determined by MIB1 monoclonal anti-
diffuse astrocytomas. BRAFfusions have also been reported in
body staining was good when six pathol-
Other neoplastic lesions that can histo- some IDH-mutant and 1p/19q-codeleted
ogists independently reviewed the same oligodendroglial tumours {104,1282}. In
logically mimic oligodendroglioma are
set of MIB1-stained slides from 30 oligo-
clear cell ependymoma, neurocytoma, children, the molecular distinction of oli-
dendrogliomas {2024}. Minigemistocytes
and dysembryoplastic neuroepithelial godendroglioma from pilocytic astrocy-
are reported to be mostly MIB1-negative
tumour. These entities and oligodendro- toma is challenging because paediatric
and thus non-proliferative, whereas gliofi-
gliomas share the feature of neoplastic oligodendrogliomas typically lack com-
brillary oligodendrocytes are more com-
cells with uniform, round nuclei and clear bined IDH mutation and 1p/19q codele-
monly positive {1371}. Other proliferation tion but occasionally demonstrate BRAF
cytoplasm, collectively referred to as
markers, such as PCNA {2096}, TOP2A
oligodendroglial-like cells. In the routine fusion genes (see Oligodendroglioma
{1344}, and MCM2 {2736} have been re-
diagnostic setting, evidence of an IDH lacking IDH mutation and 1p/19q codele-
ported to correlate with WHO grade and
mutation, typically demonstrated by posi- tion, p. 68). This differential diagnosis
survival in patients with oligodendroglial
tive R132H-mutant IDH1 immunostaining, must therefore rely primarily on histologi-
tumours, but do not provide clear advan-
rules out all these differential diagnoses. cal and ancillary radiological features,
tages over MIB1 immunostaining in the unless advanced molecular testing
In the absence of IDH mutation, immu-
routine setting.
nostaining for neuronal markers, in par- methods based on large-scale methyla-
Differential diagnosis ticular diffuse synaptophysin and at least tion and/or mutation profiling that provide
The morphological spectrum of IDH-mu- focal NeuN, provides further evidence entity-specific methylation or mutation
tant and 1p/19q-codeleted oligodendro- for neurocytoma. Similarly, rare cases of profiles can be applied. The differential
gliomas is broad, with some similarities liponeurocytoma are distinguished from diagnosis of diffuse leptomeningeal glio-
to a variety of reactive and neoplastic le- oligodendroglioma by extensive positive neuronal tumour (p. 152) is facilitated by
sions. Macrophage-rich processes such staining for neuronal markers, the ab- the clinical presentation and the charac-
as demyelinating diseases or cerebral in- sence of IDH mutation, and the presence teristic molecular profile, with combined
farcts should be readily distinguished by of lipidized cells resembling adipocytes. KIAA1549-BRAFgene fusion and solitary
immunostaining for macrophage mark- Clear cell ependymomas often show at 1p deletion (or 1p/19q codeletion) but ab-
ers and lack of IDH mutation. Reactive least focal perivascular pseudorosettes sence of IDH mutation {2156}.
changes such as the increased numbers and dot-like or ring-shaped EMA im-
Cell of origin
of oligodendrocytes sometimes seen in munoreactivity. Formation of specific
Although the designation of CNS neo-
partial lobectomy specimens performed glioneuronal elements, absence of IDH
plasms as oligodendroglial tumours
for intractable seizures can also be dis- mutation and 1p/19q codeletion, and (in
could imply histogenesis from cells of the
tinguished by lack of IDH mutation. a subset) eosinophilic granular bodies,
oligodendroglial lineage, the evidence
The differential diagnosis with diffuse a CD34-positive cell population, and/or
supporting this assumption is circum-
astrocytoma relies on histological, immu- BRAF V600E mutation, distinguish dys-
stantial, based solely on morphological
nohistochemical, and molecular features. embryoplastic neuroepithelial tumour
similarities of the neoplastic cells in these
Most importantly, IDH-mutant diffuse from IDH-mutant and 1p/19q-codeleted
tumours to normal oligodendrocytes. It
astrocytomas lack 1p/19q codeletion. oligodendroglioma {414}. A rare differen-
is also unknown whether human oligo-
In addition, TERT promoter mutations tial diagnosis is clear cell meningioma,
dendrogliomas arise from neoplastic
which can be distinguished by abundant

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted 65


Fig. 1.66 IDH-mutant and 1p/19q-codeleted oligodendroglioma. A,B Immunohistochemistry showing the expression of R132H-mutant IDH1 protein. C Retained expression of ATRX
in tumour cell nuclei.

transformation of mature oligodendro- codon 172 mutations are present, with IDH-mutant and 1p/19q-codeleted oligo-
cytes, immature glial precursors, or the proportion of IDH2 mutations being dendrogliomas lack ATRX mutation but
neural stem cells. Experimental data in higher in oligodendroglial gliomas than virtually always carry activating muta-
transgenic mice indicate that gliomas in astrocytic gliomas {953}. Combined tions in the TERT promoter region, lead-
with oligodendroglial histology may origi- whole-arm loss of 1p and 19q is invaria- ing to increased expression of TERT {89,
nate from different cell types in the CNS, bly associated with IDH mutation, indicat- 1270,1314}. In fact, TERT promoter muta-
including neural stem cells, astrocytes, ing that detection of 1p/19q codeletion in tion is strongly associated with 1p/19q
and oligodendrocyte precursor cells the absence of IDH mutation should raise codeletion in IDH-mutant gliomas and
{2872}. An oligodendroglioma-like phe- suspicion of incomplete/partial deletions, is an early event in oligodendroglioma
notype is commonly found in transgenic which have been detected in subsets of development {2464}. However, TERT
brain tumours, despite a variety of target- IDH-wildtype anaplastic astrocytomas promoter mutations are also frequent in
ed cell types and oncogenic events {589, and glioblastomas, with associated poor IDH-wildtype glioblastomas {1270}. Con-
2725}. Some studies have suggested a outcome {2658}. sequently, large-scale sequencing stud-
likely origin of oligodendrogliomas from ies have identified three major groups
NG2-positive and asymmetrical cell divi- Aberrantgenes on 1p or 19q
of cerebral gliomas, with distinct biolo-
sion-defective oligodendroglial progeni- Oligodendroglial tumours have frequent gies and clinical outcomes. These three
tor cells {1954,2449}. However, oligo- mutations in the human homologue of groups are defined, respectively, by IDH
dendroglial precursor cells may give rise the Drosophila capicua gene (CIC) on mutation associated with 1p/19q codele-
to either oligodendroglial or astrocytic 19q13.2 {183,2825}, with the majority of tion and TERT promoter mutation, IDH
gliomas, depending on the genes driv- IDH-mutant and 1p/19q-codeleted oli- mutation associated with TP53 and fre-
ing transformation {1508}, suggesting a godendrogliomas harbouring CIC muta- quent ATRX mutation, and IDH-wildtype
dominance of oncogenic signalling over tions {2219,2464,2825}. A smaller subset status associated with TERT promoter
cell of origin in determining the glioma of these tumours also carries mutations mutation and glioblastoma-associated
phenotype. in the FUBP1 gene on 1 p31.1. One study genomic aberrations {349,2464}.
identified IDH mutation, 1p/19q codele-
Genetic profile Other genetic alterations
tion, and TERT promoter mutation as ear-
Cytogenetics ly genetic changes in oligodendroglioma Mutations in NOTCH1, and less com-
Cytogenetic studies of oligodendro- pathogenesis, whereas CIC mutations monly in other NOTCH pathway genes,
glioma have revealed an unbalanced may appear later in tumour progression have been detected in approximately
translocation between chromosomes 1 {2464}. Other genes on 1p (e.g. CAMTA1, 15% of oligodendrogliomas {349,2464}.
and 19 that results in loss of the der(1;19) CHD5, CITED4, DFFB, DIRAS3, PRDX1, Other less commonly mutated genes in-
(p10;q10) chromosome, causing whole- ATRX, AJAP1, and TP73) and 19q (e.g. clude epigenetic regulator genes such
arm deletions of 1p and 19q, and reten- EMP3, ARHGAP35, PEG3, and ZNF296) as SETD2 and other histone methyltrans-
tion of the del [t({1;19)(q10;p10)] chromo- have been reported to show aberrant ferase genes, as well as genes encoding
some {887,1151}. promoter methylation and/or reduced components of the SWI/SNF chromatin-
expression in IDH-mutant and 1p/19q- remodelling complex {349,2464}. Unlike
IDH mutation and 1p/19q codeletion codeleted oligodendrogliomas {2126}. in IDH-mutant astrocytic tumours, TP53
The entity-defining alteration in oligo- Epigenetic silencing of the pH regulator mutation is usually absent and mutu-
dendrogliomas is concurrent mutation gene SLC9A1 on 1p has been linked to ally exclusive with 1p/19q deletion {349,
of IDH1 or IDH2 and whole-arm deletion lower intracellular pH and attenuation of 2464}.
of 1p and 19q. The vast majority (> 90% acid load recovery in oligodendroglioma
{953}) of IDH mutations in WHO grade II Epigenetic and transcriptional changes
cells, which may contribute to the distinc-
oligodendrogliomas are the IDH1 R132H IDH-mutant and 1p/19q-codeleted oli-
tive biology of IDH-mutant and 1p/19q-
mutation, which is readily detectable by godendrogliomas are characterized by
codeleted oligodendrogliomas {217}.
immunohistochemistry {360}. In < 10% widespread changes in DNA methylation,
of cases, other IDH1 codon 132 or IDH2 TERT promoter mutations leading to concurrent hypermethylation
Unlike IDH-mutant diffuse astrocytomas, of multiple CpG islands, a phenomenon

66 Diffuse gliomas
that is referred to as G-CIMP {1810}. and/or maturation of oligodendroglial child with hereditary non-polyposis colo-
Mechanistically, this phenomenon has cells {2085}. PDGFA and PDGFB, as well rectal cancer and oligodendroglioma
been linked with mutant IDH proteins as the corresponding receptors (PDG- {1642}; and an adolescent with Lynch
producing 2-hydroxyglutarate, which FRA and PDGFRB) are commonly co- syndrome and anaplastic oligodendro-
functions as a competitive inhibitor of expressed in oligodendrogliomas {582}. glioma {978}. One child with retinoblas-
alpha-ketoglutarate-dependent dioxy- However, PDGFRA mutations are rare, toma syndrome and anaplastic oligoden-
genases including histone demethylases and elevated expression seems to be droglioma {16} and identical twins with
and the TET family of 5-rmethylcytosine independent of 1p/19q codeletion {955}. Ollier-type multiple enchondromatosis
hydroxylases {1540,2804}. This in turn The functional role of PDGFB has been and oligodendroglioma have also been
leads to increased histone methylation demonstrated by the induction of oligo- documented {411}.
and G-CIMP {1810,2589}. One study dendrogliomas in transgenic mice with
suggested that CIC mutations cooper- targeted overexpression of this growth Prognosis and predictive factors
ate with IDH mutations to further increase factor in neural stem or progenitor cells
Prognosis
2-hydroxyglutarate levels {443}. In fact, {521,1508}. VEGF and its receptors serve
WHO grade II IDH-mutant and 1p/19q-
DNA methylation profiles in IDH-mutant as angiogenic factors in oligodendroglial
codeleted oligodendrogliomas are typi-
and 1p/19q-codeleted oligodendroglio- tumours, particularly in anaplastic oligo-
cally slow-growing tumours and are asso-
mas differ from those in IDH-mutant but dendrogliomas {402,456}.
ciated with relatively long overall survival.
1p/19q-intact astrocytomas {1723,2464,
Genetic susceptibility A population-based study from Switzer-
2751}, a distinction that has been referred
Most oligodendrogliomas develop spo- land demonstrated a median survival
to as G-CIMP type A versus G-CIMP type
radically, in the absence of an obvi- time of 11.6 years for oligodendroglioma
B {2464}, and can be exploited for clas-
ous familial clustering or a hereditary and 6.6 years for oligoastrocytoma (both
sification purposes (e.g. by 450k meth-
predisposition syndrome. Large-scale defined according to histological criteria
ylation bead array analysis {2751}). As a
genotyping data indicate a strong asso- only), as well as 10-year survival rates of
consequence of G-CIMP, many different
ciation between a low-frequency SNP at 51% and 49%, respectively {1826}. The
genes may be epigenetically inactivated
8q24.21 and increased risk of IDH-mu- CBTRUS has documented 5-year sur-
in oligodendrogliomas, including genes
tant oligodendroglioma and astrocytoma vival rates of 79.5% and 61.1%, as well
on 1p and 19q as well as genes on other
{1152}. Other genetic polymorphisms that as 10-year survival rates of 62.8% and
chromosomes, such as the tumour sup-
have been associated with increased oli- 46.9%, for oligodendroglioma and oli-
pressors CDKN2A, CDKN2B, RB1, and
godendroglioma risk include the GSTT1 goastrocytic glioma, respectively {1863}.
many others {2126}. MGMT promoter hy-
null genotype {1245} and SNPs in the However, survival estimates have varied
permethylation and reduced expression
GLTSCR1 and ERCC2 genes {2814}. markedly. Some single-institution studies
is also common {1733}. At the mRNA lev-
Germline mutations in shelterin com- have documented even longer median
el,' IDH-mutant and 1p/19q-codeleted oli-
plex genes, including the POT1 gene, overall survival times (e.g. > 15 years
godendrogliomas often show a proneural
have been linked to familial oligoden- {1845}) for patients with low-grade oli-
glioblastoma-like gene expression signa-
droglioma {110}. The largest series of godendroglioma, and others have docu-
ture {608,2731}.
non-syndromic familial glioma cases mented shorter median survivals (e.g.
Growthfactorsand receptors published to date comprised 841 pa- 3.5 years {567}). Most of the variability
About half of all WHO grade II oligoden- tients from 376 families with > 2 affected in these studies is likely due to differing
drogliomas and anaplastic oligodendro- family members each {2212}. Within this diagnostic criteria, the absence of mo-
gliomas show strong expression of EGFR cohort, 59 patients {8%) were diagnosed lecular information on IDH mutation and
mRNA and protein in the absence of with WHO grade II oligodendroglioma, 1p/19q codeletion, and differing treat-
EGFR gene amplification {2090}. The si- 29 patients {3.9%) with WHO grade II ment approaches.
multaneous expression of the mRNAs for oligoastrocytoma, 31 patients {4.2%) with Oligodendrogliomas generally recur lo-
the pre-pro forms of EGFR and/or trans- WHO grade III anaplastic oligodendro- cally. Malignant progression of recur-
forming growth factor alpha indicates the glioma, and 12 patients {1.6%) with WHO rence is common, although it takes
possibility of auto-, juxta-, or paracrine grade III anaplastic oligoastrocytoma. longer on average than in diffuse astro-
growth stimulation via the EGFR system Isolated cases of familial oligodendro- cytomas {1121}. Rare cases of gliosar-
{626}. One study reported that high EGFR glioma with 1p/19q codeletion have also coma (so-called oligosarcoma) arising
expression was linked to shorter survival been reported {713,1858}. from IDH-mutant and 1p/19q-codeleted
in patients with 1p/19q-codeleted oligo- Only a few patients with oligodendroglial oligodendroglioma have been reported
dendrogliomas of WHO grade II but long- tumours have been reported in families {1004,2152}. Unusual cases of oligoden-
er survival in patients with WHO grade III with hereditary cancer predisposition droglioma, including 1p/19q-codeleted
anaplastic oligodendrogliomas {1036}. syndromes. These include one patient tumours, have been noted in which the
Several other growth factors (including manifesting ESRCA1 mutation with oligo- patients developed systemic metasta-
basic fibroblast growth factor, platelet- dendroglioma {1165}; one patient with ses, usually at late stages of the disease
derived growth factors, transforming Turcot syndrome, germline PMS2 muta- {1148,1651}. It has been suggested that
growth factor beta, IGF1, and nerve tion, and two metachronous glioblas- oligodendroglial tumours with 1p/19q
growth factor) have been reported to be tomas showing histological features of codeletion may be more prone to extra-
involved in the regulation of proliferation oligodendroglial differentiation {2525}; a neural metastasis despite their generally

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted 67


favourable prognosis {1651}, but this hy- Oligodendroglioma lacking the other 50 cases showed histological
pothesis remains unproven. IDH mutation and 1p/19q codeletion features of other entities, such as pilo-
(paediatric-type oligodendroglioma) cytic astrocytoma, dysembryoplastic
Clinical factors
A small subset of histologically classic neuroepithelial tumour, and oligoas-
Features that have been associated
oligodendrogliomas are found to lack trocytoma {2157}. Of the 50 confirmed
with more favourable outcome include
IDH mutation and 1p/19q codeletion cases of oligodendroglioma with classic
younger patient age at operation, loca- on appropriate molecular testing. This histology, 38 tumours were low-grade
tion in the frontal lobe, presentation with
group includes the majority of oligoden- and 12 tumours were anaplastic. All
seizures, high postoperative Karnofsky
drogliomas in children and adolescents 50 cases were diffusely infiltrating glio-
score, lack of contrast enhancement
{1361,2057,2157}. In these cases, it is mas composed of uniform round cells
on neuroimaging, and macroscopically
important to check carefully for and ex- with perinuclear haloes and formation
complete surgical removal {2621}. One
clude histological mimics that may con- of secondary structures (predominantly
study found that a greater extent of re- tain oligodendrocyte-like tumours cells, perineuronal satellitosis). Calcifications
section was associated with longer over-
in particular dysembryoplastic neuro- and microcysts were also frequent.
all and progression-free survival, but did
ectodermal tumour, extraventricular However, most tumours lacked IDH1
not prolong the time to malignant pro-
neurocytoma, clear cell ependymoma, R132H and 1p/19q codeletion, and his-
gression {2386}.
and pilocytic astrocytoma (see Differ- tological progression was rare {2157}.
Histopathology ential diagnosis). However, differential High-throughput molecular profiling of
The histological features that have been diagnosis can be difficult, because in- paediatric low-grade diffuse gliomas
linked to worse prognosis include ne- dividual tumours can show overlapping revealed duplications of portions of the
crosis, high mitotic activity, increased histological features of related tumours, FGFR1 gene or rearrangements of MYB
cellularity, nuclear atypia, cellular pleo- such as oligodendroglioma, angiocen- in > 50% of cases, including tumours
morphism, and microvascular prolifera- tric glioma, and dysembryoplastic with oligodendroglial or oligoastrocytic
tion (see Anaplastic oligodendroglioma, neuroepithelial tumour {1257}. More- histology {2855}. Rearrangements in
IDH-mutant and 1p/19q-codeleted, over, molecular studies indicate that a the MYB-related MYBL1 transcription
p. 70). However, the prognostic signifi- subset of paediatric oligodendroglio- factor gene have also been reported
cance of each of these histological fea- mas carry the oncogenic BRAF fusion {2068}. These findings indicate that the
tures requires re-evaluation in patients genes {1391} that are typically detected majority of diffuse gliomas in children,
with molecularly characterized IDH-mu- in pilocytic astrocytoma {1176}. Thus, including tumours with oligodendroglial
tant and 1p/19q-codeleted tumours. The paediatric low-grade gliomas seem to or oligoastrocytic histology, are geneti-
presence of minigemistocytes and/or constitute an overlapping spectrum of cally and biologically distinct from their
gliofibrillary oligodendrocytes does not entities that can be difficult to distin- adult counterparts. However, additional
seem to influence survival {1374}. Similar- guish by histological means alone. A studies are needed to comprehensively
ly, marked desmoplasia does not relate careful review of 100 tumours originally characterize the molecular profile of
to distinct outcome {1156}. It is assumed classified as oligodendrogliomas in these rare tumours and to clarify wheth-
that an astrocytic-looking tumour compo- children and adolescents confirmed the er they constitute a distinct entity.
nent within an IDH-mutant and 1p/19q- diagnosis for only 50 tumours, whereas
codeleted oligodendroglioma does not
indicate shorter survival, but this remains an independent prognostic value of the 1216}, but others did not find longer
to be confirmed. Ki-67 proliferation index {604}, whereas progression-free survival when patients
more recent data from patients with ana- were not treated with upfront radiother-
Proliferation plastic oligodendroglioma have shown a apy or chemotherapy {951}. Similarly,
Several single-institution studies have prognostic impact of the index on univari- neither IDH mutation nor MGMT pro-
found that a higher Ki-67 prolifera- ate but not multivariate analysis {2034}. moter methylation were linked to longer
tion index, typically > 3-5%, correlates Among paediatric oligodendrogliomas, progression-free survival in patients with
with worse prognosis in patients with the Ki-67 proliferation index is higher WHO grade II glioma treated by neuro-
oligodendroglial tumours. One study, in WHO grade III tumours than in WHO surgical resection only {27,951}. In con-
of 32 patients with WHO grade II oligo- grade II tumours {2157}, but a study of 20 trast, IDH mutation, 1p/19q codeletion,
dendrogliomas, found that a Ki-67 prolif- paediatric low-grade oligodendroglioma and MGMT promoter methylation were
eration index of > 3% was indicative of cases did not show a prognostic value found to be associated with better thera-
a worse prognosis {980}. Another study, for the Ki-67 proliferation index {259}. peutic response and longer survival in
of 89 patients with oligodendroglioma, patients with low-grade glioma treated
reported a 5-year survival rate of 83% Genetic alterations
with adjuvant radiotherapy or chemo-
for patients whose oligodendrogliomas The prognostic versus predictive role of
therapy {951,1256}. A study of 360 pa-
had a Ki-67 proliferation index of < 5%, 1p and 19q loss in WHO grade II gliomas
tients with WHO grade II diffuse glioma
versus a rate of only 24% with a Ki-67 is a matter of debate. Some studies sug-
demonstrated no prognostic role for IDH
proliferation index of > 5% {567}. This gested that WHO grade II gliomas with
mutation, whereas 1p/19q codeletion
finding is similar to those of other studies deletion of 1p or with 1p/19q codeletion
was associated with longer overall sur-
{493}. In general, older studies reported are associated with longer survival in-
vival and TP53 mutation with shorter
dependent from adjuvant therapy {686,
overall survival {1281}. Thus, it is likely

68 Diffuse gliomas
that a prognostically favourable role of patients treated with radiotherapy Oligodendroglioma, NOS
IDH mutation, 1p/19q losses, and MGMT plus PCV chemotherapy versus radio-
promoter methylation in WHO grade II therapy alone {2338}. However, recent Definition
glioma is linked to higher sensitivity to cy- long-term follow-up data also showed a A diffusely infiltrating glioma with classic
totoxic treatment rather than to generally major increase in overall survival after oligodendroglial histology, in which mo-
more indolent behaviour independent radiotherapy plus PCV chemotherapy, lecular testing for combined IDH muta-
of therapy. It remains to be investigated in particular for patients with 1p/19q- tion and 1p/19q codeletion could not be
whether genetic or epigenetic alterations codeleted low-grade oligodendroglio- completed or was inconclusive.
in other genes can improve prognostic mas {2481,2612}. Adjuvant chemother- The diagnosis of oligodendroglioma,
assessment within the group of patients apy with temozolomide may also be a NOS, is reserved for diffusely infiltrat-
with IDH-mutant and 1p/19q-codeleted feasible therapeutic strategy for pa- ing WHO grade II gliomas with clas-
WHO grade II oligodendrogliomas. tients with progressive low-grade oligo- sic oligodendroglial histology but with-
dendroglioma, with 1p/19q codeletion out confirmation of IDH mutation and
Predictive factors 1p/19q codeletion, due to limited tissue
suggested as a predictive marker for
The optimal postoperative treatment of availability, low tumour-cell content, in-
better response to temozolomide {1022,
patients with IDH-mutant and 1p/19q- conclusive test results, or other circum-
1256,1476}. Another study reported that
codeleted WHO grade II oligodendro- stances impeding molecular testing. In
IDH mutation predicts better response
gliomas is a matter of ongoing discus- general, molecular testing for IDH muta-
to radiochemotherapy in patients with
sion. After tumour resection, radiotherapy tion and 1p/19q codeletion is important
WHO grade II glioma {1835}. Collec-
and chemotherapy are often deferred for WHO classification of oligodendro-
tively, these findings agree with data
until tumour progression because ther- glial tumours, implying that the diagnosis
from phase III trials in patients with ana-
apy-associated neurotoxicity is a major of oligodendroglioma, NOS, should be
plastic gliomas (WHO grade III) that in-
concern in patients with expected long- limited to a small minority of cases. Im-
dicated IDH mutation {346} and 1p/19q
term survival. Patients with symptomatic munohistochemical demonstration of
codeletion as predictive markers for
residual and progressive tumours after IDH mutation (in particular IDH1 R132H)
long-term survival after combined treat-
surgery usually receive upfront treatment and nuclear positivity for ATRX support
ment with radiotherapy and PCV chem-
with radiotherapy and/or chemotherapy. the diagnosis. However, unless success-
otherapy {344,2615}. The presence of
The European Organisation for Research fully tested for 1p/19q codeletion, glio-
MSH6 mismatch repair gene mutations
and Treatment of Cancer (EORTC) 22845 mas with oligodendroglial histology, IDH
has been linked to temozolomide resist-
trial showed that adjuvant radiotherapy mutation, and nuclear ATRX positivity still
ance independent of MGMT promoter
prolonged progression-free but not over- correspond to the diagnosis of oligoden-
methylation status {1779}. One study re-
all survival in patients with progressive droglioma, NOS. Immunohistochemical
ported that 1p/19q codeletion predict-
WHO grade II gliomas {2613}. The Ra- positivity for oligodendroglioma-associ-
ed a lower risk of pseudoprogression in
diation Therapy Oncology Group (RTOG) ated markers such as alpha-internexin
patients with oligodendroglial tumours
9802 trial initially also showed only in- {607,625} and NOGO-A {1600}, as well
despite being associated with longer
creased progression-free survival for as immunohistochemical demonstration
survival {1504}.
of loss of nuclear CIC or FUBP1 expres-
sion {146,401}, are not sufficient to substi-
tute for 1p/19q codeletion testing.
Unlike with IDH-mutant and 1p/19q-
codeleted oligodendroglioma, the pres-
ence of a conspicuous astrocytic compo-
nent is not compatible with the diagnosis
of oligodendroglioma, NOS (see Oligoas-
trocytoma, NOS, p. 75).

ICD-0 code 9450/3

Grading
Oligodendroglioma, NOS, corresponds
histologically to WHO grade II.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted 69


Reifenberger G. Cairncross J.G
Anaplastic oligodendroglioma, Collins V.P. Yokoo H.
Hartmann C. Yip S.
IDH-mutant and 1p/19q-codeleted Hawkins C. Louis D.N.
Kros J.M.

Definition analyses that do not carefully control for Epidemiology


An IDH-mutant and 1p/19q-codeleted different treatments and other prognosti- Note that these and the following para-
oligodendroglioma with focal or diffuse cally relevant parameters. Histological graphs mostly refer to epidemiological
histological features of anaplasia (in par- features that have been linked to high- and clinical data based on histological
ticular, pathological microvascular prolif- grade malignancy of oligodendroglioma tumour classification according to the
eration and/or brisk mitotic activity). in previous studies are high cellularity, previous WHO classification. For the
In IDH-mutant and 1p/19q-codeleted marked cytological atypia, high mitotic most part, this information can be con-
anaplastic oligodendroglioma, necro- activity, pathological microvascular pro- sidered to be similar for the newly defined
sis (with or without palisading) may be liferation, and necrosis with or without entity IDH-mutant and 1p/19q-codeleted
present, but does not indicate progres- palisading. Anaplastic oligodendroglioma anaplastic oligodendroglioma, as well as
sion to glioblastoma. The presence of an usually shows several of these features. for anaplastic oligodendroglioma, NOS.
astrocytic tumour component is compat- However, the individual impact of each
Incidence
ible with the diagnosis when molecular parameter is unclear, in particular be-
According to a statistical report from
testing reveals combined IDH mutation cause most of the older studies were not
the Central Brain Tumor Registry of the
and 1p/19q codeletion. The vast major- restricted to patients with IDH-mutant and
United States (CBTRUS), anaplastic oli-
ity of IDH-mutant and 1p/19q-codeleted 1p/19q-codeleted oligodendroglial tu-
godendroglioma (as defined by histology
anaplastic oligodendrogliomas manifest mours. Endothelial (microvascular) prolif-
only) has an estimated annual incidence
in adult patients. The tumours are pref- eration and brisk mitotic activity (defined
rate of 0.11 cases per 100 000 popula-
erentially located in the cerebral hemi- as > 6 mitoses per 10 high-power fields)
tion and accounts for 0.5% of all primary
spheres, with the frontal lobe being the have been suggested to be of particular
brain tumours {1863}. Approximately one
most common location. importance as indicators of anaplasia in
third of all oligodendroglial tumours are
oligodendroglial tumours {830}. Thus,
ICD-0 code 9451/3 anaplastic oligodendrogliomas {1863}.
the diagnosis of IDH-mutant and 1p/19q-
codeleted anaplastic oligodendroglioma Age and sex distribution
Grading
should require at least the presence of Anaplastic oligodendrogliomas manifest
IDH-mutant and 1p/19q-codeleted ana-
conspicuous microvascular proliferation preferentially in adults, with a median pa-
plastic oligodendroglioma corresponds
and/or brisk mitotic activity. Detection of tient age at diagnosis of 49 years {1863}.
histologically to WHO grade III.
a single mitosis in a resection specimen Patients with anaplastic oligodendroglio-
There is clear evidence from prospective
is not sufficient for classifying an oligo- mas are approximately 6 years older on
clinical trials {344,2615,2740} and large
dendroglial tumour as WHO grade III average than patients with WHO grade II
cohort studies {2464,2731} that patients
anaplastic oligodendroglioma. In border- oligodendrogliomas, but this difference
with IDH-mutant and 1p/19q-codeleted
line cases, immunostaining for MIB1 and appears to be much smaller when only
anaplastic oligodendroglial tumours have
attention to clinical and neuroradiologi- patients with IDH-mutant and 1p/19q-
a significantly better prognosis than do pa-
cal features, such as rapid symptomatic codeleted tumours are considered. Ana-
tients with IDH-mutant but 1p/19q-intact
growth and contrast enhancement, may plastic oligodendroglioma is very rare in
or IDH-wildtype anaplastic astrocytic gli-
provide additional information for assess- children. In the CBTRUS, there were no
omas. In contrast, the prognostic value of
ing the prognosis.
WHO grading within the group of patients
with IDH-mutant and 1p/19q-codeleted
oligodendroglial tumours is less clear
(see Oligodendroglioma, IDH-mutant and
1p/19q-codeleted, p. 60). Two recent un-
controlled retrospective studies suggest-
ed a limited role of WHO grading in pre-
dicting patient outcome {1836,2464}, a
finding in line with retrospective data ob-
tained from a large cohort of patients with
IDH-mutant astrocytic gliomas {2103}.
However, treatment regimens often differ
for patients with low-grade versus high-
grade oligodendroglioma, so potential Fig. 1.67 IDH-mutant and 1p/19q-codeleted anaplastic oligodendroglioma. T1-hypointense lesion with focal contrast
enhancement following gadolinium administration (+Gd). T2 (FLAIR) shows the extent of the lesion and FET-PET
bias cannot be excluded in retrospective
demonstrates increased metabolic activity.

70 Diffuse gliomas
patients with anaplastic oligodendro- {2616}. Seizures are also common but
glioma among the 12 103 children aged are less frequent than in patients with
0-14 years registered with neuroepithe- low-grade oligodendroglioma {933}.
lial tumours, and only 32 patients with Anaplastic oligodendroglioma develops
anaplastic oligodendroglioma were doc- either de novo (typically with a short pre-
umented among the 3051 children regis- operative history) or by progression from
tered with neuroepithelial tumours in the a pre-existing WHO grade II oligoden-
15-19 years age group {1863}. In an in- droglioma. The mean time to progression
stitutional cohort of 50 paediatric patients from WHO grade II oligodendroglioma to
with oligodendroglioma, 12 patients were WHO grade III anaplastic oligodendro-
diagnosed with anaplastic oligodendro- Fig. 1.68 Large, macroscopically well-delineated glioma has been estimated at approxi-
gliomas, including 4 patients with 1p/19q anaplastic oligodendroglioma of the left basal ganglia, mately 6-7 years {1446,1826}.
codeletion {2157}. compressing the adjacent lateral ventricle, with shift of
Imaging
Overall, anaplastic oligodendroglioma midline structures towards the right hemisphere. The
Anaplastic oligodendrogliomas can
shows a slight male predominance, with arrowhead points to a ventricular shunt.
show heterogeneous patterns, due to the
a male-to-female ratio of 1.2:1 reported
variable presence of necrosis, cystic de-
among 1650 patients {1863}. In the USA, a preference for the frontal lobe, followed
generation, intratumoural haemorrhages,
anaplastic oligodendroglioma is more by the temporal lobe. However, the tu-
and calcification. On CT and MRI, con-
common in Whites than in Blacks, with an mours can also originate at other sites
trast enhancement is seen in most pa-
incidence ratio of 2.4:1 {1863}. within the CNS, and there have been rare
tients and can be either patchy or ho-
cases of spinal intramedullary anaplastic
Etiology mogeneous {2616}. However, lack of
oligodendroglioma.
See Etiology (p. 61) in Oligodendroglio- contrast enhancement does not exclude
ma, IDH-mutant and 1p/19q-codeleted. Clinical features anaplastic oligodendroglioma. Ring en-
Patients with anaplastic oligodendro- hancement is less common in IDH-mu-
Localization
glioma commonly present with focal tant and 1p/19q-codeleted anaplastic
Anaplastic oligodendrogliomas and
neurological deficits, signs of increased oligodendrogliomas than in malignant
WHO grade II oligodendrogliomas share
intracranial pressure, or cognitive deficits

Fig. 1.69 Anaplastic oligodendroglioma. A Typical image of a cellular glioma with honeycomb cells and mitotic activity (arrows). B Marked nuclear atypia and brisk mitotic activity.
C Focal necrosis with palisading tumour cells. D Marked microvascular proliferation.

Anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted 71


gliomas, in particular glioblastomas with- WHO grade III IDH-mutant and 1p/19q- Cell of origin
out these molecular markers {345,2616}. codeleted anaplastic oligodendroglioma See Cell of origin(p. 65) in Oligodendrogli-
is appropriate. The presence of a con- oma, IDH-mutant and 1p/19q-codeleted.
Macroscopy spicuous astrocytic component is also
The macroscopic features are similar to compatible with this diagnosis provid- Genetic profile
those of WHO grade II oligodendroglio- ing the tumour demonstrates IDH muta-
mas, except that anaplastic oligoden- Cytogenetics
tion and 1p/19q codeletion. However, in
drogliomas may show areas of tumour The hallmark cytogenetic alteration is
cases that cannot be conclusively tested
necrosis. combined whole-arm deletion of 1p and
for combined IDH mutation and 1p/19q
19q, typically as a consequence of an
Microscopy codeletion, the presence of a conspicu-
unbalanced translocation between chro-
Anaplastic oligodendrogliomas are cel- ous astrocytic component is not compat-
mosomes 1 and 19 {887,1151}. Concur-
lular, diffusely infiltrating gliomas that ible with anaplastic oligodendroglioma,
rent polysomy of 1p and 19q seems to be
may show considerable morphological NOS (see Anaplastic oligodendroglio-
more common in anaplastic oligodendro-
variation. The majority of the tumour cells ma, NOS, p. 74). Instead, classification
gliomas than in low-grade oligodendro-
typically demonstrate features that are as anaplastic oligoastrocytoma, NOS,
gliomas and has been associated with a
reminiscent of oligodendroglial cells, i.e. or glioblastoma is more appropriate, de-
higher Ki-67 proliferation index and less
rounded hyperchromatic nuclei, perinu- pending on the absence or presence of
favourable clinical outcome {216,2748}.
clear haloes, and few cellular processes. necrosis.
Molecular cytogenetic studies have iden-
Focal microcalcifications are often pres- Immunophenotype tified various chromosomal abnormalities
ent. Mitotic activity is usually prominent, Anaplastic oligodendrogliomas have the other than 1p/19q codeletion in anaplas-
with one study suggesting a cut-off point same immunoprofile as WHO grade II oli- tic oligodendrogliomas; however, each
of 6 mitoses per 10 high-power fields godendroglioma, except that proliferative was limited to only a small proportion of
{830}. Occasional anaplastic oligoden- activity, as most commonly determined tumours. These include gains on chro-
drogliomas with 1p/19q codeletion are by MIB1 immunostaining, is generally mosomes 7, 8q, 11q, 15q, and 20, as well
characterized by marked cellular pleo- higher (i.e. MIB1-positive cells usually as losses on chromosomes 4q, 6, 9p,
morphism, with multinucleated giant cells account for > 5% of the tumour cells). 10q, 11, 13q, 18, and 22q {1084,1353,
(called the polymorphic variant of Zulch) However, a definitive MIB1 cut-off point 2577}. Double-minute chromosomes, a
{1000}. Rare cases with sarcoma-like for distinction between WHO grade II and cytogenetic hallmark of gene amplifica-
areas (called oligosarcoma) have also III oligodendrogliomas has not been es- tion, are rare {2537}, corresponding to
been observed {1004,2152}. Gliofibrillary tablished (see Immunophenotype, p. 64,
oligodendrocytes and minigemistocytes in Oligodendroglioma, IDH-mutant and
are frequent in some anaplastic oligo- 1p/19q-codeleted). Table 1.07 Genetic profile of IDH-mutant and 1p/19q-
dendrogliomas {1374}. The characteristic codeleted anaplastic oligodendroglioma
vascular pattern of branching capillaries Differential diagnosis % of
is often still recognizable, although path- The differential diagnosis includes a va- Gene Change References
cases
ological microvascular proliferation is riety of other clear cell tumour entities
IDH1/
usually prominent. Formation of second- that can be distinguished by distinct im- IDH2
Mutation 100% {349,2464}
ary structures, in particular perineuronal munohistochemical profiles and absence
1p/19q Codeletion 100% {349,2464}
satellitosis, is frequent in areas of cortical of combined IDH mutation and 1p/19q
tumour infiltration. Anaplastic oligoden- codeletion (see Differential diagnosis, TERT
Promoter
> 95% {349,2464}
mutation
drogliomas may contain necrosis, includ- p. 65, in Oligodendroglioma, IDH-mutant
ing palisading necrosis resembling that of and 1p/19q-codeleted). Distinction of Promoter
MGMT > 90% {1733,2731}
glioblastoma. However, as long as the tu- anaplastic oligodendroglioma from ma- methylation

mour shows the IDH-mutant and 1p/19q- lignant small cell astrocytic tumours CIC Mutation -60% {349,2464}
codeleted genotype, classification as (including small cell glioblastoma) is of
CDKN2A/
major importance, because malignant p14ARF
LOH -40% {45A}

small cell astrocytic tumours behave


CDKN2A/ Promoter
much more aggressively, often with a p14ARF methylation
15-30% {2702A.2779}
clinical course typical of IDH-wildtype
FUBP1 Mutation -30% {349,2464}
glioblastomas {1937}. Unlike IDH-mutant
and 1p/19q-codeleted anaplastic oligo- NOTCH1 Mutation 20-30% {349,2464}
dendrogliomas, small cell astrocytomas PIK3CA Mutation 10-20% {349,2464}
and glioblastomas lack combined IDH
PIK3R1 Mutation -9% {349,2464}
mutation and 1p/19q codeletion but of-
TCF12 Mutation 7.5% {1407}
ten demonstrate EGFR amplification and
chromosome 10 losses {1183,1937}. ARID 1A Mutation -7% {349,2464}

Homozygous
{1069,1993,
CDKN2C deletion or <5%
2464}
Fig. 1.70 Anaplastic oligodendroglioma. MIB1 mutation
immunohistochemistry shows high proliferative activity.

72 Diffuse gliomas
Fig. 1.71 Anaplastic oligodendroglioma. A R132H-mutant IDH1 stains tumour cells but is negative in blood vessels. B Cortical infiltration zone with tumour cells expressing R132H-
mutant IDH1, including perineuronal satellitosis.

the low frequency of gene amplification anaplastic oligodendrogliomas due to ho- anaplastic oligodendroglioma {1863}.
detected in molecular profiling studies mozygous deletion, mutation, or aberrant However, none of these data considered
{2464,2731}. promoter methylation {666,1084,2779}. In IDH mutation or 1p/19q codeletion sta-
isolated cases, homozygous deletion or tus, which have been strongly associated
Molecular genetics
mutation of the CDKN2C gene at 1p32 with improved response to adjuvant radi-
As the entity name suggests, IDH muta-
has been observed in tumours without otherapy/chemotherapy and longer sur-
tion and 1p/19q codeletion are the defin-
CDKN2A deletions {1069,1993}. Losses vival {344,2615}. A retrospective analysis
ing genetic aberrations of IDH-mutant
of 10q, mutations of the PTEN tumour of 1013 adult patients with anaplastic
and 1p/19q-codeleted anaplastic oligo-
suppressor gene, and amplifications of oligodendroglial tumours found a median
dendroglioma. Promoter mutations in
proto-oncogenes are infrequent in IDH- overall survival of 8.5 years in patients
TERT are also present in the vast ma-
mutant and 1p/19q-codeleted anaplastic with 1p/19q-codeleted tumours, versus
jority of these tumours, as is the case
oligodendrogliomas {666,1083,2246}. 3.7 years in patients with 1p/19q-intact
for IDH-mutant and 1p/19q-codeleted
Epigenetically, these tumours are char- tumours {1436}. Long-term follow-up
low-grade oligodendroglioma {89,1314,
acterized by G-CIMP type A {2464} and data from the Radiation Therapy Oncol-
1408,2464}. Investigation of regionally
often demonstrate a proneural glioblas- ogy Group (RTOG) 9402 and European
or spatially distinct tissue samples from
toma-like expression profile. The MGMT Organisation for Research and Treatment
individual patients has indicated that IDH
promoter is typically hypermethylated of Cancer (EORTC) 26951 trials indicate
mutation, 1p/19q codeletion, and TERT
{1733}. even higher median overall survival times
promoter mutation are early events in
(> 10 years) for patients with IDH-mutant
oligodendroglioma development that are Genetic susceptibility
and 1p/19q-codeleted anaplastic oligo-
shared by neoplastic cells from different See Genetic susceptibility (p. 67) in
dendrogliomas who were treated with
tumour areas as well as between primary Oligodendroglioma, IDH1-mutant and
combined radiotherapy and PCV chemo-
and recurrent tumours {2464}. As in low- 1p/19q-codeleted.
therapy {344,2615}. Patients rarely devel-
grade oligodendroglioma, CIC mutation
Prognosis and predictive factors op cerebrospinal fluid spread or systemic
is frequent in anaplastic oligodendro-
metastases. Local tumour progression is
glioma, whereas FUBP1 mutation occurs Prognosis the most common cause of death.
in fewer cases. Other (less commonly) Recent therapeutic advances have mark-
mutated genes include NOTCH pathway edly improved survival times of patients Predictive factors
genes (in particular, NOTCH1), various with anaplastic oligodendrogliomas. Be- Clinical factors that have been associ-
epigenetic regulator genes (e.g. SETD2)}, fore the introduction of adjuvant treat- ated with longer survival are younger
and PI3K pathway genes (e.g. PIK3CA) ment with combined radiochemotherapy, age at diagnosis, higher Karnofsky per-
{2464}. Mutations in the oligodendroglial reported median survival times ranged formance score, and greater extent of
lineage-associated transcription factor from < 1 year {567} to 3.9 years {2337}. resection {1095,2617,2740}. Previous re-
gene TCF12 have been detected in a A population-based analysis from Swit- section for lower-grade tumour has also
small subset {7.5%) of anaplastic oligo- zerland reported a median survival time been linked to more favourable prognosis
dendrogliomas and are associated with of 3.5 years for patients with anaplastic {2621}. Recursive partitioning analysis of
an aggressive tumour type {1407}. Over- oligodendroglioma, which was markedly various clinical and histological param-
all, the average number of chromosomes shorter than the median of 11.6 years for eters together with the 1p/19q codele-
involved in copy number abnormalities is patients with WHO grade II oligodendro- tion status identified five distinct prog-
higher in anaplastic oligodendrogliomas glioma {1826}. The CBTRUS calculated nostic classes, defined mainly by patient
than in low-grade oligodendrogliomas 5- and 10-year survival rates of 52.2% age, tumour location, and 1p/19q status
{1353,2160}. The CDKN2A and CDKN2B and 39.3%, respectively, for patients with {1884}. A study based on the EORTC
loci on 9p21 are altered in a subset of 26951 trial found a strong prognostic

Anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted 73


Anaplastic oligodendroglioma,
Anaplastic chromosomal imbalances (mostly NOS
oligodendroglioma genomic deletions) {1759}. Definition
lacking IDH mutation and In adult patients, anaplastic oligo- A diffusely infiltrating anaplastic glioma
1p/19q codeletion dendroglioma without combined IDH with classic oligodendroglial histolo-
In paediatric patients, isolated cases of mutation and 1p/19q codeletion is not gy, in which molecular testing for com-
tumours with classic oligodendroglial considered a distinct tumour entity or bined IDH mutation and 1p/19q codele-
histology and histological features of variant in the WHO classification. In- tion could not be completed or was
anaplasia but without IDH mutation and stead, such tumours should be carefully inconclusive.
1p/19q codeletion have been reported evaluated for genetic changes associ- As with oligodendroglioma, NOS, im-
{2157}. However, the prognostic role of ated with IDH-wildtype glioblastomas munohistochemical demonstration of
anaplastic features in these rare paedi- (in particular, gains of chromosome 7, IDH mutation (in particular IDH1 R132H)
atric oligodendroglial tumours remains losses of chromosome 10, and EGFR and nuclear positivity for ATRX supports
unknown {2157}. The genetic altera- gene amplification), to exclude, for ex- the diagnosis of an oligodendroglial tu-
tions in these rare paediatric tumours ample, small cell astrocytoma/glioblas- mour but cannot substitute for 1p/19q
are distinct from those in their adult toma (see Differential diagnosis). codeletion testing, because nuclear ATRX
counterparts and may involve diverse expression is retained in a subset of IDH-
mutant but 1p/19q-intact anaplastic astro-
impact of the Ki-67 proliferation index on RTOG 9402 trial, patients with 1p/19q- cytomas. Similarly, immunopositivity for
univariate analysis but no independent codeleted anaplastic gliomas had medi- alpha-internexin and loss of nuclear CIC
influence on multivariate analysis {2034}. an overall survival times of 14.7 years with or FUBP1 expression supports the diag-
In addition to 1p/19q codeletion and IDH radiotherapy plus PCV chemotherapy nosis of anaplastic oligodendroglioma,
mutation, G-CIMP status and MGMT pro- versus 7.3 years with radiotherapy alone. NOS, but does not suffice for diagnosis
moter methylation have been reported In the EORTC 26951 trial, median overall of IDH-mutant and 1p/19q-codeleted
to provide prognostically relevant infor- survival was not reached after > 10 years anaplastic oligodendroglioma (see the
mation for patients with anaplastic glio- of follow-up in patients with 1p/19q- box Anaplastic oligodendroglioma lack-
mas {2618,2619,2620,2740}. Long-term codeleted anaplastic gliomas treated by ing IDH mutation and 1p/19q codeletion).
follow-up data from the RTOG 9402 and radiotherapy plus PCV chemotherapy The histological features of anaplastic
EORTC 26951 trials suggest not only a versus 9.3 years in patients treated with oligodendroglioma, NOS, largely corre-
prognostic but also a predictive role of radiotherapy alone. In both trials, pa- spond to those described for IDH-mutant
1p/19q codeletion for long-term survival tients with 1p/19q-intact tumours had sig- and 1p/19q-codeleted anaplastic oligo-
after aggressive multimodal treatment nificantly shorter overall survival in both dendroglioma. However, the presence of
consisting of surgical resection followed treatment arms. These data indicate that a conspicuous astrocytic component is
by upfront combined radiotherapy and molecular testing of anaplastic gliomas is not compatible with the diagnosis of ana-
PCV chemotherapy {344,2615}. In the important and can guide therapy {2730}. plastic oligodendroglioma, NOS. Areas of
necrosis, including palisading necrosis,
are compatible with the diagnosis of ana-
plastic oligodendroglioma, NOS, provided
the tumour shows the typical cytological
characteristics and other histological hall-
marks of oligodendroglioma, such as the
branching capillary network and micro-
calcifications. However, the differential
diagnosis of glioblastoma (WHO grade IV),
in particular the small-cell variant, must
be thoroughly considered in such cases,
and is in fact more appropriate when IDH
mutations are absent and genetic features
of glioblastoma (such as gain of chro-
mosome 7, loss of chromosome 10, and
EGFR amplification) are detectable.

ICD-0 code 9451/3

Grading
Anaplastic oligodendroglioma, NOS,
corresponds histologically to WHO
grade III.

74 Diffuse gliomas
Reifenberger G. Cairncross J.G
Oligoastrocytoma, NOS Collins V.P. Yokoo H.
Hartmann C. Yip S.
Hawkins C. Louis D.N.
Kros J.M.

Definition subjected to molecular testing for IDH with immunohistochemistry for ATRX and
A diffusely infiltrating, slow-growing gli- mutation and 1p/19q codeletion. Tumours R132H-mutant IDH1, followed by testing
oma composed of a conspicuous mix- with combined IDH mutation and 1p/19q for 1p/19q codeletion, and then followed
ture of two distinct neoplastic cell types codeletion are classified as IDH-mutant by IDH sequencing of the tumours that
morphologically resembling tumour cells and 1p/19q-codeleted oligodendroglio- were negative for R132H-mutant IDH1
with either oligodendroglial or astro- ma, irrespective of a mixed or ambiguous {2105}. With this approach, the vast ma-
cytic features, and in which molecular histology. Tumours with IDH mutation but jority of diffuse and anaplastic gliomas
testing could not be completed or was without 1p/19q codeletion are classified can be assigned to one of three major
inconclusive. as IDH-mutant diffuse astrocytoma, also glioma classes: IDH-mutant diffuse as-
In oligoastrocytoma, NOS, tumour cells irrespective of mixed or ambiguous his- trocytomas, IDH-mutant and 1p/19q-
with oligodendroglial or astroglial fea- tology. Immunohistochemical testing for codeleted oligodendrogliomas, or IDH-
tures can be either diffusely intermingled loss of nuclear ATRX expression may also wildtype gliomas (including IDH-wildtype
or separated into distinct, biphasic areas. provide diagnostically helpful informa- glioblastomas). Overall, the diagnosis of
The mixed or ambiguous cellular dif- tion. Loss of ATRX positivity in the tumour oligoastrocytoma, NOS, should therefore
ferentiation precludes histological clas- cell nuclei but retained nuclear expres- remain exceptional (i.e. restricted to dif-
sification as either diffuse astrocytoma, sion in non-neoplastic cells (e.g. vascular fuse gliomas in which histology does not
NOS, or oligodendroglioma, NOS. Oli- endothelia, reactive astrocytes, and acti- allow for unequivocal stratification into ei-
goastrocytoma, NOS, is an exceptional vated microglial cells) supports the diag- ther astrocytic or oligodendroglial lineage
diagnosis, because most diffuse glio- nosis of IDH-mutant diffuse astrocytoma tumours and that cannot be subjected to
mas with mixed or ambiguous histology {2105,2220}. Similarly, strong nuclear appropriate molecular testing or in which
can be classified as either IDH-mutant immunopositivity for p53, typically as a molecular findings are inconclusive).
diffuse astrocytoma or IDH-mutant and consequence of TP53 mutation leading
1p/19q-codeleted oligodendroglioma, to nuclear accumulation of mutant p53 ICD-0 code 9382/3
based on molecular testing. Oligoastro- protein, is often associated with loss of
Grading
cytomas, NOS, usually manifest in adult nuclear ATRX expression and is virtually
Oligoastrocytoma, NOS, corresponds
patients, with preferential localization in mutually exclusive with 1p/19q codeletion
histologically to WHO grade II.
the cerebral hemispheres. {2220}. Recent data support a diagnostic
algorithm for diffuse and anaplastic glio-
Genetic classification of
mas based on stepwise analyses starting
oligoastrocytomas
The WHO classification discourages the
diagnosis of tumours as oligoastrocy-
toma or mixed glioma. Molecular genetic
analyses have clearly shown that the vast
majority of tumours previously classified
as oligoastrocytomas have a genetic pro-
file typical of either diffuse astrocytoma
(i.e. IDH mutation combined with TP53
mutation and ATRX mutation / loss of nu-
clear ATRX expression) or oligodendro-
glioma (i.e. IDH mutation combined with
1p/19q codeletion and TERT promoter
mutation) {349,2220,2464}. The histo-
logical criteria provided in previous WHO
classifications for oligoastrocytic gliomas
left room for considerable interobserver
variability {494,2611}. Thus, diffuse glio-
mas, including those with mixed or am-
biguous histological features, should be

Fig. 1.72 Oligoastrocytoma. Clearly separated tumour areas displaying oligodendroglial (left) and astrocytic (right)
differentiation.

Oligoastrocytoma, NOS 75
initial diagnosis Anaplastic oligoastrocytoma,
NOS
Definition
An oligoastrocytoma, NOS, with focal or
diffuse histological features of anaplasia,
including increased cellularity, nuclear
atypia, pleomorphism, and brisk mitotic
activity.
Anaplastic oligoastrocytoma, NOS, is
an exceptional diagnosis, because most
high-grade gliomas with mixed or am-
biguous histology can be classified as
either IDH-mutant anaplastic astrocyto-
ma or IDH-mutant and 1p/19q-codeleted
anaplastic oligodendroglioma, based on
molecular testing. Moreover, if molecu-
lar testing of an anaplastic glioma with
mixed or ambiguous histology shows an
IDH-wildtype status, IDH-wildtype glio-
blastoma must be considered as a likely
differential diagnosis, because most
IDH-wildtype anaplastic gliomas have
genetic profiles of glioblastoma and are
associated with correspondingly poor
integrated diagnosis
prognosis. Anaplastic oligoastrocyto-
Fig. 1.73 Changes from initial (purely histology-based) to integrated diagnosis in 405 adult patients with supratentorial mas, NOS, usually manifest in adult pa-
glioma. Width of bars indicates relative proportions of the initial tumour groups. A, astrocytoma; OA, oligoastrocytoma; tients, with preferential localization in the
0, oligodendroglioma; GBM, glioblastoma; GBMo, glioblastoma with oligodendroglial component; GBMs, secondary
cerebral hemispheres.
glioblastoma; gcGBM, giant cell glioblastoma; GS, gliosarcoma. Note that all oligoastrocytomas were redistributed
to other diagnoses (IDH-mutant and 1p/19q-codeleted oligodendroglioma, IDH-mutant astrocytoma, IDH-wildtype ICD-0 code 9382/3
astrocytoma, or IDH-wildtype glioblastoma) after molecular marker analysis, including IDH mutation / G-CIMP, ATRX
loss of nuclear expression, 1p/19q codeletion, and 7p gain /10q loss. Reprinted from Reuss DE et al. {2105}. Grading
Anaplastic oligoastrocytoma, NOS,
corresponds histologically to WHO
grade III.

Oligoastrocytoma, genetic alterations, including 1p/19q requires detailed molecular and immuno-
dual-genotype codeletion, in the oligodendroglial and histochemical analyses to unequivocally
Dual-genotype oligoastrocytoma is not astrocytic tumour components of the demonstrate the two genetically distinct
considered to be a distinct entity or vast majority of oligoastrocytomas {1359, tumour cell subpopulations. Care must
variant in the WHO classification. The 2050j. However, a few instances of oli- be taken to avoid misinterpretations (e.g.
designation refers to an IDH-mutant oli- goastrocytoma showing evidence of ge- due to artefactually negative nuclear im-
goastrocytoma of WHO grade II that is netically distinct oligodendroglial and munostaining for ATRX) and false-posi-
composed of a conspicuous mixture of astrocytic cell populations have been tive detection of 1p/19q-codeleted nuclei
astrocytic and oligodendroglial tumour reported {1067,2050,2754}. It can be as- by FISH (e.g. due to incomplete chro-
cell populations demonstrating molecu- sumed that dual-genotype oligoastrocy- mosomal representation in transected
lar evidence of an astrocytic genotype tomas are monoclonal tumours that arise nuclei, aneuploidy/polyploidy, or partial
(i.e. IDH mutation combined with TP53 from an IDH-mutant cell of origin but later hybridization failure) {763}. Overall, dual-
mutation / nuclear p53 accumulation, during tumorigenesis develop cytologi- genotype oligoastrocytoma seems to be
loss of nuclear ATRX expression, and cally distinct subpopulations of tumour very rare, but its true incidence is difficult
lack of 1p/19q codeletion) and an oligo- cells with an astrocytic genotype (i.e. to ascertain because tissue sampling is
dendroglial genotype (i.e. IDH mutation TP53 and ATRX alteration but no 1p/19q rarely comprehensive in diffuse gliomas
combined with 1p/19q codeletion, lack codeletion) or an oligodendroglial geno- and molecular analysis of DNA extracted
of TP53 mutation / nuclear p53 accu- type (i.e. 1p/19q codeletion but no TP53 from a bulk sample may not detect such
mulation, and retained nuclear ATRX ex- or ATRX alteration). Classification of du- molecular heterogeneity.
pression). Studies have revealed shared al-genotype oligoastrocytoma therefore

76 Diffuse gliomas
Genetic classification of anaplastic Anaplastic oligoastrocytoma, (i.e. IDH mutation combined with 1p/19q
oligoastrocytomas dual-genotype codeletion, lack of TP53 mutation / nu-
The WHO classification discourages Dual-genotype anaplastic oligoastrocy- clear p53 accumulation, and retained
the diagnosis of tumours as anaplastic toma is not considered to be a distinct nuclear ATRX expression). To date, only
oligoastrocytoma or anaplastic mixed entity or variant in the WHO classifica- isolated cases of tumours considered to
glioma. Molecular genetic analyses have tion. The designation refers to an IDH- be dual-genotype anaplastic oligoas-
not demonstrated entity-specific genetic mutant anaplastic oligoastrocytoma of trocytoma have been reported {1067,
or epigenetic profiles for these tumours. WHO grade III that demonstrates mo- 2754}. These tumours occurred in the
Instead, large-scale molecular profiling lecular evidence of genetically distinct cerebral hemispheres of adult patients.
studies have shown that the vast major- astrocytic and oligodendroglial tumour Utmost care must be taken to exclude
ity of anaplastic oligoastrocytomas have cell populations characterized by an technical shortcomings that may lead to
genetic alterations and DNA methylation astrocytic genotype (i.e. IDH mutation artefactual regional variation in immu-
profiles typical of either IDH-mutant ana- combined with TP53 mutation / nuclear nohistochemical staining for ATRX or in
plastic astrocytoma (with commonly as- p53 accumulation, loss of nuclear ATRX FISH analysis for 1p/19q codeletion.
sociated TP53 mutation and ATRX muta- expression, and lack of 1p/19q codele-
tion / loss of nuclear ATRX expression) or tion) and an oligodendroglial genotype
IDH-mutant and 1p/19q-codeleted ana-
plastic oligodendrogliomas (with com-
monly associated TERT promoter muta- including those with a mixed or ambigu- astrocytomas, IDH-mutant and 1p/19q-
tions). A third, smaller subset of cases ous histological phenotype, should be codeleted anaplastic oligodendroglio-
correspond to IDH-wildtype anaplastic subjected to thorough molecular test- mas, or IDH-wildtype anaplastic glio-
gliomas, which commonly demonstrate ing, most notably for IDH mutation and mas (most of which are characterized by
hallmark genetic aberrations of glioblas- 1p/19q codeletion. As with oligoastrocy- glioblastoma-associated genetic profiles
toma - in particular, gain of chromosome toma, NOS, immunohistochemical test- and the associated poor prognosis).
7 and loss of chromosome 10 combined ing for loss of nuclear ATRX expression Overall, the diagnosis of anaplastic oli-
with TERT promoter mutation and gene and nuclear accumulation of p53 may goastrocytoma, NOS, should therefore
amplifications (such as EGFR amplifica- provide additional, diagnostically helpful remain exceptional, i.e. restricted to
tion) {349,2464,2731,2751}. The criteria information {2105,2220}. This integrated anaplastic gliomas with astrocytic and
provided in previous WHO classifications approach enables a clear diagnostic oligodendroglial components that cannot
for anaplastic oligoastrocytoma left room stratification of the vast majority of ana- be subjected to appropriate molecular
for considerable interobserver variability plastic gliomas into one of the three testing or in which molecular findings are
{1370,2611}. Thus, anaplastic gliomas, major classes: IDH-mutant anaplastic inconclusive.

Oligoastrocytoma, NOS 77
Collins V.P. Jones D.
Pilocytic astrocytoma Tihan T. Giannini C.
VandenBerg S.R. Rodriguez F.
Burger P.C. Figarella-Branger D.
Hawkins C.

Definition 100 000 population, which declines sub- intraventricular and their site of origin dif-
An astrocytoma classically character- stantially from < 14 years to 15-19 years ficult to define.
ized by a biphasic pattern with variable {1863}. Pilocytic astrocytoma is the most
Clinical features
proportions of compacted bipolar cells common glioma in children, without a
Pilocytic astrocytomas produce focal
with Rosenthal fibres and loose, textured significant sex predilection. It accounts
neurological deficits or non-localizing
multipolar cells with microcysts and oc- for 33.2% of all gliomas in the 0-14 years
signs, such as macrocephaly, head-
casional granular bodies. age group {1862} and 17.6% of all child-
ache, endocrinopathy, and increased
Genetically, pilocytic astrocytomas are hood primary brain tumours {1863}.
intracranial pressure due to mass effect
characterized by the presence of mu- Similarly, in a study of 1195 paediatric tu-
or ventricular obstruction. Seizures are
tations in genes coding for proteins in- mours from a single institution, pilocytic
uncommon because the lesions involve
volved in the MAPK pathway {1176,2855}. astrocytoma was the single most com-
the cerebral cortex infrequently {466,
The most frequent genetic change is tan- mon tumour (accounting for 18% of cas-
725}. Given their slow rate of growth,
dem duplication of 7q34 involving the es overall) in the cerebral compartment
pilocytic tumours clinical presentation
BRAF gene resulting in oncogenic BRAF {2174}. In adults, pilocytic astrocytoma
is generally that of a slowly evolving le-
fusion proteins. Pilocytic astrocytomas tends to appear about a decade earlier
sion. Pilocytic astrocytomas of the op-
are the most common glioma in children (mean patient age: 22 years) than does
tic pathways often produce visual loss.
and adolescents, and affect males slight- WHO grade II diffuse astrocytoma {784},
Proptosis may be seen with intraorbital
ly more often than females. They are but relatively few arise in patients aged
examples. Early, radiologically detected
preferentially located in the cerebellum > 50 years.
lesions may not be associated with visual
and cerebral midline structures (i.e. the Localization
symptoms or ophthalmological deficits
optic pathways, hypothalamus, and brain Pilocytic astrocytomas arise throughout
{1054,1515}. Hypothalamic/pituitary dys-
stem) but can be encountered anywhere the neuraxis; however, in the paediat-
function, including obesity and diabetes
along the neuraxis {1533}. They are gen- ric population, more tumours arise in
insipidus, is often apparent in patients
erally circumscribed and slow-growing, the infratentorial region. Preferred sites
with large hypothalamic tumours {2159}.
and may be cystic. Pilocytic astrocytoma include the optic nerve (optic nerve
Some hypothalamic/chiasmatic lesions
largely behaves as is typical of a WHO glioma) {1054}, optic chiasm/hypothala-
in young children have been associated
grade I tumour {1533}, and patients can mus {2159}, thalamus and basal ganglia
with leptomeningeal seeding and a poor
be cured by surgical resection. However, {1622}, cerebral hemispheres {725,1994},
outcome {1934}; see Pilomyxoid astro-
complete resection may not be possible cerebellum (cerebellar astrocytoma)
cytoma (p. 88), a variant of pilocytic as-
in some locations, such as the optic path- {974}, and brain stem (dorsal exophytic
trocytoma. Pilocytic astrocytomas of the
ways and the hypothalamus. Pilocytic brain stem glioma) {311,709,1995}. Pilo-
thalamus generally present with signs of
astrocytomas, particularly those involv- cytic astrocytomas of the spinal cord are
cerebrospinal fluid obstruction or neu-
ing the optic pathways, are a hallmark of less frequent but not uncommon {1677,
rological deficits (such as hemiparesis)
neurofibromatosis type 1 (NF1). 2186}. Large hypothalamic, thalamic, and
due to internal capsule compression.
Pilomyxoid astrocytoma is considered to brain stem lesions may be predominantly
Cerebellar pilocytic astrocytomas usu-
be a variant of pilocytic astrocytoma.
ally present during the first two decades
ICD-0 code 9421/1 of life, with clumsiness, worsening head-
ache, nausea, and vomiting. Brain stem
Grading
examples most often cause hydroceph-
Pilocytic astrocytoma corresponds histo-
alus or signs of brain stem dysfunction.
logically to WHO grade I.
Unlike diffuse astrocytoma of the pons,
Epidemiology which produces symmetrical so-called
Pilocytic astrocytoma accounts for 5.4% pontine hypertrophy, pilocytic tumours of
of all gliomas {1826}. According to a the brain stem are usually dorsal and ex-
2007-2011 statistical report from the Cen- ophytic into the cerebellopontine angle.
tral Brain Tumor Registry of the United Spinal cord examples produce non-spe-
0 10 20 30 40 50 60
States (CBTRUS), pilocytic astrocytoma Age at diagnosis
cific signs of an expanding mass {1678,
is most common during the first two dec- Fig. 2.01 Cumulative age distribution (both sexes) of 2074,2186}.
ades of life, with an average annual age- pilocytic astrocytomas, based on biopsies from 205
Imaging
adjusted incidence rate of 0.84 cases per patients treated at the University Hospital Zurich {1533}.
Most cerebellar and cerebral pilocytic

80 Other astrocytic tumours


astrocytomas are well demarcated,
with a round or oval shape and smooth
margins. Calcifications are occasion-
ally present. Heterogeneity as a result
of cyst-like areas intermixed with gen-
erally intensely enhancing soft tissue
components is typical. Consistent with
the tumour's low biological activity, sur-
rounding vasogenic oedema (if present)
is much less extensive than in higher-
grade glial neoplasms. About two thirds
of cases manifest as a cyst-like mass
with an enhancing mural nodule; the
other third present either as a cyst-like
mass with a central non-enhancing zone
or as a predominantly solid mass with a
minimal or no cyst-like portion {474,1927}.
In those with a cyst-like morphology, the
cyst wall may or may not enhance {165},
and cyst wall enhancement may or may
not indicate tumour involvement {165}.
Occasional atypical imaging features of
these tumours include multiple cyst-like
masses and haemorrhage. Fig. 2.02 Most pilocytic astrocytomas are strongly and diffusely enhancing. A Left optic nerve. B Hypothalamic.
C Basal ganglia. D Tectal. E Cerebellar. F Spinal. Some tumours are solid (A, B, D) and others are cystic with an
Most optic nerve gliomas are pilocytic as-
enhancing mural nodule (C, E, F).
trocytomas, and characteristically mani-
fest as a kinked or buckled enlargement
of the optic nerve. Tumours in this loca- Macroscopy Microscopy
tion often have different imaging appear- Most pilocytic astrocytomas are soft, This astrocytic tumour of low to moderate
ances depending on whether the patient grey, and relatively discrete. Intratu- cellularity often has a biphasic pattern,
has NF1. NF1-associated tumours more moural or paratumoural cyst formation is with varying proportions of compacted
commonly affect the optic nerve, rarely common, including with a mural tumour bipolar cells with Rosenthal fibres and
extend beyond the optic pathway, and nodule. In spinal cord examples, syrinx loose-textured multipolar cells with mi-
are usually not cyst-like, whereas those formation may extend over many seg- crocysts. The biphasic pattern is best
not associated with NF1 usually involve ments {1678}. Chronic lesions may be seen in cerebellar tumours. However,
the optic chiasm, extend extraoptically, calcified or may stain with haemosiderin. pilocytic astrocytoma can exhibit a wide
and are frequently cyst-like {1342}. Optic nerve tumours often circumfer- range of tissue patterns, sometimes sev-
entially involve the subarachnoid space eral within the same lesion. A variant of
Spread the compact, piloid pattern occurs when
{2427}.
Otherwise typical pilocytic astrocytomas
very occasionally seed the neuraxis, on
rare occasions even before the primary
tumour is detected {775,1934,1996}. The
proliferation rate in such cases varies,
but is usually low {1681}. Therefore, this
atypical behaviour of pilocytic astrocyto-
ma cannot be predicted. The hypothala-
mus is usually the primary site. Neuraxis
seeding does not necessarily indicate
future aggressive growth; both the pri-
mary lesion and the implants may grow
only slowly {775,1681,1996}. The implants
may be asymptomatic, and long-term
survival is possible, even without adju-
vant treatment {1996}. The pilomyxoid
astrocytoma variant (see Pilomyxoid as-
trocytoma, p. 88), typically occurring in
the hypothalamic region, more often un- Fig. 2.03 Cerebellar pilocytic astrocytoma. A Axial T1-weighted MRI shows a left cerebellar cyst-like mass with

dergoes craniospinal spread {2555}. slightly hyperintense mural nodule along its lateral margin. B Axial T2-weighted MRI shows hyperintensity of the cyst-
like portion of the mass with lower signal intensity of the mural nodule. C Postcontrast axial T1 -weighted MRI shows
heterogeneous intense enhancement of the mural nodule.

Pilocytic astrocytoma 81
Fig. 2.04 Pilocytic astrocytoma. A Diffuse infiltration of the hippocampus and neighbouring structures. Note the focal formation of cysts. B Large, partially cystic pilocytic astrocytoma
of the cerebellum with a typical mural nodule {882}. C Large pilocytic astrocytoma extending into the basal cisterns.

the elongated cells are less compact but cytological variation, and basic cytologi- peripheral, more infiltrative areas. Cells
separated by mucin. In such cases, indi- cal patterns are often present in combi- closely resembling oligodendrocytes
vidual cell processes can be seen, and nation. Compact portions of the tumour are typically less frequent {480}, but
cell shape varies to include more full- yield bipolar piloid cells; long, hair-like can constitute a dominant component in
bodied and pleomorphic, less obviously processes that often extend across a some cases, particularly in the cerebel-
piloid cells. A distinctive lobular pattern full microscopic field; and Rosenthal fi- lum. These cells strongly express OLIG2
results when leptomeningeal involvement bres. Nuclei are typically elongated and {481}, although other tissue patterns may
induces a desmoplastic reaction. At this cytologically bland. Due to their high express OLIG2 as well. With the cells ar-
site, tissue texture varies but Rosenthal content of refractile eosinophilic fibrils, ranged in sheets or dispersed within pa-
fibres are usually abundant. Rare mi- these cells are strongly immunopositive renchyma, the overall appearance may
toses, hyperchromatic and pleomorphic for GFAP Cells derived from microcystic resemble that of an oligodendroglioma,
nuclei, glomeruloid vascular prolifera- areas have round to oval, cytologically particularly in a limited sample. The find-
tion, infarct-like necrosis, and infiltration bland nuclei; a small cell body; and rela- ing of foci of classic pilocytic astrocytoma
of leptomeninges are compatible with the tively short, cobweb-like processes that usually enables the correct classificatiort
diagnosis of pilocytic astrocytoma and are fibril-poor and only weakly positive of such lesions. Regimented palisades
are not signs of malignancy. for GFAP. This growth pattern may be as- (a so-called spongioblastoma pattern)
Due to the heterogeneity of histological sociated with eosinophilic granular bod- are a striking feature in some pilocytic
features, smear preparations of pilo- ies. Cells indistinguishable from those astrocytomas.
cytic astrocytomas show considerable of diffuse astrocytoma may populate

Fig. 2.05 Typical histological features of pilocytic astrocytoma. A Densely fibrillary areas composed of bipolar cells with long thin processes and rich in Rosenthal fibres as seen on
intraoperative cytological smears and (B) on histological sections. C Eosinophilic granular bodies. Neoplastic cell nuclei are hyperchromatic. A rare mitotic figure is present (arrow).
D Loosely arranged microcystic areas. E Pilocytic astrocytoma is typically a highly vascular tumour and shows both glomeruloid vessels and (F) thick-walled hyalinized vessels. The
vascular changes correlate with the frequent presence of contrast enhancement on imaging.

82 Other astrocytic tumours


Fig. 2.06 Pilocytic astrocytoma. A Typical biphasic pattern with alternating compact and loose architectural patterns. B Pseudo-oiigodendroglial pattern. Regular round cells with
rounded nuclei and occasional microcystic changes.

Although many pilocytic astrocytomas extent, pre-existing neurons are some- a property best seen in smear prepara-
are benign, some show considerable hy- times trapped, and some lesions even tions. Rosenthal fibres are most common
perchromasia and pleomorphism. Rare demonstrate limited cytological atypia. in compact, piloid tissue. They appear
mitoses are present, but brisk mitotic ac- Such lesions should be distinguished bright blue on Luxol fast blue staining.
tivity, in particular diffuse brisk mitotic ac- from ganglion cell tumours. The pilo- Although helpful in diagnosis, their pres-
tivity, characterizes anaplastic change, myxoid variant (see Pilomyxoid astrocy- ence is not obligatory, and they are nei-
which has prognostic implications {2150} toma, p. 88) is characterized by uniform ther specific to pilocytic astrocytoma nor
(see p. 88). In occasional (often cerebel- bipolar cells in a myxoid background indicative of neoplasia. They are often
lar) tumours, a diffuse growth pattern and frequent perivascular arrangements. seen in ganglioglioma and are a com-
overshadows more typical compact Sometimes this pattern is associated mon finding in chronic reactive gliosis.
and microcystic features. In such cases, with more conventional pilocytic regions Densely fibrillar, paucicellular lesions
the presence of hyperchromatic nuclei or so-called intermediate tumours {1168}. containing Rosenthal fibres are as likely
or mitotic figures can cause confusion Although astrocytomas in children are to be reactive gliosis as pilocytic astrocy-
with high-grade diffuse astrocytoma. usually classified as either the pilocytic toma. Ultrastructurally, Rosenthal fibres
Less worrisome are obvious degenera- or the diffuse type, many cases do not lie within astrocytic processes and con-
tive atypia with pleomorphism and nu- in fact fit clearly into either category on sist of amorphous, electron-dense ele-
clear-cytoplasmic pseudoinclusions, the basis of histology alone. Increasingly, ments surrounded by intermediate (glial)
frequently seen in long-standing lesions. molecular profiling plays an ancillary role filaments {588}. Being composed of
Multiple nuclei within large or giant cells in this distinction. In some cases, small alpha-B-crystallin {862}, they lack GFAP
are localized circumferentially (called a biopsy size contributes to difficulties in immunoreactivity except in their fibril-rich
pennies-on-a-plate arrangement) {974}. classification, especially in cases with a periphery.
Hyalinized and glomeruloid vessels are brain stem or spinal location.
Eosinophilic granular bodies
prominent features of some cases. Any
Rosenthal fibres Eosinophilic granular bodies form globu-
necrosis is often infarct-like and non-
These tapered, rounded, or corkscrew- lar aggregates within astrocytic process-
palisading. Perivascular lymphocytes
shaped, brightly eosinophilic, hyaline es. They are brightly eosinophilic in H&E
may also occur. Because pilocytic astro-
masses are intracytoplasmic in location, sections, periodic acid-Schiff-positive,
cytomas overrun normal tissue to some

Fig. 2.07 Biphasic pilocytic astrocytoma. A Cells in fibrillary areas strongly express GFAP. B OLIG2 expression is restricted to pseudo-oiigodendroglial cells.

Pilocytic astrocytoma 83
and immunoreactive for alpha-1-antichy- astrocytomas, it is not surprising that re- Growthpattern
motrypsin and alpha-1-antitrypsin {1236}. gressive features are common. Markedly Typically, pilocytic astrocytomas are
Although eosinophilic granular bodies hyalinized, sometimes ectatic vessels macroscopically somewhat discrete.
may be present in pilocytic astrocytoma, are one such feature. When neoplastic Thus, when the anatomical site permits
they are more frequent in other glial or cells are scant, it can be difficult to distin- (e.g. in the cerebellum or cerebral hemi-
glioneuronal neoplasms, in particular guish these tumours from cavernous an- spheres), many can be removed in toto
ganglion cell tumours and pleomorphic giomas with accompanying piloid gliosis. {725,974,1994}. Microscopically, howev-
xanthoastrocytomas. Evidence of previous haemorrhage (hae- er, many lesions are not well defined with
mosiderin) increases the resemblance. respect to surrounding brain. Lesions
Vasculature
Presentation with acute haemorrhage is typically permeate parenchyma for dis-
Pilocytic astrocytomas are highly vascu-
infrequent. Calcification, infarct-like ne- tances of millimetres to several centime-
lar, as evidenced by their contrast en-
crosis, and lymphocytic infiltrates are tres, often entrapping normal neurons in
hancement {761}. Although generally ob- the process. However, pilocytic tumours
additional regressive changes. Over-
vious in H&E sections, this vascularity is
all, calcification is an infrequent finding, are relatively solid compared with dif-
accentuated on immunostains for mark-
and is only rarely present in optic nerve fuse gliomas, and do not aggressively
ers of basement membrane (e.g. colla-
or hypothalamic/thalamic tumours or in overrun surrounding tissue. This prop-
gen IV and laminin) and endothelial cells
superficially situated cerebral examples. erty, evidenced by at least partial lack of
(e.g. CD31 and CD34). This glomeruloid
Cysts are a common feature of pilocytic axons on Bodian or Bielschowsky silver
vasculature may also line tumoural cyst impregnations, and NFP immunostains,
astrocytoma, especially in the locations
walls and is occasionally seen at some
specified above. Neovascularity often is of diagnostic value. Pilocytic astrocy-
distance from the lesion, but this should
lines cyst walls, resulting in a narrow tomas of the optic nerve and chiasm dif-
not prompt tumour misclassification or
band of intense contrast enhancement fer somewhat in their macroscopic and
overgrading. There may be structural
at the circumference of some cysts. microscopic patterns of growth; they are
and biological differences from similar
Dense piloid tissue with accompanying often less circumscribed and therefore
vessels occurring in glioblastomas, with difficult to delineate either macroscopi-
Rosenthal fibres external to this vascular
the microvasculature of glioblastomas
layer is sometimes seen. When this layer cally or microscopically. They share the
exhibiting a looser, more disorganized ar-
is narrow and well demarcated from the same propensity for leptomeningeal in-
chitecture and differences in expression
surrounding normal tissue, it can be as- volvement as seen in pilocytic tumours
of angiogenesis-related genes {1727}.
sumed to be reactive in nature. In other at other sites, but are somewhat more
Regressive changes instances, the glial zone is more promi- diffuse, especially within the optic nerve.
Given the indolent nature and of- nent, less demarcated, and neoplastic. This is particularly evident when patholo-
ten slow clinical evolution of pilocytic gists attempt to determine the extent of
a lesion by analysis of sequential nerve

Table 2.01 Genetic alterations affecting the MAPK pathway in pilocytic astrocytomas and their diagnostic utility; adapted from Collins VP et al. {482}

% of
Gene Change Diagnostic utility References
tumours
Tandem duplications resulting in KIAA1549-BRAF fusion proteins,
BRAF and Common in pilocytic astrocytomas, particularly cerebellar;
all having the BRAF kinase domain and with the BRAF N-terminal > 70% {1176,1178,2855}
KIAA1549 rare in other tumour forms
regulatory domain replaced by the N-terminal end of KIAA1549

BRAF and Deletions or translocations resulting in BRAF fusion proteins, all


Occur in pilocytic astrocytomas; extremely rare in other
various other having the BRAF kinase domain and with the BRAF regulatory -5% {1176,2855}
entities
genes domain replaced by the N-terminal part of another gene

Occurs mainly in supratentorial pilocytic astrocytomas;


BRAF V600E mutation -5% also in gangliogliomas, pleomorphic xanthoastrocytomas, {1176,2855}
and dysembryoplastic neuroepithelial tumours

Typically germline; closely associated with optic pathway


NF1 Loss of wild type and retained inherited mutation -8% {1176,2855}
pilocytic astrocytoma

Found mainly in midline pilocytic astrocytomas; frequency


FGFR1 Mutation <5% {1176,2855}
not established in other entities

Rare in pilocytic astrocytoma; also observed in other low-


FGFR1 Fusions / internal tandem duplication <5% {1176,2855}
grade gliomas

Rare in pilocytic astrocytoma; frequency not established


NTRK family Fusions -2% {1176,2855}
in other entities

Single Rare in pilocytic astrocytoma; frequency not established


KRAS Mutation {1176,2855}
cases in other entities

Fusions with consequences similar to those of BRAF fusions, i.e.


Single Rare in pilocytic astrocytoma; frequency not established in
RAF1 the loss of the regulatory domain and its replacement by the N- {1176,2855}
cases other entities
terminal end of SGRAP3

84 Other astrocytic tumours


margins. Microscopically, the lesion can
be followed to a point beyond which it
becomes less cellular, but there is no
clearly defined termination.
There has been considerable discus-
sion regarding the existence of a diffuse
variant of pilocytic astrocytoma, particu-
larly in the cerebellum {847,974,1882}.
Although some such cases are simply
classic pilocytic tumours in which the in-
filtrative edge is somewhat broader than
expected or an artefact of plane of sec-
tion, there are also occasional distinctly
infiltrative lesions that mimic diffuse fibril-
lary astrocytoma, even in large speci-
mens. In two large studies, the outcomes
for children with so-called diffuse pilo-
cytic astrocytoma of the cerebellum were
favourable, supporting the idea that such
tumours belong to the spectrum of pilo-
cytic astrocytoma {974,1882}. True infil-
trating diffuse astrocytomas account for
as many as 15% of all astrocytic tumours
of the cerebellum, but most are high-
grade (i.e. WHO grade III or IV) {974}.
Infiltration of the meninges
Involvement of the subarachnoid space
is common in pilocytic astrocytoma. It
is not indicative of aggressive or malig-
nant behaviour and does not portend
subarachnoid dissemination; rather, it is
a characteristic and even diagnostically
helpful feature. Leptomeningeal inva-
sion can occur at any tumour site, but is
particularly common in the cerebellum
and optic nerve. The leptomeningeal Fig. 2.08 Pilocytic astrocytoma. Illustration of the MAPK pathway components with the approximate incidence rates of
component may be reticulin-rich, more the various mutations found in a series of pilocytic astrocytomas. Adapted by permission from Jones DTW et al. {1176}.

commonly in the optic nerve than in the


cerebellum. Another typical pattern of ex- without necrosis {2150}. Tumours with in a subset of these tumours, particu-
traparenchymal spread is extension into these features should not be designated larly those developing in the cerebellum
perivascular spaces. glioblastoma, because their prognosis is {2145}, as well as absence of the R132H-
not uniformly grim. In general, the pres- mutant IDH1 protein. In the future, com-
Anaplastic transformation (pilocytic astro- ence of necrosis in pilocytic astrocyto- prehensive molecular characterization
cytoma with anaplasia) mas with anaplasia is associated with a will facilitate a more objective distinction
As a group, pilocytic astrocytomas are better prognosis than in classic cohorts from morphologically similar high-grade
remarkable in that they maintain their of glioblastoma. The diagnosis of pilo- gliomas. In a recent study of 886 cases
WHO grade I {325} status over years and cytic astrocytoma with anaplasia may be of paediatric low-grade glioma, with long
even decades. The alterations that occur preferable. Many such tumours had pre- clinical follow-up, there were no patients
over time are typically in the direction of viously been irradiated {591,2565}, and with the KIAA1549-BRAF fusion who un-
regressive change rather than anaplasia. therefore radiation therapy may be a fac- derwent anaplastic transformation and
One large study found the acquisition of tor promoting anaplastic change in some died of their disease {1683}.
atypia (in particular increased cellularity, cases. However, pilocytic astrocytomas
nuclear abnormalities, and occasional Immunophenotype
with anaplasia (including cases that de-
mitoses) to be of no prognostic signifi- Pilocytic astrocytomas are well-differen-
velop in the setting of NF1) also occur in
cance {2565}. In a subsequent series, tiated gliomas of the astrocytic lineage,
patients without prior irradiation {2150}.
anaplasia in pilocytic astrocytoma was and strongly express GFAP, S100, and
Grading criteria and nomenclature for
found to occur primarily in the form of dif- OLIG2 {1865}. Synaptophysin may dem-
these tumours are yet to be defined.
fuse, brisk mitotic activity (usually > 4 mi- onstrate partial or weak reactivity, which
Molecular studies, although limited,
toses per 10 high-power fields), with or should not be interpreted as evidence for
have demonstrated BRAF duplications

Pilocytic astrocytoma 85
gene {123,575,1961}. This is a tandem
duplication resulting in a transforming fu-
sion gene between KIAA1549 and BRAF
{1178}. The N-terminus of the KIAA1549
protein replaces the N-terminal regula-
tory region of BRAF, retaining the BRAF
kinase domain, which is consequently
uncontrolled and constitutively activates
the MAPK pathway {724,1178,2360}. This
abnormality is found at all anatomical lo-
cations, but is most frequent in cerebel-
lar tumours and somewhat less common
at other sites. The gene fusions involve
nine different combinations of KIAA1549
and BRAF exons, making identification
by RT-PCR or immunochemistry diffi-
cult, resulting in many centres accept-
ing the demonstration of a duplication at
7q34 (usually using FISH probes) as evi-
dence of the KIAA1549-BRAF fusion. In
small numbers of cases, eight additional
gene partners for BRAF fusions have
also been identified (FAM131B, RNF130,
CLCN6, MKRN1, GNA11, QKI, FXR1, and
Fig. 2.09 Pilocytic astrocytoma: the development of the KM 1549-BRAFfusion gene. The upper black box represents
MACF1), with fusions occurring by vari-
7q34. Both KM 1549 and BRAF read towards the centromere (cent.). A fragment of approximately 2 Mb is duplicated
(involving parts of both genes) and inserted at the break point, producing tandem duplication and fusion between the 5'
ous genetic rearrangements (including
end of KIAA1549 and the 3' end of the BRAF gene (which codes for the kinase domain). The fusion gene thus codes deletions and translocations) and all re-
for the BRAF kinase domain together with the N-terminal part of KIAA1549, replacing the BRAF regulatory domain. sulting in loss of the N-terminal regulatory
The red and green dots show the location of FISH probes that can be used to identify the occurrence of the tandem region of the BRAF protein, with retention
duplication, as demonstrated in the lower part of the figure, showing interphase normal and tumour nuclei with the of the kinase domain {1176,2855}.
tandem duplication hybridized with such probes. The two interphase copies of chromosome 7 in the normal nucleus In addition to harbouring BRAF fusion
each show a single red and a single green signal adjacent to each other. In contrast, the tumour cell nuclei show one genes, essentially all pilocytic astrocyto-
pair of normal chromosomal signals, but the other copy of chromosome 7 shows an additional (yellow) signal, due to the
mas studied in sufficient detail have been
fusion of the extra, now adjacent, red and green signals. Reprinted from Collins VP et al. {482}.
shown to have an alteration affecting some
a glioneuronal tumour. NFP typically out- not exclude other substitutions at posi- component of the MAPK pathway {1176,
lines a mainly solid tumour, highlighting tion 132 or mutations of the IDH2 protein. 2855}. These alterations include the well-
normal surrounding axons in compressed Because essentially all pilocytic astrocy- documented NF1 mutations, the hotspot
adjacent CNS parenchyma. Optic nerve tomas have activating genetic alterations BRAF mutation commonly known as the
tumours generally produce a fusiform in components of the MAPK pathway V600E mutation, KRAS mutations, recur-
expansion of the nerve and have axons {1176}, phosphorylated MAPK immu- rent aberrations affecting the FGFR1 and
present among tumour cells, as do oc- nostaining is a consistent feature. Label- the NTRK-family receptor kinase genes,
casional cerebellar examples. Rosenthal ling with immunohistochemical markers and very occasional RAF1 gene fusions
fibres are positive for alpha-B-crystallin, of mTOR pathway activation (e.g. phos- with SRGAP3, which occur in a similar
with GFAP staining limited to their periph- phorylated S6) is more variable {1076}. manner to the BRAF fusions: a tandem
ery. Unlike in diffuse astrocytomas, p53 Immunohistochemistry for V600E-mutant duplication at 3p25, with the fusion pro-
protein staining is weak to absent, which BRAF is positive in a small subset lacking tein lacking the RAF regulatory domain
is consistent with the rarity of TP53 mu- KIAA1549-BRAF fusion and other MAPK but retaining the kinase domain with loss
tations in pilocytic astrocytoma. Immu- pathway alterations. The Ki-67 prolifera- of kinase control. In cases with altera-
nohistochemistry for the R132Fi-mutant tion index is low in most cases of pilocytic tions of the NTRK genes, the alterations
IDH1 protein has been suggested to be astrocytoma, consistent with low prolifer- are also in the form of gene fusions, with
useful for the distinction of pilocytic as- ation rates {826}. Increases in the Ki-67 several different 5' partners that contain
trocytomas from diffuse gliomas, given proliferation index have been associated a dimerization domain. This is presumed
that reactivity is absent in essentially all with more aggressive behaviour in some to lead to constitutive dimerization of the
pilocytic astrocytomas {359}. Flowever, studies but not others {258,2552}. NTRK fusion proteins and activation of
paediatric diffuse astrocytic tumours the kinase {1176,2855}. The changes are
Genetic profile more varied in the case of FGFR1. They
may also lack IDH1 or IDH2 mutations.
The most frequent abnormality in pilocyt- include hotspot point mutations (N546K
In addition, reliable antibodies are cur-
ic astrocytomas overall (found in > 70% of and K656E), FGFR1-TACC1 fusions simi-
rently available for only the most com-
all cases) is an approximately 2 Mb dupli- lar to those seen in adult glioblastoma
mon IDH1 amino acid substitutions at
cation of 7q34, encompassing the BRAF
position 132, so a negative result does {2364}, a novel internal duplication of the

86 Other astrocytic tumours


and has also been reported in dysem-
bryoplastic neuroepithelial tumours {414,
2280}. This mutation can now be identi-
fied using a monoclonal antibody that
specifically recognizes the V600E-mu-
tant BRAF protein {355}.
A summary of genetic aberrations report-
ed to date in pilocytic astrocytoma, as
well as their diagnostic utility, is provided
in Table 2.01 (p. 84).
Genetic susceptibility
Pilocytic astrocytomas are the principal
CNS neoplasm associated with NF1,
which occurs in approximately 1 in 3000
births. Although NF1 is inherited in an au-
tosomal dominant manner, about half of
all cases are associated with a de novo
mutation (see p. 294). The NF1 gene,
located on the long arm of chromosome
17, encodes the neurofibromin protein,
which acts in the MAPK pathway as a
GAP for RAS, thereby facilitating the
Fig. 2.10 Pilocytic astrocytoma. Pie charts summarizing the known frequencies of the various MAPK pathway alterations
deactivation of RAS. Patients with NF1
in different anatomical locations of the brain (i.e. posterior fossa, diencephalon, and cerebral hemispheres), calculated
from a total of 188 pilocytic astrocytoma cases {482,1176,2855}. Reprinted from Collins VP et al. {482}.
have only one wildtype NF1 gene copy.
Subsequent functional loss of this single
wildtype copy results in the absence of
kinase domain of FGFR1, and an inter- 1176,1824,2855}. Pilocytic astrocytomas
the NF1-encoded GTPase and conse-
nal tandem duplication of FGFR1 {1176, with anaplastic change have yet to be
quent overactivity of RAS and the MAPK
2855}. A summary of the incidence of studied in any detail. However, in a recent
pathway. This so-called second hit in
all MAPK pathway alterations identified study of 26 cases that had progressed to
pilocytic astrocytomas can occur as a
to date in pilocytic astrocytomas of all high-grade glioma, none had a BRAF fu-
result of point mutation, focal or broader
anatomical sites is shown in Table 2.01 sion {1683}.
LOH, or DNA hypermethylation {909}.
(p. 84). Chromosomal polysomies (in The presence of the KIAA1549-BRAF
Reports have suggested that germline
particular of chromosomes 5, 6, 7, 11, fusion in an appropriate morphological
mutations affecting the 5'-most third of
and 15) have been reported in tumours context and together with other findings
the NF1 gene may be associated with a
of teenagers and adults {1177,2237}. supports the diagnosis of pilocytic astro-
greater chance of developing pilocytic
The incidence of the various MAPK path- cytoma. However, the absence of such
astrocytomas of the optic pathway {235,
way alterations is not consistent across a fusion provides no diagnostic informa-
2332}, although further study is needed.
all anatomical locations {123,1113,1176, tion, because there are so many other
Approximately 15% of individuals with
2855}. The KIAA1549-BRAF fusion is ways in which the MAPK pathway has
NF1 develop pilocytic astrocytomas
extremely common in the cerebellum been found to be activated in pilocytic
{1481}, particularly of the optic nerve/
(found in -90% of cases) but less com- astrocytomas. The KIAA1549-BRAF fu-
pathways (optic pathway glioma), but
mon supratentorially (found in -50%). sion has also been reported in several
other anatomical sites (sometimes multi-
FGFR1 alterations are restricted mainly adult gliomas but rarely in other histolo-
ple) can also be affected. Conversely, as
to midline structures, whereas the BRAF gies, with the exception of the rare diffuse
many as one third of all patients with a
V600E mutation and NTRK-family fusions leptomeningeal glioneuronal tumour (see
pilocytic astrocytoma of the optic nerve
are more common in supratentorial tu- p. 152; formerly referred to as dissemi-
have NF1 {1304}. These tumours typically
mours. Variation is also observed in the nated oligodendroglial-like leptomen-
arise during the first decade of life; few
transcriptome and methylome of pilocytic ingeal neoplasm), in which the fusion is
patients with NF1 develop an optic path-
astrocytomas, with infratentorial and su- frequently found together with a solitary
way glioma after the age of 10 years.
pratentorial tumours distinguishable on 1p deletion {2156}. Unfortunately, many
Pilocytic astrocytomas are also associat-
the basis of their gene expression or of the MAPK-KIAA1549-BRAF alterations
ed with Noonan syndrome (a neuro-car-
DNA methylation signatures {1424,2335, are also found to be similarly aberrant in
dio-facial-cutaneous syndrome), which is
2527}. The reason for this relationship the tumour types that are most frequently
caused by germline mutations of MAPK
between site / cell of origin and certain among the differential diagnosis of pi-
pathway genes (i.e. PTPN11, SOS1,
molecular alterations is unclear. Unlike in locytic astrocytoma. For example, the
KRAS, NRAS, RAF1, BRAF, SHOC2,
diffuse astrocytomas, the average muta- BRAF V600E mutation occurs in a small
and CBL) {83,2135}. The PTPN11 gene
tion rate is low in pilocytic astrocytomas. subset of pilocytic astrocytomas, but is
is mutated in about 50% of patients with
TP53 mutations seem to play no role in a common alteration in gangliogliomas
Noonan syndrome and is occasionally
the development of these tumours {1098, and pleomorphic xanthoastrocytomas

Pilocytic astrocytoma 87
mutated (together with FGFR1) in spo- either recur or progress, eventually lead- a wide spectrum of morphologies and
radic pilocytic astrocytomas {1176}. How- ing to death. However, this is usually after behaved in a more aggressive manner,
ever, the number of pilocytic astrocyto- a prolonged clinical course with multiple with decreased survival, than typical pi-
mas reported in patients with Noonan recurrences {725,974,1678,1996,2159}. locytic astrocytomas. However, despite
syndrome is small {744,1743,2233,2300}. Pilocytic astrocytomas of the optic nerve exhibiting morphological features of
in patients with NF1 {2148} seem to have anaplasia similar to those of diffuse as-
Prognosis and predictive factors
a more indolent behaviour than that of trocytic tumours, they did not behave as
Pilocytic astrocytoma is typically a slow-
their sporadic counterparts {1516}. aggressively. Even so-called high-grade
growing, low-grade tumour with a favour-
Histological malignancy in pilocytic as- pilocytic astrocytoma with anaplastic fea-
able prognosis. Overall survival rates at 5
trocytoma is rare; in one study of clas- tures and necrosis did not behave like a
and 10 years are > 95% after surgical in-
sic pilocytic astrocytoma, the incidence glioblastoma. Pilocytic astrocytomas with
tervention alone {291,325,688,725,1606,
of malignancy occurring spontaneously anaplastic features such as increased mi-
1826}. Stability of WHO grade is typically
was 0.9%, and the incidence of occur- totic count (i.e. > 4 mitoses per 10 high-
maintained for decades {149,325,1878}.
rence after radiation was 1.8% {2565}. power fields) and necrosis behaved, in
The tumours may even spontaneously
Descriptions of anaplastic features in pi- respective studies, more similarly to dif-
regress, although this is rare {897,1894,
locytic astrocytomas come mainly from fuse low-grade or anaplastic astrocyto-
2421}. Very occasional cases progress
isolated case reports and small series mas than to anaplastic astrocytomas or
with more anaplastic features after a vari-
{374,591,1251,2417,2682}, in which ma- glioblastomas {2150}.
able interval, most often after irradiation
lignant histological features correlate less Pilomyxoid astrocytoma (see below), a
or chemotherapy treatment {1957,2145}.
reliably with prognosis than those seen recognized pilocytic astrocytoma vari-
There are few long-term studies docu-
in patients with diffusely infiltrative astro- ant typically occurring in young children,
menting the ultimate outcome of patients
cytomas. Malignant transformation is fre- almost exclusively in the hypothalam-
with pilocytic astrocytoma.
quently reported in association with prior ic / third ventricular region, reportedly
Patient age and extent of resection are
treatment {61,176,307,1296,1364,2303, has a higher frequency of local recur-
key prognostic factors {2431}. Depend-
2312,2420,2565,2603}. A retrospective rence and may undergo cerebrospinal
ing on the location and size of the tumour,
study of 34 pilocytic astrocytomas with fluid seeding {1534,2555}.
pilocytic astrocytoma may not be ame-
spontaneous anaplastic histological fea-
nable to gross total resection and may
tures found that these tumours exhibited

Pilomyxoid astrocytoma Burger PC. Jones D. Clinical features


Tihan T. Giannini C. Pilomyxoid astrocytomas present with
Hawkins C. Rodriguez F. non-specific signs and symptoms that de-
VandenBerg S.R. Figarella-Branger D. pend on the anatomical site. Radiological
examination shows a well-circumscribed
mass with relatively distinct borders. The
Definition an increased likelihood of recurrence, it tumour is typically T1-hypointense and
A variant of pilocytic astrocytoma histo- is uncertain whether pilomyxoid astrocy- T2-hyperintense. Compared with pilo-
logically characterized by an angiocen- toma truly corresponds histologically to cytic astrocytomas, pilomyxoid astrocy-
tric arrangement of monomorphous, bi- WHO grade II. Therefore, a definite grade tomas are more likely to have necrosis
polar tumour cells in a prominent myxoid assignment is not recommended at this and more likely to have signal intensity
background {2555}. time. extending into adjacent structures. Cysts
Pilomyxoid astrocytoma is preferentially and calcifications are less common
Epidemiology
located in the hypothalamic/chiasmatic {1322}. Cerebrospinal fluid dissemination
The incidence of pilomyxoid astrocytoma
region but shares other locations with can occur before presentation.
is unknown because this entity is typi-
pilocytic astrocytoma (e.g. the thalamus,
cally grouped with pilocytic astrocytoma. Spread
temporal lobe, brain stem, and cerebel-
Pilomyxoid astrocytoma accounts for a These tumours are usually confined to
lum) {1533}. Pilomyxoid astrocytoma pre-
small proportion of tumours historically the site of origin, but they may spread
dominantly affects infants and young
classified as pilocytic astrocytoma. within cerebrospinal pathways.
children (with a median patient age of 10
months). It may grow more rapidly and Localization Macroscopy
have a less favourable prognosis than The hypothalamic/chiasmatic region is Intraoperative reports often describe a
pilocytic astrocytoma, due to local recur- the most common location, although the solid gelatinous mass. The tumours may
rence and cerebrospinal spread {270}. tumour can also occur in the thalamus, infiltrate the parenchyma, and a clear
cerebellum, brain stem, temporal lobe, surgical plane may not be identifiable.
ICD-0 code 9425/3 and spinal cord {187,480,688}.
Microscopy
Grading Pilomyxoid astrocytoma is dominated by
Although some reports have suggested

88 Other astrocytic tumours


pilocytic astrocytoma do not warrant a
diagnosis of Pilomyxoid astrocytoma.
Immunophenotype
Immunohistochemical staining demon-
strates strong and diffuse reactivity for
GFAP, S100 protein, and vimentin. Some
cases are positive for synaptophysin,
but staining for NFP or chromogranin-A
is typically negative. CD34 expression
has been reported in some cases in the
hypothalamic/chiasmatic region. Stain- Fig. 2.12 Perivascular orientation of tumour cells is a
distinctive feature of Pilomyxoid astrocytoma.
ing for V600E-mutant BRAF is negative
{480}. In limited studies, the Ki-67 prolif-
astrocytomas, although cases in patients
eration index was found to vary substan-
with neurofibromatosis type 1 and Pilo-
tially among Pilomyxoid astrocytomas,
myxoid astrocytoma have been reported
ranging from 2% to 20% {688,1326}.
{1261}. A case occurring in the context of
There is considerable overlap of Ki-67
Noonan syndrome has been reported as
proliferation index values between Pilo-
well {1743}.
Fig. 2.11 Pilomyxoid astrocytomas are usually large, myxoid and pilocytic astrocytomas.
contrast-enhancing masses that are most frequent in the Prognosis and predictive factors
Cell of origin
hypothalamic and suprasellar areas. In general, Pilomyxoid astrocytomas are
The cell of origin for Pilomyxoid astro-
more aggressive and more prone to lo-
a markedly myxoid background, mono- cytoma is unclear. Some reports of Pilo-
cal recurrence and cerebrospinal spread
morphous bipolar cells, and a predomi- myxoid astrocytoma underscore its close
than are pilocytic astrocytomas {480,
nantly angiocentric arrangement. The association with pilocytic astrocytoma,
688}, but there is considerable varia-
tumour typically has a compact, non- suggesting a common astrocytic origin.
tion in behaviour, and not all are more
infiltrative architecture, but some cases A suggested origin is from radial glia in
aggressive than WHO grade I pilocytic
are infiltrative, trapping normal brain ele- proximity to the optic nerve {437,2527}.
astrocytoma. Given the complexity of
ments such as ganglion cells. The lesion clinical, anatomical, and pathological in-
Genetic profile
is composed of small, monomorphous terrelationships, it is unclear whether the
Although very few Pilomyxoid astrocyto-
bipolar cells whose processes often ra- more aggressive behaviour of some Pi-
mas have been included in large-scale
diate from vessels, producing a form of lomyxoid astrocytomas is related to their
genomic studies, the data obtained to
pseudorosette. As strictly defined, the le- intrinsic pathological features or to their
date suggest that these tumours are ge-
sion does not contain Rosenthal fibres or unfavourable hypothalamic/chiasmatic
netically similar to WHO grade I pilocytic
eosinophilic granular bodies, but mitotic location. Complete surgical excision,
astrocytomas {1034,2855}, with some
figures may be present. Vascular prolif- which is the most reliable prognostic
showing KIAA1549-BRAF fusion {480}.
eration is present in some cases, often factor for pilocytic astrocytoma, cannot
in the form of linear glomeruloid tufts as- Genetic susceptibility usually be achieved in this anatomical
sociated with cystic degeneration. Rare To date, no genetic susceptibility has region.
examples are focally necrotic. Focal Pilo- been established for most Pilomyxoid
myxoid changes in an otherwise typical

Fig. 2.13 Pilomyxoid astrocytoma. A Monomorphous population of small, often bipolar, cells sitting in a myxoid background. B Diffuse, strong immunoreactivity for GFAP.

Pilomyxoid astrocytoma 89
Lopes M.B.S.
Subependymal giant cell astrocytoma Wiestler O.D.
Stemmer-Rachamimov A.O.
Sharma M.C.
Vinters H.V.
Santosh V.

Definition occur in infants, and several congenital dilated vessels are occasionally seen
A benign, slow-growing tumour com- cases diagnosed either at birth or by an- within the tumours. Like other brain neo-
posed of large ganglionic astrocytes, tenatal MRI have been reported {1070, plasms, SEGAs may show a high ratio
typically arising in the wall of the lateral 1630,1964,2067}. of choline to creatinine and a low ratio
ventricles. of N-acetylaspartate to creatinine on
Localization
Subependymal giant cell astrocytoma proton MR spectroscopy, which seems
SEGAs arise from the lateral walls of the to be a valuable tool for the early detec-
(SEGA) has a strong association with the
lateral ventricles adjacent to the foramen
tuberous sclerosis syndrome (p. 306). tion of neoplastic transformation of sub-
of Monro.
ependymal nodules {1979}. Leptomen-
ICD-0 code 9384/1 ingeal dissemination with drop metasta-
Clinical features
Grading Most patients present either with epilepsy ses has been described {2532}.
SEGA corresponds histologically to WHO or with symptoms of increased intracrani-
Macroscopy
grade I. al pressure. Massive spontaneous haem- SEGAs are typically located in the walls
orrhage has been reported as an acute
Epidemiology of the lateral ventricles over the basal
manifestation {2188}. With the current
ganglia. The tumours are sharply demar-
Incidence practice of early screening of patients
cated multinodular lesions. Cysts of vari-
SEGA is the most common CNS neo- with tuberous sclerosis, many SEGAs are
ous sizes are commonly seen. Areas of
plasm in patients with tuberous scle- diagnosed at an initial stage while still
remote haemorrhage may be seen due
rosis, but it is uncertain whether the tu- clinically asymptomatic {1378,2188}. to the high vascularity of the tumour. Ne-
mour also occurs outside this setting {26, crosis is rare, but focal calcifications are
Imaging
1809,2188}. The incidence rate of SEGA common.
On CT, SEGAs present as solid, partially
among patients with confirmed tuberous
calcified masses located in the walls of
sclerosis is 5-15% {26,1809,2188}, and Microscopy
the lateral ventricles, mostly near the fora-
the tumour is one of the major diagnostic SEGAs are circumscribed, often calci-
men of Monro. Ipsilateral or bilateral ven-
criteria of tuberous sclerosis {1809}. fied tumours. They are composed mainly
tricular enlargement may be apparent. of large, plump cells that resemble gemi-
Age and sex distribution On MRI, the tumours are usually hetero-
stocytic astrocytes and are arranged in
This tumour typically occurs during the geneous, isointense, or slightly hypoin-
sweeping fascicles, sheets, and nests.
first two decades of life and only infre- tense on T1-weighted images, and hy-
Clustering of tumour cells and perivascu-
quently arises de novo after the age of perintense on T2-weighted images, with
lar palisading are common features. The
20-25 years {1809}. However, cases can marked contrast enhancement {1094}.
tumour cells show a wide spectrum of
Prominent signal voids that represent phenotypes. Typical appearances range

Fig. 2.14 Subependymal giant cell astrocytom extending Fig. 2.15 Subependymal giant cell astrocytoma (postcontrast axial T1-weighted MRI). A A right subependymal giant
into the left ventricle and causing hydrocephalus. cell astrocytoma near the foramen of Monro, with avid enhancement. B After 3 months of mTOR inhibitor treatment,
the tumour shows decreased size and enhancement.

90 Other astrocytic tumours


from polygonal cells with abundant, and uniform, intense immunoreactivity for
glassy cytoplasm (resembling gemisto- S100 protein {1526,2334,2832}. Variable
cytic astrocytes) to smaller, spindle cells immunoreactivity for neuronal markers
within a variably fibrillated matrix. Giant and neuropeptides has been detected in
pyramidal-like cells with a ganglionic ap- SEGAs. The neuron-associated class III
pearance are common; these large cells beta-tubulin is more widespread in its dis-
often have an eccentric, vesicular nucle- tribution than any other neuronal epitope,
us with distinct nucleoli. Nuclear pseu- whereas neurofilament is more restricted
doinclusions can be seen in some cases. and mainly highlights cellular processes
Considerable nuclear pleomorphism and and a few ganglionic cells {1526}. Simi-
multinucleated cells are frequent. A rich larly, SEGA shows variable immunoex-
vascular stroma with frequent hyalinized pression for synaptophysin within the
vessels and infiltration of mast cells and ganglionic component {2334}. Focal
lymphocytes (predominantly T lympho- immunoreactivity for NeuN {2832} and
cytes) is a consistent feature {2334}. Pa- neuropeptides has also been detected
renchymal or vascular calcifications are {1526}. Neural stem cell markers, includ-
frequent {883,1964,2334}, and SEGAs ing nestin and SOX2 are also expressed
may demonstrate increased mitotic activ- in SEGAs {1964}; however, unlike in cor-
ity; however, these features do not seem tical dysplasias, CD34 immunoreactivity
to denote an adverse clinical course. is not seen. These findings suggest cel-
Similarly, the occasional presence of en- lular lineages with a variable capacity for
dothelial proliferation and necrosis are divergent phenotypes, including glial,
not indicative of anaplastic progression. neuronal, and neuroendocrine differen-
The rare examples of SEGA outside the tiation. Loss of either hamartin or tuberin
setting of tuberous sclerosis that recur immunoexpression is commonly seen in
have not been reported to show malig- SEGAs, and combined loss occurs in
nant transformation {2808}. rare cases {1693}.
The Ki-67 proliferation index as deter-
Cell of origin
mined by MIB1 monoclonal antibody
The histogenesis of SEGA is unclear. The
staining is generally low (mean: 3.0%),
histological and radiological features of
further supporting the benign nature of
SEGAs and subependymal nodules are
these neoplasms {913,2333}. The TOP2A
similar, and there is radiological evidence
labelling index is also low (mean: 2.9%)
Fig. 2.16 Subependymal giant cell astrocytoma. supporting the development of some
{2333}. Although extremely uncommon,
A Coronal section of the left hemisphere of a patient with subependymal nodules into SEGAs over
craniospinal dissemination has been re-
tuberous sclerosis, showing a subependymal giant cell time, suggesting that these entities may
ported in SEGA with an increased Ki-67 astrocytoma (arrowheads) and multiple cortical tubers constitute a continuum {241,468}. Evi-
proliferation index but without malignant (arrows). B Multiple subependymal nodules on the walls dence of biallelic inactivation of the TSC1
features {2532}. of the lateral ventricles. or TSC2 genes and activation of the
Ultrastructural features of neuronal differ-
mTOR pathway in SEGAs supports the
entiation, including microtubules, occa- Immunophenotype hypothesis that SEGAs arise as a con-
sional dense-core granules, and (rarely) SEGA has been designated as an as- sequence of a two-hit mechanism {406}.
synapses may be detectable, and bun- trocytoma, but due to its usually mixed SEGAs demonstrate glial, neuronal, and
dles of intermediate filaments are seen in glioneuronal phenotype, it has also been mixed neuroglial features (morphologi-
the cytoplasmic processes of the spindle called subependymal giant cell tumour cal, immunohistochemical, and ultra-
astrocytic cells {302,1009,1188}. {302,1526}. The tumour cells demon- structural), which suggests a neuroglial
strate variable immunoreactivity for GFAP

Fig. 2.17 Subependymal giant cell astrocytoma. A Cellular heterogeneity is typical for these tumours; elongated cells arranged within sweeping fascicles are admixed with large
cells. B Infiltration of inflammatory cells, including mature lymphocytes and mast cells, is a consistent feature. C Multifocal calcification within the tumour and/or blood vessels is
commonly seen.

Subependymal giant cell astrocytoma 91


Fig. 2.18 Subependymal giant cell astrocytoma. A Mixed population of polygonal to ganglionic-like cells. B Collection of large tumour cells, with perivascular pseudorosettes
reminiscent of ependymoma.

progenitor cell of origin with the capacity within the cell and form a complex {486, these two genes is 1:1 {2231}. TSC1 or
to undergo differentiation along glial, neu- 1212,1987}. A mutation of either gene re- TSC2 mutations are identified in about
ronal, and neuroendocrine lines {1526, sults in disrupted function of the tuberin- 85% of patients with tuberous sclerosis.
2334|. This hypothesis is supported by hamartin complex, with similar resulting The remaining 15% of cases may be
data from mouse models in which loss of disease phenotypes. mosaics or have a mutation in an unana-
Tsc1 or activation of the mTOR pathway Approximately 60% of patients with tu- lysed non-coding gene area. Mosaicism
in subventricular zone neural progenitor berous sclerosis have sporadic disease has been reported for TSC1 and TSC2
cells resulted in the formation of SEGA (i.e. with no family history), indicating a mutations in some parents of patients
and subependymal nodule-like lesions high rate of de novo mutations {2229A). with sporadic cases and in patients with
in the lateral ventricles {1566,2862A). In affected kindreds, the disease follows tuberous sclerosis {2229,2646}. Alter-
an autosomal dominant pattern of inherit- natively, there may be a third, unknown
Genetic profile
ance, with high penetrance but consider- locus, although to date there is no evi-
SEGA has a strong association with tu-
able phenotypic variability {2354}. dence to support this possibility {2231}.
berous sclerosis, a genetic disease
In sporadic tuberous sclerosis cases, Patients with tuberous sclerosis with no
caused by inactivating mutations in the
mutations in TSC2are 5 times more com- identified mutations have a milder pheno-
TSC1 gene at 9q or the TSC2 gene at
mon than mutations in TSC1 {51,516, type than do patients with TSC1 or TSC2
16p. The proteins encoded by the TSC
1174}, whereas in families with multiple mutations {2231}.
genes, tuberin and hamartin, interact
members affected, the mutation ratio of Like in other circumscribed astrocytomas,

Fig. 2.19 Subependymal giant cell astrocytoma. A Tumours may express primitive neural markers, including nestin. B Diffuse nuclear expression of the primitive neural marker
SOX2. C The majority of tumour cells are immunoreactive for GFAP. D Class III beta-tubulin (also called TUJ1) is the most ubiquitous neuronal-associated marker in these tumours.
E Focal expression of NFP. F MIB1/Ki-67 immunohistochemistry showing a low proliferation rate.

92 Other astrocytic tumours


including pilocytic astrocytoma and 1163,1255,1694}. LOH at 16p and 21q symptomatic lesions tend to have greater
pleomorphic xanthoastrocytomas, BRAF has been observed in two separate morbidity {551}. Careful follow-up of re-
V600E mutations have been found in cases {2782}, and partial loss of chro- sidual tumour is recommended because
SEGAs: in 6 of 14 cases in one series mosome 22q was observed in two ad- of the potential for late recurrences. Opti-
{1448} and in 1 of 3 cases in another ditional paediatric patients with tuberous mal outcome is associated with early de-
{2280}, regardless of whether the tumour sclerosis {560}. tection and treatment. In individuals with
occurred in the setting of tuberous scle- Genetic susceptibility tuberous sclerosis, surveillance by MRI
rosis. Investigations of SEGAs have also SEGA has a strong association with the every 1-3 years until the age of 25 years
demonstrated LOH in the TSC2 gene inherited tuberous sclerosis syndrome is recommended {551,1378}. Inhibition of
{992,1694}. Lost or reduced tuberin and (see Tuberous sclerosis, p. 306). mTOR1 with everolimus has been report-
hamartin expression has been described ed as a promising therapeutic approach
Prognosis and predictive factors
in SEGAs from patients with both TSC1 in patients with inoperable tuberous scle-
SEGA has a good prognosis when gross rosis-associated SEGAs {732A,733}.
and TSC2 germline mutations, suggest-
total resection is achieved. Larger or
ing a two-hit tumour suppressor model
for the pathogenesis of SEGAs {992,

Subependymal giant cell astrocytoma 93


Giannini C.
Pleomorphic xanthoastrocytoma Paulus W.
Louis D.N.
Liberski P.P.
Figarella-Branger D.
Capper D.

Definition
An astrocytic glioma with large pleomor-
phic and frequently multinucleated cells,
spindle and lipidized cells, a dense peri-
cellular reticulin network, and numerous
eosinophilic granular bodies.
Pleomorphic xanthoastrocytoma tumour
cells are neoplastic astrocytes, but there
is often neuronal differentiation {828,
1007,1254}. Mitotic activity is low (< 5 mi-
toses per 10 high-power fields). BRAF
V600E mutation is common in pleomor-
phic xanthoastrocytoma, and its pres-
ence in the absence of an IDH mutation
strongly supports the diagnosis. Pleo-
morphic xanthoastrocytoma is rare (con- Fig. 2.21 Pleomorphic xanthoastrocytoma. T1-weighted MRI with contrast enhancement. A,B The neoplasms in the
stituting < 1% of all astrocytic neoplasms) temporal lobe present as superficial nodular enhancing cystic tumours. Note the scalloping of overlying bone (A).
and most commonly affects children and
young adults, with a median patient age
at diagnosis of 22 years {825}. The tu- Epidemiology function is also possible. The rare TP53
mour has a typical superficial location in Pleomorphic xanthoastrocytoma is a rare mutations encountered do not suggest
the cerebral hemispheres, most frequent- brain tumour, accounting for < 1% of all particular carcinogenic insults {824,1238,
ly in the temporal lobe, with involvement primary brain tumours. The 2014 statisti- 1917}.
of the adjacent leptomeninges and with cal report published by the Central Brain
Localization
cyst formation. Despite its alarming his- Tumor Registry of the United States (CB-
A superficial location, involving the lep-
tological appearance, pleomorphic xan- TRUS) lists pleomorphic xanthoastrocy-
tomeninges and cerebrum (meningoce-
thoastrocytoma has a relatively favour- toma among the unique astrocytoma
rebral) is characteristic of this neoplasm.
able prognosis compared with diffusely variants and reports an annual inci-
Approximately 98% of cases occur su-
infiltrative astrocytoma, with 70.9% re- dence of 0.3 cases per 100 000 popula-
pratentorially, most commonly in the tem-
currence-free and 90.4% overall survival tion {1863}.
poral lobe {825,1254}. Cases involving
rates at 5 years {1081}. Pleomorphic xanthoastrocytoma typical-
the cerebellum and spinal cord have also
ly develops in children and young adults
ICD-0 code 9424/3 be reported {836,1749}, and two cases of
{825}, with mean and median patient
primary pleomorphic xanthoastrocytoma
ages of 25.9 and 22 years, respectively
Grading of the retina in children have been report-
{1935}, but occurrence in older patients,
Pleomorphic xanthoastrocytoma corre- ed {2847}.
including patients in their seventh and
sponds histologically to WHO grade II.
eighth decades of life, has also been re- Clinical features
ported {1935}. There is no sex bias. One Due to the superficial cerebral location of
study in the USA found these tumours to the lesion, many patients present with a
be more common in the Black population fairly long history of seizures. Cerebellar
{1935}. and spinal cord cases have symptoms
that reflect these sites of involvement.
Etiology
No specific etiologies have been im- Imaging
plicated in the genesis of pleomorphic Pleomorphic xanthoastrocytoma is usu-
xanthoastrocytoma. The occasional ally a supratentorial mass, peripherally lo-
association with cortical dysplasia or cated and frequently cystic, involving cor-
with ganglion cell lesions suggests that tex and overlying leptomeninges. CT and
their formation may be facilitated in MRI scans outline the tumour mass and/
malformative states {1409}. Given re- or its cyst. On CT, tumour appearance
Number of cases Number of cases ports in patients with neurofibromatosis is variable (hypodense, hyperdense, or
Fig. 2.20 Age and sex distribution of patients with
type 1 {2023}, a relation to defective NF1
pleomorphic xanthoastrocytoma.

94 Other astrocytic tumours


Fig. 2.22 Histological features of pleomorphicxanthoastrocytoma. A Leptomeningeal pleomorphic xanthoastrocytoma, sharply delineated from the underlying cerebral cortex.
B Granular bodies, intensely eosinophilic or pale, are an almost invariable finding. C Tumour cells showing nuclear and cytoplasmic pleomorphism and xanthomatous change.
D Mature ganglion cell and lymphocytic infiltrates; reprinted from Kros JM et al. {1375}.

mixed), with strong, sometimes heteroge- Microscopy also frequent {825}. The third histologi-
neous contrast enhancement {1857}. Tu- The adjective pleomorphic refers to the cal hallmark of pleomorphic xanthoas-
mour cysts are hypodense. On MRI, the variable histological appearance of the trocytoma is the presence of reticulin
solid portion of the tumour is either hy- tumour, in which spindled cells are in- fibres, which are best seen using silver
pointense or isointense to grey matter on termingled with mononucleated or multi- impregnation. Reactive changes in the
T1 -weighted images and shows a hyper- nucleated giant astrocytes, the nuclei of meninges are not the only source of re-
intense or mixed signal on T2-weighted which show great variation in size and ticulin fibres; individual tumour cells may
and FLAIR images, whereas the cystic staining. Intranuclear inclusions are fre- be surrounded by basement membranes
component is isointense to cerebrospinal quent {825}, as are prominent nucleoli. that also stain positively for reticulin, and
fluid. Postcontrast enhancement is mod- In some cases, the neoplastic astrocytes these can be recognized ultrastructurally
erate or strong {1857}. Perifocal oedema are closely packed, creating a so-called as pericellular basal laminae. By defini-
is usually not pronounced, due to the epithelioid pattern {1106}. In other cases, tion, the mitotic count is < 5 mitoses per
slow growth of the tumour. sheets of fusiform cells are encountered. 10 high-power fields. Necrosis is rarely
The term xanthoastrocytoma refers to present in WHO grade II pleomorphic
Macroscopy
the presence of large, often multinucleat- xanthoastrocytoma in the absence of
Pleomorphic xanthoastrocytomas are
ed xanthomatous cells that have intracel- brisk mitotic activity, but necrosis in itself
usually superficial tumours extending to
lular accumulation of lipids. This is usually is insufficient for a WHO grade III desig-
the leptomeninges. They are frequently
in the form of droplets, which often oc- nation (see Anaplastic pleomorphic xan-
accompanied by a cyst, sometimes thoastrocytoma, p. 98).
cupy much of the cell body, pushing cy-
forming a mural nodule within the cyst
toplasmic organelles and glial filaments
wall. Features such as invasion of the Differential diagnosis
to the periphery. This feature generally
dura {543}, predominantly exophytic Because pleomorphic xanthoastrocyto-
makes the astrocytic character easy to
growth {1688}, multifocality {1629}, and ma often includes a diffusely infiltrating,
recognize by H&E or GFAP stains. Gran-
leptomeningeal dissemination {1905} are non-pleomorphic component, diffuse
ular bodies (either intensely eosinophilic
exceptional. astrocytoma is a common differential
or pale) are a nearly invariable finding
diagnosis. In addition to the presence of
{825}. Focal collections of small lympho-
histologically more typical pleomorphic
cytes, occasionally with plasma cells, are
Pleomorphic xanthoastrocytoma 95
xanthoastrocytoma. The tumours are
predominantly diploid {1047,2701}, occa-
sionally with polyploid populations {1047},
possibly due to subgroups of particularly
bizarre, multinucleated tumour cells.
Comparative genomic hybridization of 50
cases identified loss of chromosome 9 as
the hallmark alteration (present in 50% of
cases) {2713}. Homozygous 9p21.3 de-
letions involving the CDKN2AICDKN2B
Fig. 2.23 Pleomorphic xanthoastrocytoma. A GFAP expression in large pleomorphic and xanthomatous cells. loci were identified in 6 of 10 cases {60%)
B Synaptophysin immunostaining in tumour cells {828}. {2713}. Accordingly, loss of CDKN2A
protein expression was documented by
immunohistochemistry in 61% of pleo-
xanthoastrocytoma components, the expressed in pleomorphic xanthoastro- morphic xanthoastrocytomas {1316}.
combination of BRAF V600E mutation cytoma cells {2083}. BRAF V600E muta- BRAF point mutations occur in approxi-
and absence of an IDH mutation sup- tion, a common alteration in pleomorphic mately 50-78% of cases {584,601,1082,
ports the diagnosis of pleomorphic xanthoastrocytoma, can be detected by 1316,2277,2280}. Most are of the V600E
xanthoastrocytoma. Uncommonly, gan- immunohistochemistry using a specific type, with only a single documented ex-
glioglioma can present with a glial com- antibody {1082,2280}. The immunophe- ception {2280}. However, BRAF V600E
ponent resembling pleomorphic xan- notype with V600E-mutant BRAF expres- mutations are not specific to pleomor-
thoastrocytoma; rare cases of composite sion and loss of CDKN2A expression phic xanthoastrocytoma, and are also
tumours with features of pleomorphic (secondary to homozygous deletion of observed in other primary CNS tumours,
xanthoastrocytoma and ganglioglioma CDKN2A) is frequently observed in pleo- in particular ganglioglioma and pilocytic
in which the two neoplastic compo- morphic xanthoastrocytoma {1316}. astrocytoma {414,599,1297,2277,2280}.
nents coexist side by side with minimal The occurrence of BRAF mutations
intermingling have been reported {1339, Proliferation
seems to be unrelated to the presence of
In most pleomorphic xanthoastrocyto-
1943}. Pleomorphic xanthoastrocytoma histological features of anaplasia.
mas, mitotic figures are rare or absent,
areas showing eosinophilic granular Two studies investigating a total of 7 non-
and the Ki-67 proliferation index is gener-
bodies and spindle-shaped cells may BRAF-mutant pleomorphic xanthoastro-
ally < 1% {825}.
be reminiscent of pilocytic astrocytoma, cytomas identified 1 tumour harbouring
but areas with more typical histology, Cell of origin a TSC2mutation, 1 with an NF1 mutation,
in the absence of BRAF translocations As originally proposed by Kepes, Rubin- and 1 with an ETV6-NTRK3 fusion {184,
or other genetic aberrations leading to stein, and Eng in 1979 {1254}, it has been 2855}. In four series (one published only
MAPK activation, support the diagnosis postulated that pleomorphic xanthoas- in abstract form) with a total of 123 tu-
of pleomorphic xanthoastrocytoma. Mes- trocytoma originates from subpial astro- mours, mutations in the TP53 gene were
enchymal tumours may also enter the dif- cytes. This hypothesis would explain the found in only 7 cases {6%) {824,1238,
ferential diagnosis, but this consideration superficial location of most cases, and 1917}, and were unrelated to the pres-
is usually refuted by positivity for GFAP in is supported by ultrastructural features ence of histological features of anaplasia.
unequivocal tumour (non-reactive) cells, shared between subpial astrocytes and Amplifications of the EGFR, CDK4, and
although GFAP positivity may be focal or the neoplastic cells in pleomorphic xan- MDM2 genes were absent in a series of
even absent in small specimens. thoastrocytoma, in particular the pres- 62 tumours {1238}. No IDH11 mutations
ence of a basal lamina surrounding indi- were detected in a series of 7 tumours
Immunophenotype
vidual cells. However, the expression of (by sequencing) {118} or in a series of
Although the essential nature of pleo-
neuronal markers {828} and CD34 {1316, 60 cases (by immunohistochemistry for
morphic xanthoastrocytoma is clearly
2083} in many pleomorphic xanthoastro- R132H-mutant IDH1) {1081}. These find-
and uniformly glial, with nearly invariable
cytomas, as well as the occasional as- ings molecularly distinguish pleomorphic
immunoreactivity for GFAP and S100
sociation with cortical dysplasia {1271}, xanthoastrocytoma from diffusely infiltrat-
protein {825,828}, the tumours have a
suggests a more complex histogenesis ing cerebral astrocytoma.
significant tendency to exhibit neuronal
and a possible origin from multipotent Although there are few data on the oc-
differentiation. Expression of neuronal
neuroectodermal precursor cells or from currence of BRAFfusions in pleomorphic
markers (including synaptophysin, neu-
a pre-existing hamartomatous lesion. xanthoastrocytoma, there was no evi-
rofilament, class III beta-tubulin, and
dence of 7q34 duplication, which is often
MAP2) has been reported with variable Genetic profile associated with BRAF fusion, in a series
frequency in tumours that have otherwise Complex karyotypes have been docu- of 10 cases analysed by microarray-
typical histological features of pleomor- mented, with gains of chromosomes 3 based comparative genomic hybridiza-
phic xanthoastrocytoma {828,2013}. In and 7 and alterations of the long arm of tion {1961}.
some cases, this biphenotypic glioneu- chromosome 1 {1495,2253,2254}, but
ronal appearance has been confirmed ul- these are not specific to pleomorphic Genetic susceptibility
trastructurally {1007}. CD34 is frequently There are no distinct associations with

96 Other astrocytic tumours


hereditary tumour syndromes, with the
exception of several reports of pleo-
morphic xanthoastrocytoma in patients
with neurofibromatosis type 1 {14,1380,
1761,1870}. Given the high frequency of
MAPK pathway alterations observed in
sporadic pleomorphic xanthoastrocy-
toma, an association with NF1 is not un-
expected. Familial clustering of pleomor-
phic xanthoastrocytoma has not been
documented. One case of a pleomorphic
xanthoastrocytoma with classic histologi-
cal and molecular features developing in
DiGeorge syndrome has been reported
{860}.
Prognosis and predictive factors
Pleomorphic xanthoastrocytoma behaves
in a less malignant fashion than might be
suggested by its highly pleomorphic his-
tology {1254}, but it has an only relatively
favourable prognosis. In a retrospective Fig. 2.24 Pleomorphic xanthoastrocytoma. Molecularly confirmed BRAF V600E-mutant tumours showing: (A) strong
series of 74 cases, 54 patients with WHO granular cytoplasmic immunostaining of a characteristic pleomorphic multinucleated giant tumour cell, (B) weak
grade II pleomorphic xanthoastrocytoma granular cytoplasmic immunostaining of pleomorphic and spindle tumour cells, and (C) strong granular cytoplasmic
had an average 5-year recurrence-free immunostaining of a cluster of isolated tumour cells (A-C: V600E-mutant BRAF immunohistochemistry). D The V600E-
survival rate of 70.9% and 5-year over- mutant BRAF peak in addition to the wildtype BRAF peak is consistent with the presence of a BRAF V600E mutation
all survival rate of 90.4% {1081}. Extent of {1082}.
resection was confirmed to be the most
significant predictive factor of recurrence
{74.4%) {1081}. The estimated 5-year grade III) pleomorphic xanthoastrocy-
{825,1081}. Among patients whose tu-
overall survival rate for these patients was toma. BRAFM600E mutation status is not
mours had low mitotic activity (i.e. < 5 mi-
89.4%, and was similar between children significantly different between paediatric
toses per 10 high-power fields), the esti-
{92.9%) and adults (86.8%) {1081}. and adult tumours (1081). It is unclear
mated recurrence-free survival rate was
BRAF V600E mutation is more com- whether the presence of BRAF V600E
73.7%, and was similar between paedi-
mon in WHO grade II pleomorphic xan- mutation has prognostic significance.
atric patients {73.5%) and adult patients
thoastrocytoma than in anaplastic (WHO

Pleomorphic xanthoastrocytoma 97
Giannini C.
Anaplastic pleomorphic Paulus W.
Louis D.N.
xanthoastrocytoma Liberski P.P.
Figarella-Branger D.
Capper D.

Definition pleomorphic xanthoastrocytoma. In one xanthoastrocytoma, manifesting both at


A pleomorphic xanthoastrocytoma with series of 74 cases, anaplasia was pres- initial diagnosis and at recurrence, may
> 5 mitoses per 10 high-power fields. ent in 23 cases {31%) at first diagnosis, demonstrate less pleomorphism and a
Patients with anaplastic pleomorphic in 23% of paediatric cases, and in 37% of more diffusely infiltrative pattern than
xanthoastrocytoma have significantly adult cases {1081}. typical classic WHO grade II pleomor-
worse survival than those whose tumours phic xanthoastrocytoma. Although his-
Localization tological patterns of anaplasia have not
show < 5 mitoses per 10 high-power
Like WHO grade II pleomorphic xan-
fields {825,1081}. Necrosis may be pres- been formally studied in pleomorphic
thoastrocytoma, anaplastic pleomor-
ent, but its significance in the absence xanthoastrocytoma, small-cell, fibrillary,
phic xanthoastrocytoma is typically a
of increased mitotic activity is unknown and epithelioid/rhabdoid transformation
supratentorial tumour, with the temporal
{1081}. have been reported {1248}.
lobe being the most commonly involved
The frequency of BRAF V600E mutation Anaplastic pleomorphic xanthoastrocy-
lobe. toma may be difficult to distinguish from
is lower among anaplastic pleomorphic
xanthoastrocytomas than among WHO Clinical features epithelioid glioblastoma (see p. 50) both
grade II pleomorphic xanthoastrocyto- The signs and symptoms of anaplastic histologically and molecularly, because
mas, and the prognostic significance of pleomorphic xanthoastrocytoma are sim- both tumour types commonly exhibit
the mutation is unknown {1081,2290}. ilar to those of WHO grade II pleomorphic BRAF V600E mutations {1297}; in fact,
xanthoastrocytoma. Seizures are the pleomorphic xanthoastrocytoma recur-
ICD-0 code 9424/3 most common presenting symptom. ring as epithelioid glioblastoma has also
been described {2508}. Anaplastic pleo-
Grading Imaging morphic xanthoastrocytomas lack the
Anaplastic pleomorphic xanthoastrocy- Like WHO grade II pleomorphic xan- cytological uniformity typical of epithe-
toma corresponds histologically to WHO thoastrocytoma, anaplastic pleomorphic lioid glioblastomas and have eosinophilic
grade III. xanthoastrocytoma is often a circum- granular bodies, which are not seen in
scribed supratentorial mass, peripherally epithelioid glioblastoma {1297,1299}. In
Epidemiology
located and frequently cystic, involving many anaplastic pleomorphic xanthoas-
No specific epidemiological data are
the cortex and overlying leptomeninges. trocytomas, a lower-grade component
available regarding anaplastic pleomor-
phic xanthoastrocytoma compared with Microscopy with features typical of pleomorphic xan-
Anaplasia in pleomorphic xanthoastro- thoastrocytoma is present at least focally
cytoma typically manifests as brisk mi- {825}. There have been rare reports of
totic activity in a tumour that otherwise a SMARCB1-deficient, atypical teratoid/
retains all the diagnostic histological rhabdoid tumour-like lesion arising in
features of pleomorphic xanthoastrocy- pleomorphic xanthoastrocytoma, associ-
toma. High levels of mitotic activity may ated with loss of SMARCB1 expression in
be focal or diffuse. Necrosis is frequently the morphologically distinct high-grade
present, almost always in association rhabdoid component {396,1157}. Such
with brisk mitotic activity. Microvascular clonal evolution may be associated with
proliferation is uncommon and usually a highly aggressive biology even when
associated with brisk mitotic activity and the original tumour is low-grade; the term
necrosis. Anaplasia may be present at SMARCB1-deficient anaplastic pleo-
the time of first diagnosis or at the time morphic xanthoastrocytoma has been
of recurrence, suggesting progression suggested for such a lesion.
from a lower-grade to an anaplastic pleo- Immunophenotype
morphic xanthoastrocytoma. However, The phenotypic profile of anaplastic
some tumours that display features of pleomorphic xanthoastrocytoma is simi-
anaplasia at first resection occasionally lar to that of WHO grade II pleomorphic
demonstrate features at the upper lim- xanthoastrocytoma.
its of a WHO grade II tumour at the time
Fig. 2.25 Anaplastic pleomorphic xanthoastrocytoma. of recurrence, likely reflecting tumour Genetic profile
T1 -weighted MRI with contrast sequences demonstrates heterogeneity. Anaplastic pleomorphic The genetic alterations specific to ana-
a large non-homogeneously enhancing tumour with plastic pleomorphic xanthoastrocytoma
mass effect and moderate surrounding oedema.

98 Other astrocytic tumours


Fig. 2.26 Anaplastic pleomorphic xanthoastrocytoma. A The tumour shows classic features with pleomorphic and xanthomatous (arrow) cells and (B) brisk mitotic activity (arrows),
including atypical mitoses. C The tumour recurred 1 year later and showed remaining areas with pleomorphic morphology and (D) monomorphous areas with epithelioid and rhabdoid
cells with mitotic activity (arrows).

are unknown. Although some anaplas- Prognosis and predictive factors survival rate for patients with tumour ne-
tic xanthoastrocytomas may develop A consistent relationship between mitotic crosis was worse than that for those with-
through malignant progression from activity and outcome in pleomorphic xan- out (42.2% vs 90.2%, P = 0.0002). The
WHO grade II pleomorphic xanthoastro- thoastrocytoma has emerged, whereas dataset was insufficient to detect a differ-
cytoma, the sequence of underlying ge-the relationship between necrosis and ence in survival between patients whose
outcome remains unclear {825,1081}.
netic events has not yet been determined. tumours had > 5 mitoses per 10 high-
The frequency of BRAFM600E mutation One study found that a mitotic count of power fields and necrosis (n = 14; 7 pa-
> 5 mitoses per 10 high-power fields (with
is lower in anaplastic pleomorphic xan- tients died and 6 cases recurred) and
thoastrocytoma (9 of 19 cases [47.4%] one high-power field covering 0.23 mm2) those whose tumours had > 5 mitoses
in one study) than in pleomorphic xan-can be used to establish the diagnosis. per 10 high-power fields but no necrosis
thoastrocytoma (30 of 40 cases [75.0%]In that study, significant mitotic activ- (n = 5; 2 patients died and 3 cases re-
ity (defined as > 5 mitoses per 10 high-
in a separate study), and its prognostic curred). Of the 2 patients whose tumours
significance is unknown {1081,2290}. power fields) and/or necrosis was en- had necrosis but not increased mitotic
BRAF V600E mutation status is not sig-countered in 31% of tumours at initial activity, one had no evidence of disease
presentation {1081}. These features were
nificantly different between paediatric after 10 years of follow-up; the other had
and adult cases {1081}. found to be associated with shorter sur- only limited follow-up {1 month), but was
vival [1081}. The 5-year overall survival still alive at that time. Between children
Genetic susceptibility rate for patients whose tumours showed
No distinct associations between ana- > 5 mitoses per 10 high-power fields was and adults, there were no significant
plastic pleomorphic xanthoastrocytoma significantly worse than that for patients differences in 5-year recurrence-free
and hereditary tumour syndromes have whose tumours showed < 5 mitoses per survival (67.9% vs 62.4%, P = 0.39) or
been reported. 5-year overall survival {87.4% vs 76.3%,
10 high-power fields (89.4% vs 55.6%, P = 0.83). The prognostic significance of
P = 0.0005). And the 5-year overall BRAFM600E mutation remains unknown.

Anaplastic pleomorphic xanthoastrocytoma 99


Subependymoma McLendon R.
Schiffer D.
Rushing E.J.
Hirose T.
Rosenblum M.K. Santi M.
Wiestler O.D.

Definition
A slow-growing, exophytic, intraventric-
ular glial neoplasm characterized by
clusters of bland to mildly pleomorphic,
mitotically inactive cells embedded in an
abundant fibrillary matrix with frequent
microcystic change.
Subependymomas are often detected in-
cidentally, by neuroimaging or at autopsy,
and have a very favourable prognosis
{1126,1211,1533,2794}. Some tumours
have the admixed histological features of
both subependymoma and ependymoma.
ICD-0 code 9383/1
Grading
Subependymoma corresponds histologi-
cally to WHO grade I.
Epidemiology
The true incidence of subependymoma
is difficult to determine, because these Fig. 3.02 A Subependymoma filling the right lateral ventricle, with displacement of the septum pellucidum to the
tumours frequently remain asymptomatic contralateral hemisphere. The tumour is sharply delineated and only focally attached to the ventricular wall; the
and are often found incidentally at autop- cut surface is greyish-white with some small haemorrhages; note the old cystic infarct in the left corpus caudatum
(arrowhead). B Large subependymoma filling the left ventricle and a smaller one in the right ventricle. C Posterior fossa
sy. In two studies, subependymomas ac- subependymoma in the caudal region of the fourth ventricle. Note the compression of the dorsal medulla (arrowheads).
counted for approximately 8% of ependy- D Third ventricle subependymoma (arrowheads).
mal tumours {1398,2274}, and in one of
the studies, they accounted for 0.51% of
Localization with motor and sensory deficits accord-
all CNS tumours resected at a single in-
Subependymomas are distinguished by ing to the affected anatomical segment.
stitution {1398}.
their intraventricular location, sharp de- Incidental detection of asymptomatic
Subependymomas develop in both sex-
marcation, slow growth, and usually non- subependymomas at autopsy is common
es and in all age groups, but occur most
invasive behaviour. The most frequent {2201}.
frequently in middle-aged and elderly
site is the fourth ventricle (accounting for
patients. The male-to-female ratio is ap- Imaging
50-60% of cases), followed by the lateral
proximately 2.3:1 {2056,2201}. Subependymomas present as sharply
ventricles (accounting for 30-40%). Less
common sites include the third ventricle demarcated nodular masses that are
and septum pellucidum. In rare cases, usually non-enhancing. Calcification and
tumours occur intraparenchymally in the foci of haemorrhage may be apparent.
cerebrum {1279}. In the spinal cord, sub- Intramedullary cases are typically ec-
ependymomas manifest as cervical and centric in location, rather than centrally
cervicothoracic intramedullary or (rarely) positioned as is typical of intraspinal
extramedullary masses {1130,2201}. ependymomas. The lesions are hypoin-
tense to hyperintense on both T1- and T2-
Clinical features weighted MRI, with minimal to moderate
Subependymomas may become clinical- enhancement {2056,2201}.
ly apparent through ventricular obstruc-
tion and increased intracranial pressure. Macroscopy
Spontaneous Intratumoural haemorrhage These tumours present as firm nodules of
has been observed {31,369}. Rare in- various sizes, bulging into the ventricular
traparenchymal tumours exhibit marked lumen. In most cases, the diameter does
Fig. 3.01 Age and sex distribution of subependymoma, oedema and are associated with sei- not exceed 1-2 cm. Intraventricular and
based on 167 cases; data from the Central Brain Tumor
zures {2056}. Spinal tumours manifest spinal subependymomas are generally
Registry of the United States (CBTRUS), 1995-2002.

102 Ependymal tumours


Fig. 3.03 Subependymoma. A Subependymomas have a coarse fibrillar matrix and contain clusters of uniform nuclei. B Microcysts are common. C Cells are uniform, often
appearing as bare nuclei against the fibrillary matrix.

well demarcated. Large subependymo- Immunophenotype a set of 41-year-old Identical twins {1799},
mas of the fourth ventricle may cause Immunoreactivity for GFAP is usually in a set of 22-year-old identical twins
brain stem compression. Rare cases present, although to various extents, and {464}, and in a brother and sister aged
arising in the cerebellopontine angle immunoreactivity can also be found for 28 and 31 years, respectively {430}. In a
have been described in both adults and neural markers of low specificity, such family with several brain tumours, three
children {1048}. as NCAM1 and neuron-specific enolase siblings developed subependymomas of
{2832}. Unlike in classic ependymomas, the fourth ventricle: two brothers (aged
Microscopy 27 and 57 years) and a sister (aged
EMA is rarely expressed in subependy-
Subependymomas are characterized by 49 years). In addition, a younger sibling
momas. One study of potential therapeu-
clusters of small uniform nuclei embedded (aged 13 years) had a pontine tumour
tic targets reported that TOP2B, MDM2,
in a dense fibrillary matrix of glial cell pro- of undetermined pathology and an el-
nucleolin, HIF1-alpha, and phosphoryl-
cesses with frequent occurrence of small der brother (aged 57 years) developed
ated STAT3 are frequently expressed in
cysts, particularly in lesions originating in a fourth ventricular ependymoma {1032}.
subependymomas {1329}.
the lateral ventricles. Tumour cell nuclei A prenatal, maldevelopmental origin of
appear isomorphic and resemble those of Cell of origin familial subependymomas has been
subependymal glia. In solid tumours, occa- Proposed cells of origin include sub- suggested {464}, but the occurrence in
sional pleomorphic nuclei may be encoun- ependymal glia {101,1716}, astrocytes a family with several brain tumours and
tered; however, nuclear variation is typical of the subependymal plate, ependymal in a father (aged 47 years) and son (aged
in multicystic tumours. Some subependy- cells {2205}, and a mixture of astrocytes 22 years) is more suggestive of a genetic
momas exhibit low-level mitotic activity, and ependymal cells {746,2257}. susceptibility {1032,2209}.
but this is exceptional. Calcifications and
Genetic profile Prognosis and predictive factors
haemorrhage can occur. Prominent tumour
A recent study using DNA methylation Subependymomas have a good progno-
vasculature may rarely be accompanied by
profiles of ependymomas from all age sis {1126}. To date, no recurrences after
microvascular proliferation. Occasionally,
groups and subependymomas from adult gross total resection have been reported
cell processes are oriented around ves-
patients to characterize the full range of {2257}. Complete excision may not be fea-
sels, forming ependymal pseudorosettes.
disease identified nine molecular groups sible for all tumours arising from the floor
In some cases, a subependymoma consti-
of ependymoma across three anatomical of the fourth ventricle; however, debulking
tutes the most superficial aspect of a clas-
sites: the supratentorial compartment, alone usually yields an excellent progno-
sic ependymoma or (more rarely) a tany-
posterior fossa, and spinal compartment sis, given that these tumours grow slowly
cytic ependymoma {1279}; such combined
{1880}. Groups dominated by subepen- and residual tumour may take decades to
tumours are classified as mixed ependymo-
dymomas were found to occur in all three manifest as a symptomatic mass {321}. Al-
ma-subependymoma and are graded on
of these anatomical locations. Posterior though recurrences are generally not ex-
the basis of the ependymoma component
fossa and spinal subependymomas har- pected with subtotally resected tumours
{2201}. In one rare example, the subepen-
boured chromosome 6 copy number al- {2028}, rare cases have been reported,
dymomatous element predominated and
terations, whereas supratentorial tumours and cerebrospinal fluid spread has been
seemed to signify a good overall prognosis
showed virtually none. The supratento- documented as well {2321,2677}. Mitotic
{2201}. Examples of subependymoma with
rial and posterior fossa subependymoma activity is usually low or absent. Scattered
melanin formation {2179}, rhabdomyosarco-
groups showed excellent overall survival. mitoses and cellular pleomorphism are
matous differentiation {2566}, and sarcoma-
tous transformation of vascular stromal ele- Genetic susceptibility of no clinical significance {2020,2201}.
ments {1532} have been reported. Familial occurrence of subependymo- KJ-67/MIE51 immunohistochemical studies
At the ultrastructural level, subependymo- mas is rare, but well documented. All have found proliferation index values of
mas show cells with typical ependymal published cases have been located in < 1%, compatible with the slow growth of
characteristics, including cilium formation the fourth ventricle. Reports have de- this entity, although one study of 2 cases
and microvilli, and sometimes with abun- scribed the simultaneous manifestation indicated that recurrence rate may corre-
dant intermediate filaments {101, 1716, of fourth ventricular subependymomas in late with proliferation index {1354}.
2274}.

Subependymoma 103
McLendon R.
Myxopapillary ependymoma Schiffer D.
Rosenblum M.K.
Wiestler O.D.

Definition The average patient age at presentation


A glial tumour arising almost exclusive- is 36 years, with a range of 6-82 years.
ly in the region of the conus medullaris, In one study of 320 ependymomas of the
cauda equina, and filum terminate, and filum terminale, 83% were of the myxo-
histologically characterized by elongat- papillary type, with a male-to-female ratio
ed, fibrillary processes arranged in radial of 2.2:1 {395}. The youngest patient was
patterns around vascularized, mucoid, an infant aged 3 weeks {459}.
fibrovascular cores.
Myxopapillary ependymoma is a slow- Localization
growing variant of ependymoma. It typi- Myxopapillary ependymomas occur
cally occurs in young adults. The tumour almost exclusively in the region of the
Fig. 3.05 This macroscopic photograph of a transected
generally has a favourable prognosis, conus medullaris, cauda equina, and fi-
myxopapillary ependymoma shows its typical sausage
but can be difficult to resect completely. lum terminale. They may originate from appearance externally, with the mucinous, pinkish-white
When this is the case, residual tumour ependymal glia of the filum terminale to variegated appearance on cut surface.

may recur repeatedly, as the tumour be- involve the cauda equina, and only rarely
comes entangled with spinal nerves. invade nerve roots or erode sacral bone.
Multifocal tumours have been described exhibiting spinal metastatic dissemina-
ICD-0 code 9394/1 {1748}. Myxopapillary ependymomas can tion at presentation {674,2108}.
occasionally be observed at other loca- Macroscopy
Grading
tions, such as the cervicothoracic spinal Myxopapillary ependymomas are lobu-
Histologically, myxopapillary ependymo-
cord {2396}, the fourth ventricle {1502}, lated, soft, and grey or tan. They are of-
ma corresponds to WHO grade I. How-
the lateral ventricles {2247}, and the brain ten encapsulated. Gelatinous alterations,
ever, this variant may have a more ag-
parenchyma {2698}. Subcutaneous sac- cyst formation, and haemorrhage may be
gressive biological behaviour in children
rococcygeal or presacral myxopapillary apparent.
and a poor outcome after incomplete
ependymomas constitute a distinct sub-
resection. Microscopy
group. They are thought to originate from
Epidemiology ectopic ependymal remnants {1089}. In classic cases, cuboidal to elongated
Myxopapillary variants account for Intrasacral variants can clinically mimic tumour cells are radially arranged in pap-
9-13% of all ependymomas {1398,2274}. chordoma. illary fashion around hyalinized fibrovas-
In the conus medullaris / cauda equina cular cores. Some examples show little
Clinical features or no papillary structuring and consist
region, myxopapillary ependymomas
Myxopapillary ependymomas are typi- largely of confluent, polygonal tumour
are the most common intramedullary
cally associated with back pain, often of cell sheets or fascicles of spindled cells.
neoplasm, with annual incidence rates of
long duration. Alcian blue-positive myxoid material ac-
about 0.08 cases per 100 000 males and
0.05 cases per 100 000 females {1863}. Imaging cumulates between tumour cells and
Myxopapillary ependymomas are typi- blood vessels, also collecting in micro-
cally sharply circumscribed and con- cysts (which help to identify largely solid,
trast-enhancing. Extensive cystic change non-papillary examples). Rounded eo-
and haemorrhage may be seen. sinophilic structures (so-called balloons)
that are periodic acid-Schiff-positive
Spread and exhibit spiculated reticulin staining
In a recent review of 183 patients with are seen in some cases. Mitotic activity
myxopapillary ependymomas, distant and the Ki-67 proliferation index are low
spinal metastases were found in 17 pa- {2019}. Histological features of anaplasia
tients {9.3%) and brain metastases in are most exceptional {98}.
11 {6.0%). Factors associated with dis- Ultrastructurally, the cells do not show
tant treatment failure included young polarity, but do show adherens junctions
age, lack of initial adjuvant radiotherapy, with cytoplasmic thickening and wide
Number of cases Number of cases
and incomplete excision {2711}. Paedi- spaces containing amorphous material
Fig. 3.04 Age and sex distribution of myxopapillary atric patients are particularly prone to or loose filaments {2076,2402}. Extracel-
ependymoma, based on 311 cases; data from the Central lular spaces, delineated by cells with
Brain Tumor Registry of the United States (CBTRUS), basal membranes, contain projected
1995-2002.

104 Ependymal tumours


Fig. 3.06 Myxopapillary ependymoma. A Tumour cells accumulate around vessels with mucoid degeneration. B Tumour cells interspersed between large vessels with mucoid
degeneration. C Elongated fibrillary processes extend through myxoid regions to reach a blood vessel. D Myxopapillary ependymoma of the cauda equina. Perivascular tumour
cells consistently express GFAP.

villi {2076}. Few cilia, complex interdigi- myxopapillary ependymomas, whereas survival rate of 98.4% after total or par-
tations, and abundant basement mem- labelling for CAM5.2, CK5/6, CK7, CK20, tial resection {2770}. Late recurrence
brane structures have been described or 34betaE12 has been reported as ab- and distant metastases can occur after
{2019}, with the distinctive feature of sent or exceptional in this setting {1427, incomplete resections in both adults and
some examples being aggregations of 2641}. children {35,674}. Children have had a
microtubules within endoplasmic reticu- less predictable outcome in some stud-
lum complexes {1018,1019}. The pres- Genetic profile ies, even with apparent gross total resec-
ence of adherens junctions and intra- A recent study using DNA methylation tion {2216,2426}. In a series of 183 cases,
cytoplasmic lumina with microvilli was profiles to characterize the full range of treatment failure occurred in approxi-
recently confirmed {2686}. disease identified nine molecular groups mately one third of the patients. Recur-
of ependymoma across three anatomical rence was mainly local and was more fre-
Immunophenotype quent in younger patients and those not
sites: the supratentorial compartment,
Diffuse immunoreactivity for GFAP dis- posterior fossa, and spinal compartment treated initially with adjuvant radiotherapy
tinguishes myxopapillary ependymomas {1388,2711}. Gross total resection plays
{1880}. Myxopapillary ependymomas
from metastatic carcinomas, chordomas, an important role in improving outcome,
were found in one molecular group from
myxoid chondrosarcomas, paraganglio- and adjuvant radiotherapy improves pro-
the spinal compartment. They were char-
mas, and schwannomas {1427,2641}. gression-free survival {1389,2578}.
acterized by polyploidy (in particular
Labelling for S100 or vimentin is also Although age seems to be the strongest
gains across multiple chromosomes) and
typical, and reactivity for CD99 and an excellent outcome. predictor of recurrence, expression of
NCAM1 is frequently seen {1427}. Im- EGFR has also been cited as a potential
munoreactivity for the AE1/AE3 cytoker- Prognosis and predictive factors biomarker of recurrence {2647}.
atin cocktail is a common feature of Prognosis is favourable, with a 5-year

Myxopapillary ependymoma 105


Ellison D.W. Korshunov A
Ependymoma McLendon R. Ng H.-K.
Wiestler O.D. Witt H.
Kros J.M. Hirose T.

Definition anaplastic ependymoma are consid- 0-14 years) to 4.5% (at 15-19 years) to
A circumscribed glioma composed of ered to correspond histologically to WHO 4.0% (at 20-34 years) {1863}. In children
uniform small cells with round nuclei in grades II and III, respectively. However, aged < 3 years, as many as 30% of all
a fibrillary matrix and characterized by no association between grade and bio- CNS tumours are ependymomas. In Can-
perivascular anucleate zones (pseu- logical behaviour or survival has been ada, a mean annual incidence of 4.6 cas-
dorosettes) with ependymal rosettes also definitively established {248,633,703}. es per 100 000 population was estimated
found in about one quarter of cases. Of the various studies of prognostic for ependymomas in infants {2046}. In
Classic ependymoma generally has a variables and outcome in ependymoma, the USA, ependymoma is more common
low cell density and a low mitotic count. those that have not found an association in Whites than in African-Americans, with
It very rarely invades adjacent CNS pa- between grade (II vs III) and progression- an incidence rate ratio of 1.67:1. No such
renchyma to any significant extent. Cilia free or overall survival outnumber those difference is found between Hispanic
and microvilli are seen on ultrastructural that have. The published ratios of grade II and non-Hispanic populations {1863}.
examination. to grade III tumours in series of ependy- In the spinal cord, ependymomas are
Classic ependymomas are mainly in- momas vary widely, from 17:1 to 1:7, and the most common neuroepithelial neo-
tracranial tumours; they do occur in the the explanation for such inconsistent data plasms, accounting for 50-60% of all
spinal cord, but the myxopapillary vari- is multifactorial {633,856,2557}. The inter- spinal gliomas in adults {2653}, but they
ant is more common at this site. Classic pretation of most histopathological varia- are rare in children {164}.
ependymomas occur in both adults and bles used in this classification for grading
Age and sex distribution
children, although most posterior fossa purposes is subjective, and ependymo-
tumours present in childhood. Ependy- mas are morphologically heterogeneous. Ependymomas can develop in patients
momas have a variable clinical outcome, For example, the significance of grading of any age, with reported patient ages
which is primarily dependent on extent of on the basis of focal microvascular prolif- ranging from birth to 81 years [http://
surgical resection, the use of irradiation eration or focally increased mitotic counts www.cbtrus.org]. However, incidence is
as an adjuvant therapy, and molecular within large areas of bland architectural greatly dependent on histological variant,
group {857,1880}. and cytological features is difficult to molecular group, and location. Posterior
Three distinct histopathological pheno- determine. There have been few studies fossa ependymomas are most common
types, which are classified as ependymo- of the prognostic significance of WHO among children, with a mean patient
ma variants (although without particular grade or individual pathological features age at presentation of 6.4 years {2295},
clinicopathological significance) can be across large trial cohorts in which proper and spinal tumours dominate a second
a prominent component of both classic multivariate analyses of prognostic vari- age peak at 30-40 years. Supratentorial
and anaplastic ependymoma: papillary ables can be performed, and there have ependymomas affect paediatric as well
ependymoma, clear cell ependymoma, been only three studies in which evalua- as adult patients. The overall male-to-
and tanycytic ependymoma. tion of histological variables was defined female ratio is 1.77:1, but this ratio varies
stringently and undertaken by several significantly across different anatomical
ICD-0 code 9391/3 observers {633,856,2557}. Due to these sites and molecular groups {1171,1880,
limiting factors, grading is almost never 2046}. In the USA, classic and anaplastic
Grading
used for therapeutic stratification of pa- ependymoma have an approximate com-
Traditionally, classic ependymoma and
tients with ependymoma. Given that spe- bined annual incidence of 0.29 cases in
cific genetic alterations and molecular males and 0.22 in females.
groups have recently been proposed as
prognostic or predictive factors for these Localization
tumours {1560,1880,2767}, the practice Ependymomas may occur along the
of histologically grading ependymoma ventricular system or spinal canal, in
may soon become obsolete altogether. the cerebral hemispheres, or at extra-
CNS sites. Overall, 60% of the tumours
Epidemiology develop in the posterior fossa, 30% in
the supratentorial compartment, and
Incidence 10% in the spinal canal [http://seer.
In the USA, ependymomas account for cancer.gov/archive/csr/1975_2004].
6.8% of all neuroepithelial neoplasms. The In adult patients, infratentorial and spi-
Age at diagnosis
incidence rate decreases with increasing nal ependymomas occur with almost
Fig. 3.07 Cumulative age distribution (both sexes) of
patient age at diagnosis, from 5.6% (at equal frequency, whereas infratentorial
ependymoma, based on 298 cases {2274}.

106 Ependymal tumours


and lung. Myxopapillary ependymomas
occur in the subcutaneous tissue of the
sacrococcygeal area.
Clinical features
The clinical manifestations depend on
tumour localization. Ependymomas of
the posterior fossa can present with
signs and symptoms of hydrocephalus
and raised intracranial pressure, such
as headache, nausea, vomiting, and diz-
ziness. Involvement of cerebellar and Fig. 3.09 Ependymoma in a child, filling the entire
lumen of the fourth ventricle. Note the compression and
brain stem structures may cause ataxia,
displacement of the medulla.
visual disturbance, paresis, or cranial
nerve deficits. Patients with supratento-
demonstrate histopathological overlap
rial ependymomas may show focal neu-
with small cell glioblastoma {1463}.
rological deficits or epilepsy, as well as
features of raised intracranial pressure. Microscopy
Enlargement of the head or separation Classic ependymoma is a well-delineat-
of the cranial sutures can be evident in ed glioma with monomorphic cells char-
young babies. Spinal ependymomas can acterized by a variable density and round
present with back pain and focal motor to oval nuclei with speckled nuclear chro-
and sensory deficits or paraparesis. matin. The key histological features are
perivascular anucleate zones (pseudoro-
Imaging
settes) and (true) ependymal rosettes.
Gadolinium-enhanced MRI shows
The pseudorosettes are composed of
well-circumscribed masses with vari-
tumour cells radially arranged around
ous degrees of contrast enhancement.
blood vessels, creating perivascular anu-
Ventricular obstruction or brain stem
cleate zones of fine fibrillary processes.
displacement and hydrocephalus are
The ependymal rosettes and tubular ca-
common accompanying features. Su-
nals are composed of bland cuboidal or
Fig. 3.08 A Fourth ventricle ependymoma. Note the pratentorial tumours often exhibit cystic
columnar tumour cells arranged around
enlargement of the aqueduct and hydrocephalus of the components. Intratumoural haemor-
a central lumen. Pseudorosettes can be
third ventricle. B Cervical ependymoma. Sagittal MRI rhage and calcification are occasionally
shows an ependymoma in the upper cervical spinal cord
found in practically all ependymomas,
observed. Gross infiltration of adjacent
(left, arrowhead) with marked gadolinium enhancement whereas ependymal rosettes are present
brain structures and oedema are very
(right), delineated on both sides by a typical cyst. in only a minority.
rare. MRI is particularly useful for deter-
Cell density can vary considerably in
mining the relationship with surrounding
ependymoma, and a high nuclear-to-
ependymomas predominate in children structures, invasion along the cerebro-
cytoplasmic ratio may not necessarily
{1385}. In children aged < 3 years at spinal fluid pathway, and syrinx forma-
be associated with brisk mitotic activity
presentation, 80% of ependymomas are tion. Cerebrospinal fluid spread is a key
or other anaplastic features, particularly
in the posterior fossa {2046}. Posterior factor for staging, prognostication, and
in supratentorial vascular ependymoma,
fossa ependymomas are located in the treatment.
which demonstrates a distinctive branch-
fourth ventricle and sometimes involve ing network of delicate capillary blood
Macroscopy
the cerebellopontine angle; in the fourth vessels and focal clear-cell change.
Ependymomas are well-circumscribed
ventricle, 60%, 30%, and 10% of the Some posterior fossa ependymomas
tumours usually arising in or near the
tumours originate in the floor, lateral as- contain nodules of high tumour cell
ventricular system. They are tan-coloured
pect, and roof, respectively {1087,2234}. density, often with an increased mitotic
and are soft and spongy, occasionally
Supratentorial ependymomas arise from count. This biphasic pattern can accom-
with gritty calcium deposits. Tumours
the lateral or third ventricles (in 60% of pany a distinctive cerebriform folding of
arising in the caudal fourth ventricle often
cases) or from the cerebral hemispheres, the tumour surface.
flow through the foramina of Luschka and
without obvious connection to a ventri- Other histological features include re-
Magendie to wrap around the brain stems
cle (in 40% of cases). In the spinal cord, gions of myxoid degeneration, Intratu-
cranial nerves and vessels, and have
cervical or cervicothoracic localization is moural haemorrhage, dystrophic calci-
been termed plastic ependymomas
common among classic ependymomas. fication, and (occasionally) metaplastic
{503}. Rarely, ependymomas can occur
In contrast, the myxopapillary variant cartilage or bone. Prominent hyalinization
within the cerebral hemisphere, where
predominantly affects the conus and of tumour vessels is sometimes found,
they are well circumscribed {2356}. Other
cauda equina. Rare extra-CNS ependy- especially in posterior fossa and spinal
rare examples, often recurrent tumours,
momas have been observed in the ova- ependymomas. Regions of geographi-
infiltrate the cerebral parenchyma and
ries {1327}, broad ligaments {159}, pelvic cal necrosis may be observed in classic
and abdominal cavities, mediastinum,

Ependymoma 107
Fig. 3.10 Ependymoma. A Ependymal rosettes are characterized by columnar tumour cells arranged around a central lumen; they are infrequent, but a diagnostic hallmark of
ependymoma {1291}. B Ependymal canals. C High tumour-cell density and perivascular pseudorosettes. D This ependymoma shows extensive hyalinization, which may precede
calcification {1291}.

ependymoma, but palisading necrosis located at the luminal surface, junctional other gliomas {1101,1865,2031}. Focal cy-
and microvascular proliferation are only complexes at the lateral surface, and tokeratin immunoreactivity can be seen in
focal features in this tumour, with its lack of a basement membrane at the some cases {2641}. Rarely, ependymo-
bland cytology and low mitotic count. internal surface. The cells may form mi- mas can express neuronal antigens {72,
The interface between tumour and CNS crorosettes into which microvilli and cilia 2036,2154}. L1CAM expression is evident
parenchyma is typically well demarcated, project. Junctional complexes (zonulae in supratentorial ependymomas with a
although evidence of brain tissue infiltra- adherentes) irregularly linked by zonu- C11orf95 rearrangement {1891}.
tion may occasionally be encountered. lae occludentes or gap junctions, as well
Cell of origin
Three distinct histopathological pheno- as cell processes filled with intermedi-
Stem cells isolated from ependymomas
types, which are classified as ependymo- ate filaments, may also be encountered
have a radial glia phenotype, suggesting
ma variants (although without particular {858}. A basal lamina may be present at
that radial glia cells are the histogenetic
clinicopathological significance) can be the interface between tumour cells and
source of these tumours {2526}. Further
a prominent component of both classic vascularized stroma.
research has implicated distinct groups
and anaplastic ependymoma: papillary
Immunophenotype of stem cells that are specific to anatomi-
ependymoma, clear cell ependymoma,
Immunoreactivity for GFAP is usually ob- cal site; cerebral neural stem cells and
and tanycytic ependymoma.
served in pseudorosettes, but is more adult spinal neural stem cells are poten-
Rare ependymomas have been reported
variable in other elements of the tumour, tial cells of origin for cerebral and spinal
with lipomatous metaplasia, widespread
such as rosettes and papillae. Ependy- ependymomas, respectively, and these
pleomorphic giant cells, extensive tu-
momas typically express S100 protein origins would explain the predominant
mour cell vacuolation, melanotic differen-
and vimentin {1285}. EMA Immunoreac- locations of these tumours in the differ-
tiation, signet ring cells, and neuropil-like
tivity can be found in most ependymo- ent age groups {1171,1891}. The impor-
islands.
mas, with expression along the luminal tance of anatomical site in ependymoma
Ultrastructure surface of some ependymal rosettes or biology is demonstrated by the molecu-
Ependymomas retain the characteristic manifesting as dot-like perinuclear or lar groups of the disease as defined by
ultrastructural properties of ependymal ring-like cytoplasmic structures {1241}. methylome profiling, which is considered
cells, such as cilia with a 9 + 2 microtubu- OLIG2 expression is characteristically to reflect histogenesis {1880}.
lar pattern, blepharoblasts and microvilli sparse in ependymomas compared with

108 Ependymal tumours


Fig. 3.11 Ependymoma. A GFAP immunoreactivity is largely restricted to perivascular tumour cells {1291}. B EMAstaining with dot-like cytoplasmic reactivity; immunohistochemical
detection of EMA has been used to identify intracytoplasmic microrosettes, a feature found in both typical and tanycytic ependymomas, but infrequently (if at all) in myxopapillary
ependymomas. C EMA immunoreactivity in ependymoma demonstrates round intracytoplasmic microrosettes.

Genetic profile ependymomas {1891}, characterize the a standardized incidence ratio of 3.70
Molecular alterations are very common in other two supratentorial groups: ST-EPN- {1722,2570}. However, ependymomas
ependymoma and comprise cytogenetic, RELA and ST-EPN-VAP1. The other two do not demonstrate mutations in ARC
genetic, epigenetic, and transcriptomic posterior fossa groups (PF-EPN-A and {1849}. In a Japanese family, two of four
changes. Ependymomas display a broad PF-EPN-B) match those previously called siblings developed a cervical spinal cord
range of cytogenetic aberrations, most group A and group B in some molecu- ependymoma and one had a schwan-
commonly gains of chromosomes 1q, 5, lar studies {1026,1560,2696,2767}. The noma. Neurofibromatosis type 2 was
7, 9, 11, 18, and 20 and losses of chro- final two molecular groups for the spinal excluded, and genetic analysis revealed
mosomes 1 p, 3, 6q, 6, 9p, 13q, 17, and cord (including the cauda equina) con- a common allelic loss at 22q11.2-qter in
22 {1267,1351}. Supratentorial tumours tain myxopapillary ependymomas and two of the affected siblings. The authors
preferentially show loss of chromosome classic ependymomas, respectively, who studied this family suggested the ex-
9 {372,888,1159,1171,2767,2860}; in par- and are termed SP-MPE and SP-EPN. istence of a tumour suppressor gene on
ticular, homozygous deletion of CDKN2A In infants and young children, posterior chromosome 22 related to the genesis of
has been recurrently demonstrated in su- fossa ependymomas mainly fall into the familial ependymomas {2827}.
pratentorial ependymomas {1639,2008, PF-EPN-A group, whereas PF-EPN-B
Prognosis and predictive factors
2526}. Gain of chromosome 1q has been tumours occur mainly in adolescents
The identification of clinicopathological
reported as a reproducible prognostic and adults. Copy number alterations,
variables of prognostic value in ependy-
marker in several trial cohorts, being as- particularly gains and losses of whole
momas is an important but challenging
sociated with poor outcome in posterior chromosomes and chromosome arms,
issue {2275}. In particular, the clinical util-
fossa tumours {1266,1351,2767}. Mono- characterize PF-EPN-B ependymomas,
ity of individual histopathological features
somy 22 and deletions or translocations whereas PF-EPN-A ependymomas show
or tumour grade remains highly contro-
of chromosome 22q are particularly com- few copy number alterations. Two molec-
versial {633,776}. Gain of chromosome
mon in spinal cord tumours and tumours ular groups, ST-EPN-RELA and PF-EPN-
1q has been reported to be a potential
associated with neurofibromatosis type 2 A, are associated with a particularly poor
outcome indicator among tested molecu-
{936}. The NF2 gene is involved in epen- prognosis {1880,2696,2767}.
lar markers {372,857,1266,1351,1639},
dymoma tumorigenesis, and NF2 muta- Posterior fossa ependymomas have a
and outcome correlates of molecular
tions occur frequently in spinal ependy- very low mutation rate and lack recurrent
groups may prove significant in the future
momas {207,621}. somatic mutations on analysis by whole-
{1560,1880,2696,2767}.
Using DNA methylation profiling, several genome sequencing methods {1560,
studies have provided support for the 1891}. Supratentorial ependymomas are Patient age and extent of resection
existence of distinct molecular groups characterized by a recurrent structural Children with ependymoma fare worse
among ependymomas {1049,1424,1560, variant, the C11orf95-RELA fusion gene, than adults. This difference may reflect
1880}. These groups show strong re- which is a by-product of chromothrip- the more frequent occurrence of paediat-
lationships to certain anatomical sites sis and occurs in 70% of paediatric su- ric tumours in the posterior fossa versus
(see Table 3.01, p. 110). In a large cohort pratentorial ependymomas. the predominantly spinal location for adult
(containing > 500 tumours), three groups tumours. Children aged < 1 year have a
Genetic susceptibility
were identified in each of the three CNS 5-year overall survival rate of 42.4% {791}.
Spinal ependymomas occur in neurofi-
compartments (i.e. supratentorial, poste- With increasing age, the 5-year overall
bromatosis type 2, indicating a role of the
rior fossa, and spinal) {1880}. Tumours survival rate improves, to 55.3% among
NF2 gene in these neoplasms. Other he-
with a subependymomatous morphology 1-4-year-olds, 74.7% among 5-9-year-
reditary forms of ependymoma are rarely
were classified into separate spinal, pos- olds, and 76.2% among 10-14-year-olds.
observed {309}. Two patients with Tur-
terior fossa, and supratentorial groups, Extent of surgical resection is consistent-
cot syndrome and ependymomas have
called SP-SE, PF-SE, and ST-SE, re- ly reported to be a reliable indicator of
been reported, and parental colon can-
spectively. Fusion genes involving either outcome; gross total resection is associ-
cer is associated with an increased risk
RELA or YAP1, as previously described ated with significantly improved survival
of ependymomas among offspring, with
for a large proportion of supratentorial

Ependymoma 109
Table 3.01 Key characteristics of the nine molecular groups of ependymoma; based on data from a single study {1880}

Anatomical Genetic Dominant Age at Molecular groups of ependymoma


Group Outcome
location characteristic pathology presentation
Transcriptome and methylome profil-
Infancy to
ST-EPN-RELA RELA fusion gene Classic/anaplastic Poor ing have established the relevance of
adulthood
anatomical site to ependymoma biol-
Infancy to ogy. In a recent study that will likely
Supratentorial ST-EPN-VAP7 YAP1 fusion gene Classic/anaplastic Good
childhood
serve as the basis for the future mo-
ST-SE Balanced genome Subependymoma Adulthood Good lecular classification of the disease
PF-EPN-A Balanced genome Classic/anaplastic Infancy Poor
{1880}, nine groups of ependymoma
were described; three for each of the
Genome-wide Childhood to
Posterior fossa PF-EPN-B
polyploidy
Classic/anaplastic Good three major CNS anatomical compart-
adulthood
ments (i.e. the supratentorial com-
PF-SE Balanced genome Subependymoma Adulthood Good
partment, posterior fossa, and spinal
SP-EPN NF2 mutation Classic/anaplastic
Childhood to
Good
compartment). The modal patient
adulthood age at presentation, clinical outcome,
Spinal SP-MPE
Genome-wide
Myxopapillary Adulthood Good
and frequencies of histopathological
polyploidy
variants and genetic alterations vary
SP-SE 6q deletion Subependymoma Adulthood Good across these groups.

{238,1604,1644}. In the Children's Oncol- occur. Metastatic disease is associated and grade III ependymomas is so unreli-
ogy Group (COG) ACNS0121 trial, re- with a poor prognosis. able {633}.
section was an independent risk factor,
irrespective of pathological grade {776}. Histopathology Molecular groups
In another study, which included children One major and unresolved issue con- A molecular classification of the disease
aged < 3 years at presentation, a better cerns the accurate definition of anapla- will likely supersede attempts to use
5-year survival rate was achieved after sia, because an inconsistent relationship histopathological variables in the strati-
complete resection {43%) than after in- between pathological variables and out- fication of patients for adjuvant therapy.
complete resection {36%) {2046}. come has emerged over several dec- Nine molecular groups of ependymoma
ades of study {650,704,857,1643,2178, have recently been identified, three from
Tumour location 2778}. Of the features usually associated each principal anatomical compartment
Tumour site has been identified as an with anaplastic change in gliomas, only across the neuraxis {1880}. There is a
important prognostic factor. Supratento- mitotic index, several other indices of strong association between two of these
rial ependymomas are associated with proliferation, and foci of poorly differenti- groups, ST-EPN-RELA and PF-EPN-A,
better survival rates than are posterior ated tumour cells seem to be consistently and a poor outcome (Table 3.01).
fossa neoplasms, especially in children associated with survival in ependymoma,
{649,2060}. Spinal ependymomas have and not in all studies {857,1345,1398,
a significantly better outcome than do 2275,2557}. As a result, very few clini-
intracranial tumours, although late re- cal trials use grade to stratify therapy,
currences (> 5 years after surgery) can because the distinction between grade II

Fig. 3.12 Papillary ependymoma. A Discohesive growth, pseudopapillae, and perivascular pseudorosettes. B Finger-like projections lined by single or multiple layers of cuboidal
tumour cells with smooth contiguous surfaces. C This ependymoma variant is characterized by well-formed papillae in which a central vessel is covered by layers of tumour cells.
The differential diagnosis includes choroid plexus papilloma, the rare papillary meningioma, and metastatic carcinoma.

110 Ependymal tumours


Fig. 3.13 Clear cell ependymoma, characterized by a Fig. 3.14 Tanycytic ependymoma. A Bipolar spindle cells with elongated processes arranged around a central vessel.
relatively high cell density without significant increase B Nuclei exhibit the typical salt-and-pepper speckling of ependymomas.
in proliferation. Note the clear perinuclear cytoplasm
resembling tumour cells in an oligodendroglioma.

Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma


Definition Definition Definition
A rare histological variant of ependy- A histological variant of ependymoma A histological variant of ependymoma
moma characterized by well-formed characterized by an oligodendrocyte-like characterized by arrangement of tumour
papillae. appearance, with perinuclear haloes due cells in fascicles of variable width and
to cytoplasmic clearing. cell density and by elongated cells with
ICD-0 code 9393/3 The clear cell ependymoma variant is spindle-shaped nuclei.
most frequently located in the supraten-
Microscopy torial compartment of young patients. ICD-O code 9391/3
Ependymomas form linear, epithelial-like
surfaces along their cerebrospinal fluid ICD-0 code 9391/3 Microscopy
exposures. Some ependymomas have The tanycytic phenotype is most com-
a papillary architecture that results when Microscopy monly found in spinal cord ependymo-
exuberant growths occasionally arise in Clear cell ependymomas display an oli- mas and manifests as irregular fascicles
which finger-like projections are lined by godendroglial phenotype, with cytoplas- of elongated cells. The fascicles are of
a single layer of cuboidal tumour cells mic clearing that creates clear perinucle- variable width and cell density. Rosettes
with smooth contiguous surfaces and ar haloes. Most ependymomas with this are rarely seen in these ependymomas,
GFAP-immunopositive tumour cell pro- phenotype are supratentorial vascular and pseudorosettes can be subtle. Like
cesses; in contrast, choroid plexus pap- tumours in young patients {727,1673}, but in other ependymomas, the nuclei display
illomas and metastatic carcinomas form the clear-cell phenotype can occasion- speckled (salt-and-pepper) chromatin,
bumpy, hobnail cellular surfaces that ally be found in posterior fossa or spinal and anaplastic features are uncommon.
do not feature extensive GFAP reactiv- tumours. The term tanycytic ependymoma is
ity. Unlike the papillae in choroid plexus Clear cell ependymoma must be distin- used for this variant because its spindly,
tumours, the papillae in ependymomas guished from oligodendroglioma, cen- bipolar elements resemble tanycytes -
lack a basement membrane beneath the tral neurocytoma, clear cell (renal cell) the paraventricular cells with elongated
(neuro-)epithelial cells, which in ependy- carcinoma, and haemangioblastoma. cytoplasmic processes that extend to
momas send fibrillary processes down to Ependymal and perivascular rosettes, ependymal surfaces {711}. Because
a vascular core in the same architectural immunoreactivity for GFAP and EMA, ependymal rosettes are typically absent
arrangement as a pseudorosette. and ultrastructural studies can be helpful and pseudorosettes only vaguely deline-
in this differential diagnosis. Some data ated, these lesions may be mistaken for
suggest that clear cell ependymoma may astrocytomas, in particular pilocytic as-
follow a more aggressive course than trocytomas. However, their ultrastructural
other variants {727}. The clear cell tumour characteristics are ependymal.
of the lateral ventricles once classified as
ependymoma of the foramen of Monro
{2876} is now recognized as central neu-
rocytoma in most instances (see Central
neurocytoma, p. 156).

Ependymoma 111
Ellison D.W.
Ependymoma, RELA fusion-positive Korshunov A.
Witt H.

Definition not have a specified morphology {1891}.


A supratentorial ependymoma character- They exhibit the standard range of archi-
ized by a RELA fusion gene. tectural and cytological features found in
The genetically defined RELA fusion- supratentorial ependymomas, but they
positive ependymoma accounts for often have a distinctive vascular pat-
approximately 70% of all childhood su- tern of branching capillaries or clear-cell
pratentorial tumours {1891} and a lower change. Uncommon variants of ependy-
proportion of such ependymomas in moma (e.g. tanycytic ependymoma) do
adult patients {1880}. Ependymomas in not tend to be RELA fusion-positive.
the posterior fossa and spinal compart-
Immunophenotype
ments do not harbour this fusion gene.
RELA fusion-positive ependymomas
RELA fusion-positive ependymomas
demonstrate the immunoreactivities
exhibit a range of histopathological fea-
for GFAP and EMA described in other
tures, with or without anaplasia.
ependymomas. Expression of L1CAM
ICD-0 code 9396/3 correlates well with the presence of a
RELA fusion in supratentorial ependymo-
Grading mas {1891}, but L1CAM can also be ex-
RELA fusion-positive ependymomas are pressed by other types of brain tumours. Fig. 3.16 RELA fusion-positive ependymoma.
classified according to their histopatho- Interphase FISH with break-apart probes around the
logical features into WHO grade II or Genetic profile RELA gene. Overlapping probes (yellow) indicate an

grade III. No grade I ependymoma has The C11orf95-RELA fusion is the most intact RELA gene, but probe separation (red/green)

been recorded as containing this genetic common structural variant found in occurs with rearrangement of the RELA gene.

alteration. ependymomas {1880,1891,1974}. It forms


in the context of chromothripsis, a shat-
tering and reassembly of the genome formalin-fixed, paraffin-embedded tis-
Microscopy that rearranges genes and produces sue is interphase FISH with break-apart
RELA fusion-positive ependymomas do oncogenic gene products {2852}. RELA probes around both genes. Rearrange-
fusion-positive ependymomas show ment in the context of chromothripsis
constitutive activation of the NF-kappaB splits the dual-colour signals in probe
pathway, the F?ELA-encoded transcrip- sets for C11orf95 and RELA {1891}.
tion factor p65 being a key effector in this
Prognosis and predictive factors
pathway. Rarely, C11orf95 or RELA can
The data available to date (which come
be fused with other genes as a result of
from only a single study) suggest that
chromothripsis {1891}.
RELA fusion-positive ependymomas
The presence of a C11orf95-RELA fu-
have the worst outcome of the three su-
sion gene can be detected by various
pratentorial molecular groups {1880}.
methods, but a simple approach using

Fig. 3.15 RELA fusion-positive ependymoma. L1CAM


protein expression correlates well with the presence of a
RELA fusion gene.

112 Ependymal tumours


Ellison D.W. Korshunov A.
Anaplastic ependymoma McLendon R. Ng H.-K.
Wiestler O.D. Witt H.
Kros J.M. Hirose T.

Definition
A circumscribed glioma composed of
uniform small cells with round nuclei in
a fibrillary matrix and characterized by
perivascular anucleate zones (pseudoro-
settes), ependymal rosettes in about one
quarter of cases, a high nuclear-to-cyto-
plasmic ratio, and a high mitotic count.
A diagnosis of anaplastic ependymo-
ma can be confidently made when an
ependymal tumour shows a high cell
Fig. 3.17 Sagittal, gadolinium-enhanced, T1-weighted Fig. 3.18 Anaplastic ependymoma of the lateral ventricle
density and elevated mitotic count along-
MRI of an anaplastic ependymoma of the fourth ventricle. in a 4-year-old boy, with extensive involvement of the
side widespread microvascular prolif- right frontal lobe.
eration and necrosis. Like the classic
tumour, anaplastic ependymoma rarely In a recent study that will likely serve as and biological behaviour or survival has
invades adjacent CNS parenchyma to the basis for the future molecular classifi- been definitively established {248,633,
any significant extent. Cilia and microvilli cation of the disease {1880}, nine groups 703}. Of the various studies of prognostic
are seen on ultrastructural examination. of ependymoma were described (three variables and outcome in ependymoma,
Anaplastic ependymomas are mainly for each of the three major CNS ana- those that did not find an association be-
intracranial tumours; they are rare in the tomical compartments: the supratentorial tween grade (II vs III) and progression-
spinal cord. Anaplastic ependymomas compartment, posterior fossa, and spinal free or overall survival outnumber those
occur in both adults and children, al- compartment). The modal patient age at that did. The published ratios of grade II
though most posterior fossa tumours presentation, clinical outcome, and fre- to grade III tumours in series of ependy-
present in childhood. Clear cell, papil- quencies of histopathological variants momas vary widely, from 17:1 to 1:7, and
lary, or tanycytic morphology can be a and genetic alterations vary across these the explanation for such inconsistent
feature of both classic and anaplastic groups (see Table 3.01, p. 110). data is multifactorial {633,856,2557}.
ependymomas. Anaplastic ependymo- The interpretation of most histopathologi-
mas have a variable clinical outcome, ICD-0 code 9392/3 cal variables used in this classification
which is primarily dependent on extent of Grading for grading purposes is subjective, and
surgical resection and molecular group Traditionally, classic ependymoma and ependymomas are morphologically het-
{857,1880}. erogeneous. There have been few stud-
anaplastic ependymoma are consid-
In defining molecular groups of epen- ies of the prognostic significance of WHO
ered to correspond histologically to
dymoma, transcriptome or methylome WHO grades II and III, respectively. grade or individual pathological features
profiling has established the relevance of However, no association between grade in large trial cohorts in which proper mul-
anatomical site to ependymoma biology. tivariate analyses of prognostic variables

Fig. 3.19 Anaplastic ependymoma. A Poorly differentiated tumour cells with brisk mitotic activity. B Large foci of necrosis.

Anaplastic ependymoma 113


can be performed, and there have been
only three studies in which evaluation of
histological variables was defined strin-
gently and undertaken by several ob-
servers {633,856,2557}. Due to these
limiting factors, grading is hardly ever
used for therapeutic stratification of pa-
tients with ependymoma. Given that spe-
cific genetic alterations and molecular
groups have recently been proposed as
prognostic or predictive factors for these
tumours {1560,1880,2767}, the practice
of histologically grading ependymoma
may soon become obsolete altogether.
Microscopy
Anaplastic ependymomas almost always
remain circumscribed masses, but can
rarely invade adjacent brain tissue in
the manner of diffuse glioma. Anaplastic
ependymomas generally have a high nu-
clear-to-cytoplasmic ratio. Occasionally,
the cell density is so high that anaplastic
ependymomas can be mistaken for em-
bryonal tumours. All anaplastic ependy-
momas demonstrate brisk mitotic activity,
and high mitotic counts have been asso-
ciated with a poor outcome in posterior
fossa tumours. Microvascular prolifera-
tion and palisading necrosis often ac-
company the mitotic activity, although
these features can also be focal in clas-
sic ependymomas with lower cell density
and few mitotic figures. Pseudorosettes
are a defining feature, but in some poorly Fig. 3.20 Anaplastic ependymoma. A Densely packed tumour cells and microvascular proliferation. B GFAP
differentiated supratentorial anaplastic highlighting radial perivascular processes.
ependymomas, they can be difficult to
find.
Immunophenotype
Anaplastic ependymoma has the same
immunoprofile as classic ependymoma,
except that indices of tumour growth
fraction, such as the Ki-67 proliferation
index, are higher.

Fig. 3.19C Anaplastic ependymoma. High Ki-67 labelling


index.

114 Ependymal tumours


Brat D.J.
Chordoid glioma of the third ventricle Fuller G.N.

Definition Chordoid gliomas arise in the region of


A slow-growing, non-invasive glial tumour the lamina terminalis in the ventral wall of
located in the third ventricle, histological- the third ventricle {1461,1904}. In at least
ly characterized by clusters and cords some cases, radiological studies have
of epithelioid tumour cells expressing demonstrated an intraparenchymal hy-
GFAP, within a variably mucinous stroma pothalamic component {2001}.
typically containing a lymphoplasmacytic
Clinical features
infiltrate.
Chordoid gliomas occur in adults and to
Chordoid gliomas of the third ventricle
date have arisen only in the third ventricu-
occur in adults and have a favourable
lar region. Most cases present with signs
prognosis, particularly in the setting of
and symptoms of obstructive hydroceph-
gross total resection.
alus, including headache, nausea, vomit-
ICD-0 code 9444/1 ing, and ataxia {272,576}. Other clinical
features include endocrine abnormalities
Grading reflecting hypothalamic compression Fig. 4.02 MRI of a Chordoid glioma of the third ventricle
Chordoid glioma of the third ventri- (e.g. hypothyroidism, amenorrhoea, and demonstrating a large, contrast-enhancing, sharply
cle corresponds histologically to WHO diabetes insipidus), visual field distur- delineated mass that fills the anterior third ventricle and
grade II. bances due to compression/displace- compresses adjacent structures.
ment of the optic chiasm, and personality
Epidemiology a fibrosing pattern with abundant fibrosis.
changes including psychiatric symptoms
These tumours are rare, with slightly more The fibrosing pattern tends to be more
and memory abnormalities.
than 80 cases ever reported. Chordoid common in older patients {196}. Other
gliomas occur most frequently in adults, Imaging (rare) tissue patterns include papillary,
although patient age at presentation var- On neuroimaging, Chordoid gliomas alveolar, and pseudoglandular patterns.
ies widely {5-71 years). Most patients present as well-circumscribed ovoid Individual tumour cells have abundant
present between the ages of 35 and masses within the anterior third ventri- eosinophilic cytoplasm. In some cases,
60 years (mean: 46 years), and there is a cle. On MRI, they are T1-isointense to limited glial differentiation in the form of
2:1 female predominance {272,576}. Pae- brain and show strong, homogeneous coarsely fibrillar processes can also be
diatric examples are rare {379}. contrast enhancement {2001}. Mass ef- seen {272}. Neoplastic nuclei are moder-
fect is generally distributed symmetri- ate in size, ovoid, and relatively uniform.
Localization
cally and causes vasogenic oedema in Mitoses are absent in most tumours; when
Chordoid gliomas occupy the anterior
compressed adjacent CNS structures, present, they are rare (< 1 mitosis per
portion of the third ventricle, with larger
including the optic tracts, basal ganglia, 10 high-power fields). A stromal lympho-
tumours also filling the middle and poste-
and internal capsules. Most tumours are plasmacytic infiltrate, often containing
rior aspects {2001}. They generally arise
continuous with the hypothalamus and numerous Russell bodies, is a consistent
in the midline and displace normal struc-
some appear to have an intrinsic anterior finding. Consistent with their radiographi-
tures in all directions as they enlarge.
hypothalamic component, suggesting a cal appearance, the tumours are archi-
Neuroimaging findings, including reports
potential site of origin {1461}. tecturally solid and show little tendency
of small, localized tumours, suggest that
to infiltrate surrounding brain structures.
Microscopy
Reactive astrocytes, Rosenthal fibres,
Chordoid gliomas are solid neoplasms,
and often chronic inflammatory cells in-
most often composed of clusters and
cluding lymphocytes, plasma cells, and
cords of epithelioid tumour cells within a
Russell bodies are seen in adjacent non-
variably mucinous stroma that typically
neoplastic tissue.
contains a lymphoplasmacytic infiltrate.
Three less common histological patterns Electron microscopy
have also been reported: a solid pattern Parallels have been drawn with the ultra-
with sheets of polygonal epithelioid tu- structural morphology of ependymoma
mour cells without mucinous stroma, a {1904} and specialized ependymoma of
0 10 20 30 40 50 60 70 80 fusiform pattern with groups of spindle- the subcommissural organ {389}. The fea-
Age at diagnosis
shaped cells among loose collagen, and tures of Chordoid glioma include interme-
Fig. 4.01 Cumulative age distribution (both sexes) of
diate filaments, intercellular lumina, apical
Chordoid glioma of the third ventricle, based on 43 cases.

116 Other gliomas


Fig. 4.03 Chordoid glioma of the third ventricle. A Histologically, tumours are characterized by cohesive clusters of epithelioid cells with abundant pink cytoplasm and a bubbly,
bluish, mucin-rich stroma. B At higher magnifcation, nuclei are oval, moderate in size, and bland, and have dispersed chromatin. Mitotic activity and nuclear atypia are absent.
C In almost every instance, tumour cells also form solid arrangements of either nests or linear arrays. D,E Lymphoplasmacytic infiltrate is present in nearly all Chordoid gliomas, and
Russell bodies can be identifed (E, arrows). F The border between Chordoid glioma and adjacent brain is well defined, with little evidence of tumour infiltration, often with chronic
inflammation (arrow) and Rosenthal fibres in the neighbouring brain.

microvilli, hemidesmosomes, and basal and the intensity of immunostaining vary are consistently negative {2089}. The
lamina. Some have also been suggested depending on the antibody clone used proliferative potential of Chordoid gliomas
to contain secretory granules {389}. {196}. Staining for vimentin and CD34 corresponds to that of other low-grade
is also strong, whereas immunoreactiv- gliomas. The Ki-67 proliferation index is
Immunophenotype
ity for S100 protein, EMA, and cytokera- low, with values of 0-1.5% in one study
The most distinctive immunohistochemi-
tin is variable. Epidermal growth factor {272} and < 5% in other reports {2089}.
cal feature of Chordoid gliomas is their
receptors and merlin are expressed, R132H-mutant IDH1 immunostaining is
strong, diffuse reactivity for GFAP {272,
whereas nuclear accumulation of p53 is negative {196}.
2235}. These tumours consistently ex-
weak or absent. Neuronal and neuroen- Immunohistochemistry can be useful in
press TTF1 in most nuclei, although the
docrine markers (e.g. synaptophysin, the differential diagnosis of Chordoid gli-
percentage of immunoreactive nuclei
neurofilaments, and chromogranin-A) oma versus other Chordoid neoplasms.

Chordoid glioma of the third ventricle 117


demonstrated losses at 11q13 and 9p21
{1035}. No EGFR amplifications, chromo-
some 7 gain, or TP53 mutations were
noted. Another study (which used PCR-
based techniques, DNA sequencing,
and comparative genomic hybridization)
detected no consistent chromosomal
imbalances or consistent alterations of
TP53, CDKN2A, EGFR, CDK4, or MDM2
{2089}. Neither IDH mutations (i.e. IDH1
or IDH2 mutations) nor BRAF V600E mu-
tations were found in a series of 16 Chor-
doid gliomas {196}.
Prognosis and predictive factors
Chordoid gliomas are slow-growing and
Fig. 4.04 Chordoid glioma of the third ventricle. Tumour cells with diffuse Immunoreactivity for GFAP. histologically low-grade. Gross total re-
section is the treatment of choice and
can result in long-term recurrence-free
Chordoid meningiomas usually contain supplied by a report of abnormal cilia
survival {576}. However, the tumours lo-
small foci of classic meningioma with in a juxtanuclear location {1904}. The
cation within the third ventricle and their
whorl formation and psammoma bodies; presence of a cytological zonation pat-
attachment to hypothalamic and supra-
they are also immunopositive for EMA, tern and secretory vesicles indicated a
sellar structures often make complete re-
but negative for GFAP and CD34 {2235}. specialized ependymal differentiation, as
section impossible. Postoperative tumour
Chordomas strongly express cytokerat- might be expected of cells derived from a
enlargement has been noted in half of
ins and brachyury, but lack immunoreac- circumventricular organ such as the lam-
all patients who undergo subtotal resec-
tivity for GFAP and CD34. ina terminalis. A recent study reported
tion. Among the reported cases of Chor-
strong expression of TTF1 in both Chor-
Cell of origin doid gliomas, approximately 20% of the
doid gliomas and the organum vasculo-
The ultrastructural demonstration of mi- patients died in the perioperative period
sum of the lamina terminalis, suggesting
crovilli and hemidesmosome-like struc- or from tumour regrowth {1394}. Specific
an organum vasculosum origin {196}.
tures in Chordoid glioma supports an postoperative complications include dia-
ependymal histogenesis {389}. Further Genetic profile betes insipidus, amnesia, and pulmonary
evidence of ependymal or specialized A study using microarray-based com- embolism {576}.
ependymal differentiation has been parative genomic hybridization and FISH

118 Other gliomas


Burger P.C.
Angiocentric glioma Jouvet A.
Preusser M.
Rosenblum M.K.
Ellison D.W.

Definition
An epilepsy-associated, stable or
slow-growing cerebral tumour primarily
affecting children and young adults; his-
tologically characterized by an angiocen-
tric pattern of growth, monomorphous
bipolar cells, and features of ependymal
differentiation.
Angiocentric glioma (also called mono-
morphous angiocentric glioma {2691}
and angiocentric neuroepithelial tumour Fig. 4.05 Angiocentric glioma. A T2-weighted, fluid-suppressed MRI demonstrates the neoplasm as a well-defined
{1467}) has an uncertain relationship to hyperintense mass in close proximity to the cingulate gyrus of the right frontal lobe. Note the lesion's primarily cortical
other neoplasms exhibiting ependymal localization. B The bright lesion with little mass effect is based largely in the amygdala.
differentiation. Examples with this pattern
have been reported as cortical ependy- involve children. Males and females are Spread
moma {1465}. Tumours harbouring both affected equally frequently. Angiocentric glioma has an infiltrative
angiocentric glioma and ependymoma Localization appearance, locally trapping neurons
patterns have also been reported {2623}. A superficial, cerebrocortical location is and other pre-existing parenchymal ele-
The relationship between angiocentric typical. ments. Extensions along parenchymal
glioma and classic ependymoma thus vessels and the subpial zone are com-
Clinical features mon {2691}.
remains to be defined.
Angiocentric gliomas are epilepto-
ICD-0 code 9431/1 genic lesions, with chronic and intrac- Macroscopy
table partial epilepsy being particularly Gross features have not been detailed.
Grading
characteristic. One temporal lobe example was de-
Angiocentric glioma corresponds histo-
scribed at surgery as producing hip-
logically to WHO grade I. Imaging
pocampal enlargement with darkening
On MRI, the superficial, if not cortically and induration of the amygdala. The grey
Synonym
based, lesion is well circumscribed, bright
Angiocentric neuroepithelial tumour (not matter-white matter boundary may be
on FLAIR images, and non-contrast-en-
recommended) blurred.
hancing. A cortical band of T1 -hyperinten-
Epidemiology sity is present in some cases. A stalk-like Microscopy
Incidence figures are not yet available extension to the subjacent lateral ventricle A unifying feature is the structure of re-
for this uncommon lesion. Most cases is another variable feature {1337}. markably monomorphic, bipolar spin-
died cells oriented around cortical blood

Fig. 4.06 Angiocentric glioma. A Elongated tumour cells forming occasionally perivascular pseudorosettes. B Perivascular rosettes.

Angiocentric glioma 119


Cell of origin
It has been suggested that these tumours
derive, via a maldevelopmental or neo-
plastic process, from the bipolar radial
glia that span the neuroepithelium during
embryogenesis, and that they may share
similar ependymoglial traits or be capa-
ble of generating ependymocytes {1467}.
Genetic profile
Limited numbers of angiocentric gliomas
have been studied for genetic alterations.
However, all 4 cases analysed in two
genomic studies showed copy number
alterations or rearrangements at the MYB
locus on 6q23 {2068,2855}. In the re-