Review Article

2016 World Health

Address correspondence to
Dr Patrick Y. Wen, Center
for Neuro-Oncology,
Dana-Farber/Brigham and

Organization Women’s Cancer Center, 450

Brookline Ave, Boston, MA
02215, pwen@partners.org.

Classification of Relationship Disclosure:

Dr Wen has received personal
compensation for serving on

Central Nervous the advisory boards of AbbVie

Inc; Agios, Inc; AstraZeneca;
Cavion; Genentech, Inc/F.
Hoffman-La Roche Ltd; INYS

System Tumors Therapeutics, Inc; Kadmon;

Merck & Co, Inc; Monteris
Medical, Inc; Novartis;
Patrick Y. Wen, MD, FAAN; Jason T. Huse, MD, PhD Novogen; Vascular Biogenics
Ltd; VBI Vaccines Inc; and
ZIOPHARM oncology; and
serves on the data safety
ABSTRACT monitoring board of Monteris
Medical, Inc and Tocagen.
Purpose of Review: Since 1979, the World Health Organization (WHO) has periodically Dr Wen receives personal
published a consensus classification and grading of tumors of the central nervous system compensation for serving as a
(CNS) to ensure uniform histopathologic diagnostic criteria worldwide. In 2016, the WHO consultant for AbbVie Inc;
Agios, Inc; AstraZeneca;
published an update of the fourth edition of the classification of CNS tumors. This article Aurora Biopharma; and
summarizes the major changes in the update and discusses their impact on clinical practice. Genentech, Inc/F. Hoffman-La
Recent Findings: For the first time, the 2016 revision of the WHO classification uses Roche Ltd; for serving
on the speaker’s bureau of
molecular parameters in addition to traditional histology to diagnose many CNS Merck & Co, Inc; and for
tumors, resulting in major restructuring of the classification of many tumors, especially serving as Editor-in-Chief of
gliomas, ependymomas, and medulloblastomas. Accordingly, nomenclature for selected Neuro-Oncology. Dr Wen has
received research support
entities now includes both a histopathologic diagnosis and defining molecular features. from Agios, Inc; Angiochem;
Summary: The use of integrated phenotypic and genotypic parameters for the AstraZeneca; Genentech,
classification of CNS tumors introduces greater objectivity to the diagnosis but also Inc/F. Hoffman-La Roche Ltd;
GlaxoSmithKline;
requires more widespread availability of molecular testing. It is hoped that these ImmunoCellular Therapeutics,
changes will lead to greater diagnostic accuracy with more biologically homogeneous Ltd; Karyopharm Therapeutics;
diagnostic entities and improved patient management and determination of prognosis. Merck & Co, Inc; Novartis;
Oncoceutics, Inc;
Sanofi-Aventis, LLC; and
Continuum (Minneap Minn) 2017;23(6):1531–1547. Vascular Biogenics Ltd.
Dr Huse has received
personal compensation as a
consultant for Champions
INTRODUCTION published in 1979,2 followed by a Oncology, Inc and receives
It is estimated that the annual age- second edition in 1993 that intro- research/grant support from
the American Cancer Society
adjusted incidence of primary tumors duced immunohistochemical analysis (RSG-16-170-01-DMC) and
of the central nervous system (CNS) in to diagnostic pathology.3 In 2000, the the National Cancer Institute/
National Institutes of Health
the United States is 28.57 per 100,000 third edition introduced genetic pro- (P50CA127001, GC227828).
population, resulting in approximately files as additional aids to defining Unlabeled Use of
77,000 new cases diagnosed each brain tumors,4 while the fourth edi- Products/Investigational
Use Disclosure:
year.1 To ensure uniform histopatho- tion in 2007 added several new histo- Drs Wen and Huse report no
logic diagnostic criteria worldwide, the pathologic entities.5 In 2016, the WHO disclosures.
classification and grading of these published an update to the fourth * 2017 American Academy
of Neurology.
tumors has been based on the con- edition of the classification of CNS
sensus of an international working tumors that represents the consensus
group and published by the World of 117 contributors and for the first time
Health Organization (WHO). The first uses molecular parameters in addition
edition of the WHO classification of to traditional histology to diagnose
tumors of the nervous system was CNS tumors.6,7 This has resulted in

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 2016 WHO Classification of CNS Tumors
KEY POINTS
h In 2016, the World
Health Organization
introduced an important
update on the
classification of central
nervous system tumors.
h For the first time,
the 2016 update of
the World Health
Organization classification
integrates molecular
testing with traditional
histology in the
diagnosis of selected
brain tumors, including
gliomas and
medulloblastomas.
These updates will
improve accuracy in
diagnosing and
classifying central
nervous system tumors.
h The integrated
nomenclature
recommended by the
2016 World Health
Organization update for
selected entities now
includes a histopathologic
diagnosis followed by
defining molecular
features. If molecular
testing is not available
or is incomplete, the
diagnostic designation
not otherwise specified
is used.
h Diffusely infiltrating
gliomas of astrocytic
and oligodendroglial
lineage are now
classified largely based
on two highly
recurrent molecular
alterationsVIDH
mutation and 1p/19q
codeletionVin addition
to more conventional
histopathologic
parameters.
1532 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
major restructuring of the classification
of many tumors, especially gliomas,
ependymomas, and medulloblastomas.
This article summarizes the 2016 WHO
update on the classification of CNS
tumors and discusses some of the
implications for routine clinical care as
well as clinical research.6,7 The major
changes in the 2016 WHO update are
summarized in Table 1-1.
GENERAL PRINCIPLES OF THE
2016 WORLD HEALTH
ORGANIZATION CLASSIFICATION
Until recently, the classification of
brain tumors has been based entirely
on their histologic appearance, their
similarities with potential cells of ori-
gin, and the level of differentiation.6
However, significant progress has
been made in understanding the mo-
lecular pathogenesis of many brain
tumors, allowing them to be separated
into distinct subtypes with different
prognoses.8Y17 In particular, the im-
portance of isocitrate dehydrogenase
(IDH) mutations in the pathogenesis
of gliomas and the association with
improved prognosis has been recog-
nized.9,18 Recognition has also been
growing of the limitations of histologic
diagnosis based entirely on micros-
copy and the significant interobserver
variability that frequently occurs,
which limits the reliability of the
diagnoses and impedes the conduct
of clinical trials and epidemiologic
studies.19 In 2014, the International
Society of Neuropathology held a
meeting in the Netherlands to establish
guidelines for incorporating molecular
findings into brain tumor diagnoses.20
This meeting set the stage for the
current update of the WHO CNS
classification. The integrated nomen-
clature recommended by the 2016
WHO classification for selected enti-
ties now includes a histopathologic
diagnosis followed by defining molecular
features, eg, oligodendrogliomas, IDH-
mutant and 1p/19q-codeleted. If molec-
ular testing is not available or the testing
is incomplete, the diagnostic designation
not otherwise specified (NOS) is used.
The NOS category also contains the rare
tumors for which molecular testing was
performed but did not show diagnostic
alterations.6
The use of integrated phenotypic
and genotypic parameters for the
classification of CNS tumors introduces
greater objectivity to the diagnosis.6
However, the introduction of geno-
typing also raises the possibility of
identifying more subgroups, and dis-
crepancies between tumor genotype
and histology may arise. In cases in
which such discrepancies occur, the
genotype trumps the histology. For
example, for a tumor that resembles
an oligodendroglioma histologically
but has the genotype of an astrocytoma
(IDH-mutant, 1p/19q non-codeleted,
ATRX and TP53 mutated), the diagnosis
of astrocytoma should be rendered.
Diffuse Gliomas
The 2016 WHO update introduces
important changes to the classification
of gliomas, the most common type of
malignant primary brain tumor. Dif-
fusely infiltrating gliomas of astrocytic
and oligodendroglial lineage are now
classified largely based on two highly
recurrent molecular alterationsVIDH
mutation and 1p/19q codeletionVin
addition to more conventional histo-
pathologic parameters (Figure 1-1).
Mutations in either IDH1 or IDH2 can
be detected by a variety of sequencing-
based approaches in the clinical setting.
Moreover, the most common glioma-
associated IDH mutation, IDH1 R132H,
can be demonstrated immunohisto-
chemically.21 Negative testing should
prompt the designation of a glioma as
IDH-wildtype. 1p/19q codeletion refers
to whole arm loss of chromosomes 1p
December 2017
TABLE 1-1 Summary of the Major Changes in the 2016 World Health
Organization Classification of Central Nervous System
Tumorsa,b

b Major Changes
Integrates molecular parameters with traditional histology to diagnose
central nervous system tumors
Restructures the classification of diffuse gliomas, with incorporation of
genetically defined entities
Restructures the classification of medulloblastomas, with incorporation of
genetically defined entities
Restructures other embryonal tumors, with incorporation of genetically
defined entities and removal of the term primitive neuroectodermal tumor
Incorporates a genetically defined ependymoma variant

b Other Changes
Distinguishes pediatric look-alikes, including designation of novel genetically
defined entities
Addition of newly recognized entities, variants, and patterns:
IDH-wildtype and IDH-mutant glioblastoma (entities)
Diffuse midline glioma, H3 K27MYmutant (entity)
Embryonal tumor with multilayered rosettes, C19MC-altered (entity)
Ependymoma, RELA fusionYpositive (entity)
Diffuse leptomeningeal glioneuronal tumor (entity)
Anaplastic pleomorphic xanthoastrocytoma (entity)
Epithelioid glioblastoma (variant)
Glioblastoma with primitive neuronal component (pattern)
Multinodular and vacuolated pattern of ganglion cell tumor (pattern)
Deletion of former entities, variants, and terms:
Gliomatosis cerebri
Protoplasmic and fibrillary astrocytoma variants
Cellular ependymoma variant
Primitive neuroectodermal tumor terminology
Addition of brain invasion as a criterion for atypical meningioma
Restructuring of solitary fibrous tumor and hemangiopericytoma as one
entity and adapting a grading system to accommodate this change
Expansion and clarification of entities included in nerve sheath tumors
Expansion of entities included in hematopoietic/lymphoid tumors of the
central nervous system (lymphomas and histiocytic tumors)
a
Data from Louis DN, et al, Acta Neuropathol.6 link.springer.com/article/10.1007/s00401-016-1545-1.
b
Entities: Well-characterized pathologic diagnoses. Variants: Sufficiently well-characterized
subtypes of accepted entities. Patterns: Readily recognizable histologic features that do not have
clear clinicopathologic significance.

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 2016 WHO Classification of CNS Tumors

Diffuse astrocytomas and anaplastic

Astrocytoma with hypercellularity and nuclear
FIGURE 1-1
atypia. The nuclei circled show one of several
areas of nuclear atypia.
KEY POINT and 19q, which is typically detected by
h IDH1 R132H, which in situ hybridization or polymerase
accounts for chain reaction (PCR)-based analyses in
approximately 90% of most clinical laboratories, although
IDH mutations, can
global copy number approaches, such as
be detected
array comparative genomic hybridization,
immunohistochemically.
If this testing is
yield more specific results. Importantly,
negative, sequencing multiple large retrospective analyses
of IDH1 and IDH2 is have now shown that in the setting of
necessary to ensure that molecular stratification, conventional
no other IDH mutations histopathologic parameters designating
are present. the WHO grade II to WHO grade III
transition in diffuse glioma do not
correlate well with disease prognosis.22,23
This is particularly true for IDH-mutant
astrocytomas and oligodendrogliomas.
astrocytomas. Diffuse astrocytomas
(WHO grade II) and anaplastic astrocy-
tomas (grade III) are now divided into
three categories: IDH-mutant, IDH-
wildtype, and NOS. Most astrocytomas
are IDH-mutant and, by definition, have
intact 1p/19q (no codeletion of 1p/19q).
Loss-of-function mutations in TP53 and
ATRX, the latter of which can be easily
demonstrated immunohistochemically,
are also seen in the majority of these tu-
mors (Case 1-1). IDH-wildtype astrocyto-
mas are less common and often have the
genetic alterations found in glioblastomas
and a much worse prognosis, prompting
some to postulate that these tumors
should be considered the molecular
equivalent of glioblastoma (Case 1-2).
However, other low-grade glial neo-
plasms with astrocytic histology, such
as ganglioglioma and pleomorphic
xanthoastrocytoma, may occasionally be
misdiagnosed in the IDH-wildtype cat-
egory, further complicating this issue.
If molecular testing is not available or
cannot be fully performed because of
limited resources or inadequate tissue,
the diagnosis will be astrocytoma NOS
or anaplastic astrocytoma NOS.
Two variants of astrocytoma are
deleted from the 2016 WHO classifi-
cation: protoplasmic astrocytoma and
fibrillary astrocytoma. Gemistocytic
astrocytoma remains a variant of
diffuse astrocytoma, IDH-mutant.6

Case 1-1
A 38-year-old woman presented with a generalized seizure. MRI showed a medial left temporal lobe
tumor with some enhancement (Figure 1-2A). The tumor had both astrocytic (Figure 1-2B) and
oligodendroglial (Figure 1-2C) components on histology. However, immunohistochemistry showed that
the tumor was positive for the IDH1 R132H (Figure 1-2D) and TP53 mutations (Figure 1-2E) and negative
for ATRX expression (Figure 1-2F), indicating that it was an anaplastic astrocytoma, IDH-mutated.
Sequencing of the tumor confirmed point mutations in IDH1 R132H, ATRX, and TP53. The tumor was
resected, and she received radiation therapy. She remained stable for 6 years but then developed
increasing problems with speech and memory, and MRI showed new enhancement, indicative of
recurrent disease (Figure 1-2G).
Continued on page 1535

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 Continued from page 1534

FIGURE 1-2 Imaging of the patient in Case 1-1 with a medial left temporal lobe tumor that
was resected and treated with radiation alone. Axial MRI at diagnosis (A) shows
medial posterior left temporal lobe tumor with some enhancement
(fluid-attenuated inversion recovery [FLAIR] on left, postcontrast T1-weighted image on right,
arrow). The tumor had both astrocytic (B) and oligodendroglial (C) components on histology.
However, immunohistochemistry showed that the tumor was positive for IDH R132H (D) and
TP53 mutations (E), but negative for ATRX mutation (F), indicating that it was an anaplastic
astrocytoma, IDH-mutated. Axial MRI 6 years later (G) (FLAIR on left, postcontrast T1-weighted
image on right) shows new enhancement, indicative of recurrent disease.

Continued on page 1536

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 2016 WHO Classification of CNS Tumors
Continued from page 1535
Comment. Although histologically this patient’s tumor was an anaplastic oligoastrocytoma, genetic
analysis determined it to be an anaplastic astrocytoma, IDH-mutated, with a good prognosis.
KEY POINTS
h Most astrocytomas are
IDH-mutant and, by
definition, have intact
1p/19q (no codeletion
of 1p/19q) and often
loss-of-function
mutations in TP53
and ATRX.
h IDH-wildtype
astrocytomas are less
common than
IDH-mutant
astrocytomas and often
have the genetic
alterations found in
glioblastomas and a
much worse prognosis.
h Oligodendrogliomas
have IDH mutation and
1p/19q codeletion.
Promoter mutations in
the TERT gene are also
invariably identified,
while TP53 and ATRX
mutations are rare.
h The 2016 World Health
Organization update
strongly discourages the
diagnosis of
oligoastrocytoma.
Molecular studies
suggest that tumors
with histologic
components of
oligodendroglioma and
astrocytoma can almost
always be classified as
oligodendroglioma or
astrocytoma with the
appropriate molecular
testing.
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Oligodendrogliomas and anaplastic molecular testing.24,25 Oligoastrocytoma
oligodendrogliomas. The diagnoses of and anaplastic oligoastrocytoma are
oligodendroglioma (WHO grade II) both assigned NOS designations. This
and anaplastic oligodendroglioma indicates that they can only be diag-
(WHO grade III) have traditionally been nosed if no molecular testing is avail-
made based on characteristic histologic able. Recently, rare cases have emerged
appearances (Figure 1-4) but now that show genetic evidence of both
also require the presence of IDH muta- oligodendroglioma (1p/19q codeletion)
tion and 1p/19q codeletion (Figure 1-5 and astrocytoma (TP53 and ATRX muta-
and Table 1-2).6,7 Promoter mutations tions) arising in distinct cellular subpop-
in the TERT gene are also almost invari- ulations within the same IDH-mutant
ably identified, while TP53 and ATRX parental clone.26Y28 However, these really
mutations are rare. As with astrocyto- constitute two independent neoplasms
ma, if molecular testing is not possible or and, as such, are entirely consistent with
is incomplete, the NOS designation is the larger molecular framework of dif-
used. Pediatric oligodendrogliomas of- fuse glioma.
ten do not have IDH mutations and are Glioblastomas. Glioblastomas, the
included in the oligodendroglioma, most common malignant primary brain
NOS category. However, it is important tumor, are characterized histologically
to differentiate these from pilocytic astro- by endothelial proliferation and pseudo-
cytomas, clear cell ependymomas, and palisading necrosis (Figure 1-6A). In
dysembryoplastic neuroepithelial tu- the 2016 WHO classification, glioblasto-
mors, all of which may have a somewhat mas (WHO grade IV) are divided into
similar appearance. glioblastoma, IDH-wildtype; glioblas-
Oligoastrocytomas. The 2016 WHO toma, IDH-mutant; and glioblastoma,
CNS classification strongly discourages NOS (Table 1-3). Glioblastoma, IDH-
the diagnosis of oligoastrocytoma. wildtype accounts for approximately
Molecular studies suggest that tumors 90% of glioblastomas and corresponds
with histologic components of oligoden- to primary glioblastomas that typically
drogliomas and astrocytoma can almost present after the age of 55.29 Glioblastoma,
always be classified as oligodendroglioma IDH-mutant accounts for approximately
or astrocytoma with the appropriate 10% of cases and typically occurs in
Case 1-2
A 48-year-old woman presented with seizures. MRI showed a left temporal
enhancing tumor (Figure 1-3A). Biopsy showed the histologic characteristics of
an anaplastic astrocytoma (Figure 1-3B). Immunohistochemistry for IDH1
R132H was negative (Figure 1-3C). Sequencing showed no IDH mutations and
the presence of molecular alterations in NF1, KIT, PDGFRA, KDR, CDK4, MDM2,
MDM4, and CDKN2A/CDKN2B, which are frequently found in glioblastoma.
The diagnosis was anaplastic astrocytoma, IDH-wildtype. Despite treatment
with radiation and chemotherapy, her tumor recurred after 1 year.
Continued on page 1537
December 2017
 KEY POINT
Continued from page 1536
h Glioblastomas are
divided into
glioblastoma,
IDH-wildtype;
glioblastoma,
IDH-mutated; and
glioblastoma, not
otherwise specified.
Ninety percent of
glioblastomas are
IDH-wildtype and have a
worse prognosis than
glioblastoma,
IDH-mutated.

FIGURE 1-3 Imaging and biopsy of the patient in Case 1-2. Axial
MRI (A) shows a left temporal enhancing tumor
(fluid-attenuated inversion recovery [FLAIR] on
left, postcontrast T1-weighted image on right). Biopsy showed
histologic characteristics of an anaplastic astrocytoma (B), and
immunohistochemistry for IDH R132H was negative (C).

Comment. While this patient’s tumor was histologically an anaplastic

astrocytoma, the fact that it was IDH-wildtype resulted in a poor
prognosis, similar to that of a glioblastoma.

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 2016 WHO Classification of CNS Tumors

younger patients. They usually corre-

spond to secondary glioblastomas that
arise from preexisting lower-grade
gliomas and are usually associated
with a better prognosis than wildtype
glioblastomas. The diagnosis of glio-
blastoma, NOS is reserved for those
tumors for which IDH evaluation was
not possible.
Variants of IDH-wildtype glioblas-
toma, including giant cell glioblas-
toma and gliosarcoma, are retained
in the 2016 WHO classification and
usually correspond to unusual histo-
pathologic patterns of glioblastoma,
FIGURE 1-4 Typical oligodendroglioma with a ‘‘fried egg’’ IDH-wildtype. However, a new variant
appearance with nuclei surrounded by
perinuclear halo. was also added: epithelioid glioblas-
toma (Figure 1-6B). These tumors

FIGURE 1-5 Algorithm for classification of diffuse gliomas based on histologic and genetic features. Colored lines distinguish situations
where molecular testing is available and conclusive (blue) from situations where it is unavailable/inconclusive (red).
ATRX = alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler;
IDH = isocitrate dehydrogenase; NOS = not otherwise specified; TP53 = tumor protein p53.
a
Characteristic but not required for diagnosis.
Reprinted with permission from Louis DN, et al, Acta Neuropathol.6 B 2016 Springer.
link.springer.com/article/10.1007/s00401-016-1545-1.

1538 ContinuumJournal.com December 2017

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TABLE 1-2 Classification of
Lower-grade
Gliomas Based on Isocitrate
Dehydrogenase and 1p/19q
Status, If Available

b Astrocytoma
Diffuse astrocytoma,
isocitrate dehydrogenase
(IDH)-mutant
Gemistocytic astrocytoma,
IDH-mutant
Diffuse astrocytoma,
IDH-wildtype
Diffuse astrocytoma, not
otherwise specified (NOS)
b Oligodendroglioma
Oligodendroglioma,
IDH-mutant and 1p/19q
codeleted
Oligodendroglioma, NOS
b Oligoastrocytoma, NOS
b Anaplastic Astrocytoma
Anaplastic astrocytoma,
IDH-mutant
Anaplastic astrocytoma,
IDH-wildtype
Anaplastic astrocytoma,
NOS
b Anaplastic
Oligodendroglioma
Anaplastic
oligodendroglioma,
IDH-mutant and 1p/19q
codeleted
Anaplastic
oligodendroglioma, NOS
b Anaplastic
Oligoastrocytoma, NOS

FIGURE 1-6 Glioblastoma. A, Glioblastoma with typical

typically occur in children and young
adults and are located in the cerebrum
or diencephalon. Histologically, they
have large epithelioid cells with abun-
dant eosinophilic cytoplasm, prominent
nucleoli, vesicular chromatin, and var-
pseudopalisading necrosis (arrows). B, Smear
of epithelioid glioblastoma showing typical
epithelioid cells. C, Cells stain positive for BRAF V600E
mutations on immunohistochemistry.
iably present rhabdoid cells. Fre-
quently they will have BRAF V600E
mutations30,31 (Figure 1-6C) and may

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 2016 WHO Classification of CNS Tumors
KEY POINTS
h Epithelioid glioblastoma
is a new variant of
glioblastoma occurring
in children and young
adults. Epithelioid
glioblastomas often have
BRAF V600E mutations.
h The 2016 World Health
Organization update
introduces a new
pediatric tumor termed
diffuse midline glioma,
H3 K27MYmutant. These
tumors are characterized
by a diffuse growth
pattern, midline
localization (thalamus,
brainstem, or spinal
cord), and the presence
of K27M mutations in
the histone H3F3A gene.
h The entity gliomatosis
cerebri, an invasive
glioma involving three
or more cerebral lobes,
has been deleted from
the 2016 World Health
Organization update,
as histologically and
genetically it does not
appear to be a
distinct entity.
1540 ContinuumJournal.com
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TABLE 1-3 Classification of
Glioblastomas
b Glioblastoma, Isocitrate
Dehydrogenase
(IDH)-Wildtype
Giant cell glioblastoma
Gliosarcoma
Epithelioid glioblastoma
b Glioblastoma, IDH-Mutant
b Glioblastoma, Not
Otherwise Specified
exhibit loss of INI1 expression. Evi-
dence exists linking epithelioid glioblas-
toma with anaplastic pleomorphic
xanthoastrocytoma.30Y32
Designations based on histopatho-
logic patterns of glioblastoma have
previously included small cell glio-
blastoma, which often resembles
oligodendroglioma and harbors epider-
mal growth factor receptor amplifica-
tion, and granular cell glioblastoma,
which contains granular to macro-
phagelike lysosomal-rich cells. In the
2016 WHO classification, glioblastoma
with primitive neuronal component is
added as a pattern. These tumors have
well-demarcated nodules containing
primitive cells with neuronal differenti-
ation and have a tendency for CSF
dissemination.33
Pediatric diffuse gliomas. Pediatric
diffuse gliomas were previously grouped
with their adult counterparts. How-
ever, increasing evidence exists that they
have distinct underlying genetic alter-
ations.34 The 2016 WHO classification
introduces a new entity termed diffuse
midline glioma, H3 K27MYmutant.
These tumors occur in children and
young adults and are characterized by a
diffuse growth pattern, midline locali-
zation (thalamus, brainstem, or spinal
cord), and the presence of K27M muta-
tions in the histone H3F3A gene or,
much less often, in the HIST1H3B
gene.35,36 The identification of tumors
with these mutations may potentially
allow them to be specifically targeted by
drugs in the future.
Other Astrocytomas
Pleomorphic xanthoastrocytomas usu-
ally occur in children and young adults
and have well-defined encapsulation
and peripheral localization. They are
characterized by large pleomorphic
and frequently multinucleated cells,
spindle and lipidized cells, and numer-
ous eosinophilic granular bodies. Sixty
percent of these tumors have BRAF
V600E mutations. In the 2016 WHO
classification, the entity anaplastic
pleomorphic xanthoastrocytoma,
WHO grade III, has been added,
requiring five or more mitoses per 10
high-power fields.7 Pilomyxoid astro-
cytomas were previously designated as
a grade II tumor, but it is unclear if
they have a more aggressive course
than pilocytic astrocytomas; definitive
grading is no longer recommended.7
Gliomatosis Cerebri
The entity gliomatosis cerebri has
been deleted from the 2016 WHO
CNS Classification.7 Previously, it was
considered a distinct form of glioma
characterized by invasive tumor growth
involving three or more cerebral lobes,
often extending to both hemispheres
and infratentorial structures and associated
with a poor prognosis. However, his-
tologically and genetically, it does not
appear to be a distinct entity, consisting
of a variety of tumor types, including
IDH-wildtype glioblastoma, IDH-mutant
astrocytoma, and oligodendroglioma
with invasive growth.37
Ependymomas
Ependymomas are gliomas that typi-
cally arise in children and young adults;
they can be located in the posterior
December 2017

fossa or arise in the supratentorial
compartment or spinal cord. Tradi-
tionally, they have been divided into
grade II tumors (classic ependymomas)
and grade III tumors (anaplastic
ependymomas). However, the correla-
tion of tumor grade to outcome is poor
and of questionable utility.38 Recently,
significant advances have taken place
in the understanding of the molecular
alterations in ependymomas, but these
have not yet been translated into the
2016 CNS WHO classification.13,39
However, the ependymoma, RELA
fusionYpositive variant, which accounts
for the majority of supratentorial
ependymomas in children and is asso-
ciated with a poor prognosis, has been
accepted in the new classification as a
genetically defined subtype.40
Neuronal and Mixed
Neuronal-Glial Tumors
Neuronal and mixed neuronal-glial tu-
mors are generally slow-growing tu-
mors in children and young adults. A
newly recognized entity called diffuse
leptomeningeal glioneuronal tumor
has been introduced.7 These tumors
present with diffuse leptomeningeal
disease, often without a parenchymal
component.41 They have a monomor-
phic clear cell glial morphology that
somewhat resembles oligodendrogliomas.
These tumors are IDH-wildtype but
may harbor BRAF fusions and tend to
grow slowly. A multinodular and vacuo-
lated pattern in ganglion cell tumors has
also been recognized. These multinodular
and vacuolated tumors of the cerebrum
are low-grade lesions.42
Medulloblastomas
Medulloblastomas are the most com-
mon embryonal tumor of childhood.
Significant progress has been made in
understanding the molecular character-
istics of these tumors in recent years.15,43
By consensus, medulloblastomas have
Continuum (Minneap Minn) 2017;23(6):1531–1547
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
been distilled into four main groups: h A new subtype of
WNT-activated medulloblastomas, ependymoma,
which have the best prognosis; SHH- ependymoma, RELA
activated medulloblastomas, which fusionYpositive, which
occur in both infants and adults; accounts for the
group 3 medulloblastomas, which are majority of
associated with the worst outcome; supratentorial
and group 4 medulloblastomas.15,43 ependymomas in
The 2016 WHO update includes major children and is associated
restructuring of the classification of with a poor prognosis,
has been added to the
medulloblastoma, incorporating a mod-
2016 World Health
ular and integrated approach to diag-
Organization
nosis that combines histologic and classification.
molecular features (Table 1-4).6 In
particular, WNT-pathway and SHH- h Medulloblastomas have
been distilled into four
pathway medulloblastomas are now des-
main groups:
ignated explicitly. For more information WNT-activated
about medulloblastomas, refer to the medulloblastomas,
article ‘‘Pediatric Brain Tumors’’ by Mai which have the
Dang, MD, PhD, and Peter C. Phillips, best prognosis;
MD,44 in this issue of Continuum. SHH-activated
medulloblastomas,
Meningiomas which occur in
Meningioma, the most common pri- both infants and
mary brain tumor, remains divided into adults; group 3
three histologic grades (WHO grade I medulloblastomas,
which are associated
[Figure 1-7A], grade II [atypical], and
with the worst
grade III [malignant]), which correlate
outcome; and group 4
with prognosis. However, the diagnosis medulloblastomas.
of WHO grade II (atypical) meningio-
h The diagnosis of World
mas can now be made by the presence
Health Organization
of brain invasion, given its association
grade II (atypical)
with a worse outcome (Figure 1-7B), in meningioma can
addition to the previous criteria of now be made by the
mitotic counts of four or more per 10 presence of brain
high-power fields or the presence of invasion, given its
three out of five high-grade histologic association with a
features (prominent nucleoli, spontane- worse outcome.
ous necrosis, sheeting [loss of whorling
or fascicular architecture], small cells, and
high cellularity).7 The inclusion of brain
invasion in the diagnosis of WHO grade II
(atypical) meningiomas may require neu-
rosurgeons to collect adjacent normal
tissue during the course of surgery, a
change from current clinical practice.
For more information on meningiomas,
refer to the article ‘‘Common Histologi-
cally Benign Tumors of the Brain’’ by Roy
ContinuumJournal.com 1541
 2016 WHO Classification of CNS Tumors

TABLE 1-4 Summary of the Most Common Integrated

Medulloblastoma Diagnoses, With Clinical Correlatesa

Genetic Profile Histology Prognosis

Medulloblastoma, Classic Low-risk tumor;
WNT-activated classic morphology
found in almost all
WNT-activated tumors
Large cell/anaplastic Tumor of uncertain
(very rare) clinicopathologic
significance
Medulloblastoma, Classic Uncommon high-risk tumor
SHH-activated,
Large cell/anaplastic High-risk tumor; prevalent
TP53-mutant
in children 7Y17 years old
Desmoplastic/nodular Tumor of uncertain
(very rare) clinicopathologic significance
Medulloblastoma, Classic Standard-risk tumor
SHH-activated,
Large cell/anaplastic Tumor of uncertain
TP53-wildtype
clinicopathologic significance
Desmoplastic/nodular Low-risk tumor in infants;
prevalent in infants and
adults
Extensive nodularity Low-risk tumor of infancy
Medulloblastoma, Classic Standard-risk tumor
non-WNT/
Large cell/anaplastic High-risk tumor
non-SHH, group 3
Medulloblastoma, Classic Standard-risk tumor;
non-WNT/ classic morphology
non-SHH, group 4 found in almost all
group 4 tumors
Large cell/anaplastic Tumor of uncertain
(rare) clinicopathologic
significance
SHH = sonic hedgehog; WNT = wingless.
a
Reprinted with permission from Louis DN, et al, Acta Neuropathol.6 B 2016 Springer.
link.springer.com/article/10.1007/s00401-016-1545-1.

E. Strowd III, MD, and Jaishri O. Blakeley,
MD,45 in this issue of Continuum.
Solitary Fibrous Tumors/
Hemangiopericytomas
Hemangiopericytomas are rare tumors
that resemble meningiomas in radio-
graphic appearance and tend to have
high recurrence rates and risk for sys-
temic metastases. For tumors outside the
brain, the term hemangiopericytoma
has largely been replaced by its incor-
poration into the family of solitary fibrous
tumors as solitary fibrous tumor/
hemangiopericytoma. Both solitary fi-
brous tumors and hemangiopericytomas
share inversions at 12q13, fusing the
STAT6 gene with the NAB2 gene, leading
to STAT6 nuclear expression that can be
detected with immunohistochemistry.46

1542 ContinuumJournal.com December 2017

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINT
h Hemangiopericytomas
are now termed solitary
fibrous tumors/
hemangiopericytomas,
as they are overlapping,
if not identical, entities.

FIGURE 1-7 Meningioma. A, Grade I meningioma showing

typical whorl appearance. B, Meningioma
showing brain invasion. In the 2016 World
Health Organization update, this histologic finding results in
the tumor being classified as a grade II (atypical) meningioma.

In the 2016 WHO classification, the
combined term solitary fibrous tumor/
hemangiopericytoma has been intro-
duced for this entity, with two possible
grades (WHO grades II and III).
Nerve Sheath Tumors
Relatively modest changes have been
made in the classification of cranial and
paraspinal nerve sheath tumors. Since
melanotic schwannomas have clinical
and genetic behavior that is distinct
from conventional schwannomas, they
are now classified as a separate entity
rather than a variant.7 Malignant periph-
eral nerve sheath tumors (MPNST)
now have two subtypes: epithelioid
MPNST and MPNST with perineural
differentiation. Hybrid nerve sheath
tumors, composed of both schwannoma
and neurofibroma, have also been
included.6,7
CLINICAL IMPLICATIONS OF
THE 2016 WORLD HEALTH
ORGANIZATION CENTRAL
NERVOUS SYSTEM TUMOR
CLASSIFICATION
The 2016 update of the WHO CNS tu-
mor classification integrating molecular

Continuum (Minneap Minn) 2017;23(6):1531–1547 ContinuumJournal.com 1543

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 2016 WHO Classification of CNS Tumors
KEY POINT
h Given the importance of
IDH mutational status
in the diagnosis of
gliomas, at a minimum,
it will be important that
most institutions have
the capacity to both
stain tumor specimens
for IDH1 R132H by
immunohistochemistry
and, ideally, sequence
those tumors that are
negative for both IDH1
and IDH2 mutations.
1544 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
alterations with histologic diagnosis
represents important progress and will
help improve the diagnosis and classifi-
cation of brain tumors; it also has a
number of implications impacting clin-
ical practice. Given the importance of
IDH mutational status in the diagnosis
of gliomas, at a minimum, it will be
important that most institutions have
the capacity to both stain tumor spec-
imens for IDH1 R132H by immuno-
histochemistry and, ideally, sequence
those tumors that are negative for
both IDH1 and IDH2 mutations. A
growing number of centers are acquir-
ing this capacity, but much more work
will be necessary to ensure that these
tests become widely available in a
timely manner. Similarly, the ability to
routinely determine 1p/19q codeletion
or ATRX deficiency, as well as other
molecular alterations, will be impor-
tant. Molecular stratification of medul-
loblastoma subtypes, particularly the
good-prognosis WNT pathwayYactivated
variants, will also be of increasing
importance moving forward, as stan-
dard therapeutic regimens are altered
to minimize toxicity. The need to wait
for the results of molecular testing for
the final integrated diagnosis may lead
to some delay. Nonetheless, the identi-
fication of better-defined tumor en-
tities will, it is hoped, allow for improved
assignment of therapies and better pa-
tient outcomes.
RESEARCH IMPLICATIONS OF
THE 2016 WORLD HEALTH
ORGANIZATION CENTRAL
NERVOUS SYSTEM TUMOR
CLASSIFICATION
The improved classification of CNS tu-
mors with the 2016 WHO CNS update
will help epidemiologic and clinical re-
search. Until recently, eligibility for clini-
cal trial enrollment was based simply on
the histologic diagnosis. In this frame-
work, all tumors designated glioblastoma
were eligible for glioblastoma clinical
trials. Given the significantly improved
outcomes for glioblastomas with IDH
mutations compared to wildtype coun-
terparts,18 consideration should be
given to excluding patients with IDH-
mutant glioblastoma from glioblastoma
trials, especially those with small patient
numbers, since an imbalance in the
number of patients with IDH-mutant
glioblastoma may skew the results. For
lower-grade gliomas, the outcomes for
grade II and III tumors were historically
considered to be different, and separate
clinical trials were conducted for these
groups of patients.47 However, as indi-
cated above, once IDH-wildtype tumors
are excluded, the difference in progno-
sis between IDH-mutant grade II and III
gliomas is significantly reduced,22,23
and it may be conceivable to enroll
both patients with grade II gliomas and
patients with grade III gliomas into the
same studies.
The design of clinical trials for brain
tumors is in flux, and it will take some
time to adjust to the 2016 WHO CNS
update. Ultimately, these changes
should lead to accrual of more uniform
populations of patients with better-
defined outcomes; it is hoped this will
improve our ability to accurately evalu-
ate novel therapies. Given the increasing
importance of molecular findings in the
diagnosis and grading of CNS tumors, a
new entity called cIMPACT-NOW: the
Consortium to Inform Molecular and
Practical Approaches to CNS Tumor
Taxonomy has been formed to provide
more timely updates in the future.48
CONCLUSION
The 2016 WHO update introduces the
use of molecular parameters in addition
to traditional histology to diagnose
CNS tumors. This has led to major
restructuring of the classification of
many tumors, especially gliomas and
medulloblastomas. The use of integrated
December 2017
phenotypic and genotypic parameters for
classifying CNS tumors improves the
objectivity of diagnoses but also requires
more widespread availability of molecular
testing and may introduce some delay in
receiving the final integrated report. As
the understanding of the molecular alter-
ations in CNS tumors and their prognos-
tic significance improves, it is likely that
these molecular features will assume an
increasing role in the diagnosis and
grading of CNS tumors.
REFERENCES
1. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS
statistical report: primary brain and central
nervous system tumors diagnosed in the United
States in 2008Y2012. Neuro Oncol 2015;
17(suppl 4):iv1Yiv62. doi:10.1093/neuonc/nov189.
2. Zulch KJ, ed. Histological typing of tumours
of the central nervous system. Geneva,
Switzerland: World Health Organization, 1979.
3. Kleihues P, Burger PC, Scheithauer BW. The
new WHO classification of brain tumours.
Brain Pathol 1993;3(3):255Y268. doi:10.1111/
j.1750-3639.1993.tb00752.x.
4. International Agency for Research on
Cancer; Kleihues P, Cavenee WK, eds. World
Health Organization classification of tumours:
pathology and genetics of tumours of the
nervous system. Lyon, France: IARC Press, 2000.
5. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007
WHO classification of tumours of the central
nervous system. Acta Neuropathol 2007;114(2):
97Y109. doi:10.1007/s00401-007-0243-4.
6. Louis DN, Perry A, Reifenberger G, et al.
The 2016 World Health Organization
classification of tumors of the central
nervous system: a summary. Acta
Neuropathol 2016;131(6):803Y820.
doi:10.1007/s00401-016-1545-1.
7. International Agency for Research on Cancer;
Louis DN, Ohgaki H, Wiestler OD, Cavenee
WK, editors. WHO classification of tumours
of the central nervous system. 4th ed. Lyon,
France: World Health Organization, 2016.
8. Brennan CW, Verhaak RG, McKenna A,
et al. The somatic genomic landscape of
glioblastoma. Cell 2013;155(2):462Y477.
doi:10.1016/j.cell.2013.09.034.
9. Ceccarelli M, Barthel FP, Malta TM, et al.
Molecular profiling reveals biologically
discrete subsets and pathways of progression
in diffuse glioma. Cell 2016;164(3):550Y563.
doi:10.1016/j.cell.2015.12.028.
Continuum (Minneap Minn) 2017;23(6):1531–1547
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
10. Brat DJ, Verhaak RG, et al. Cancer Genome
Atlas Research Network. Comprehensive,
integrative genomic analysis of diffuse
lower-grade gliomas. N Engl J Med 2015;
372(26):2481Y2498. doi:10.1056/
NEJMoa1402121.
11. Eckel-Passow JE, Lachance DH, Molinaro AM,
et al. Glioma groups based on 1p/19q, IDH,
and TERT promoter mutations in tumors.
N Engl J Med 2015;372(26):2499Y2508.
doi:10.1056/NEJMoa1407279.
12. Suzuki H, Aoki K, Chiba K, et al. Mutational
landscape and clonal architecture in grade II
and III gliomas. Nat Genet 2015;47(5):458Y468.
doi:10.1038/ng.3273.
13. Pajtler KW, Mack SC, Ramaswamy V, et al.
The current consensus on the clinical
management of intracranial ependymoma
and its distinct molecular variants. Acta
Neuropathol 2017;133(1):5Y12. doi:10.1007/
s00401-016-1643-0.
14. Sturm D, Orr BA, Toprak UH, et al. New
brain tumor entities emerge from molecular
classification of CNS-PNETs. Cell 2016;164(5):
1060Y1072. doi:10.1016/j.cell.2016.01.015.
15. Ramaswamy V, Remke M, Bouffet E, et al.
Risk stratification of childhood medulloblastoma
in the molecular era: the current consensus.
Acta Neuropathol 2016;131(6):821Y831.
doi:10.1007/s00401-016-1569-6.
16. Pajtler KW, Witt H, Sill M, et al. Molecular
classification of ependymal tumors across all
CNS compartments, histopathological grades,
and age groups. Cancer Cell 2015;27(5):
728Y743. doi:10.1016/j.ccell.2015.04.002.
17. Northcott PA, Korshunov A, Witt H, et al.
Medulloblastoma comprises four distinct
molecular variants. J Clin Oncol 2011;29(11):
1408Y1414. doi:10.1200/JCO.2009.27.4324.
18. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2
mutations in gliomas. N Engl J Med 2009;360(8):
765Y773. doi:10.1056/NEJMoa0808710.
19. Giannini C, Scheithauer BW, Weaver AL,
et al. Oligodendrogliomas: reproducibility
and prognostic value of histologic diagnosis
and grading. J Neuropathol Exp Neurol 2001;
60(3):248Y262. doi:10.1093/jnen/60.3.248.
20. Louis DN, Perry A, Burger P, et al. Interna-
tional Society of NeuropathologyVHaarlem
consensus guidelines for nervous system
tumor classification and grading. Brain
Pathol 2014;24(5):429Y435.
doi:10.1111/bpa.12171.
21. Capper D, Weissert S, Balss J, et al.
Characterization of R132H mutation-specific
IDH1 antibody binding in brain tumors.
Brain Pathol 2010;20(1):245Y254.
doi:10.1111/j.1750-3639.2009.00352.x.
ContinuumJournal.com 1545
 2016 WHO Classification of CNS Tumors
22. Reuss DE, Mamatjan Y, Schrimpf D, et al. IDH
mutant diffuse and anaplastic astrocytomas
have similar age at presentation and little
difference in survival: a grading problem
for WHO. Acta Neuropathol 2015;129(6):
867Y873. doi:10.1007/s00401-015-1438-8.
23. Olar A, Wani KM, Alfaro-Munoz KD, et al. IDH
mutation status and role of WHO grade and
mitotic index in overall survival in grade II-III
diffuse gliomas. Acta Neuropathol 2015;129(4):
585Y596. doi:10.1007/s00401-015-1398-z.
24. Sahm F, Reuss D, Koelsche C, et al. Farewell
to oligoastrocytoma: in situ molecular
genetics favor classification as either
oligodendroglioma or astrocytoma.
Acta Neuropathol 2014;128(4):551Y559.
doi:10.1007/s00401-014-1326-7.
25. Wiestler B, Capper D, Sill M, et al. Integrated
DNA methylation and copy-number profiling
identify three clinically and biologically
relevant groups of anaplastic glioma. Acta
Neuropathol 2014;128(4):561Y571.
doi:10.1007/s00401-014-1315-x.
26. Huse JT, Diamond EL, Wang L, et al. Mixed
glioma with molecular features of composite
oligodendroglioma and astrocytoma: a true
‘‘oligoastrocytoma’’? Acta Neuropathol 2015;
129(1):151Y153. doi:10.1007/s00401-014-1359-y.
27. Qu M, Olofsson T, Sigurdardottir S, et al.
Genetically distinct astrocytic and
oligodendroglial components in
oligoastrocytomas. Acta Neuropathol
2007;113(2):129Y136. doi:10.1007/
s00401-006-0142-0.
28. Wilcox P, Li CC, Lee M, et al. Oligoastrocytomas:
throwing the baby out with the bathwater?
Acta Neuropathol 2015;129(1):147Y149.
doi:10.1007/s00401-014-1353-4.
29. Ohgaki H, Kleihues P. The definition of
primary and secondary glioblastoma. Clin
Cancer Res 2013;19(4):764Y772. doi:10.1158/
1078-0432.CCR-12-3002.
30. Kleinschmidt-DeMasters BK, Aisner DL, Birks
DK, et al. Epithelioid GBMs show a high
percentage of BRAF V600E mutation. Am J
Surg Pathol 2013;37(5):685Y698. doi:10.1097/
PAS.0b013e31827f9c5e.
31. Kleinschmidt-DeMasters BK, Aisner DL,
Foreman NK. BRAF VE1 immunoreactivity
patterns in epithelioid glioblastomas
positive for BRAF V600E mutation. Am J
Surg Pathol 2015;39(4):528Y540. doi:10.1097/
PAS.0000000000000363.
32. Tanaka S, Nakada M, Nobusawa S, et al.
Epithelioid glioblastoma arising from
pleomorphic xanthoastrocytoma with the
BRAF V600E mutation. Brain Tumor
Pathol 2014;31(3):172Y176. doi:10.1007/
s10014-014-0192-2.
1546 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
33. Perry A, Miller CR, Gujrati M, et al.
Malignant gliomas with primitive
neuroectodermal tumor-like components:
a clinicopathologic and genetic study of
53 cases. Brain Pathol 2009;19(1):81Y90.
doi:10.1111/j.1750-3639.2008.00167.x.
34. Korshunov A, Ryzhova M, Hovestadt V,
et al. Integrated analysis of pediatric
glioblastoma reveals a subset of biologically
favorable tumors with associated molecular
prognostic markers. Acta Neuropathol
2015;129(5):669Y678. doi:10.1007/
s00401-015-1405-4.
35. Wu G, Broniscer A, McEachron TA, et al.
Somatic histone H3 alterations in pediatric
diffuse intrinsic pontine gliomas and
non-brainstem glioblastomas. Nat Genet
2012;44(3):251Y253. doi:10.1038/ng.1102.
36. Khuong-Quang DA, Buczkowicz P,
Rakopoulos P, et al. K27M mutation in
histone H3.3 defines clinically and
biologically distinct subgroups of pediatric
diffuse intrinsic pontine gliomas. Acta
Neuropathol 2012;124(3):439Y447.
doi:10.1007/s00401-012-0998-0.
37. Herrlinger U, Jones DTW, Glas M, et al.
Gliomatosis cerebri: no evidence for a
separate brain tumor entity. Acta
Neuropathol 2016;131(2):309Y319.
doi:10.1007/s00401-015-1495-z.
38. Ellison DW, Kocak M, Figarella-Branger D, et al.
Histopathological grading of pediatric
ependymoma: reproducibility and clinical
relevance in European trial cohorts. J Negat Results
Biomed 2011;10:7. doi:10.1186/1477-5751-10-7.
39. Ramaswamy V, Taylor MD. Treatment
implications of posterior fossa ependymoma
subgroups. Chin J Cancer 2016;35(1):93.
doi:10.1186/s40880-016-0155-6.
40. Parker M, Mohankumar KM, Punchihewa C, et al.
C11orf95-RELA fusions drive oncogenic NF-0B
signalling in ependymoma. Nature 2014;
506(7489):451Y455. doi:10.1038/nature13109.
41. Rodriguez FJ, Perry A, Rosenblum MK, et al.
Disseminated oligodendroglial-like
leptomeningeal tumor of childhood: a
distinctive clinicopathologic entity. Acta
Neuropathol 2012;124(5):627Y641.
doi:10.1007/s00401-012-1037-x.
42. Huse JT, Edgar M, Halliday J, et al.
Multinodular and vacuolating neuronal tumors
of the cerebrum: 10 cases of a distinctive
seizure-associated lesion. Brain Pathol
2013;23:515Y524. doi:10.1111/bpa.12035.
43. Taylor MD, Northcott PA, Korshunov A, et al.
Molecular subgroups of medulloblastoma:
the current consensus. Acta Neuropathol
2012;123(4):465Y472. doi:10.1007/
s00401-011-0922-z.
December 2017
44. Dang M, Phillips PC. Pediatric brain tumors.
Continuum (Minneap Minn) 2017;23
(6 Neuro-oncology):1727Y1757.
45. Strowd RE, Blakeley JO. Common
histologically benign tumors of the brain.
Continuum (Minneap Minn) 2017;23
(6 Neuro-oncology):1680Y1708.
46. Chmielecki J, Crago AM, Rosenberg M,
et al. Whole-exome sequencing identifies a
recurrent NAB2-STAT6 fusion in solitary
fibrous tumors. Nat Genet 2013;45(2):
131Y132. doi:10.1038/ng.2522.
Continuum (Minneap Minn) 2017;23(6):1531–1547
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
47. Ohgaki H, Kleihues P. Population-based
studies on incidence, survival rates, and
genetic alterations in astrocytic and
oligodendroglial gliomas. J Neuropathol Exp
Neurol 2005;64(6):479Y489. doi:10.1097/
01.jnen.0000166799.76946.08.
48. Louis DN, Aldape K, Brat DJ, et al.
cIMPACT-NOW (the consortium to
inform molecular and practical approaches
to CNS tumor taxonomy): a new initiative
in advancing nervous system tumor
classification. Brain Pathol 2016. doi:10.1111/
bpa.12457.
ContinuumJournal.com 1547