Adult Gliomas

REVIEW ARTICLE


Adult Gliomas
C O N T I N UU M A UD I O By Howard Colman, MD, PhD, FAAN
I NT E R V I E W A V AI L A B L E
ONLINE
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CITE AS: ABSTRACT

CONTINUUM (MINNEAP MINN) PURPOSE OF REVIEW: Thisarticle highlights important aspects of the
2020;26(6, NEURO-ONCOLOGY):
evaluation, diagnosis, and treatment of adult gliomas, including
1452–1475.
lower-grade astrocytomas and oligodendrogliomas, glioblastomas, and
Address correspondence to ependymomas.
Dr Howard Colman, Huntsman
Cancer Institute, Departments of
RECENT FINDINGS: Theappropriate initial evaluation and accurate diagnosis of
Neurosurgery, Neurology, and
Internal Medicine (Oncology), gliomas require an understanding of the spectrum of clinical and
University of Utah, 1950 Circle of radiographic presentations. Recent advances in the understanding of
Hope, Ste 2100, Salt Lake City,
UT 84112-5550, howard.colman@ distinct molecular prognostic subtypes have led to major revisions in the
hci.utah.edu. diagnostic classification of gliomas. Integration of these new diagnostic
and molecular classifications is an important part of the modern
RELATIONSHIP DISCLOSURE:
Dr Colman has served as an
management of gliomas and facilitates better understanding and
associate editor for Neuro- interpretation of the efficacy of different therapies in specific glioma
Oncology and on the editorial subtypes.
board for Neuro-Oncology
Practice and has received
personal compensation for SUMMARY: The management of adult gliomas is a multidisciplinary endeavor.
serving on the advisory boards for However, despite recent molecular and treatment advances, the
AbbVie Inc, Bayer AG, Deciphera
Pharmaceuticals, Inc, Forma majority of diffuse gliomas remain incurable, and efforts aimed at the
Therapeutics, Karyopharm, development and testing of new therapies in clinical trials are ongoing.
NewLink Genetics Corporation,
and Orbus Therapeutics and as a
consultant for Best Doctors/
Teladoc Health, Inc, and Private
Health. Dr Colman has received INTRODUCTION
G
grant support from the Alliance
for Clinical Trials in Oncology liomas are a heterogeneous group of primary brain tumors that
(LAPS-UT003), The Hope present multiple diagnostic and therapeutic challenges. Important
Foundation, the Huntsman issues facing the clinician evaluating a patient with possible or
Cancer Foundation, the
Musella Foundation confirmed glioma include the initial (prediagnosis) evaluation,
Continued on page 1475 need for neurosurgical referral, prognostic considerations, and
decisions about treatment. Recent developments have demonstrated the central
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
role of molecular markers in the diagnosis, subtyping, and treatment of
USE DISCLOSURE: gliomas and their relationship with specific clinical and radiographic
Dr Colman discusses the presentations. This article highlights some of the important clinical,
unlabeled/investigational use of
agents targeting mutations/ radiographic, pathologic, and molecular considerations when evaluating a
alterations in BRAF (including patient with a possible or confirmed diagnosis of glioma.
vemurafenib), EGFR, FGFR, IDH,
and NTRK to treat gliomas that
harbor alterations in those genes PRESENTATION AND INITIAL EVALUATION
and the use of checkpoint Gliomas most commonly present with signs and symptoms related to a
inhibitors, chimeric antigen
receptor T cells, and
space-occupying lesion with symptoms often related to anatomic location. The
pembrolizumab to treat time course and nature of symptoms vary significantly based on growth rate,
glioblastoma. location, degree of associated edema, degree of increased intracranial pressure,
© 2020 American Academy
and whether seizures are part of the presentation. In general, lower-grade and
of Neurology. slower-growing tumors present with gradually progressive symptoms and more
1452 DECEMBER 2020
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

subtle neurologic deficits, except in the case of a new-onset seizure. Higher-grade KEY POINTS
and faster-growing tumors can present more acutely in terms of progressive
● Adult gliomas are a
neurologic deficits. clinically, radiographically,
For initial diagnosis, contrast-enhanced MRI is much more sensitive for histologically, and
gliomas and other primary or metastatic brain tumors than CT imaging.1 Thus, molecularly heterogeneous
CT alone is not a sufficient evaluation, and MRI should be performed promptly group of tumors.
for patients in whom brain tumor is part of the differential.

● The clinical presentation
and symptoms of gliomas
Indeterminate MRI Abnormalities and Neurosurgical Decision Making are often related to
While some combinations of clinical presentation and radiographic findings are anatomic location.
more definitive for glioma, other presentations can be more difficult to interpret
● The acuity of symptoms
with certainty. One important aspect of the initial evaluation is assessment of and presentation are often
the likelihood that a patient with an MRI abnormality actually has a glioma versus related to the tumor growth
other neoplastic or non-neoplastic diseases because the assessed probabilities rate.
drive appropriate next steps in the diagnostic workup. When clinical and
● MRI is more sensitive than
radiographic presentations suggest a high-grade neoplasm, early maximal safe
CT for the diagnosis of
resection for diagnosis, reduction of mass effect, and therapeutic benefit is potential gliomas and other
usually the first step. However, care must be taken for potential mimickers of brain tumors.
glioma in which surgery or more extensive surgery is not indicated, including
tumefactive multiple sclerosis, central nervous system lymphoma, abscess,
and stroke.2
One of the most significant challenges facing a neurologist in practice is how to
approach the patient with an MRI abnormality, particularly if asymptomatic,
for which glioma is a consideration but imaging and clinical presentation
are indeterminate. It should be noted that conventional MRI and even advanced
imaging modalities alone are not sufficiently sensitive and specific to make a
definitive diagnosis of glioma, particularly when imaging is suggestive of a
lower-grade neoplasm. The indications and limitations of both conventional MRI
and advanced imaging for diagnosis of glioma have been well described in prior
publications and reviews.1,3
Given the limitations of conventional and advanced imaging in the absence of
pathologic confirmation, neurologists need to be aware that anecdotal
interpretation of the significance of various clinical or radiographic findings can
sometimes lead to an early or incorrect conclusion regarding the certainty of the
underlying diagnosis. In the situation where interpretation of the initial clinical
and radiographic presentation leads to an incorrect diagnosis of something other
than glioma (eg, demyelination, stroke, herpes encephalitis, and others), a delay
in neurosurgical intervention and the diagnosis of and treatment of glioma is the
main danger. However, a mistaken presumptive diagnosis of a glioma when a
different underlying diagnosis is present can result in exposure of the patient to
unnecessary neurosurgical interventions and risk, as well as delay in the
treatment of the real diagnosis (eg, demyelination, cortical dysplasia, infection).
The goal of additional diagnostic evaluation is often to provide confidence that
the diagnosis is something other than glioma, and one that does not require
neurosurgical intervention, with higher confidence. However, care must be
taken not to delay neurosurgical intervention unnecessarily in the case of an
apparently higher-grade neoplasm or rapidly progressive symptoms. In these
cases, the benefits of arriving at a definitive pathologic diagnosis quickly
(whether glioma or not) often outweighs the additional risk of delay that more
extensive preoperative diagnostic evaluations may incur.
CONTINUUMJOURNAL.COM 1453

ADULT GLIOMAS
One of the key decisions in the evaluation of a patient with a possible glioma is
whether to pursue immediate referral for neurosurgical intervention and tissue
diagnosis, pursue additional diagnostic evaluations, or initially observe with
follow-up MRI studies to better determine the natural history and refine the
differential diagnosis before pursuing a tissue diagnosis. Some of the key
considerations in whether a patient requires immediate biopsy or resection of an
indeterminate lesion include the pattern and timing of clinical presentation,

imaging features (including size, location, and mass effect), whether the MRI
abnormality is symptomatic or asymptomatic, patient age, and assessment of the
likelihood that the lesion represents an infiltrating glioma versus a lower-grade
(grade I neoplasm) or non-neoplastic process, among others. The use of steroids
should also be avoided, when possible, when lymphoma, immune/inflammatory,
or infectious processes are in the differential diagnosis because of the potential to
decrease diagnostic yield from a biopsy or to negatively affect disease course.
These considerations highlight the need for a comprehensive history and
evaluation of symptoms and time course, careful evaluation of clinical and
radiographic findings, and when appropriate, consultation with a neuro-
oncologist or a neurosurgeon with experience in this area before going to surgery.
In one study, the time to diagnosis, length of hospitalization, and number of
unnecessary diagnostic studies were reduced by establishing a dedicated
TABLE 1-1 Molecular and Clinical Features of Selected World Health Organization
2016 Glioma Diagnoses
World Health Organization Diagnostic Molecular Other Common Characteristic Clinical and
2016 Integrated Diagnosis Markers Genomic Alterations Radiographic Features
Diffuse astrocytoma and IDH-mutant, 1p/19q-intact ATRX, TP53 Younger adults, supratentorial,
anaplastic astrocytoma, frontal predominance
IDH-mutant (grade II and III)
Glioblastoma, IDH-mutant IDH-mutant, 1p/19q-intact ATRX, TP53; some Younger adults, supratentorial,
(grade IV) cases: CDKN2 loss frontal predominance,
enhancement common
Oligodendroglioma and IDH-mutant, 1p/19q CIC, FUBP1, TERT Younger adults, supratentorial,
anaplastic codeleted promoter frontal predominance
oligodendroglioma,
IDH-mutant and 1p/
19q-codeleted (grade II and III)
Diffuse midline glioma, IDH-wildtype, None Midline (infratentorial and

H3K27M-mutant H3K27M-mutant supratentorial), younger adults
Diffuse astrocytoma, IDH-wildtype Chromosome 7 gain, Older adults, supratentorial more

IDH-wildtype (grade II and III) chromosome 10 loss, common than infratentorial
EGFR amplification,
PTEN; rare: BRAF,
NTRK, FGFR
Glioblastoma, IDH-wildtype IDH-wildtype Chromosome 7 gain, Older adults, supratentorial more

(grade IV) chromosome 10 loss, common than infratentorial,
EGFR amplification, enhancement common
PTEN; rare: BRAF,
NTRK, FGFR
1454 DECEMBER 2020

inpatient service for the evaluation of patients presenting with new brain masses KEY POINTS
on MRI,4 highlighting the early and critical role of subspecialty expertise in the
● Careful consideration of
management of these complex cases. history, clinical factors, and
imaging is needed to
DIAGNOSIS AND GRADING OF GLIOMAS develop an accurate
Historically, gliomas were diagnosed based on histopathology alone. differential diagnosis in the
evaluation of a newly
Astrocytoma and oligodendroglioma were named for the similarity in

presenting patient with
morphology of these tumor types to normal astrocytes and oligodendrocytes. imaging potentially
Also, in the past, the term mixed oligoastrocytomas was used for tumors with consistent with glioma.
mixed histology. Gliomas have also been graded based on histopathologic
findings. The World Health Organization (WHO) grade for gliomas ranges from ● The differing molecular
features of diffuse gliomas
I to IV. Grade I gliomas are more common in children and young adults and are are associated with distinct
often either observed or treated primarily with surgical resection; for more diagnoses and prognoses.
information about this group of tumors, refer to the article “Pediatric Brain
Tumors” by Sonia Partap, MD, and Michelle Monje, MD, PhD,5 in this issue of ● The revised 2016 World
Health Organization (WHO)
Continuum. The most common gliomas seen in adults are the diffuse gliomas and classification of gliomas
include astrocytomas, which range from grade II (astrocytoma) to III (anaplastic incorporates histologic and
astrocytoma) to IV (glioblastoma), whereas oligodendrogliomas are limited to molecular features into an
grade II (oligodendroglioma) and III (anaplastic oligodendroglioma). The integrated diagnosis.
incidence of grade II and III diffuse gliomas is less than glioblastoma, with
● The major molecular
approximately 5000 new cases of grade II/III astrocytomas and alterations used for
oligodendrogliomas each year in the United States.6 Grade III (anaplastic) diagnosis and classification
tumors are differentiated from grade II gliomas by increased features of of gliomas include isocitrate
malignancy, including atypia, hypercellularity, and increased mitotic rate. Grade dehydrogenase (IDH)
mutation status,
IV astrocytomas, also known as glioblastomas, are characterized by the presence chromosome 1p/19q status,
of either vascular proliferation or necrosis. Glioblastoma is the most common and H3K27M mutation
glioma seen in adults with an incidence of approximately 3 per 100,000 people status.
and 10,000 new cases in the United States each year.6 Historically, both
histologic diagnosis and grading of gliomas have been prone to significant
interobserver variability under prior WHO diagnostic criteria.7
Revised 2016 World Health Organization Classification of Gliomas

The identification of distinct molecular subtypes of glioma (often with
overlapping histologies) within this complex group of tumors has led to the 2016
revised classification by the WHO that has significantly improved diagnostic
accuracy, reduced interobserver variability, and clarified the prognosis and
treatment for distinct molecular subtypes. The revised 2016 World Health
Organization Classification of Tumors of the Central Nervous System8,9
combines histopathologic, molecular, and grading features into an integrated
glioma diagnosis. Under this revised system, the prior WHO classification of
tumors that covered diagnoses of astrocytoma, oligodendroglioma, and
glioblastoma has been separated into a series of molecular subtypes (and
grades) based on the presence or absence of several molecular alterations.8,9
The major diagnostic molecular alterations that subdivide gliomas into
different diagnostic categories are the presence or absence of (1) isocitrate
dehydrogenase (IDH) mutations, (2) chromosome 1p/19q loss, and (3) H3K27M
mutation. A summary of the key molecular and clinical features for these
tumors is shown in TABLE 1-1 and discussed in the following paragraph. The
cIMPACT-NOW (Consortium to Inform Molecular and Practical Approaches
to CNS Tumor Taxonomy) project is a multidisciplinary initiative to make

ADULT GLIOMAS
ongoing recommendations for the classification of central nervous system

tumors before the next edition of the World Health Organization Classification
of Tumors of the Central Nervous System is to be issued in 2021.10
IDH-MUTANT GLIOMAS. The majority of low-grade astrocytomas and

oligodendrogliomas, particularly in younger patients (median age of 35 to 40 years
for IDH-mutant gliomas versus median age of 55 to 60 years for IDH-wildtype

glioblastoma), have mutations in either IDH1 or IDH2, with mutations in IDH1

being much more common. Thus, one of the first major diagnostic steps after
determining that a newly diagnosed brain tumor is an infiltrating glioma is to
determine IDH status either by immunohistochemical testing or by gene
sequencing. The molecular marker used to differentiate IDH-mutant tumors into
astrocytoma or oligodendroglioma is the combined loss of chromosomes 1p and
19q. The loss of both chromosomal arms (1p and 19q) through a balanced
translocation is the molecular hallmark of oligodendroglial tumors. In the 2016
WHO classification, the official names for these entities are as follows:
u oligodendroglioma, IDH-mutant and 1p/19q codeleted (grade II)

u anaplastic oligodendroglioma, IDH-mutant and 1p/19q codeleted (grade III)
In addition to IDH mutation and 1p/19q loss, oligodendroglial tumors also

demonstrate mutations in other genes, including CIC and FUBP1.11–13 In contrast,
intact chromosome 1p/19q (no loss) is part of the molecular diagnosis of
IDH-mutant astrocytomas. When 1p/19q is intact or there is loss of only one
chromosomal arm, additional testing for evidence of mutations in ATRX or TP53
is often performed. Evidence of mutation of either of these genes in a tumor that
is IDH-mutant and in which chromosome 1p or 19q is intact is generally
consistent with an astrocytoma diagnosis. In the 2016 WHO classification, the
official names for these entities are as follows:
u diffuse astrocytoma, IDH-mutant (grade II)

u anaplastic astrocytoma, IDH-mutant (grade III)
u glioblastoma, IDH-mutant (grade IV)
An example of the presentation, diagnostic findings, and treatment for a

newly diagnosed grade II IDH-mutant astrocytoma is shown in CASE 1-1.
The 2016 WHO criteria have essentially eliminated the prior diagnosis of mixed
oligoastrocytoma (when molecular features are known). Under the new criteria,
tumors with a mixture of astrocytic and oligodendroglial histology are classified
under either astrocytoma or oligodendroglioma based on IDH and 1p/19q status. It is
also important to note that the diagnostic utility and presence or absence of these
molecular alterations are often dependent on the histologic and molecular context.
For instance, chromosome 1p/19q loss essentially occurs only in IDH-mutant
tumors. However, the reciprocal is not necessarily true, in that a tumor can be intact
for chromosome 1p/19q and show either IDH mutation or IDH-wildtype phenotype.
In addition, TERT promoter mutations are common in oligodendroglial tumors but
can also be seen in glioblastoma. TERT promoter mutation with IDH mutation is
strongly suggestive of the diagnosis of oligodendroglioma, whereas TERT promoter
mutation without IDH mutation is strongly suggestive of glioblastoma or other less
common glioma diagnoses. Thus, specific molecular alterations may have different
1456 DECEMBER 2020

diagnostic and prognostic implications depending on context and other molecular KEY POINTS
alterations that are present (or absent).
● The majority of
Glioblastoma, IDH-mutant (WHO grade IV) accounts for approximately 10% lower-grade (grade II and III)
of newly diagnosed glioblastoma. It is thought that virtually all of these astrocytomas and
grade IV IDH-mutant tumors represent so-called secondary glioblastomas that oligodendrogliomas have
originated as a lower-grade astrocytoma that was not recognized clinically at an IDH mutations.
earlier time point and was diagnosed only after malignant transformation to
● Loss of chromosomes
grade IV. However, while currently given the name glioblastoma and/or the 1p/19q is the molecular
same grade as histologically similar IDH-wildtype tumors, the IDH-mutant hallmark that distinguishes
tumors have a prognosis that is significantly better within any particular oligodendroglial from
grade.11–13 In addition, developing data suggest that the presence or absence of astrocytic gliomas within the
IDH-mutant group.
additional molecular features including CDKN2 loss and others may be a better
predictor of prognosis within IDH-mutant tumors than traditional histologic ● For the diagnosis of either
grading.14–16 Furthermore, growing data suggest that traditional histologic astrocytoma or anaplastic
features of grading, such as atypia and proliferation rate, may be less important astrocytoma with IDH
mutation, the presence or
in IDH-mutant tumors compared with IDH-wildtype tumors.16 absence of other molecular
alterations including CDKN2
IDH -WILDTYPE GLIOMAS AND GLIOBLASTOMAS. The vast majority of glioblastomas loss may be more important
in older patients are glioblastoma, IDH-wildtype and represent the so-called than the actual WHO grade
for prognosis.
primary glioblastoma (that do not arise from a known lower-grade precursor). In
contrast to lower-grade gliomas, the majority of these glioblastomas demonstrate ● The vast majority of
no mutation in IDH (IDH-wildtype). In general, patients with IDH-wildtype primary glioblastomas
tumors have a worse prognosis than those with IDH-mutant tumors of the same in older adults are
histology and grade. IDH-wildtype astrocytomas and glioblastomas often share a IDH-wildtype, and even
lower-grade IDH-wildtype
mutational profile that can include alterations in EGFR, NF1, TP53, PTEN, TERT astrocytic tumors with
promoter, CDKN2 loss, chromosome 7 gain, chromosome 10 loss, and others. A appropriate molecular
2018 publication by the cIMPACT-NOW group specifically recommended that alterations (EGFR or
infiltrating gliomas that are IDH-wildtype and demonstrate (1) EGFR chromosome 7 gain/
chromosome 10 loss or TERT
amplification, or (2) combined whole chromosome 7 gain and whole chromosome promoter) can be classified
10 loss, or (3) TERT promoter mutation should be more appropriately given the as diffuse astrocytic glioma,
diagnosis of diffuse astrocytic glioma, IDH-wildtype, with molecular features of IDH-wildtype, with
glioblastoma, WHO grade IV.17 Thus, even if histopathology is found to be lower molecular features of
glioblastoma, WHO grade IV.
grade (grades II and III), astrocytomas that harbor these glioblastomalike
alterations tend to have a poor prognosis and behave similarly to histologic grade
IV tumors. The recommended cIMPACT-NOW diagnosis for these patients (with
diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma,
WHO grade IV) is an attempt to assign a diagnosis appropriate with that
prognosis, despite the lower-grade histologic features.17–19 An example of a patient
with lower-grade histology but molecular findings consistent with glioblastoma is
shown in CASE 1-2.
OTHER CLINICALLY IMPORTANT IDH-WILDTYPE GLIOMA SUBTYPES. Although the

majority of infiltrating gliomas fall into the WHO subtypes discussed earlier,
several other clinically significant entities are important to identify from a
diagnostic, prognostic, or therapeutic standpoint. These rarer subtypes are
clinically relevant because they are associated with distinct clinical, radiographic,
or molecular findings. In particular, the range of clinical behavior and prognoses
within this group of IDH-wildtype (but not molecular glioblastomalike) tumors
is quite broad. Some of these distinct diagnostic and molecular entities are
described below.

ADULT GLIOMAS
DIFFUSE MIDLINE GLIOMA, H3K27M-MUTANT. This is a new and distinct diagnosis

in the 2016 WHO criteria and is generally associated with younger age,
midline (thalamic, basal ganglia) or posterior fossa location, diffuse
infiltration, and typically a poor prognosis. A significant proportion of diffuse
intrinsic pontine gliomas in children or younger adults are also members of
this molecular subtype. In addition to the clinical and radiographic findings,
this diagnosis is confirmed by molecular testing (either immunohistochemistry

or DNA sequencing) that demonstrates the characteristic H3K27M mutation in
CASE 1-1 A 39-year-old woman presented with a new-onset seizure. Brain MRI
demonstrated a nonenhancing mass in the left lateral frontoparietal
regions, with fluid-attenuated inversion recovery (FLAIR) and T1
postcontrast images at diagnosis shown in FIGURES 1-1A and 1-1B,
respectively. She underwent resection with pathology of diffuse
astrocytoma, World Health Organization (WHO) grade II. Molecular
testing at that time showed the tumor was mutant for IDH1, ATRX, and
TP53, and chromosome 1p/19q was intact. By using the new WHO
diagnostic criteria, this tumor would be classified as diffuse astrocytoma,
IDH-mutant, WHO grade II. After surgery, she was treated with radiation
to a dose of 54 Gy with concurrent temozolomide and six cycles of
adjuvant temozolomide. She had been off treatment since, and MRI
8 years after diagnosis is shown in FIGURES 1-1C and 1-1D (FLAIR and T1
postcontrast, respectively) with no evidence of progression since the
initial treatment. At her most recent visit, she had a Karnofsky
Performance Status Scale score of 100, was working full time, and was
seizure free.
COMMENT This case illustrates some of the common clinical, radiographic, and
diagnostic molecular features of IDH-mutant astrocytomas. The patient’s
good response to treatment, long progression-free interval, and excellent
clinical status highlight the potential for good outcomes with this tumor
type (as well as oligodendrogliomas, IDH-mutant and 1p/19q codeleted).
1458 DECEMBER 2020

the histone 3 protein. An example of a midline glioma for which H3K27 testing
confirmed the diagnosis of diffuse midline glioma, H3K27M-mutant is shown in
CASE 1-3. Other rarer histone mutations are also seen but fall outside this
narrower diagnostic entity.
DIFFUSE ASTROCYTOMAS, IDH-WILDTYPE, CHROMOSOME 1P/19Q-INTACT OF VARIABLE

GRADES WITH BRAF GENE ALTERATIONS. This group of tumors can have variable
histologic findings, with some indistinguishable from more typical IDH-mutant
FIGURE 1-1
Imaging of the patient in CASE 1-1. Axial fluid-attenuated inversion recovery (FLAIR) (A) and
postcontrast T1-weighted (B) brain MRI demonstrates a nonenhancing mass in the left
lateral frontoparietal region at diagnosis. FLAIR (C) and postcontrast T1-weighted (D)
images 8 years after diagnosis show a resection cavity with no evidence of progression
since the initial treatment.

ADULT GLIOMAS
astrocytomas and others having potential overlap in histologic and molecular

findings with other (often circumscribed) glioma variants. These variants are
potentially clinically important as several therapies exist that specifically target
BRAF alterations, and data are increasing regarding the therapeutic benefit of
these agents in gliomas and other primary brain tumors. The most common
BRAF alterations seen in infiltrating gliomas are a point mutation (BRAF V600E)
and BRAF gene fusions (BRAF-KIAA1549), and these alterations are mutually
CASE 1-2 A 45-year-old man presented with a new-onset seizure and some subtle
but progressive speech difficulty. Brain MRI demonstrated a
nonenhancing mass in the medial left temporal lobe, with
fluid-attenuated inversion recovery (FLAIR) and postcontrast
T1-weighted images at diagnosis as shown in FIGURES 1-2A and 1-2B,
respectively. He underwent almost complete resection of the tumor in
the left temporal lobe with pathology of diffuse astrocytoma, World
Health Organization (WHO) grade II. The tumor was determined to be
IDH-wildtype by immunohistochemistry and sequencing. Next-generation
DNA sequencing showed that the tumor was EGFR amplified and had
chromosome 7 gain, PTEN loss, and a TERT promoter mutation. If the
patient had been diagnosed by using the revised 2016 WHO criteria, this
tumor would have been classified as diffuse astrocytoma, IDH-wildtype,
WHO grade II. O-6-methylguanine-DNA methyltransferase (MGMT)
promoter was unmethylated.
He received radiation to 60 Gy with concurrent temozolomide followed
by six cycles of adjuvant temozolomide. Despite treatment typical for
higher-grade astrocytoma (due to the unfavorable molecular findings), the
patient experienced rapid recurrence involving the left insula, frontal
lobe, and corpus callosum approximately 2 years later
(FIGURES 1-2C and 1-2D).
COMMENT This case illustrates the importance of the molecular alterations in diffuse
gliomas relative to prognosis. Although age, presentation, imaging,
pathology, and histologic grade were similar to those in CASE 1-1, this patient
experienced a very different and much worse outcome despite receiving
similar treatment. The findings of EGFR mutation, chromosome 7 gain, TERT
promoter mutation, and others in a histologically low-grade IDH-wildtype
astrocytoma are generally associated with a prognosis that is similar to
glioblastoma, and the cIMPACT-NOW (Consortium to Inform Molecular and
Practical Approaches to CNS Tumor) group recently published
recommendations that these tumors are given the diagnosis diffuse
astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma,
WHO grade IV.16 This case highlights the need for clinicians to be aware of
these subtleties in the diagnosis and treatment of diffuse gliomas.
1460 DECEMBER 2020

exclusive within a particular tumor.20 BRAF fusions are seen most commonly in
pilocytic astrocytomas but can also occur rarely in infiltrating gliomas. BRAF
mutations exist in a variety of glioma histologies including pleomorphic
xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, ganglioglioma,
and rarely in lower-grade infiltrating astrocytoma and glioblastoma. Epithelioid
glioblastoma is recognized as a distinct glioblastoma subtype in the 2016 WHO
classification, is seen predominantly in children and young adults, and has a

FIGURE 1-2
postcontrast T1-weighted (B) brain MRI demonstrates a nonenhancing mass in the medial left
temporal lobe at diagnosis. FLAIR (C) and postcontrast T1-weighted (D) images show aggressive
recurrence approximately 2 years after initial treatment with radiation and temozolomide.

ADULT GLIOMAS
distinct cell morphology in which greater than 50% of tumors harbor the BRAF
V600E mutation. Some debate exists about the overlap of epithelioid
glioblastoma and anaplastic pleomorphic xanthoastrocytoma and whether these
really represent distinct diagnoses.20 Case reports and small series in the
literature describe radiographic responses of various glioma subtypes harboring
BRAF alterations to drugs targeting either BRAF V600E mutation and drugs that
target mitogen-activated protein kinase, a downstream component in this

pathway.21 Thus, it is important to recognize these rare variants because of the

potential for the use of targeted therapies in the appropriate clinical situation.
DIFFUSE ASTROCYTOMAS, IDH-WILDTYPE, CHROMOSOME 1P/19Q-INTACT THAT

HARBOR OTHER DISCRETE AND POTENTIALLY THERAPEUTICALLY TARGETABLE
MOLECULAR ALTERATIONS. These alterations are rare (often less than 2% to 3%
each in gliomas) but have shown promise in other tumor types as therapeutic
CASE 1-3 A 31-year-old woman presented with a 2- to 3-month history of

progressive headaches. Brain MRI demonstrated a relatively
well-circumscribed, nonenhancing mass involving the hypothalamus and
inferior basal ganglia bilaterally, shown in FIGURES 1-3A and 1-3B
(fluid-attenuated inversion recovery [FLAIR] and postcontrast
T1-weighted images, respectively). Biopsy was performed, and the
pathologic diagnosis was initially diffuse astrocytoma, World Health
Organization (WHO) grade II, negative for IDH mutation by
immunohistochemistry. However, subsequent tumor sequencing
demonstrated an isolated H3K27M mutation, which under current WHO
criteria would be diagnosed as diffuse midline glioma, H3K27M-mutant.
Although the patient was diagnosed before the current WHO guidelines,
the negative prognostic impact of this finding was known, and the patient
was treated aggressively with radiation to 60 Gy with concurrent
temozolomide followed by six cycles of adjuvant temozolomide.
The patient was lost to follow-up and presented again approximately
2.5 years later with seizures, encephalopathy, and left hemiparesis, and
repeat brain MRI was performed (FIGURE 1-3C). Based on the patient’s poor
performance status requiring intensive care unit admission, the family
chose not to pursue additional treatment.
COMMENT As in the previous cases, this case demonstrates another example of the
spectrum of molecular findings and prognoses that can occur in diffuse
gliomas, sometimes with similar clinical and radiographic findings. Although
this patient’s tumor has a relatively “benign” and well-circumscribed
appearance on the initial imaging, which might suggest a diagnosis of
several grade I tumors such as pilocytic astrocytoma, dysembryoplastic
neuroepithelial tumor (DNET), or ganglioglioma based on imaging alone, the
molecular findings here are diagnostic of the grade IV H3K27M midline
tumor, and accurately predicted the poor prognosis of this patient despite
aggressive treatment.
1462 DECEMBER 2020

targets. These include FGFR gene fusions,22 NTRK gene fusions, microsatellite
instability–high, and ROS1 gene fusions. In the case of NTRK fusions and
microsatellite instability–high tumors, the US Food and Drug Administration
(FDA) has approved targeted and immunotherapy agents, respectively, where
the drug approval is “tissue agnostic.” Thus, testing for these rare alterations
can be important to identify those patients for whom these targeted or
immunotherapies may be appropriate in addition to or instead of standard

therapies in selected situations.
EPENDYMAL TUMORS. Ependymal tumors are glial neoplasms that are distinct from
the diffuse gliomas and can present in both childhood and adulthood.6 In contrast
to the diffuse gliomas, this group of tumors is thought to arise from the
ependymal lining of the ventricular cavities or from radial glia precursors in these
regions.23 Ependymal tumors comprise different histologies including
FIGURE 1-3
postcontrast T1-weighted (B) brain MRIs demonstrate a relatively well-circumscribed,
nonenhancing mass involving the hypothalamus and inferior basal ganglia bilaterally. A
repeat brain postcontrast T1-weighted sequence (C) approximately 2.5 years after initial
treatment with radiation and temozolomide shows aggressive recurrence in the midline and
anteriorly and superiorly in the frontal lobe on the right.

ADULT GLIOMAS
ependymoma, subependymoma, and myxopapillary ependymoma that are

associated with different clinical, radiographic, molecular, and grading features.
Subependymomas are grade I tumors, most commonly located in the lining of the
fourth ventricle, but they can be found elsewhere. These are slow-growing
tumors that are often diagnosed as an incidental finding but when symptomatic
are often associated with CSF obstruction and increased intracranial pressure.
Subependymomas that are incidental, asymptomatic, or not clearly progressing

might be observed without intervention. When symptomatic, the primary
treatment is usually resection alone, with radiation used only in rare cases of
multiply recurrent or unresectable and progressive subependymoma.
Myxopapillary ependymomas are also WHO grade I tumors, most commonly
found in the conus medullaris and cauda equina regions of the spine. Resection is
the primary treatment, with radiation reserved for incomplete resection or
tumors that progress after maximal resection. Rarely, myxopapillary
ependymomas can behave much more aggressively than the grade I histology
would suggest, with cases of CSF dissemination or invasion of adjacent bony
structures. Ependymomas are either grade II or grade III (anaplastic
ependymoma) with grading based on histologic findings. The histopathologic
hallmark of ependymoma is the perivascular pseudorosette (FIGURE 1-4). As in
diffuse gliomas, recent advances in the molecular understanding of ependymomas
have led to the identification of distinct molecular subtypes. An important subtype
is the RELA-C11orf95 fusion variant observed in a high percentage of
supratentorial ependymomas,23,24 which led to the inclusion of ependymoma,
RELA fusion–positive as a distinct diagnostic category in the 2016 revised WHO
classification.9,23,24 There are two subtypes of posterior fossa ependymoma (group
A and group B) based on gene expression and epigenetic profiling.25 Negative
prognostic factors for ependymoma include intracranial (versus spinal) location,
younger age, male sex, higher grade, and incomplete resection.23
In terms of treatment, maximal safe resection is the primary initial treatment
for ependymoma. Staging of the neuraxis with contrast-enhanced MRI of both
brain and spine and CSF cytology before surgery is preferred when ependymoma
is suspected preoperatively, but staging can also be performed after a histologic
diagnosis is made. Adjuvant radiation after surgery is generally part of treatment
for all grade III ependymomas
and incompletely resected grade
II ependymomas.26 In addition,
one retrospective series indicated
that, even with complete
resection, posterior fossa grade II
ependymomas have a higher
recurrence rate without adjuvant
radiation.27 The role for adjuvant
radiation for completely resected
supratentorial ependymoma is a
topic of debate.
DIFFUSE GLIOMA TREATMENT

FIGURE 1-4
A perivascular pseudorosette (arrow)
Several treatment modalities
characteristic of ependymoma. including surgical resection,
Image courtesy of Cheryl Ann Palmer, MD. radiation, chemotherapy, and
1464 DECEMBER 2020

more recently tumor treating fields have been shown to have overall or KEY POINTS
progression-free survival benefits in gliomas. However, the relative benefit of
● H3K27M mutations are
each modality can differ based on specific histologic, grade, and molecular the hallmark of diffuse
features. The current evidence for these treatment modalities in specific clinical midline glioma, which most
situations is reviewed here. commonly occur in the pons
and diencephalon in
younger patients and are

Surgery
associated with poor
Initial treatment for all grades of gliomas starts with maximal safe resection. In prognosis.
addition to providing definitive histologic and molecular diagnosis, surgery
also can provide a clinical benefit from a reduction of mass effect, and more ● Initial treatment for most
extensive resection has been associated with better survival in several glioma diffuse gliomas starts with
maximal safe resection.
subtypes. For newly diagnosed glioblastoma (and by extension higher-grade
IDH-wildtype gliomas), a greater extent of resection of an enhancing tumor has
been associated with better overall survival. In some retrospective studies,
resection of greater than 95% of presurgical enhancement is needed for
significant improvement in survival,28,29 although in one analysis from a large
retrospective series the volume of residual enhancement after resection was
more important than the percentage of resection.30
Only recently have outcomes relative to the extent of resection in gliomas been
analyzed based on molecular subtypes. In the case of lower-grade gliomas, a
greater extent of resection and a smaller volume of residual (often
nonenhancing) tumor have been found to be positive prognostic factors in
several retrospective analyses.31 In analyses of gliomas that compared surgical
outcomes of IDH-mutant versus IDH-wildtype gliomas, the extent of resection
of enhancing disease (but not nonenhancing tumor) was prognostic in
IDH-wildtype tumors, whereas the extent of resection of total tumor volume
(enhancing and nonenhancing disease) was prognostic in IDH-mutant tumors.32
These findings suggest that the role and surgical target for maximal resection
may differ based on the molecular subtype of glioma.
In suspected lower-grade gliomas, the timing of surgery is also an important
clinical decision. The effect of early resection versus initial observation of
presumed low-grade gliomas has not been evaluated in a randomized trial.
Uncontrolled and retrospective analyses have suggested a survival benefit of
early and more complete resection.31–33 To date, no studies have convincingly
defined a population of patients in which delayed or incomplete resection has
demonstrated clinical benefit. As a result, the most common approach in
specialized centers is to proceed with maximal safe resection in patients with
suspected lower-grade gliomas, as recommended in National Comprehensive
Cancer Network guidelines for suspected low-grade gliomas.17,34
Radiation, Chemotherapy, and Tumor Treating Fields for Newly Diagnosed

Glioblastoma
The benefit of radiation in prolonging survival with high-grade gliomas dates
back several decades. In terms of radiation dosage for glioblastoma, historical
studies have suggested that dosages greater than 65 Gy have efficacy similar
to that of 60 Gy but with higher toxicity and increased risk of radiation necrosis.
Thus, current guidelines recommend a standard dose of 60 Gy in 2.0-Gy
fractions or 59.4 Gy in 1.8-Gy fractions.35 Tumor volumes (enhancing and
nonenhancing) for radiation treatments are defined by the postoperative
(preradiation) MRI and include the volume of abnormalities on T1-weighted and

ADULT GLIOMAS
T2-weighted sequences (gross tumor volume) plus a margin that can range from
1 cm to 3 cm. The therapeutic effect of radiation is generally related to dose, not
modality (eg, photons versus protons), with current clinical trials comparing
intensity-modulated radiation therapy to proton therapy mainly aimed at determining
if there is any benefit of proton therapy in terms of reduced neurotoxicity.
The role of chemotherapy as a standard part of treatment in newly diagnosed
glioblastoma was established in a 2005 randomized trial of temozolomide plus

radiation versus radiation alone. This study showed a significant survival benefit
(14.6 months versus 12.1 months) with the addition of temozolomide to radiation
and 6 additional months of postradiation temozolomide.35 Dosing of temozolomide
was 75 mg/m2 daily during the 6 weeks of radiation, 150 mg/m2 days 1 to 5 of the
first 28-day adjuvant cycle after radiation, and then (if tolerated) 200 mg/m2 for
days 1 to 5 of the 28-day cycles 2 through 6 after radiation. Longer-term follow-up
of patients from this study also demonstrated an improvement in long-term
survival, with overall 5-year survival of 9.8% in the radiation plus temozolomide
group versus 1.9% in the radiation alone group.36 The most common adverse
effects of temozolomide include fatigue, nausea, constipation, and bone marrow
suppression, with lymphopenia and thrombocytopenia the most common
cytopenias. Temozolomide remains the only chemotherapy that is FDA approved
specifically for newly diagnosed glioblastoma. As a result of this study, radiation
plus temozolomide is the standard initial treatment for patients with newly
diagnosed glioblastoma, particularly in patients with favorable clinical prognostic
factors (younger age, better performance status, better extent of resection) and in
those patients in whom the tumor shows evidence of O-6-methylguanine-DNA
methyltransferase (MGMT) promoter methylation.
MGMT Promoter Methylation

The initial randomized study of temozolomide in newly diagnosed glioblastoma
also identified MGMT promoter methylation as a marker of better prognosis
and a predictive marker of temozolomide benefit.37 MGMT removes methyl
groups from DNA, thereby conferring resistance to methylating agents such as
temozolomide. Thus, high MGMT levels act as a potential resistance mechanism
to temozolomide treatment. High levels of methylation of the MGMT promoter
are associated with lower expression levels of MGMT resistance enzyme and
increased sensitivity to temozolomide treatment. Longer-term follow-up from
the 2005 temozolomide study also demonstrates a strong prognostic and
predictive effect of MGMT promoter methylation.36 In patients who received
radiation alone, patients with MGMT promoter methylation had better 5-year
survival than those without MGMT promoter methylation (5.2% versus 0%),
suggesting a better prognosis even without chemotherapy (at least at initial
diagnosis). However, the benefit of MGMT promoter methylation was strongest
in the patients who received temozolomide with radiation as the initial treatment
with a 5-year survival of 23.4% (methylated) versus 12.6% (unmethylated). These
data indicate that when patients with IDH-wildtype glioblastoma have a combination
of positive clinical prognostic factors and MGMT promoter methylation, the
likelihood of longer-term survival with standard treatments is higher.38
Tumor Treating Fields

The only other treatment modality beyond radiation and temozolomide that has
a survival benefit in newly diagnosed glioblastoma is tumor treating fields.39 The
1466 DECEMBER 2020

potential mechanism of action that led to the development of tumor treating KEY POINTS
fields as a treatment modality is the concept that DNA and mitotic spindles
● O-6-methylguanine-DNA
within a cell are electrically charged, and it was hypothesized that an electrical methyltransferase (MGMT)
field of sufficient strength delivered across the tumor cells could inhibit DNA promoter methylation is
replication and mitosis. The tumor treating fields are delivered to the glioblastoma both a prognostic marker in
tumor by using multiple electrode arrays that are attached to the shaved scalp glioblastoma and a
predictive marker of a
of the patient, and the electric fields are delivered via a battery pack that is worn
better outcome with
as a shoulder or backpack and attached to the electrodes via a wiring harness. temozolomide.
The randomized study examining the effect of tumor treating fields in newly
diagnosed glioblastoma involved random assignment of patients after they ● Standard treatment
completed radiation and temozolomide to either temozolomide alone (control) or options with survival benefit
in randomized studies for
temozolomide and tumor treating fields (experimental) groups. This was not a newly diagnosed
placebo-controlled study, and thus, it is not possible to determine whether glioblastoma include
differences in supportive care or follow-up between arms played some role in radiation, temozolomide,
the outcomes.40 However, the study did demonstrate a survival benefit in the and tumor treating fields.
tumor treating fields group versus control (20.9 months versus 16.0 months,
respectively).39 Tumor treating fields are FDA approved for use in newly diagnosed
glioblastoma along with temozolomide after radiation based on these data.
Recurrent Glioblastoma
Despite initial therapy, glioblastoma progresses in virtually every patient. While
clinical and molecular prognostic markers such as IDH mutation and MGMT
promoter methylation have been associated with better outcomes in recurrent
tumors in at least some studies, the survival of recurrent glioblastoma is generally
poor, with one randomized study showing a median survival of approximately
9 months from the time of first progression.41 Patients with poor prognostic
factors (eg, older age, poor performance status) have even worse survival
outcomes. Despite the testing of many different agents with various mechanisms
of action in recurrent glioblastoma, no treatment has been shown to improve
overall survival in this group of patients. Cytotoxic chemotherapies have very
low radiographic response rates in recurrent glioblastoma.42 Thus, the
antiangiogenic agent bevacizumab (a humanized monoclonal antibody against
vascular endothelial growth factor [VEGF]) created some excitement when it
was found to have a high response rate (40% to 60%) in initial single-arm
studies, as well as improved progression-free survival compared with historical
controls.43 The observation of a high response rate and improved progression-
free survival with bevacizumab led to accelerated approval by the FDA for the
treatment of recurrent glioblastoma. However, the provisional FDA approval in
2009 stipulated that confirmatory phase 3 studies be performed. Two phase 3
randomized, placebo-controlled studies of radiation, temozolomide, plus
bevacizumab versus radiation and temozolomide alone were performed with
patients with newly diagnosed glioblastoma,44,45 and subsequently a separate
phase 3 study of bevacizumab plus lomustine versus lomustine alone in recurrent
glioblastoma.41 The results of all of these studies were similar (despite the
different patient populations) in that all confirmed a high proportion of
radiographic responses to bevacizumab in glioblastoma and improvement of
progression-free survival in the 3- to 5-month range. However, none of these
studies demonstrated a significant benefit on overall survival. Despite these
findings, it was concluded that the net clinical benefit observed in terms of
response rate, progression-free survival, and maintenance of performance status

ADULT GLIOMAS
was important, and this led to conversion of bevacizumab to full approval by the
FDA in 2019. Several other agents including lomustine, tumor treating fields,
carmustine, carboplatin, and others have shown some activity in recurrent
glioblastoma and are listed in National Comprehensive Cancer Network
guidelines,34 but as with bevacizumab, none of these have demonstrated an overall
survival benefit in recurrent glioblastoma in a randomized study.
Older Adults With Glioblastoma

Older age is generally associated with worse prognosis in glioblastoma. Randomized
studies have examined the role of a shorter course (hypofractionated) of radiation
with and without temozolomide in older patients (generally older than 60 or
65 years depending on the study). In one randomized study examining standard
versus hypofractionated radiation alone (before temozolomide was part of the
standard of care), no significant difference in survival was found between a total
dose of 40 Gy in 15 fractions compared with standard 60 Gy in 30 fractions.46 In a
separate study of anaplastic astrocytoma and glioblastoma in patients older than 65,
patients were randomly assigned to standard radiation (60 Gy) alone versus a
regimen of temozolomide alone.47 This study demonstrated that temozolomide
alone was not inferior to radiation in the overall population and that, within the
group of patients with MGMT promoter methylation, survival was better in the
temozolomide monotherapy group versus the radiation group. Results of a
three-arm study of standard-dose temozolomide versus standard radiation (60 Gy)
versus a hypofractionated schedule (34 Gy in 3.4-Gy fractions) in patients older than
60 showed that survival with temozolomide was longer than with standard
radiation but similar to hypofractionated radiation.48 Again, patients whose tumors
had MGMT promoter methylation had better survival with temozolomide
treatment. These studies led to the concept that, in older patients with
glioblastoma with MGMT promoter methylation, temozolomide alone (no
radiation) is an option for initial treatment, and, in MGMT unmethylated
tumors, hypofractionated radiation may be a reasonable alternative to standard
radiation. However, a subsequent phase 3 study comparing hypofractionated
radiation alone to hypofractionated radiation (40 Gy in 15 fractions) plus
temozolomide in patients older than 65 with newly diagnosed glioblastoma
showed an improvement in median survival with the addition of temozolomide
in the overall population (9.3 months versus 7.6 months). Somewhat
surprisingly, the benefit of the addition of temozolomide was seen in both the
MGMT unmethylated (10.0 months versus 7.9 months) and MGMT methylated
groups (13.5 months versus 7.7 months).49 Based on these results in older patients
with glioblastoma, National Comprehensive Cancer Network guidelines for
patients older than 70 with good performance status currently include all
combinations of standard and hypofractionated radiation with or without
temozolomide as reasonable treatment options for MGMT methylated or
unmethylated tumors and temozolomide alone as an additional potential option
for MGMT methylated tumors.34 Tumor treating fields are also part of National
Comprehensive Cancer Network guidelines for treatment of both methylated
and unmethylated tumors in this age group.
Grade II and III Diffuse Infiltrating Astrocytoma and Oligodendroglioma

As described earlier, recent developments have clarified the molecular
distinctions between lower-grade (grades II and III) astrocytomas and
1468 DECEMBER 2020

oligodendrogliomas, and 2016 updated WHO diagnostic criteria combine KEY POINTS
histologic findings with IDH mutation status and chromosome 1p/19q deletion
● Bevacizumab is US Food
status into an integrated diagnosis and grading system. The majority of lower- and Drug Administration
grade gliomas are IDH-mutant, and, in general, lower-grade IDH-wildtype (FDA)-approved for
tumors either fall into the glioblastomalike category or represent rarer recurrent glioblastoma
molecular variants (eg, H3K27 mutant, BRAF alterations). This discussion of based on improved
progression-free survival in
lower-grade gliomas focuses on the more common IDH-mutant subtypes, with

randomized studies, but this
the majority of IDH-wildtype tumors falling under the category of glioblastoma agent has not demonstrated
in terms of recommended treatment. Prognosis is generally much better for an overall survival benefit in
lower-grade IDH-mutant astrocytoma and oligodendroglioma compared with glioblastoma.
grades II through IV IDH-wildtype and better than IDH-mutant grade IV
● In older patients with
tumors.12,13 Prognosis is generally better for oligodendroglioma, IDH-mutant newly diagnosed
compared with astrocytoma, IDH-mutant across grades II and III, regardless of glioblastoma, a
whether the treatment being tested in the study was radiation, chemotherapy, or hypofractionated course of
some combination. In addition, within all IDH-mutant lower-grade gliomas, radiation is a consideration
with or without
several important clinical prognostic factors have been identified including age, temozolomide or tumor
performance status, size of tumor at presentation, the amount of residual tumor treating fields.
burden after resection, tumor location, and other molecular features beyond IDH
mutation (discussed earlier), and all appear to play an important role in
outcomes, regardless of treatment modality.
Radiation dosage for grade II and III gliomas has been evaluated in several
randomized trials. Based on the results of these studies, lower radiation doses
(eg, 50.4 Gy in 28 fractions) are often used for grade II tumors, whereas higher
doses (59.4 Gy) are commonly used in grade III tumors.34 These dosages were
determined before the understanding of molecular subtypes and determinants in
infiltrating gliomas. The finding that traditional histopathologic grading is not
prognostic in IDH-mutant gliomas does suggest that these differences in
radiation dose based on histologic grade may need to be revisited in the modern
era, but, to date, no comparative data on the use of different doses in molecularly
defined subtypes of glioma are available to guide these decisions. Relevant to this
issue, current National Comprehensive Cancer Network guidelines suggest that
patients with grade II diffuse gliomas receive 45 Gy to 54 Gy in 1.8- to 2.0-Gy
fractions, but dose escalation to 59.4 Gy to 60 Gy should be considered for
IDH-wildtype grade II gliomas.34 For anaplastic gliomas, National Comprehensive
Cancer Network recommendations are to treat to 60 Gy in 2.0-Gy fractions or
59.4 Gy in 1.8-Gy fractions, regardless of IDH status.
A key long-standing question in the treatment of lower-grade gliomas has
been the issue of whether radiation alone, chemotherapy alone, or the
combination of radiation and chemotherapy is optimal in different subtypes
or glioma grades. In particular, the observation, along with the discovery of
chromosome 1p/19q loss in oligodendrogliomas, was that these tumors
appeared particularly sensitive to chemotherapy,50 which led to the
hypothesis that treatment with chemotherapy alone (no radiation) may be
sufficient for some or all patients with these tumors. However, a series of
randomized trials has demonstrated a survival benefit of radiation plus
chemotherapy (most trials used either procarbazine, lomustine [CCNU], and
vincristine [PCV] or temozolomide) versus radiation alone in either grade II
gliomas51 or grade III oligodendrogliomas52,53 and grade III astrocytoma.54
Subset analyses of these studies have confirmed that the largest magnitude of
benefit of combined radiation and chemotherapy in grade II and III diffuse

ADULT GLIOMAS
gliomas is observed in the IDH-mutant and chromosome 1p/19q-codeleted

tumors (oligodendrogliomas) followed by the IDH-mutant and chromosome
1p/19q-intact (astrocytoma) tumors. The smallest benefit is observed in the
IDH-wildtype grade II and III tumors.54,55 In addition, randomized studies
comparing chemotherapy alone (PCV56 or temozolomide57) to radiation alone
did not show a benefit of chemotherapy alone and showed some indication of
worse survival in some subgroups. The interpretation of these studies is that,

despite the goal of seeking to spare patients the toxicity of either radiation or
chemotherapy when possible, data from randomized trials indicate that when
the decision is made to initiate treatment for lower-grade gliomas, the
treatment with the best data for prolonging survival is a combination of
radiation and chemotherapy. In terms of which radiation and chemotherapy
combination to use (radiation followed by PCV or radiation with concurrent
temozolomide followed by adjuvant temozolomide), a subsequent
randomized clinical trial potentially supports the use of radiation and
temozolomide in tumors that are IDH mutated and 1p/19q intact,54 although
this study did not evaluate the relative benefit of PCV versus temozolomide in
addition to radiation. For IDH-mutated and 1p/19q-deleted tumors, some
retrospective analyses suggested a better outcome with PCV compared with
temozolomide but at the cost of higher toxicity with PCV.58 The relative
outcome of radiation plus PCV versus radiation and temozolomide in grade III
IDH-mutated and 1p/19q-codeleted tumors is the central question being tested
in the ongoing CODEL (Phase III Intergroup Study of Radiotherapy With
Concomitant and Adjuvant Temozolomide Versus Radiotherapy With
Adjuvant PCV Chemotherapy in Patients With 1p/19q Co-deleted Anaplastic
Glioma or Low Grade Glioma) trial (NCT00887146), but results of that trial
are not expected for years.
FUTURE DIRECTIONS AND CLINICAL TRIALS

While surgery, radiation, chemotherapy, and tumor treating fields represent
the standard and FDA-approved therapies for adult gliomas, the overall
clinical benefit of these approaches is modest at best in the majority of
patients with higher-grade tumors. As a result, the neuro-oncology field has
continued to evaluate a wide variety of treatment options in the setting of
clinical trials to identify more effective therapies for selected subgroups
of patients.
Targeted Therapy
One of the modern breakthroughs in oncology was the identification of multiple
genomic alterations that drive tumor initiation or maintenance, rendering such
tumors to functional blockade by drugs that target the mutant protein or kinase
or one of its downstream effectors. Examples of such targetable alterations in
oncology are numerous but began with ones such as BCR-ABL fusions
(in chronic myelogenous leukemia), HER2 amplification (in breast cancer), and
EGFR mutations (in lung cancer). There are several potentially targetable
alterations observed in different subtypes of lower-grade glioma and
glioblastoma. In IDH-mutant tumors, the IDH mutation itself has been a
potential target with a number of drugs developed to inhibit the neomorphic
function of the mutant IDH enzyme to block the production of 2-hydroxyglutarate.
Two of these IDH inhibitors are FDA approved in acute myeloid leukemia with
1470 DECEMBER 2020

IDH mutation, and other IDH inhibitors are in development. To date, the evidence KEY POINT
of efficacy for IDH-mutant gliomas with these drugs is that they can alter the
● The combination of
growth rate and result in stabilization of disease in a subset of patients with glioma radiation and chemotherapy
with IDH-mutant tumors, but no drug has received FDA approval for gliomas. In (either procarbazine,
glioblastoma and IDH-wildtype lower-grade gliomas, potential druggable targets lomustine [CCNU], and
include EGFR amplification and mutation (EGFRvIII), which are observed at vincristine [PCV] or
temozolomide) has been

higher frequencies, as well as other alterations that are seen at lower frequencies
proven more effective for
including FGFR gene fusions, NTRK gene fusions, and BRAF mutations and prolonging survival than
fusions. For NTRK and BRAF mutations and fusions, drugs that are FDA approved radiation alone in lower-
in other tumor types have potential efficacy in glioma. Case reports and small grade diffuse gliomas with
IDH mutation.
series suggest clinical benefit of specific FGFR, BRAF, and NTRK inhibitors, but
the rarity of these alterations in glioblastoma has complicated attempts at larger
studies to verify activity in this tumor type. In the case of inhibitors of the BRAF
V600E mutation, initial data from a larger basket-type trial of multiple histologies,
unfortunately, suggest that the activity of one drug, vemurafenib, may be less in
higher-grade gliomas harboring this mutation than in other tumor types.20
Multiple attempts to target EGFR alterations have been made with targeted
tyrosine kinase inhibitors, vaccines, and EGFR-specific antibodies, but in all cases,
the phase 3 studies of these drugs or vaccines have not demonstrated any survival
benefit. Despite these disappointments, development continues on other
approaches including newer kinase inhibitors, bifunctional antibodies, as well as
chimeric antigen receptor (CAR) T cells engineered to target EGFRvIII mutation
and other glioblastoma alterations.
Another breakthrough in oncology was the demonstration in multiple tumor
types that drugs that modulate the immune response can have significant clinical
efficacy. In some cases, these immunotherapy agents are possibly curative in
subsets of patients who were previously incurable. Most of the currently
FDA-approved immunotherapy agents are humanized monoclonal antibodies
that act by blocking cell surface signaling proteins that inhibit activation of
immune responses against tumor cells and/or tumor neoantigens. Several phase 2
and 3 studies have tested the activity of immune checkpoint inhibitors in newly
diagnosed and recurrent glioblastoma. To date, all studies of single-agent
checkpoint inhibitors in glioblastoma have been negative for a survival benefit. A
small randomized phase 2 study of the checkpoint inhibitor pembrolizumab
given before and after surgery for recurrent glioblastoma was the first to
demonstrate a potential survival benefit in glioblastoma.59 The fact that the
benefit was observed in combination with surgery raises the hope that
immunotherapy can be used successfully in the treatment of glioblastoma but
also suggests that additional factors beyond the presence of a checkpoint
inhibitor alone are necessary for efficacy in glioblastoma (in contrast to other
solid tumors). However, the benefit of surgery plus pembrolizumab in a limited
number of patients requires validation in larger studies.
Clinical Trials
To date, the only treatments that have demonstrated a survival benefit in diffuse
gliomas and glioblastoma are radiation, cytotoxic chemotherapy, and tumor
treating fields. Despite the growing evidence and information regarding genomic
and epigenetic alterations that define molecular subgroups of glioma, no
FDA-approved drug targeting a specific mutation or molecular alteration
(beyond bevacizumab), or any immunomodulatory drug is FDA approved

ADULT GLIOMAS
KEY POINT specifically for gliomas. This situation highlights the need to increase enrollment
of all histologies and grades of gliomas in clinical trials. In the current National
● Participation in a clinical
trial is an important
Comprehensive Cancer Network guidelines, clinical trial enrollment is the
consideration in the preferred option for the treatment of both newly diagnosed and recurrent glioma
treatment of all histologies, for eligible patients.33
grades, and molecular
subtypes of glioma.
CONCLUSION
Adult gliomas represent a clinically and molecularly heterogeneous group of
tumors. An understanding of the differences in presentation, diagnosis, and
treatment is important for neurologists. The recent advances in the
understanding of molecular subtypes of tumors have led to a dramatic revision of
the approach to the diagnosis and treatment of adult gliomas. Much of this
new knowledge is described in the 2016 World Health Organization
Classification of Tumors of the Central Nervous System, although this field
continues to evolve rapidly, and some diagnostic entities, such as the diagnosis of
diffuse astrocytic glioma, IDH-wildtype, with molecular features of
glioblastoma, WHO grade IV, remain consensus recommendations and will
presumably be incorporated into future WHO classifications. Despite the
dramatic advances in the biologic understanding and classification of adult
gliomas, the majority of these tumors remain incurable with standard approaches
of surgery, radiation, chemotherapy, and tumor treating fields, and efforts
aimed at the development and testing of new therapies for specific glioma
subtypes in clinical trials are ongoing.
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1474 DECEMBER 2020

DISCLOSURE
Continued from page 1452 Stroke (1R01NS107810), and SWOG Cancer Research
Network and has received research support from
For Brain Tumor Research & Information, Inc, the NewLink Genetics Corporation, Orbus Therapeutics,
National Cancer Institute (R21CA245577), the Inc, and Plexxikon.
National Institute of Neurological Disorders and

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REVIEW ARTICLE

CITE AS: ABSTRACT

1452 DECEMBER 2020

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for patients in whom brain tumor is part of the differential.

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

indeterminate lesion include the pattern and timing of clinical presentation,

Diffuse midline glioma, IDH-wildtype, None Midline (infratentorial and

Diffuse astrocytoma, IDH-wildtype Chromosome 7 gain, Older adults, supratentorial more

Glioblastoma, IDH-wildtype IDH-wildtype Chromosome 7 gain, Older adults, supratentorial more

1454 DECEMBER 2020

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Astrocytoma and oligodendroglioma were named for the similarity in

Revised 2016 World Health Organization Classification of Gliomas

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

ongoing recommendations for the classification of central nervous system

IDH-MUTANT GLIOMAS. The majority of low-grade astrocytomas and

for IDH-mutant gliomas versus median age of 55 to 60 years for IDH-wildtype

glioblastoma), have mutations in either IDH1 or IDH2, with mutations in IDH1

u oligodendroglioma, IDH-mutant and 1p/19q codeleted (grade II)

In addition to IDH mutation and 1p/19q loss, oligodendroglial tumors also

u diffuse astrocytoma, IDH-mutant (grade II)

An example of the presentation, diagnostic findings, and treatment for a

1456 DECEMBER 2020

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OTHER CLINICALLY IMPORTANT IDH-WILDTYPE GLIOMA SUBTYPES. Although the

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

DIFFUSE MIDLINE GLIOMA, H3K27M-MUTANT. This is a new and distinct diagnosis

this diagnosis is confirmed by molecular testing (either immunohistochemistry

1458 DECEMBER 2020

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DIFFUSE ASTROCYTOMAS, IDH-WILDTYPE, CHROMOSOME 1P/19Q-INTACT OF VARIABLE

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

astrocytomas and others having potential overlap in histologic and molecular

1460 DECEMBER 2020

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classification, is seen predominantly in children and young adults, and has a

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

target mitogen-activated protein kinase, a downstream component in this

pathway.21 Thus, it is important to recognize these rare variants because of the

DIFFUSE ASTROCYTOMAS, IDH-WILDTYPE, CHROMOSOME 1P/19Q-INTACT THAT

CASE 1-3 A 31-year-old woman presented with a 2- to 3-month history of

1462 DECEMBER 2020

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immunotherapies may be appropriate in addition to or instead of standard

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

ependymoma, subependymoma, and myxopapillary ependymoma that are

Subependymomas that are incidental, asymptomatic, or not clearly progressing

DIFFUSE GLIOMA TREATMENT

1464 DECEMBER 2020

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younger patients and are

Radiation, Chemotherapy, and Tumor Treating Fields for Newly Diagnosed

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

glioblastoma was established in a 2005 randomized trial of temozolomide plus

MGMT Promoter Methylation

Tumor Treating Fields

1466 DECEMBER 2020

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