Version May 2024
INTRODUCTION — Gliomas account for the great majority of primary tumors that arise within the central nervous system (CNS). The term "glioma" refers to tumors that have histologic features similar to normal glial cells (ie, astrocytes, oligodendrocytes, and ependymal cells). Each of these types of gliomas contains neoplasms spanning a broad spectrum of biologic aggressiveness.
Historically, the slower-growing lesions, corresponding to World Health Organization (WHO) grades 1 and 2, have been commonly referred to as "low-grade gliomas," while the more rapidly progressive, grade 3 and 4 tumors are referred to as "high-grade gliomas." The WHO classification recommends avoiding these terms since they lump together heterogenous groups of tumors, many of which have significantly different biologic properties, prognoses, and treatment approaches [1-3]. Among grade 1 and grade 2 gliomas, for example, current classification favors a distinction between diffuse gliomas (eg, isocitrate dehydrogenase [IDH] mutant astrocytoma and oligodendroglioma) and more circumscribed astrocytic tumors (eg, grade 1 pilocytic astrocytoma). Additionally, it is clear that among grade 3 and grade 4 tumors, there can be markedly different courses, including responses to therapies.
The classification and diagnosis of gliomas will be reviewed here. Pathogenesis of diffuse gliomas is reviewed separately. (See "Molecular pathogenesis of diffuse gliomas".)
HISTORY OF GLIOMA CLASSIFICATION — The classification and grading of gliomas have evolved over time, beginning in 1926 with a system devised by Bailey and Cushing [4] and later revised by Kernohan, Ringertz, and others [5-7]. Modern classification of gliomas is based on the World Health Organization (WHO) Classification of Central Nervous System Tumors, first published in 1979 and revised five times since then, most recently in 2021 [1-3,8].
Since the 2016 edition of the WHO classification, gliomas have been classified based not only on histopathologic appearance but also on well-established molecular parameters [1]. The incorporation of molecular features notably impacted the classification of astrocytic and oligodendroglial tumors, which are grouped together as diffuse gliomas, on the basis of growth pattern, behavior, and shared isocitrate dehydrogenase (IDH) genetic status. Additional molecular approaches, including those articulated in the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) updates one through seven [9-15], have been incorporated into the 2021 (5th) edition [8].
KEY MOLECULAR DIAGNOSTIC TESTS
IDH1/IDH2 mutation — Mutations in isocitrate dehydrogenase type 1 (IDH1) and, less commonly, type 2 (IDH2) are a defining feature of the majority of World Health Organization (WHO) grade 2 and 3 diffuse astrocytic and oligodendroglial tumors and confer significantly improved prognosis compared with IDH-wildtype tumors [16-18]. (See 'Adult-type diffuse gliomas' below.)
Immunohistochemical staining for the most common mutant form of IDH1 (R132H) should be performed on all diffuse glioma specimens for diagnostic purposes. This test can also help distinguish infiltrating astrocytoma cells from reactive gliosis in biopsy specimens [19,20].
Less common mutations in IDH1 and all IDH2 mutations will not be identified using this antibody but can be detected using DNA sequencing approaches. These mutations make up approximately 10 to 20 percent of IDH mutations in grade 2 and 3 diffuse astrocytic and oligodendroglial tumors and, like IDH1 R132H mutations, are found primarily in patients younger than 55 years of age [21,22]. Noncanonical IDH mutations are more common in oligodendroglial tumors [21]. The IDH1 R132C mutation appears to be enriched in Li-Fraumeni syndrome (LFS) associated gliomas, and its presence should prompt consideration of germline tumor protein p53 (TP53) testing [23,24]. (See "Risk factors for brain tumors", section on 'Li-Fraumeni syndrome'.)
If immunohistochemistry for mutant IDH1 R132H is negative, sequencing of IDH1 (codon 132) and IDH2 (codon 172) should be performed in patients with grade 2 and grade 3 diffuse gliomas and in younger patients (<55 years) with grade 4 tumors, as the distinction between IDH-mutant and IDH-wildtype is central to an integrated diagnosis. When no IDH mutations are detected by sequencing in such tumors, further molecular testing is required in most cases to reach an integrated diagnosis:
●IDH-wildtype astrocytomas located in midline structures should be evaluated for H3 K27M mutations to exclude diffuse midline glioma, H3 K27-altered. (See 'H3 K27M mutation' below.)
●IDH-wildtype hemispheric astrocytomas, particularly in younger patients, should be evaluated for H3 G34 mutations to exclude diffuse hemispheric glioma, H3 G34-mutant. (See 'H3 G34 mutation' below.)
●IDH-wildtype, H3-wildtype grade 2 and 3 astrocytomas in children should be tested for the presence of molecular alterations found in pediatric-type diffuse gliomas (eg, fibroblast growth factor receptor 1 [FGFR1] alterations). (See 'Diffuse low-grade glioma, MAPK pathway-altered' below and 'Diffuse high-grade glioma, H3-wildtype and IDH-wildtype' below.)
●IDH-wildtype, H3-wildtype grade 2 and 3 astrocytomas in adults should be tested for high-risk molecular features, which establish a grade 4 glioblastoma diagnosis independent of histologic features. (See 'EGFR, TERT, +7/-10 genotype' below.)
Mutations in IDH lead to the accumulation of R(-)-2-hydroxyglutarate (2HG), which can be detected by magnetic resonance spectroscopy (MRS) and may play a key role in glioma formation, epigenetic dysregulation, and seizure risk. (See "Molecular pathogenesis of diffuse gliomas", section on 'Isocitrate dehydrogenase (IDH) gene'.)
1p/19q codeletion — Whole-arm deletion of 1p and 19q due to an unbalanced translocation between chromosomes 1 and 19 is a defining feature of oligodendroglial tumors and a powerful predictor of favorable therapeutic response and survival among patients with diffuse gliomas [25-27]. Testing for 1p/19q-codeletion status should be performed on all tumors with oligodendroglial differentiation but is not necessary in more astrocytic IDH-mutant tumors that have clear evidence of TP53 or ATRX mutations [9].
Most diagnostic laboratories currently assess 1p/19q status using fluorescence in situ hybridization (FISH), since this technique provides information on chromosomal losses, polysomies, and intratumoral variation, but FISH risks false-positive results in the presence of partial 1p and/or 19q losses. Copy number assessments of 1p and 19q can also be derived from broader molecular profiling approaches such as next-generation sequencing (NGS) and methylome profiling, and these provide information across the chromosomal arms.
Combined whole-arm loss of 1p and 19q is nearly invariably associated with IDH mutation [1]. Therefore, detection of 1p/19q codeletion (by a technique such as FISH) in the absence of an IDH mutation (confirmed by sequencing of IDH1 and IDH2 if immunohistochemistry for IDH1 R132 is negative) should raise suspicion for partial or incomplete deletions, which have been associated with some subsets of IDH-wildtype high-grade astrocytomas and a more aggressive clinical course.
ATRX mutation — Mutations in the chromatin regulator gene, ATRX, are commonly found in diffuse astrocytic gliomas. ATRX mutations are closely correlated with IDH1/2 and TP53 mutations and are mutually exclusive with 1p/19q codeletion. Immunohistochemical staining for ATRX expression has diagnostic utility for confirming a diffuse astrocytic tumor, in which loss of nuclear staining for ATRX indicates the presence of an ATRX mutation. (See "Molecular pathogenesis of diffuse gliomas", section on 'ATRX gene'.)
TP53 mutation — Missense somatic mutations in the TP53 gene are present in the vast majority of IDH-mutant astrocytomas, and strong nuclear staining for mutant p53 is frequently observed in these tumors. Immunopositivity for mutant p53 is not entirely sensitive or specific for TP53 mutation. (See 'ATRX mutation' above and "Molecular pathogenesis of diffuse gliomas", section on 'TP53 gene'.)
Of note, somatic TP53 mutations are common in astrocytoma and do not generally indicate an increased likelihood of a germline TP53 mutation and LFS in the absence of a personal or family history of other tumors. One potential exception is when there is mutant p53 and an IDH1 R132C mutation, since such mutations are more common in patients with LFS; in this situation, germline testing should be considered [23,24]. (See "Li-Fraumeni syndrome".)
CDKN2A/B deletion — In IDH-mutant diffuse gliomas, homozygous deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a negative prognostic marker, and its presence helps to establish an integrated diagnosis in two specific cases:
●In oligodendrogliomas with histologic features that are borderline between grade 2 and 3, the presence of a CDKN2A homozygous deletion is consistent with a central nervous system (CNS) WHO grade 3 tumor. (See 'Oligodendroglioma, IDH-mutant and 1p/19q-codeleted' below.)
●In IDH-mutant diffuse astrocytomas, the presence of homozygous CDKN2A/B deletion establishes the tumor as CNS WHO grade 4, even in the absence of high-grade histology. Additional studies have raised the possibilities that CDKN2A hemizygous deletion [28,29] and CDKN2A mutation [29,30] also may be negative prognostic markers among IDH-mutant astrocytomas, but these do not by themselves designate a tumor as WHO grade 4. (See 'Astrocytoma, IDH-mutant' below.)
Homozygous CDKN2A/B deletions can be detected in a variety of ways, including FISH and NGS. Copy-number profiles calculated from methylome data can also be used.
H3 K27M mutation — H3 K27M mutations in either H3F3A (one of two genes encoding the histone H3.3 variant) or HIST1H3B/C (encoding the histone H3.1 variant) are present in a majority of diffuse gliomas in the pons and other midline locations (eg, thalamus, spinal cord), most commonly in children. They occur rarely in other glial tumors, including ependymomas. (See "Diffuse intrinsic pontine glioma" and "Intracranial ependymoma and other ependymal tumors".)
The H3F3A K27M mutation can be detected by immunohistochemistry using a mutation-specific antibody, which should be used in the workup of diffuse gliomas in the spinal cord, brainstem, and thalamus, both in children and adults. H3F3A mutations are approximately three times more common than HIST1H3B/C mutations, which can be detected by sequencing. These mutations are also present in some pediatric glioblastomas and confer a worse prognosis.
Evaluating H3 K27me3 (trimethylation at K27) by immunohistochemistry may also be useful in diagnosing these tumors, since some tumors may alter this pathway via different mechanisms (eg, enhancer of zeste homologs inhibitory protein [EZHIP] overexpression) [31].
H3 G34 mutation — Missense mutations in the H3F3A gene can result in G34R or G34V mutations, which can be detected by sequencing or mutant-specific immunohistochemistry. These alterations are a defining feature of diffuse hemispheric glioma, H3 G34-mutant, a newly recognized tumor type in the 2021 WHO classification [8]. (See 'Diffuse hemispheric glioma, H3 G34-mutant' below.)
EGFR, TERT, +7/-10 genotype — For IDH-wildtype, H3-wildtype astrocytic tumors without high-grade histologic features, the presence of any one of the following molecular features establishes a diagnosis of glioblastoma, even in the absence of microvascular proliferation or necrosis:
●Epidermal growth factor receptor (EGFR) amplification
●Telomerase reverse transcriptase (TERT) promoter mutation
●Concurrent gain of chromosome 7 and loss of chromosome 10 (+7/-10 genotype)
EGFR amplification and the +7/-10 genotype can be detected by FISH, and TERT promoter mutations can be detected by sequencing technologies. Copy number alterations can also be detected by broader profiling technologies like NGS and methylome profiling.
BRAF alterations — Alterations in BRAF characterize specific subsets of gliomas:
●KIAA1549-BRAF fusion – Tandem duplication of chromosome 7q34 resulting in fusion of the BRAF and KIAA1549 genes is observed in 60 to 80 percent of sporadic pilocytic astrocytomas [32]. Many centers use a FISH probe to demonstrate duplication at 7q34 and take this as evidence of KIAA1549-BRAF fusion [1]. Reverse transcription polymerase chain reaction (RT-PCR) or immunohistochemistry can also be used but are made difficult by the large number of different combinations of KIAA1549 and BRAF exons involved in the duplication.
●BRAF V600E mutation – V600E point mutations in the BRAF gene are present in a variety of glioma subsets, including approximately two-thirds of pleomorphic xanthoastrocytomas, 20 percent of gangliogliomas, and 10 percent of pilocytic astrocytomas [33,34]. Occasional diffuse gliomas may also have BRAF V600E mutations [35]. A specific antibody is available to detect the BRAF V600E mutation by immunohistochemistry; it can also be detected by sequencing. In pediatric low-grade gliomas, BRAF V600E confers an increased risk of recurrence after standard therapy, particularly in combination with CDKN2A deletion [36].
ZFTA fusion — Fusion between zinc finger translocation-associated (ZFTA; previously known as C11orf95) on chromosome 11 and another gene, most commonly RELA, defines approximately 70 percent of all childhood supratentorial ependymomas, and ZFTA fusion-positive ependymoma (previously known as RELA fusion-positive ependymoma) is a recognized tumor type in the 2021 WHO classification system [3,8]. (See "Intracranial ependymoma and other ependymal tumors", section on 'Molecular subgroups'.)
A ZFTA-RELA fusion gene is most commonly detected using interphase FISH with break-apart probes. L1CAM expression by immunohistochemistry also correlates closely with the presence of a RELA fusion in supratentorial ependymomas.
YAP1 fusion — Fusion between the Yes1-associated transcriptional regulator (YAP1) gene and other genes (typically mastermind-like domain containing 1 [MAMLD1]) is characteristic of a small subset of childhood supratentorial ependymomas [37,38]. Such fusions can be detected using FISH or NGS fusion assays.
Methylome profiling — Methylome profiling uses arrays to determine DNA methylation patterns across the genome. Although not yet widely available, it is now recommended as an effective method for classification when used alongside standard technologies [8]. Circumstances in which methylome profiling may be most useful to pathologists include:
●Diagnostically challenging neoplasms, including some rare tumor types and subtypes that can only be diagnosed by methylome profiling
●Small biopsy samples, which may be limiting for standard technologies
Methylome profiling may also be used as a surrogate marker for genetic events, for example, when a methylome signature is characteristic of an IDH-wildtype glioblastoma in the absence of IDH mutation testing [8]. However, optimal methods for calibration, interpretation, and regulation of methylome profiling have not been established, and it is not clear if results should be used for treatment selection or clinical trials.
HISTOPATHOLOGIC AND MOLECULAR CLASSIFICATION — The backbone of glioma classification is light microscopy, aided by immunohistochemistry and molecular testing. The following section highlights the important histopathologic and most salient molecular findings in the common gliomas. The World Health Organization (WHO) classification [1,3,8] and International Society of Neuropathology-Haarlem guidelines [39] encourage the use of integrated and layered diagnoses, which accommodate histologic and genetic parameters into a single diagnosis.
Adult-type diffuse gliomas — Diffuse astrocytic and oligodendroglial tumors are classified on the basis of isocitrate dehydrogenase (IDH) mutation status along with several other key molecular genetic alterations, rather than strictly by histopathologic features (algorithm 1 and table 1) [1,8]. (See 'Key molecular diagnostic tests' above.)
On this basis, three tumor types emerge: IDH-mutant astrocytomas, IDH-mutant and 1p/19q-codeleted oligodendrogliomas, and IDH-wildtype glioblastoma (table 1).
General features — Astrocytic tumors are composed of cells with elongated or irregular, hyperchromatic nuclei and eosinophilic, glial fibrillary acidic protein (GFAP) positive cytoplasm (picture 1). By contrast, oligodendrogliomas have rounded nuclei, often with perinuclear halos, calcification, and delicate, branching blood vessels (picture 2). All of these tumors can have significant regional heterogeneity, and the tumors are graded histologically according to their most anaplastic-appearing areas.
As tumors increase in histologic grade, additional features of malignancy are noted. In general, nuclear atypia and increased mitotic activity characterize grade 3 tumors (picture 3), while microvascular proliferation and necrosis define grade 4 tumors (picture 4). However, specific neuropathologic grading criteria vary between astrocytomas and oligodendroglial tumors [8]. Moreover, traditional histologic grading criteria do not necessarily provide prognostic power when IDH gene status is taken into account [18,40], and certain molecular markers are more powerful and have been incorporated into grading, as discussed below.
Astrocytoma, IDH-mutant — Among IDH-mutant astrocytomas, the WHO classification system recognizes three grades (central nervous system [CNS] WHO grades 2, 3, and 4) based on histopathologic and molecular features [1,8]. Tumors that contain a cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion have a poor prognosis [41-43] and are assigned a grade of 4, independent of histologic findings [8,14]. Other CDKN2A alterations may also have negative prognostic significance. (See 'CDKN2A/B deletion' above.)
●Astrocytoma, IDH-mutant, grade 2 – Grade 2 IDH-mutant astrocytomas are diffusely infiltrative astrocytic gliomas with atypia and mildly to moderately increased cellularity compared with that of normal brain, but without significant mitotic activity, endothelial proliferation, or necrosis (picture 1). Tumor cells are well differentiated and lack histologic features of anaplasia.
Grade 2 astrocytomas are most common in younger adults, with a peak incidence in the mid-thirties; they are slow growing but may progress toward more malignant astrocytoma grades over the course of years, with a median survival of approximately 11 years [18]. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Prognosis'.)
●Astrocytoma, IDH-mutant, grade 3 – Grade 3 IDH-mutant astrocytomas (previously called IDH-mutant anaplastic astrocytomas) are distinguished from grade 2 tumors by higher cellularity, more marked nuclear atypia and hyperchromasia, and significant mitotic activity (picture 3). By definition, endothelial proliferation and necrosis are not present. Historically (pre-IDH era), a threshold of two or more mitoses in a specimen (or one mitosis for very small biopsies) was used to differentiate between grade 2 and 3 astrocytoma and was shown to be associated with differences in overall survival. This threshold is still in use for IDH-mutant astrocytomas, but its validity as a stratification factor is not yet established [8,14,44].
Median survival for grade 3 IDH-mutant astrocytomas is approximately nine years [18]. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Prognosis'.)
●Astrocytoma, IDH-mutant, grade 4 – Grade 4 IDH-mutant astrocytomas (previously called IDH-mutant glioblastomas) make up approximately 10 percent of all grade 4 astrocytic gliomas (ie, the majority being IDH-wildtype glioblastomas). They are histologically similar to IDH-wildtype glioblastoma (picture 5), although less likely to contain areas of palisading necrosis and more likely to contain cells with oligodendroglial morphology [8]. Tumors with CDKN2A/B deletion are also included in this category, even in the absence of high-grade histologic features.
Compared with IDH-wildtype glioblastomas, grade 4 IDH-mutant astrocytomas occur in younger adults (mean age 45 years) and have a more favorable prognosis, with a median survival approximately two times longer than that of IDH-wildtype tumors [45,46]. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted — Oligodendrogliomas are histologically and molecularly defined tumors harboring both IDH1/2 mutations and codeletion of chromosomal arms 1p and 19q. They exist on a spectrum ranging from well-differentiated, slow-growing tumors to malignant tumors with rapid growth [1,8].
●Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grade 2 – Oligodendroglial tumors have cells that on light microscopy have round nuclei with perinuclear halos (a "fried egg" appearance) and an acutely branching (chicken wire) capillary pattern (picture 2). They are diffusely infiltrating tumors, typically involving the white matter and cerebral cortex, most commonly in the frontal and temporal lobes. (See "Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas".)
●Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grade 3 – Grade 3 oligodendrogliomas (previously called anaplastic oligodendrogliomas) are characterized by increased cellularity, pleomorphism, readily identifiable mitotic activity, and microvascular proliferation.
In the pre-IDH era, grade 3 oligodendrogliomas were associated with a shorter median survival compared with grade 2 oligodendrogliomas. The prognostic significance of grade 2 versus 3 has not been well defined for IDH-mutant, 1p/19q-codeleted oligodendrogliomas, however, and may be less important than in prior classifications [47,48]. Homozygous deletion of CDKN2A/B in a small subset of tumors (<10 percent) is associated with reduced survival and may be a molecular correlate of higher grade [8]. (See "Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas".)
Oligodendrogliomas are associated with improved responsiveness to radiation therapy and chemotherapy compared with other adult-type diffuse gliomas, with a median survival of approximately 15 to 20 years with standard treatment. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Prognosis'.)
Glioblastoma, IDH-wildtype — IDH-wildtype glioblastoma is the most common malignant primary brain tumor in adults. These tumors are diffusely infiltrating, highly cellular, pleomorphic tumors with mitotic activity and either microvascular proliferation or necrosis, or both (picture 5).
By definition, glioblastomas lack mutations in IDH1/2, H3 K27M, and H3 G34. In IDH- and H3-wildtype diffuse gliomas, the presence of either microvascular proliferation or necrosis is sufficient for the diagnosis of glioblastoma (grade 4). For IDH-wildtype diffuse astrocytomas that do not contain features of anaplasia, further molecular testing is required for an integrated diagnosis (see '"Astrocytoma, IDH-wildtype"' below). Such tumors with epidermal growth factor receptor (EGFR) amplification, telomerase reverse transcriptase (TERT) promoter mutation, or concurrent chromosome 7 gain/chromosome 10 loss follow a similar clinical course to that of glioblastoma [10,49] and are classified as IDH-wildtype glioblastoma as of the 2021 WHO revision [8].
Histologic variants include giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma. The epithelioid variant is often characterized by BRAF V600E mutation, superficial location, and younger age at diagnosis.
The prognosis for all glioblastoma variants is poor, with survival commonly less than two years. The clinical features, diagnosis, and treatment of glioblastoma are reviewed in detail separately. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas" and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults" and "Management of glioblastoma in older adults".)
NOS and NEC designations — Tumors that lack necessary diagnostic molecular information or are nondiagnostic for a WHO diagnosis fall under one of two categories:
●Not otherwise specified (NOS) – The NOS designation can be added to most of the above tumor types (algorithm 1 and table 1); this signifies that a complete, integrated histopathologic and molecular diagnosis is not available because necessary molecular testing was not performed or was not successful. Use of the NOS designation is discouraged but, if necessary, serves as a cautionary suffix that the tumor may require further diagnostic workup.
●Not elsewhere classified (NEC) – NEC indicates that necessary diagnostic testing was performed successfully but the results do not readily allow for a specific WHO diagnosis [11]. An example would be a tumor with a mismatch between clinical, histologic, immunologic, and/or genetic features. NEC diagnoses are descriptive.
Oligoastrocytoma (historical entity) — The diagnosis of oligoastrocytoma no longer exists in the WHO classification for fully characterized tumors, since tumors with mixed histology and a molecular signature of astrocytoma (eg, ATRX loss and tumor protein p53 [TP53] mutation) are diagnosed as astrocytomas, and mixed tumors with a molecular signature of oligodendroglioma (ie, IDH mutation and 1p/19q codeletion) are diagnosed as oligodendrogliomas.
The diagnosis of oligoastrocytoma NOS is thus reserved for histologically mixed tumors when molecular testing is either unavailable or inconclusive. Rare cases in which two genetically distinct tumor cell populations are present in the same tumor have been reported and are provisionally classified as dual-genotype oligoastrocytoma NEC [8].
"Astrocytoma, IDH-wildtype" — As of the 2021 revision of the WHO classification system, the diagnoses of IDH-wildtype diffuse astrocytoma, grade 2 and grade 3 are no longer recognized. As discussed above, most IDH-wildtype diffuse astrocytomas in adults harbor molecular markers of high-grade behavior, even when they lack the defining histologic features (ie, microvascular proliferation and necrosis), or they have molecular features of pediatric-type gliomas. With further molecular testing, most of these tumors represent one of the following:
●Glioblastoma, IDH-wildtype, when positive for either EGFR amplification, TERT mutation, or concurrent chromosome 7 gain/chromosome 10 loss. (See 'Glioblastoma, IDH-wildtype' above.)
●Diffuse midline glioma, H3 K27-altered, when testing reveals an H3 K27M mutation. (See 'H3 K27M mutation' above and 'Diffuse midline glioma, H3 K27-altered' below.)
●Diffuse hemispheric glioma, H3 G34-mutant, when testing reveals an H3 G34 mutation. (See 'H3 G34 mutation' above and 'Diffuse hemispheric glioma, H3 G34-mutant' below.)
●Pediatric-type gliomas, when testing reveals alterations such as fibroblast growth factor receptor 1 (FGFR1) mutations or fusions, or a host of other specific changes. (See 'Pediatric-type diffuse low-grade gliomas' below and 'Pediatric-type diffuse high-grade gliomas' below.)
For tumors with none of these alterations following a comprehensive sequencing and fusion screen, methylome profiling can be considered. If no diagnostic information is found in these assays, an NEC diagnosis should be rendered.
Pediatric-type diffuse low-grade gliomas — The 2021 edition of the WHO classification is the first to separate diffuse gliomas that primarily occur in children from those that primarily occur in adults, recognizing the clinically and biologically distinct nature of these groups [3,8]. Four pediatric-type diffuse low-grade gliomas are recognized (table 1).
Diffuse astrocytoma, MYB- or MYBL1-altered — Genetic alterations in the MYB or MYB-like 1 (MYBL1) proto-oncogenes define this diffusely infiltrative astroglial tumor, WHO grade 1. Patients typically present with drug-resistant seizures in childhood. Tumors have cortical and subcortical components, most commonly in the temporal or frontal lobes. Next-generation sequencing (NGS) or interphase fluorescence in situ hybridization (FISH) demonstrate a fusion between MYB or MYBL1 and a partner gene. DNA methylation profiling can also be used to identify these tumors.
Limited clinical information supports a benign clinical course with high rates of seizure freedom and a low rate of recurrence after resection alone [13,50,51].
Angiocentric glioma — Angiocentric gliomas are diffuse gliomas, WHO grade 1, composed of bipolar cells aggregating at least partly around blood vessels. Almost all tumors harbor a MYB-QKI gene fusion [52,53].
Angiocentric glioma occurs primarily in children and young adults, with a mean age at diagnosis of 17 years. Most cases present with intractable seizures. Tumors are located superficially in the cerebral hemispheres. On magnetic resonance imaging (MRI), they are discrete, nonenhancing lesions that are hyperintense on T2-weighted sequences. Unique MRI features observed in some cases include intrinsic hyperintensity of the margins of the cortical gyri on T1-weighted sequences and a band of T2 hyperintensity extending from the tumor to the ventricular wall [54]. Surgery is frequently curative.
Polymorphous low-grade neuroepithelial tumor of the young — Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is an indolent, WHO grade 1 cerebral tumor characterized by refractory seizures, frequent oligodendroglial-like histologic components, calcification, CD34 immunoreactivity, and mitogen-activated protein kinase (MAPK) pathway-activating genetic alterations [8,55]. The temporal lobe is a common location. Surgery is usually curative, although recurrences and high-grade progression have been reported [56].
Diffuse low-grade glioma, MAPK pathway-altered — These tumors are low-grade gliomas with diffuse astrocytic or oligodendroglial morphology that contain a pathogenic alteration in a gene coding for a MAPK pathway protein, most commonly BRAF V600E or an alteration of FGFR1 [8]. The clinical behavior of tumors in this group may be heterogeneous, and outcomes depend on multiple factors including age, tumor location, morphology, and molecular alterations.
Pediatric-type diffuse high-grade gliomas — The 2021 edition of the WHO classification also recognizes the clinically and biologically distinct nature of some high-grade gliomas [3,8]. Four pediatric-type diffuse high-grade gliomas are recognized (table 1).
Diffuse midline glioma, H3 K27-altered — H3 K27M-mutant diffuse midline gliomas are infiltrative tumors, usually with astrocytic morphology, located in the pons, thalamus, or spinal cord. Most cases have high-grade features (ie, mitotic figures, microvascular proliferation, necrosis) and are histologically consistent with WHO grade 4. To diagnose a tumor as diffuse midline glioma, H3 K27M-mutant, all four criteria must be met (ie, the tumor must be diffuse, in the midline, a glioma, and H3 K27-mutant or H3 K27 pathway-altered) [3,8,9]. These tumors are typical in younger patients but have also been reported well into adulthood. (See "Diffuse intrinsic pontine glioma".)
Diffuse hemispheric glioma, H3 G34-mutant — H3 G34-mutant diffuse hemispheric gliomas are WHO grade 4 tumors that occur primarily in adolescents and young adults [57-59]. Histologic characteristics are variable, and tumors may resemble anaplastic astrocytoma, glioblastoma, or CNS embryonal tumor [57]. They frequently have co-occurring TP53 and ATRX mutations, and a subset have additional activating mutations in platelet-derived growth factor receptor A (PDGFRA) or alterations in the CDK4/6 pathway [59]. The prognosis is poor, with a median progression-free survival of nine months and median overall survival ranging from 18 to 22 months [8,60]. Antibodies are present for both the R and V mutations in H3 G34 and can be used for immunohistochemical diagnosis [3].
Diffuse high-grade glioma, H3-wildtype and IDH-wildtype — H3- and IDH-wildtype diffuse pediatric-type high-grade gliomas are malignant, WHO grade 4 tumors that occur in children, adolescents, and young adults. Molecular alterations in PDGFRA, TP53, neurofibromin 1 (NF1), EGFR, and MYCN are most common and help subtype these lesions. The prognosis is poor, with a median overall survival of approximately 1.5 years [58].
Infant-type hemispheric glioma — Infant-type hemispheric glioma is a high-grade cellular astrocytoma that arises in the first year of life and usually contains receptor tyrosine kinase (RTK) fusions involving the neurotrophic tyrosine receptor kinase (NTRK) family, ROS1, ALK, or MET. [8,61] Tumors are subtyped according to the specific molecular alteration (eg, infant-type hemispheric glioma, ROS1-altered). Some of these fusions can be targeted therapeutically, and survival may be more favorable than in older children with high-grade gliomas.
Circumscribed astrocytic tumors — In contrast with the diffuse gliomas, several astrocytic gliomas are more circumscribed and tend to have a more indolent natural history. These include pilocytic astrocytoma, high-grade astrocytoma with piloid features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma (SEGA), chordoid glioma, and astroblastoma, MN1-altered (table 2). (See "Uncommon brain tumors", section on 'Circumscribed astrocytic gliomas'.)
Glioneuronal and neuronal tumors — A wide variety of less common primary brain tumors display either neuronal or mixed glioneuronal tumors (table 3). Most are relatively circumscribed tumors associated with a favorable course, often managed with surgery alone. These tumors are reviewed separately. (See "Uncommon brain tumors", section on 'Glioneuronal and neuronal tumors'.)
The most common of these tumors is ganglioglioma, an often partially cystic, well-demarcated tumor that has a low-grade astrocytic component accompanied by collections of neoplastic ganglion cells. Gangliogliomas sometimes have BRAF gene mutations [34]. Their behavior corresponds to WHO grade 1. In addition to BRAF alterations, some glioneuronal tumors harbor oncogenic fusions involving genes such as the NTRK family that may be therapeutically relevant [62].
Ependymal tumors — Ependymomas are a heterogenous group of well-circumscribed gliomas with histologic features that resemble the ependymal cells that line the ventricular system (picture 6). Ependymomas have a propensity for the ventricles of the brain and for the spinal cord. (See "Intracranial ependymoma and other ependymal tumors".)
The 2021 WHO classification of ependymomas incorporates anatomic site (supratentorial, posterior fossa, spinal), histology (subependymoma, myxopapillary ependymoma, ependymoma), and molecular alterations into classification and recognizes several new molecularly defined types of ependymomas. The following tumor types are recognized:
●Subependymoma – Subependymomas are WHO grade 1 gliomas characterized by clustering of small, round nuclei in a relatively anuclear matrix of fibrillary cytoplasmic processes. Microcystic change and calcification are common. They can arise in any of the three anatomic compartments, most commonly the posterior fossa (fourth ventricle; 50 to 60 percent) or supratentorial region (lateral ventricles; 30 to 35 percent). Third ventricle and spinal cord subependymomas are rarer. Most subependymomas are asymptomatic and detected incidentally on neuroimaging. (See "Intracranial ependymoma and other ependymal tumors", section on 'Subependymoma'.)
●Myxopapillary ependymoma – Myxopapillary ependymomas are WHO grade 2 gliomas characterized by spindle-shaped or epithelioid tumor cells arranged radially around blood vessels with perivascular myxoid change and microcyst formation. They have a recognizable DNA methylation profile but lack recurrent molecular alterations in a single gene. Myxopapillary ependymomas arise most commonly in the spinal cord, almost exclusively in the conus medullaris and filum terminale. Other locations are rare but well described, including the lateral and fourth ventricles, upper spinal cord, and outside the CNS. (See "Spinal cord tumors", section on 'Myxopapillary ependymoma'.)
●Ependymoma – Ependymomas are circumscribed glial tumors characterized by uniform, small cells with round nuclei embedded in a fibrillary matrix and focal pseudorosettes or ependymal rosettes. They occur in each of the three anatomic compartments, most commonly posterior fossa and spine; within each compartment, in addition to NOS/NEC-designated tumors, two molecular subtypes are recognized.
•Supratentorial ependymoma, zinc finger translocation-associated (ZFTA) fusion-positive
•Supratentorial ependymoma, Yes1-associated transcriptional regulator (YAP1) fusion-positive
•Posterior fossa ependymoma, group PFA, in which expression of H3K27 trimethylation is lost
•Posterior fossa ependymoma, group PFB, in which expression of H3K27 trimethylation is present
•Spinal ependymoma (ie, MYCN nonamplified)
•Spinal ependymoma, MYCN amplified
Supratentorial ependymomas that do not harbor either characteristic fusion are classified as supratentorial ependymoma, NEC. Ependymomas are generally considered grade 2 tumors, but high cellularity and the presence of mitoses may warrant a grade 3 designation (formerly anaplastic ependymoma) (table 4). Whether grade 3 ependymomas have a markedly worse prognosis than typical ependymomas remains unknown, particularly in younger patients.
The clinical features, diagnosis, prognosis, and treatment of ependymomas are reviewed in detail separately. (See "Intracranial ependymoma and other ependymal tumors".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Astrocytoma (The Basics)")
●Beyond the Basics topic (see "Patient education: Low-grade glioma in adults (Beyond the Basics)")
SUMMARY
●What is a glioma? – Gliomas are central nervous system (CNS) tumors that have histologic features similar to normal glial cells (ie, astrocytes, oligodendrocytes, and ependymal cells), from which they derive their respective names. Other related tumors share features of both glial cells and neurons (glioneuronal tumors) or primarily neurons (neuronal tumors). Gliomas account for the great majority of primary tumors that arise within the parenchyma of the CNS. (See 'Introduction' above.)
●Classification of gliomas – Gliomas are classified according to the World Health Organization (WHO) Classification of Central Nervous System Tumors, which was revised most recently in 2021. Since 2016, diagnoses are made based on a combination of histopathologic features and a growing number of key molecular genetic alterations. (See 'History of glioma classification' above and 'Key molecular diagnostic tests' above.)
●Adult-type diffuse gliomas – Diffusely infiltrating gliomas in adults are divided into three main types on the basis of histology, isocitrate dehydrogenase (IDH) mutation status, and several other key molecular alterations (algorithm 1 and table 1):
•IDH-mutant astrocytomas – IDH-mutant astrocytomas are assigned a WHO grade of 2, 3, or 4 based on histologic features (eg, nuclear atypia, mitoses, endothelial proliferation, necrosis) and molecular alterations. Tumors that contain a cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion are assigned a grade of 4, independent of histologic findings. (See 'Astrocytoma, IDH-mutant' above.)
•IDH-mutant and 1p/19q-codeleted oligodendrogliomas – Oligodendrogliomas are histologically and molecularly defined diffuse gliomas characterized by the presence of both an IDH1/2 mutation and codeletion of chromosomal arms 1p and 19q. A WHO grade of 2 or 3 is assigned based primarily on histologic features. Tumors that contain a CDKN2A/B deletion correspond to a WHO grade of 3. (See 'Oligodendroglioma, IDH-mutant and 1p/19q-codeleted' above.)
•IDH-wildtype glioblastoma – IDH-wildtype glioblastoma (WHO grade 4) is the most common malignant primary brain tumor in adults. Most glioblastomas are diffusely infiltrating, highly cellular and pleomorphic tumors with mitotic activity and either microvascular proliferation, necrosis, or both. Others lack high-grade histologic features but contain a qualifying molecular alteration (epidermal growth factor receptor [EGFR] amplification, telomerase reverse transcriptase [TERT] mutation, or chromosome 7 gain/chromosome 10 loss). (See 'Glioblastoma, IDH-wildtype' above.)
●Pediatric-type diffuse gliomas – The 2021 edition of the WHO classification is the first to separate diffuse gliomas that primarily occur in children from those that primarily occur in adults, recognizing the clinically and biologically distinct nature of these groups (table 1). Many of these tumors are defined by recurrent alterations in one or more genes or pathways, including histone genes (H3F3A, HIST1H3B/C) and the mitogen-activated protein kinase (MAPK) pathway. (See 'Pediatric-type diffuse low-grade gliomas' above and 'Pediatric-type diffuse high-grade gliomas' above.)
●Glioneuronal and neuronal tumors – Glioneuronal tumors are most often lower-grade tumors that combine glioma components with neuronal differentiation (table 3). The most common glioneuronal tumor is the ganglioglioma. (See 'Glioneuronal and neuronal tumors' above.)
●Ependymomas – Ependymomas are classified according to anatomic site (supratentorial, posterior fossa, spinal), histology (subependymoma, myxopapillary ependymoma, ependymoma), and several key molecular alterations, including gene fusions involving zinc finger translocation-associated (ZFTA) or Yes1-associated transcriptional regulator (YAP1), histone H3K27 trimethylation, and MYCN amplification. (See 'Ependymal tumors' above.)
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