Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas

INTRODUCTION — There are significant differences between oligodendrogliomas and other glial tumors in pathology, molecular pathogenesis, and natural history. These differences have important prognostic implications, which can affect treatment.

In the World Health Organization (WHO) classification of central nervous system tumors, oligodendroglial tumors are defined by molecular diagnostics to include only those diffuse gliomas harboring both a mutation in isocitrate dehydrogenase (IDH) type 1 or type 2 and codeletion of chromosomes 1p and 19q [1]. Mixed oligoastrocytoma no longer exists for fully characterized tumors, but the terminology is retained when referring to historically diagnosed tumors and for tumors with mixed oligoastrocytoma histology for which molecular testing is not available (ie, oligoastrocytoma not otherwise specified [NOS]). (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)

The clinical manifestations, classification, pathologic classification, and molecular prognostic factors associated with IDH-mutant, 1p/19q-codeleted oligodendrogliomas (grades 2 and 3) will be reviewed here. The treatment of these tumors is discussed separately. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults" and "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults".)

EPIDEMIOLOGY — Oligodendroglial tumors are rare tumors, constituting approximately 5 percent of all malignant primary tumors of the central nervous system [2]. Together, grade 2 and 3 oligodendrogliomas are one-tenth as common as glioblastoma, the most commonly occurring malignant primary brain tumor in adults. Approximately 1000 oligodendroglial tumors are diagnosed in the United States each year, with an age-adjusted incidence of 0.27 per 100,000 people [2].

Environmental and genetic risk factors for primary brain tumors are reviewed separately. (See "Risk factors for brain tumors".)

CLINICAL FEATURES

Age of onset — Most oligodendrogliomas present in adults between 25 and 50 years of age. The median age at diagnosis is 43 years for World Health Organization (WHO) grade 2 tumors and approximately 5 to 10 years late for WHO grade 3 tumors [2]. Oligodendrogliomas are occasionally diagnosed in teenagers and in adults over the age of 65 years [3].

Signs and symptoms — Oligodendrogliomas are slowly-growing, infiltrative tumors that may be clinically silent for many years. The most common presenting symptom is seizure, which can be focal or evolving to a bilateral convulsive (secondarily generalized) seizure. Some patients are asymptomatic and diagnosed based on incidental findings at the time of brain imaging performed for another reason (eg, trauma, migraine headaches).

Focal neurologic deficits and generalized symptoms such as headache are uncommon at the time of diagnosis. As tumors progress, symptoms vary based on tumor location, size, and rate of tumor growth. (See "Overview of the clinical features and diagnosis of brain tumors in adults".)

Most oligodendroglial tumors arise in the white matter of the cerebral hemispheres, predominantly in the frontal lobes [4]. Rarely, they arise at infratentorial sites and in the spinal cord [5]. A multifocal, gliomatosis pattern of involvement can be seen, although it is more commonly associated with astrocytic histology. Leptomeningeal spread can occur but is typically a late development.

As with other glial tumors, oligodendrogliomas only rarely metastasize outside the central nervous system.

Neuroimaging — On magnetic resonance imaging (MRI), most low-grade oligodendrogliomas have hyperintense or mixed signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images and hypointense or mixed signal intensity on T1-weighted images (image 1) [6]. Compared with isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas, oligodendrogliomas are more likely to have indistinct borders (image 2), involve the gray matter, and have nonuniform signal on T1- and T2-weighted images [7-9]. They lack the so-called T2/FLAIR mismatch sign, which can be seen in IDH-mutant astrocytomas (image 3). (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Low-grade glioma'.)

Calcifications, which are characteristic of oligodendroglial tumors but not highly sensitive or specific, are well visualized on computed tomography (CT) and can be seen as low signal intensity on T2-weighted images and dark signal on susceptibility-weighted sequences (image 2) [7].

Most grade 3 oligodendrogliomas are associated with some contrast enhancement, which presumably reflects microvascular proliferation and blood-brain barrier leakage (image 2). However, the absence of contrast enhancement does not exclude anaplastic histopathology, nor does its presence exclude low-grade (grade 2) histopathology. Up to 50 percent of low-grade oligodendrogliomas have some faint contrast enhancement.

On the whole, none of these imaging findings is sufficiently specific in clinical practice to replace histopathologic examination to establish both the tumor type and grade. Sampling error, particularly in patients who undergo only a biopsy, can lead to misclassification and undergrading of a brain tumor. The neuroimaging characteristics of a lesion may guide the surgeon in choosing a site for biopsy, and the presence of enhancement is suggestive of a high-grade tumor.

EVALUATION AND DIAGNOSIS — Patients with a suspected infiltrative glioma should undergo history, neurologic examination, and brain magnetic resonance imaging (MRI) with contrast. Additional tests, such as lumbar puncture and magnetic resonance spectroscopy, are not routinely indicated but can provide useful information in selected cases, such as when a demyelinating process is being considered on the differential diagnosis. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Differential diagnosis' and "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Initial evaluation'.)

Accurate diagnosis of oligodendroglioma and other infiltrative gliomas requires an adequate tissue sample for histopathologic and molecular study. This may be obtained by stereotactic biopsy for deep-seated tumors or at the time of maximal safe resection for tumors in accessible locations. Patients should be referred to a neurosurgeon with subspecialty expertise in brain tumor neurosurgery when possible. Procedure selection is individualized based on suspected tumor type and grade, location, and operability. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Diagnosis'.)

PATHOLOGY — Oligodendrogliomas are genetically defined, diffusely infiltrating gliomas that contain both an IDH1 or IDH2 mutation and whole-arm codeletion of chromosomes 1p and 19q (algorithm 1 and table 1) [1]. Although the most typical histopathologic appearance is that of oligodendroglioma, microscopically, tumors may have astrocytic features as well.

Histopathology — Oligodendrogliomas are histologically well-differentiated, diffusely infiltrating tumors composed predominantly of cells resembling oligodendrocytes [10,11].

The classic appearance is that of sheets of isomorphic round nuclei surrounded by clear cytoplasm ("fried egg" appearance) (picture 1). Delicate, branching capillaries and microcalcifications are typical. More elongated, astrocytic tumor cells can be present and are compatible with the diagnosis of oligodendroglioma; it is the presence of an IDH1/2 mutation and 1p/19q codeletion that defines an oligodendroglioma [12]. If mixed oligoastrocytic histology is present and genetic testing cannot be performed, such a tumor is diagnosed provisionally as oligoastrocytoma not otherwise specified (NOS). (See 'Tumors previously called oligoastrocytoma' below.)

The World Health Organization (WHO) grading system distinguishes two histopathologic grades of oligodendroglioma: grade 2 (low-grade) and grade 3 (anaplastic) oligodendroglioma [1]. Grade 3 tumors are characterized by the presence of anaplastic features (high cell density, mitosis, nuclear atypia, microvascular proliferation, and necrosis) and are associated with modestly worse prognosis compared with grade 2 tumors.

The natural history of oligodendrogliomas is a gradual progression from low-grade (well-differentiated) tumors into high-grade lesions with anaplastic features. These morphologic changes appear gradually within a tumor, and an objective distinction between oligodendroglioma (low-grade) and anaplastic oligodendroglioma (high-grade) is not always possible. Some patients present with an anaplastic oligodendroglioma without evidence of a prior low-grade lesion.

Key molecular alterations — Assessment of IDH mutational status and 1p/19q loss is required for all diffuse oligodendroglial and astrocytic tumors. ATRX expression is virtually always retained in oligodendrogliomas and most have telomerase reverse transcriptase (TERT) promoter mutations, whereas tumor protein p53 (TP53) mutations are rare in oligodendroglioma. Assessment of ATRX and TP53 by immunohistochemistry is therefore sometimes used in gliomas with a proven IDH mutation to diagnose oligodendroglioma instead of assessment of 1p/19q codeletion status.

IDH1/2 mutational testing — Mutations in IDH1 and, less commonly, IDH2 are a very early event in the tumorigenesis and a defining feature of the majority of WHO grade 2 and 3 diffuse gliomas. IDH1/2 mutations can be present with and without 1p/19q codeletion. The combined presence of 1p and 19q loss defines oligodendroglioma, whereas IDH1/2 mutation without 1p/19q codeletion is typical of diffuse astrocytomas [13]. (See "Molecular pathogenesis of diffuse gliomas", section on 'Formation of oligodendroglial tumors'.)

Immunohistochemical staining for the most common mutant form of IDH1 (R132H), which identifies 90 percent of all IDH mutations, can be performed on all diffuse glioma specimens for diagnostic purposes as a first screen for IDH mutations. If R132H-mutant IDH1 immunohistochemistry is negative on a glioma specimen, sequencing of IDH1 (codon 132) and IDH2 (codon 172) for hotspot mutations must be performed, especially in the presence of astrocytic or oligodendroglial histologic features. In some centers, IDH1/2 sequencing has replaced immunohistochemistry as the routine investigation for diffuse glioma specimens. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'IDH1/IDH2 mutation'.)

Oligodendrogliomas with noncanonical IDH1 and IDH2 mutations may have improved outcomes compared with IDH1 R132H-mutant tumors [14]. However, this is not well established yet, and further studies are needed.

Loss of 1p and 19q — Combined loss of chromosome arms 1p and 19q, together with IDH mutation, defines oligodendroglioma. All diffuse gliomas should be tested for an IDH mutation, and all IDH-mutant gliomas should be tested for 1p/19q loss [15].

Loss of heterozygosity (LOH) studies including state-of-the-art next-generation sequencing panels and whole-genome methylation that assess multiple regions on 1p and 19q are the preferred tools to detect whole-arm 1p/19q codeletion [16]. Fluorescence in situ hybridization (FISH) alone is not an ideal technique because it does not assess loss of the entire arms of 1p and 19q.

Typical combined whole-arm loss of 1p and 19q is invariably associated with IDH mutation. Detection of 1p/19q codeletion by FISH in the absence of an IDH mutation (confirmed by IDH1/2 sequencing) suggests loss of 1p and/or 19q as part of other copy number alterations and should prompt additional investigation for genetic changes associated with glioblastoma (in particular, gain of chromosome 7, loss of 10 or 10q, amplification of the epidermal growth factor receptor [EGFR] gene). (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on '1p/19q codeletion'.)

The 1p/19q codeletion arises from an unbalanced translocation of the short arm of chromosome 19 (19p) to the long arm of chromosome 1 (1q), after which the derivative chromosome with the short arm of 1 and the long arm of 19 is lost [17,18]. In tumors in which this abnormality is identified, the deletions of 1p and 19q persist as the tumor progresses, suggesting that this translocation is an early event in tumorigenesis [19]. Additional chromosomal abnormalities are frequent in anaplastic oligodendroglial tumors [19,20]. (See "Molecular pathogenesis of diffuse gliomas", section on 'Formation of glioblastoma and transition from low-grade to high-grade glioma'.)

Among patients with grade 3 oligodendroglioma and the characteristic 1p/19q codeletion, the presence of polysomy of chromosomes 1 and 19 may identify a subset of patients with a poorer prognosis [21,22]. In a series of 46 patients with 1p/19q loss, those with polysomy had a significantly shorter median progression-free survival compared with those without polysomy (47 versus 87 months) [21].

CDKN2A/B deletion — Testing for the presence of homozygous CDNK2A/B deletion may be performed in IDH-mutant gliomas, including oligodendrogliomas. The presence of a deletion, although relatively uncommon in oligodendrogliomas (7 percent of 483 grade 3 oligodendrogliomas in one series), has been associated with shorter progression-free and overall survival, and it is consistent with a WHO grade 3 tumor but is virtually always observed in the presence of anaplastic features [1,23]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Histopathologic and molecular classification'.)

Additional molecular testing — Immunohistochemical staining for ATRX and mutant p53 expression is routinely performed on glioma specimens and can suggest the presence or absence of 1p/19q codeletion. ATRX mutation (indicated by loss of ATRX staining) and TP53 gene mutation (indicated by positive p53 staining) are both common in astrocytomas and rare in oligodendrogliomas. Therefore, in the presence of an IDH mutation, the combination of retained ATRX expression and negative p53 staining is sometimes used to diagnose oligodendroglioma instead of assessment of 1p/19q codeletion status.

Virtually all oligodendrogliomas have the CpG island hypermethylated phenotype (CIMP), in which the O6-methylguanine-DNA methyltransferase (MGMT) promoter region as a rule is also methylated. MGMT promoter methylation should be assessed in all glioblastoma specimens, but its clinical value in IDH-mutant gliomas is limited. Therefore, testing for MGMT promoter methylation status is not recommended for oligodendrogliomas [15].

Virtually all IDH-mutant, 1p/19q-codeleted oligodendrogliomas harbor a TERT mutation. TERT promoter mutations are not exclusive to oligodendroglioma, however, and their prognostic significance is dependent on the genetic background of the tumor. TERT promoter mutations in oligodendroglioma are mutually exclusive with mutations in ATRX, which occur in most IDH-mutant astrocytomas. When present in IDH-wildtype diffuse astrocytomas, TERT promoter mutations are associated with a poor prognosis, similar to that of glioblastoma.

Many oligodendrogliomas have additional mutations in the capicua transcriptional repressor (CIC) and far upstream binding element protein 1 (FUBP1) genes [24,25]. However, assessment of CIC and FUBP1 does not have clinical relevance. The prognostic significance of CIC inactivating mutations in oligodendroglial tumors is unclear [26].

Tumors previously called oligoastrocytoma — In the past, tumors containing histopathologic characteristics of both oligodendroglioma and astrocytoma were classified as oligoastrocytoma. Studies have shown if molecular criteria are applied, these tumors have either an oligodendroglial genotype (IDH mutated, 1p/19q codeleted) or an astrocytic genotype (IDH, ATRX, and TP53 mutated) [12]. As a result, diffuse gliomas are characterized as either oligodendroglioma or astrocytoma [1]. Only if genetic testing fails or is not possible should the diagnosis of oligoastrocytoma NOS be made. True mixed tumors with genetic lesions reflecting both lineages are rare. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Oligoastrocytoma (historical entity)'.)

Mechanism of chemosensitivity — The responsiveness of oligodendrogliomas to chemotherapy was initially observed in studies using the procarbazine, lomustine, and vincristine (PCV) chemotherapy regimen in patients with recurrent tumors. Subsequent studies have shown a high response rate with single-agent temozolomide as well.

The mechanism underlying the chemosensitivity of oligodendrogliomas is an area of ongoing research. IDH mutations result in metabolic alterations, including decreased alpha-ketoglutarate (AKG), increased levels of 2-hydroxyglutarate (2HG), and changes in nicotinamide adenine dinucleotide phosphate (NADP) levels [27]. This leads to epigenetic alterations and the development of a CIMP, which as a rule includes MGMT promoter methylation [28]. MGMT is a nuclear enzyme responsible for DNA repair following alkylating-agent chemotherapy and may mediate part of the cellular resistance to alkylating agents. MGMT expression can be silenced by methylation of its promoter [29].

In parallel with the increase of 2HG, AKG levels are decreased. These changes are required for other resistance mechanisms against alkylating chemotherapy, such as AKG-dependent alkB homolog (ALKBH) DNA repair enzymes [30].

SUMMARY

●Epidemiology – Oligodendroglial tumors are uncommon primary brain tumors, constituting approximately 5 percent of all neuroepithelial tumors of the central nervous system. They typically present in adults between 25 and 45 years of age but are occasionally diagnosed in teenagers and adults over the age of 65 years. (See 'Epidemiology' above.)

●Clinical features – Oligodendrogliomas are slow-growing, infiltrative tumors that may be clinically silent for many years. The most common presenting symptom is seizure. Focal neurologic deficits are uncommon at the time of diagnosis. (See 'Signs and symptoms' above.)

●Neuroimaging – Most low-grade oligodendrogliomas have hyperintense or mixed signal on T2-weighted magnetic resonance imaging (MRI) and hypointense or mixed signal intensity on T1-weighted images (image 1). Contrast enhancement is variable and does not necessarily indicate anaplastic (grade 3) pathology (image 2). (See 'Neuroimaging' above.)

●Diagnosis – Diagnosis requires an adequate tissue sample for histopathologic and molecular study, including testing for isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion (algorithm 1). Diagnostic tissue may be obtained by stereotactic biopsy for deep-seated tumors or at the time of maximal safe resection for tumors in accessible locations. Patients should be referred to a neurosurgeon with subspecialty expertise in brain tumor neurosurgery when possible. (See 'Evaluation and diagnosis' above and 'Pathology' above.)

●Pathology – Pathologically, grade 2 and 3 oligodendrogliomas are genetically defined, diffusely infiltrating gliomas (picture 1) that contain both an IDH1 or IDH2 mutation and codeletion of chromosome arms 1p and 19q (algorithm 1). Retained nuclear ATRX expression and absence of a TP53 mutation in an IDH-mutated glioma suggest 1p/19q codeletion. (See 'Pathology' above.)

●Chemosensitivity – Compared with other diffuse gliomas, oligodendrogliomas are highly chemosensitive. The mechanism of chemosensitivity likely relates in large part to metabolically induced epigenetic changes, including CpG island hypermethylated phenotype (CIMP) and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. (See 'Mechanism of chemosensitivity' above.)