Adult-Type Diffuse Gliomas

Main Text

Preamble

Gliomas, glioneuronal tumors, and neuronal tumors are the most common and most varied neoplasms that affect the brain parenchyma. Of the six different groups that comprise these tumors, the largest is adult-type diffuse gliomas. As noted in the WHO, 5th edition, these neoplasms constitute the bulk of adult neurooncology practice. The most common of all CNS parenchymal neoplasms—glioblastoma, IDH-wildtype—is the prototypical example.

Adult-Type Diffuse Gliomas

Preamble

Historically, diffuse adult gliomas were divided into 15 entities with different grades assigned to different entities. In the 5th edition, classification of adult-type diffuse gliomas was greatly simplified and now includes only three neoplasms: (1) Astrocytoma, IDH-mutant, (2) oligodendroglioma, IDH-mutant and 1p/19q codeleted, and (3) glioblastoma, IDH-wildtype. All three are delineated in detail in this chapter. In addition, we include a discussion of IDH-wildtype diffuse gliomas that do not meet the histologic or molecular definitions of glioblastoma, IDH-wildtype.

Astrocytoma, IDH-Mutant

Terminology

Astrocytoma, IDH-mutant, is a diffusely infiltrating glioma that exhibits IDH1 or IDH2 mutations. 1p/19q codeletion (typical of oligodendroglioma) is mutually exclusive and, by definition, absent. ATRX&/or TP53 mutations are common.

Etiology

The origin of IDH-mutant astrocytomas is unknown. Astrocytomas have been posited to originate from different cell types, including a distinct population of neural precursor-like cells, oligodendrocyte precursor cells, and astrocytes.

IDH mutations are an early event in gliomagenesis of both astrocytomas and oligodendrogliomas and generally persist during tumor progression. Mutant IDH1 can induce extensive DNA hypermethylation in gene-promoter regions that may silence expression of cellular differentiation, inducing a stem cell-like state prone to self-renewal and tumorigenesis. MGMT encodes a DNA repair protein, and MGMT promoter methylation is commonly observed in IDH-mutant gliomas.

Recent studies have shown that over 2/3 of CNS WHO grade 4 IDH-mutant astrocytomas arise de novo rather than occurring as malignant degeneration of a lower grade glioma.

Pathology

Location

Although IDH-mutant diffuse gliomas can arise anywhere, the cerebral hemispheres are the most common overall site with a preferential location in the frontal and temporal lobes (17-1).

Size and Number

Frontal lobe IDH-mutant astrocytomas may reach a relatively large size before producing symptoms. Temporal lobe lesions are often smaller at initial presentation because of their propensity to cause partial complex seizures. Most IDH-mutant astrocytomas are solitary lesions.

Gross Pathology

Low-grade IDH-mutant astrocytomas are expansile, infiltrating lesions that enlarge, distort, and invade anatomic structures. The gray-white matter interface is often effaced (17-2). Occasional cysts may be present and are sometimes extensive. Calcification is not uncommon in lower grade tumors. Necrosis and gross hemorrhage may be present in higher grade lesions.

Microscopic Features

IDH-mutant astrocytomas range from well-differentiated, slow-growing tumors with low mitotic activity (CNS WHO grade 2) to highly anaplastic, hypercellular masses with rapid growth, microvascular proliferation, necrosis, and significant mitotic activity (CNS WHO grade 4).

Staging, Grading, and Classification

CNS WHO grade 2

Grade 2 IDH-mutant astrocytomas are diffusely infiltrative, well differentiated, and lack histologic anaplasia. Mitotic activity is low. Microvascular proliferation and necrosis are absent.

CNS WHO grade 3

Grade 3 IDH-mutant astrocytomas exhibit focal or dispersed anaplasia and exhibit significant mitotic activity. Microvascular proliferation and necrosis are absent.

CNS WHO grade 4

CNS WHO grade 4 IDH-mutant astrocytomas are diffusely infiltrative tumors that exhibit microvascular proliferation &/or necrosis. If present, homozygous deletions of the cyclin-dependent kinase inhibitor CDKN2A&/or CDKN2B overrules histologic grade, making a diffuse IDH-mutant astrocytoma a grade 4 lesion regardless of histopathologic features. Note that in the 5th edition, diffuse astrocytoma, IDH-mutant, CNS WHO grade 4 tumors are NOT called “glioblastoma” (that term is reserved for IDH-wildtype diffuse astrocytomas).

Diagnostic Molecular Pathology

Immunohistochemistry is essential in establishing the diagnosis of IDH-mutant astrocytomas. A routine panel for initial diagnostic work-up of all adult diffuse gliomas includes IDH1 (codon p.R132H), p53, and ATRX.

Immunostaining for the IDH1 p.R132H mutation is both sensitive and specific. This mutation accounts for ~ 90% of all IDH mutations in supratentorial astrocytomas. Identifying IDH2 codon 172 missense mutation and so-called “noncanonical” IDH1mutations (other than R132H) requires DNA sequencing and should be performed in all WHO grade 4 gliomas in patients < 55 years of age.

Because IDH-mutant astrocytomas and oligodendrogliomas are both diffusely infiltrating gliomas and share IDH1 or IDH2 mutations, loss of nuclear ATRX expression or excluding combined whole-arm deletions of 1p and 19q are also required diagnostic criteria for the diagnosis of diffuse astrocytoma, IDH-mutant.

Clinical Issues

Epidemiology

IDH-mutant diffuse astrocytomas account for between 10-15% of astrocytic neoplasms in adults.

Demographics

Mean age at presentation is mid-30s (range: 20-50 years). Older age at presentation is more common in CNS WHO grade 4 lesions. IDH-mutant astrocytomas are rare over the age of 55 years.

Presentation

Symptoms are location dependent. Seizures are a common presenting sign.

Natural History

Younger age and lower grade are associated with increased survival in patients with adult-type IDH-mutant astrocytomas. Resection extent and presence of postoperative residual tumor are strongly associated with overall survival.

Presence of CDKN2A&/or CDNK2B homozygous deletion is a negative prognostic factor. Therefore, even in the absence of microvascular proliferation or necrosis, tumors with this molecular profile are designated as CNS WHO grade 4 lesions.

Imaging

CT Findings

Findings vary with tumor grade. For lower grade IDH-mutant astrocytomas, NECT shows an ill-defined homogeneously hypodense mass. Calcification is seen in 20% of cases. Gross cystic change and hemorrhage are rare but can be seen in grade 4 lesions.

Lower grade lesions typically do not enhance on CECT, but higher grade lesions may exhibit patchy enhancement.

MR Findings

IDH-mutant astrocytomas are typically hypointense on T1WI, hyperintense on T2WI (17-4), and hyperintense on FLAIR (17-4B). A hyperintense FLAIR rim with hypointense core is sometimes present (17-7)and has been called the T2/FLAIR “mismatch” sign, helpful in identifying IDH-mutant, non-1p/19q codeleted tumors and differentiating them from oligodendroglioma (17-5C). Tumor borders may appear relatively sharp on imaging studies, but these are unencapsulated neoplasms that infiltrate adjacent normal-appearing brain.

Lower grade lesions typically do not enhance or enhance minimally (17-5), but there is a stepwise positive association with WHO grade. Grades 3 and 4 tumors may exhibit some enhancement (17-7D) (17-9). Diffusion restriction is absent. ADC is negatively associated with WHO grade.

MRS shows elevated choline, decreased NAA, and a high mI:Cr ratio. Myoinositol is reduced. 3T MRS may exhibit an elevated 2-hydroxyglutarate (2-HG) peak, resonating at 2.25 ppm.

DCE MR perfusion shows relatively low rCBV in grade 2 lesions. ADC (lower) and rCBV (higher) are with increasing WHO grade.

Differential Diagnosis

The major imaging differential diagnosis of IDH-mutant astrocytoma is oligodendroglioma. Oligodendrogliomas are more often cortically based, more frequently calcify, and may be associated with remodeling of the overlying calvarium. The definitive diagnosis and grading of IDH-mutant astrocytomas require histologic confirmation and diagnostic molecular pathology.

Oligodendroglioma, IDH-Mutant and 1p/19q Codeleted

Terminology

Oligodendroglioma, IDH-mutant and 1p/19q codeleted, is a diffuse glioma with IDH1 or IDH2 mutation + codeletion of chromosome arms 1p and 19q. Oligodendrogliomas constitute a spectrum ranging from well-differentiated, relatively indolent tumors to frankly malignant neoplasms with rapid growth.

Etiology

As with IDH-mutant astrocytomas, the cell of origin remains unknown. Oligodendrogliomas contain malignant oligodendroglial, astrocytic, and neural precursor-like cells.

Pathology

Location

Most oligodendrogliomas arise at the gray-white matter junction (17-10). The vast majority (85-90%) are supratentorial. The most common site is the frontal lobe (50-65%) followed by the parietal, temporal, and occipital lobes. Posterior fossa and spinal cord oligodendrogliomas are uncommon.

Gross Pathology

Oligodendrogliomas are solid, fleshy, cortically based tan-to-pink masses (17-11). They are poorly circumscribed and blend gradually into adjacent structures, blurring the gray-white matter boundaries, expanding one or more gyri, and extending into the adjacent brain in a diffuse manner (17-12). Some oligodendrogliomas occasionally spread in a more diffuse, multifocal, gliomatosis cerebri-like pattern.

Calcification is frequent, and zones of cystic degeneration are common, although frank necrosis is rare. Intratumoral hemorrhage is common, especially with larger or higher grade oligodendrogliomas.

Microscopic Features

Oligodendrogliomas vary in cellularity. Most are highly cellular lesions with uniform round or slightly oval hyperchromatic nuclei surrounded by a prominent perinuclear “halo.” This gives the tumors a classic microscopic fried-egg appearance. Microcalcifications are common.

Oligodendrogliomas typically have a dense network of branching chicken-wire capillaries. Intratumoral hemorrhages are relatively common.

Staging, Grading, and Classification

Oligodendrogliomas comprise a continuous spectrum of tumors that ranges from well-differentiated, slow-growing neoplasms to frankly malignant tumors with rapid growth.

Two grades are recognized: CNS WHO grade 2 and grade 3. Mitotic activity is low or absent in CNS WHO grade 2 oligodendrogliomas but is prominent in grade 3 lesions. However, criteria for distinction between these grades remains controversial and poorly defined.

Microvascular proliferation and necrosis are linked to shorter survival; a clear cut-off point for mitotic count is less clear. CDKN2A homozygous deletion is generally accepted as designating grade 3 tumor.

Diagnostic Molecular Pathology

Oligodendrogliomas are molecularly defined by IDH1 or IDH2 mutations and combined whole-arm 1p/19q codeletions. 1p/19q status is decisive for separation of oligodendroglioma from IDH-mutant astrocytoma.

Nearly all oligodendrogliomas have a TERT promoter mutation and preserved nuclear ATRX expression. Homozygous deletion of CDKN2A has been detected in a small proportion of CNS WHO grade 3 oligodendrogliomas.

Clinical Issues

Epidemiology

Oligodendrogliomas account for 1-2% of all primary CNS neoplasms and 5-20% of gliomas. Approximately 2/3 of oligodendrogliomas are CNS WHO grade 2 and 1/3 are grade 3 lesions. The term “anaplastic” oligodendroglioma has been eliminated.

Demographics

Oligodendrogliomas are tumors of middle-aged adults. The median age at diagnosis is 43 years. Patients with CNS WHO grade 2 lesions are slightly younger (41 years), while those with grade 3 tumors are slightly older (47 years).

Oligodendrogliomas in children are very rare. Some diffuse gliomas in children have microscopic features that resemble oligodendroglioma but are biologically and molecularly distinct from their adult counterparts. They lack 1p/19q codeletions while MYB, MYBL1, FGFR1, or BRAF alterations are typical.

Presentation

Because oligodendrogliomas commonly involve the cortical gray matter, seizures are the most common presenting symptom. Headache is the second most common presentation.

Natural History

CNS WHO grade 2 oligodendrogliomas are slow-growing but locally aggressive neoplasms. The five-year survival rate is nearly 80%, and the median survival time is 10-12 years. Local recurrence following resection is very common. Leptomeningeal spread may occur in late-stage disease in some patients.

Treatment Options

Gross total resection is the primary treatment and improves outcome. IDH-mutant 1p/1pq codeleted oligodendrogliomas are generally chemosensitive, so combined radiation and chemotherapy is standard.

Imaging

General Features

Oligodendrogliomas are round or ovoid, relatively sharply delineated masses that involve the cortex and subcortical white matter. Differentiation of CNS WHO grade 2 and grade 3 oligodendrogliomas (formerly called anaplastic oligodendroglioma) on imaging studies is difficult.

CT Findings

Typical oligodendrogliomas are peripheral and cortically based lesions, often in the frontal lobe. Focal gyral expansion with thinning and remodeling of the overlying calvarium is common (17-15). Almost 2/3 are hypodense on NECT while 1/3 exhibit mixed-density patterns.

Coarse, nodular, or clumped calcification is seen in 70-90% of cases. Gyriform calcification is very suggestive of oligodendroglioma (17-13). Foci of cystic degeneration are present in 20%. Petechial hemorrhages may be present, but gross hemorrhage and peritumoral edema are less common.

Enhancement varies from none to moderate; ~ 50% of oligodendrogliomas exhibit some degree of enhancement. Contrast enhancement generally correlates with a worse outcome in both CNS WHO grades 2 and 3 oligodendrogliomas.

MR Findings

Oligodendrogliomas often appear relatively well delineated and are usually hypointense relative to gray matter on T1WI and heterogeneously hyperintense on T2/FLAIR, and they may exhibit calcified foci or microhemorrhages on T2* sequences (17-17). Oligodendrogliomas do not exhibit a T2/FLAIR “mismatch” sign.

Contrast enhancement varies. Many oligodendrogliomas—especial CNS WHO grade 2 lesions—exhibit little or no enhancement. Approximately 50% exhibit patchy, multifocal contrast enhancement (17-19), which has been associated with higher grade and shorter progression-free survival.

MRS shows moderately elevated Cho and decreased NAA. A 2-HG peak resonating at 2.25 ppm can be detected in some cases. Because of their relatively increased vascularity, oligodendrogliomas may exhibit high rCBV foci that does not necessarily indicate high-grade histopathology.

Differential Diagnosis

The major differential diagnosis of oligodendroglioma is astrocytoma, IDH-mutant. The T2/FLAIR “mismatch” sign, if present, is helpful in distinguishing astrocytoma from oligodendroglioma.

Other cortically based, slow-growing tumors that typically present with seizures include ganglioglioma and dysembryoplastic neuroepithelial tumor (DNET). Both lack IDH mutation and are more common in children, while oligodendrogliomas are vanishingly rare in this age group.

IDH-wildtype glioblastoma and H3 G34-mutant diffuse hemispheric glioma can resemble highly cellular CNS WHO grade 3 oligodendrogliomas on imaging studies but can be distinguished by their IDH-wildtype status and other specific molecular markers.

Extraventricular neurocytoma is a rare, cortically based tumor that may be indistinguishable from oligodendroglioma on imaging studies.

Glioblastoma, IDH-Wildtype

Glioblastoma (GBM), IDH-wildtype is the most common, most aggressive, and most invasive of primary brain tumors.

Terminology

GBM is a diffusely infiltrating astrocytic tumor that is IDH-wildtype and H3-wildtype with one or more histologic &/or genetic features specified in the WHO, 5th edition. In the WHO, 5th edition, the term “glioblastoma” is exclusively for an adult-type, IDH-wildtype grade 4 diffuse glioma.

Etiology

As with the other adult-type diffuse gliomas, the precise origin of GBMs is unknown. Genetic sequencing studies suggest that neural precursor cells in the subventricular zone are likely cells of origin. Whether self-renewing glioma stem cell-like elements in GBMs result from transformation of a neural precursor or dedifferentiation of a lineage-restricted cell type is unknown. Recent evidence suggests noncoding RNAs in glioma stem cells may play a key role in tumor development and disease progression.

Pathology

Location

GBMs can occur anywhere in the CNS but are most commonly found in the subcortical white matter of the cerebral hemispheres. Extension into the cortex and through the corpus callosum into the contralateral hemisphere is common. Symmetric involvement of the corpus callosum is common, the so-called butterfly glioma pattern. Tumor spread tends to occur along compact white matter tracts.

GBMs may also occur in the thalami, brainstem, cerebellum, and even the spinal cord. When midline or juxtamidline tumors are identified, diffuse midline glioma, H3 K27-altered should be considered in the differential diagnosis.

Size and Number

GBMs vary widely in size from relatively small focal lesions to massive tumors infiltrating multiple lobes in the so-called gliomatosis cerebri pattern. Up to 20% of GBMs appear as multifocal lesions at the time of initial diagnosis, but only 2-5% of multifocal GBMs are true synchronous, independently developing tumors.

Gross Pathology

GBMs are poorly delineated masses. The most frequent appearance is a reddish-gray tumor “rind” surrounding a central necrotic core (17-20). Central necrosis can occupy over 80% of tumor volume. Intratumor hemorrhage is common, and macroscopic cysts with liquefied necrotic tumor tissue are often present.

Microscopic Features

GBM, IDH-wildtype, is a diffusely infiltrating, highly cellular tumor composed mostly of astrocytic, poorly differentiated tumor cells with nuclear atypia and marked pleomorphism. Necrosis and microvascular proliferation are common throughout the lesion.

Microscopic extension into the so-called peritumoral brain zone bordering the tumor along white matter tracts and seeding of the CSF spaces (e.g., along the ventricular ependyma, pial surfaces, and subarachnoid spaces) is common (17-23) (17-24). Extension into the dura and skull are rare, as are systemic metastases.

Staging, Grading, and Classification

GBM, IDH-wildtype is a CNS WHO grade 4 neoplasm.

Diagnostic Molecular Pathology

IDH-wildtype GBMs lack IDH1 and IDH2 mutations and do not carry H3 K27 or H3 G34 mutations. The probability of a noncanonical IDH mutation is < 1% in GBMs in patients ≥ 55 years of age, so further sequencing is generally considered unnecessary.

However, in patients < 55 years or in patients with a history of a lower grade glioma, the WHO, 5th edition recommends negative standard IDH1 immunostaining to be followed by DNA sequencing for less common IDH1 or IDH2 mutations. Further, if the tumor is in or adjacent to midline structures, H3 K27-altered mutations should also be excluded.

TERT promoter mutations, EGFR gene amplification, and a +7/-10 genotype allow for the diagnosis of IDH-wildtype GBM even if microvascular proliferation &/or necrosis is absent. Demonstration of a DNA methylation profile of IDH-wildtype GBM is also sufficient for the diagnosis.

BRAF p.V600E mutation is rare but can be identified in up to 50% of GBMs with epithelioid histology. TP53 mutations are present in ~ 25% of all GBMs but are frequent in giant cell GBMs.

MGMT promoter methylation is typically determined in IDH-wildtype GBMs because it is clinically relevant, indicating response to chemotherapy in patients treated with temozolomide.

DIAGNOSTIC PATHOLOGIC CRITERIA FOR GLIOBLASTOMA, IDH-WILDTYPE

Essential

• IDH-wildtype, H3-wildtype diffuse astrocytic glioma

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