Non-astrocytic gliomas

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Non-astrocytic gliomas

The following glial neoplasms are considered in this chapter: oligodendrogliomas, ependymomas, and mixed gliomas.

OLIGODENDROGLIOMAS

Oligodendrogliomas usually present in adulthood. They show a broad range of behaviors; some neoplasms with bland cytologic features grow extremely slowly and are associated with a long history of epilepsy, yet anaplastic oligodendrogliomas can have a poor prognosis (Table 36.1). Attempts to categorize this heterogeneity in a variety of grading systems have been successful in separating groups of patients with distinct outcomes, but consensus supports the view that two broad categories are sufficient. These correspond to ‘oligodendroglioma’ and ‘anaplastic oligodendroglioma’, grade 2 and grade 3, respectively in the WHO classification.

Table 36.1

Prognostic indicators in oligodendrogliomas

Age (young age – favorable)

Postoperative Karnofsky score (high score – favorable)

Pathologic distinction between WHO grade 2 and WHO grade 3 (anaplastic) neoplasms (WHO grade 2 – favorable)

Ki-67 labeling index (<5% – favorable)

Chromosomes 1p/19q co-deletion (presence – favorable)

MGMT methylation (presence – favorable)

IDH1 mutation (presence – favorable in anaplastic oligodendroglioma)

Proneural gene expression profile (presence – favorable)

Anaplastic neoplasms with homozygous CDKN2A deletion (absence – favorable)

While oligodendrogliomas share the IDH1 mutation in common with astrocytomas, oligodendroglial tumors have distinctive chromosomal losses that correlate with prognosis. These losses were the first example of an association between biologic heterogeneity and genetic profile in a histologically uniform class of CNS neoplasm.

MACROSCOPIC APPEARANCES

Oligodendrogliomas have a variety of macroscopic appearances. Small diffuse examples may be difficult to locate in resection specimens. Distortion of the normal cortical gray and white matter interface and discoloration of tissue provide clues to their location (Fig. 36.1). Other neoplasms are more obvious, appearing as moderately well-circumscribed, gray masses. The propensity of superficial oligodendrogliomas to invade the subarachnoid space may produce a neoplasm that sits partially on the cortical surface of the cerebrum.

36.1 Oligodendroglioma.
This infiltrating neoplasm expands the gyri and deep white matter in the frontal lobe, distorting the striatum and lateral ventricles and causing subfalcine herniation of the cingulate gyrus.

Oligodendrogliomas are composed of uniform cells (Figs 36.2–36.5). These readily infiltrate gray matter, but tend to produce a more abrupt edge in white matter (Fig. 36.2). A lobular architecture is sometimes seen and microcysts can be prominent, particularly in myxoid tumors. Small foci of dystrophic calcification are usually found, often at the edge of the neoplasm or in infiltrated gray matter. A delicate vasculature consisting of branching capillaries runs through typical oligodendrogliomas.

36.2 Oligodendroglioma.
(a) Perioperative smear preparations generally reveal little cytologic pleomorphism. The round nuclei and ill-defined cytoplasm are typical. (b) A relatively circumscribed border to what is generally an infiltrating neoplasm may be observed in white matter. (c) Dystrophic calcification is a common feature. (d) The cerebral cortex is diffusely infiltrated by neoplastic cells, which encircle neurons (satellitosis). (e) A network of delicate bifurcating capillaries is typical, and sometimes divides the cells into lobules. (f) The oligodendroglioma is one of several neuroepithelial neoplasms that may show rhythmic nuclear palisading.

36.3 Oligodendroglioma.
Cytological features include round cells with (a) or without (b) artefactual clearing of the cytoplasm, and (c) loosely arranged elongated cells with uniform round nuclei. (d) Foci of small ‘minigemistocytic’ cells with eosinophilic cytoplasm and an eccentric, round nucleus are seen in some oligodendrogliomas. The nuclear form is similar to that in the round cells, and these foci do not indicate a diagnosis of mixed glioma.

36.4 Oligodendroglioma.
Invasion of the subarachnoid space.

36.5 Oligodendroglioma.
Immunoreactivity for GFAP is variable in oligodendrogliomas.

GENETIC ASPECTS OF GLIOMAS WITH OLIGODENDROGLIAL FEATURES

A white matter oligodendrocyte progenitor cell has been implicated as the cell of origin for oligodendroglioma.

Isocitrate dehydrogenase 1 (IDH1) mutation is a common and early genetic event in oligodendroglial tumors (Fig. 36.6). This finding is shared with other low- or intermediate-grade astrocytic and oligoastrocytic neoplasms as well as secondary glioblastomas.

Allelic loss on chromosome 1p and chromosome 19q is present in as many as 80% of both oligodendrogliomas and anaplastic oligodendrogliomas and is considered an early neoplastic event (Fig. 36.7). Combined 1p/19q loss is not specific for oligodendrogliomas, occurring in oligoastrocytomas. In contrast to IDH1 mutation, 1p/19q loss is rare in astrocytomas.

In many cases, combined loss of chromosomes 1p and 19q is mediated by an unbalanced translocation, t(1;19)(q10;p10).

1p/19q loss is common in frontal, parietal, and occipital oligodendroglial tumors, but infrequent in temporal lobe tumors. Pediatric oligodendrogliomas hardly ever show 1p/19q co-deletion, and then only in tumors from adolescents.

In oligodendroglial tumors, IDH1 mutation, MGMT methylation, and 1p/19q loss are strongly associated with each other and with a good prognosis.

A proneural gene expression profile (expression of genes found in normal brain and in neurogenesis) in oligodendroglial tumors is also linked with 1p/19q co-deletion and with improved outcome.

Several studies indicate an association between response to alkylating chemotherapy or to radiotherapy and co-deletion of chromosomes 1p and 19q in anaplastic oligodendrogliomas. There is consensus that 1p/19q loss is an outcome indicator, but whether this marker is specifically predictive of therapeutic response has recently been questioned.

Allelic loss on chromosome 17p and TP53 mutation are uncommon in oligodendrogliomas, but TP53 mutation occurs in up to 20% of anaplastic oligodendrogliomas.

Anaplastic progression of oligodendrogliomas is associated with supplementary losses on chromosomes 9p and 10.

Homozygous deletion of CDKN2A (p16) on 9p occurs in up to 40% of anaplastic oligodendrogliomas.

EGFR overexpression that is not due to gene amplification is frequent in oligodendrogliomas and anaplastic oligodendrogliomas.

Between 20% and 65% of oligoastrocytomas have the 1p/19q loss profile found in oligodendrogliomas, and an oligodendroglioma phenotype predominates in mixed gliomas with this profile.

Astrocytic and oligodendroglial components of an oligoastrocytoma show the same genetic profile.

Allelic loss on 17p/TP53 mutation and 1p/19q loss are inversely associated in oligoastrocytomas.

Cytoplasm is rather sparse and not easily identifiable in some cells. Artefactual clearing of the cytoplasm is common in paraffin-embedded material, particularly when fixation is delayed, and gives a ‘fried-egg’ appearance to the cells (Fig. 36.3a). Nuclei are round and usually contain faintly speckled chromatin. A single small nucleolus may be present. Cells occasionally adopt a slightly elongated form, but nuclei retain their characteristic uniformity. Some cells, termed ‘minigemistocytes’, have eccentrically placed nuclei and eosinophilic cytoplasm that is strongly immunoreactive for GFAP (Fig. 36.3d). This overlap with an astrocytic morphophenotype is not on its own indicative of mixed glioma status, but should prompt a search for anaplastic features. Exceptionally, ‘signet-ring’ cells may be evident. Invasion of the subarachnoid space is common (Fig. 36.4). Immunohistochemistry with antibodies to GFAP generally reveals labeling of only a small proportion of cells (Fig. 36.5). Immunoreactivity for myelin-specific proteins is rare. Mitoses are sparse, except in neoplasms with other anaplastic characteristics such as cytologic pleomorphism, microvascular proliferation, and areas of necrosis (Fig. 36.8).