Final Diagnosis: Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3
Discussion
The 2021 5th edition of the WHO classification of tumors of the central nervous system distinguishes between only three adult-type diffuse gliomas. These entities are segregated by IDH status: the IDH-mutant astrocytoma and oligodendroglioma (the latter with 1p/19q-codeletion), and the IDH-wildtype glioblastoma (1). While glioblastomas are, as always, the high-grade, aggressive malignancies which preferentially affect older adults (>55), the IDH-mutant entities typically occur in younger adult populations and have slightly better to much improved prognoses. Median overall survival is typically greater than 5 years for grade 3 oligodendrogliomas, and greater than 10 years for grade 2 (2,3).
Oligodendrogliomas most commonly present in the frontal lobe, with a median age of 43 at diagnosis, and classically present with seizures (4,5). Imaging will typically demonstrate a heterogenous mass with indistinct borders, occasionally cystic, with calcifications (6). On cytology preparations, oligodendrogliomas will demonstrate increased cellularity comprised of relatively monotonous cells with thin cytoplasm, round nuclei, with mild to moderate atypia. Histologically, oligodendrogliomas typically consist of glial tumor cells resembling nonneoplastic oligodendrocytes, with a “fried egg” appearance consisting of round nuclei and cytoplasmic clearing. Characteristically, they also exhibit “chicken wire” vasculature, microcalcifications, and microcysts. Occasionally, tumors will also show astrocytoma-like or atypical features, and molecular findings will define the entity.
The WHO distinguishes two histologic grades of oligodendroglioma, CNS WHO grade 2 and CNS WHO grade 3, but the criteria for distinguishing between grades are not well defined. Some studies utilize a cutoff of at least 5 mitoses per 10 high power fields for grade 3 (or previously, anaplastic oligodendroglioma), along with high cellularity, marked cytologic atypia, microvascular proliferation, and necrosis (7). Within this group, microvascular proliferation and necrosis confer a worse prognosis. Homozygous deletion of CDKN2A or CDKN2B also confers a worse prognosis. It is not seen in grade 2 oligodendrogliomas, but a small subset of grade 3 oligodendrogliomas carry them.
Greater than 90% of IDH mutations in gliomas are of the canonical IDH1 p.R132H missense mutation, which is commonly screened for using immunohistochemistry with an antibody designed to recognize the IDH1 R132H mutant protein (8,9). The remainder consists of less common IDH1 and IDH2 mutations. Oligodendrogliomas without the IDH1 p.R132H mutation are more likely than similar astrocytomas to harbor an IDH2 mutation, which typically involves the codon for R172 (10,11). Molecular studies in the case presented confirmed a mutation in IDH2, p.R172K, as well as TERT, TP53, and NOTCH1 mutations.
While IDH-mutant glial neoplasms share the commonality of IDH alterations, they can typically be differentiated by additional genetic alterations that tend to segregate with oligodendroglial and astrocytic differentiation. 1p/19q codeletions are seen in oligodendrogliomas, as was identified in this case, and TERT promoter mutations are common. Astrocytomas, on the other hand, frequently show both loss of nuclear ATRX and clonal p53 patterns by immunohistochemistry. TP53 mutations in oligodendrogliomas are much less common, but can be present, as in our case.
References
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