• Mutations in isocitrate dehydrogenase (IDH) genes are commonly observed in grade II astrocytomas and oligodendrogliomas. These mutations may occur in IDH1 or IDH2 and lead to increased production of 2-hydroxyglutarate, which interferes with the activity of several enzymes that regulate gene expression (Chapter 6).
Mutations in the promoter for telomerase, which contribute to the immortalization of tumor cells (Chapter 6), are seen in glioblastomas and other astrocytic tumors. In tumors with IDH mutations, telomerase mutations are uncommon; instead, these tumors often have loss of function mutations in ATRX, which normally suppresses recombination events that can preserve telomere length, a mechanism called alternative lengthening of telomeres.
Co-deletion of 1p and 19q chromosomal segments are present in oligodendrogliomas. The mechanism through which these chromosomal alterations shape tumor morphology and response to treatment is not known.
Other genetic alterations, which are also common in tumors outside the CNS, include mutations that lead to overexpression of the EGF receptor and other receptor tyrosine kinases or disable p53 or RB (Chapter 6).
Midline gliomas arise most commonly in the brain stem (specifically in the pons) and also occur in the spinal cord and thalamus. They are infiltrative and result in significant neurologic impairment because of the disruption of critical nearby structures. Although they may not show typical high-grade features such as necrosis or vascular proliferation, they often behave aggressively. These lesions typically have acquired point mutations in histone H3, the consequence of which is loss of a lysine residue that is the target of post-translational modifications that regulate gene expression, another example of oncogenesis via alteration of the cancer cell “epigenome”. Precisely how this mutation contributes to cellular transformation remains to be determined.
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Fig. 23.30 Inoligodendroglioma,tumorcellshaveroundnuclei,oftenwithaclearcytoplasmichalo.Bloodvesselsinthebackgroundarethinandcanformaninterlacingpattern.
Pilocytic astrocytomas are relatively benign tumors that typically affect children and young adults. Most commonly located in the cerebellum, they also may involve the third ventricle, the optic pathways, the spinal cord, and occasionally the cerebral hemispheres. There is often a cyst associated with the tumor, and symptoms appearing after the incomplete resection of the lesions may be associated with cyst enlargement, rather than growth of the solid component. Tumors that involve the hypothalamus are especially problematic because they cannot be resected completely.
A high proportion of pilocytic astrocytomas have activating mutations or translocations involving the gene encoding the serine-threonine kinase BRAF, which result in activation of the MAPK signaling pathway. Pilocytic astrocytomas do not have mutations in IDH1 and IDH2, supporting their distinction from the low-grade diffuse gliomas.
MORPHOLOGYApilocyticastrocytomaofteniscystic,withamuralnoduleinthewallofthecyst;ifsolid,itisusuallywellcircumscribed.Thetumoriscomposedofbipolarcellswithlong,thin“hairlike”processesthatareGFAP-positive.Rosenthalfibers,eosinophilicgranularbodies,andmicrocystsareoftenpresent,whilenecrosisandmitosesarerare.