Diffuse glioma is a term used to encompass a variety of tumors of the central nervous system, which histologically appear similar to glial cells, specifically astrocytomas, oligodendrogliomas and oligoastrocytomas, ranging from WHO grade II to grade IV tumors 1. Importantly, it does not include circumscribed astrocytomas (e.g. pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma etc...) nor tumors with admixed neuronal elements (e.g. ganglioglioma) although there is overlap particularly with the latter.
Traditionally, diffuse gliomas were separated according to histological appearance based on whether tumor cells resembled astrocytes, oligodendrocytes or contained a mixture of both cell types and according to grade. As of the 2016 update to the WHO classification of CNS tumors, the distinction now hinges on molecular marker, particularly IDH mutations and 1p19q co-deletion status.
- diffuse astrocytoma (IDH mutant or IDH wildtype; 1p19q not co-deleted)
- oligodendroglioma (IDH mutant and 1p19q co-deleted)
An additional diffuse glioma is the (usually pediatric) diffuse midline glioma H3 K27M-mutant.
In addition to WHO grade and IDH mutation/1p19q co-deletion status, both of which have a profound impact on prognosis (e.g. grade II IDH mutant and 1p19q co-deleted has the best prognosis; grade IV IDH wildtype has the worst prognosis) a number of additional molecular markers are helpful in estimating prognosis.
Methylation (and thus deactivation) of MGMT is an important predictor of favourable response to temozolomide.
TERT promoter mutations
TERT promoter mutations is encountered in all grades of diffuse gliomas, ranging from WHO grade II oligodendrogliomas (best prognosis) to WHO IV glioblastoma (worst prognosis), although the prevalence of TERT mutations varies significantly within different molecular groups; glioblastomas (IDH wildtype, 1p19q not co-deleted) and oligodendrogliomas (IDH mutant, 1p19q co-deleted) account for most cases 3.
Interestingly, the interaction of TERT mutations with IDH mutation status and 1p19q co-deletion status is not straightforward with various combinations having a strikingly different impact on survival 3. For example in IDH wild-type diffuse astrocytomas (not 1p19q co-deleted) of all grades (II to IV), having a TERT mutation significantly reduces survival, most striking on grade II and III tumors. It is also encountered in a significantly older age group than other molecular subgroups (~60-years-of-age) 3.
In contrast in IDH mutated diffuse gliomas, with or without 1p19q co-deletion, having a TERT mutation has only marginal impact on survival, and may actually be a positive prognostic factor 3.
- 1. Richard A. Prayson. Neuropathology. ISBN: 9781437709490
- 2. Louis DN, Ohgaki H, Wiestler OD et-al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114 (2): 97-109. Acta Neuropathol. (full text) - doi:10.1007/s00401-007-0243-4 - Free text at pubmed - Pubmed citation
- 3. Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, Sarkar G, Caron AA, Kollmeyer TM, Praska CE, Chada AR, Halder C, Hansen HM, McCoy LS, Bracci PM, Marshall R, Zheng S, Reis GF, Pico AR, O'Neill BP, Buckner JC, Giannini C, Huse JT, Perry A, Tihan T, Berger MS, Chang SM, Prados MD, Wiemels J, Wiencke JK, Wrensch MR, Jenkins RB. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. The New England journal of medicine. 372 (26): 2499-508. doi:10.1056/NEJMoa1407279 - Pubmed