Differential Diagnosis:

  • Diffuse Glioma, MAPK pathway altered
  • Diffuse Glioma, NEC
  • Diffuse Glioma, MYB or MYBL-1altered
  • Glioblastoma, molecularly defined
  • Pilocytic astrocytoma
  • Ganglioglioma
  • Pleomorphic xanthoastrocytoma
  • Polymorphous low-grade neuroepithelial tumour of the young (PLNTY)

Diagnosis and Discussion:

Diagnosis: The final diagnosis is diffuse low-grade glioma, MAPK pathway altered. Next generation sequencing revealed a BRAF (p.V600E) mutation. IDH1 and IDH2 mutations were not detected, and there was no evidence of CDKN2A/B mutation. Tumor cells are typically positive for OLIG2 and GFAP, which highlights the fine cell processes. Immunoreactivity for BRAF p.V600E is present when this is the mutation driving MAPK pathway activity. Molecularly, these tumors are IDH-wildtype, H3-wildtype, CDKN2A intact, and lack the chromosomal alterations seen in glioblastoma and oligodendroglioma. In the 2020 WHO, diffuse gliomas with BRAF mutations are placed in a pediatric category and tumor grade for these tumors are indeterminate due to lack of follow up information.

Diffuse low-grade gliomas, MAPK pathway altered are somewhat heterogeneous but often share characteristics with the IDH mutant diffuse low grade gliomas, astrocytoma and oligodendroglioma. BRAF p.V600E mutant cases are usually composed of well-differentiated glial cells with bland, occasionally spindle-shaped nuclei and fine fibrillary processes. Subpial aggregation of tumor cells may be present, as seen in IDH mutant astrocytoma. These tumors generally lack the Rosenthal fibers and eosinophilic granular bodies that are frequently seen in the well-circumscribed low grade gliomas, such as pilocytic astrocytoma, which may also harbor BRAF mutations. Unlike glioblastoma and the H3 mutated high grade gliomas, these tumors lack mitotic activity, microvascular proliferation, or necrosis.

Since the division of glioblastoma (GBM) and IDH mutant astrocytomas into separate entities, a quandary developed in categorizing tumors with low-grade histology, but no IDH mutation - particularly for those in the "young adult" age range. The presence of a "molecular GBM" category has somewhat clarified this analysis, with amplifications of chromosome 7, deletions of chromosome 10, and EGFR amplification (TERT promoter mutations, to a lesser degree) enabling the identification of a grade 4 phenotype. Likewise, the histone 3 mutations, H3 K27 and H3 G34 have helped identify a subset of these high grade "misfits."

MAP kinase pathway activating mutations, such as BRAF V6OOE, have helped identify those gliomas that could benefit from targeted treatments, but the diversity of both adult and pediatric entities showing these mutations has not quite alleviated the grading conundrum. For these tumors, mitotic activity, pleomorphism, level of infiltration, and the presence of dysmorphic neurons have become the main drivers in categorizing these tumors. DNA methylation arrays have become a tiebreaker in these circumstances where contradictions apply, such as when dysmorphic neurons or pleomorphism AND a high level of infiltration may leave one torn between a diffuse astrocytoma with BRAF mutation, pleomorphic xanthoastrocytoma, and ganglioglioma. Coexisting mutations and mitotic activity may further indicate the presence of high-grade features in these tumors, regardless of tumor type.

Since the publication of the 2020 WHO, two notable papers have used methylation profile arrays to identify a methylation group associated with this low grade, young adult, infiltrating glioma category. These papers profiled 45 and 32 patients, from United States  and Germany-based groups, respectively, and saw a large spectrum of tumor morphologies and secondary mutations. Additionally, both groups had an overall better prognosis than GBM, where there was sufficient follow-up data for analysis. Unlike the pediatric entity, many of these tumors also carried CDKN2A/B deletions and large chromosomal alterations, which were associated with higher histologic grade and poor prognosis.

Time and longitudal evaluation of patients with these “misfit” tumors will solidify whether it is most important to stratify these by age, anatomic location, secondary mutation, methylation profile, and/or morphology. Likewise, it will hopefully help us identify which distinctions are esoteric. Lastly, and most importantly, they will hopefully allow us to provide meaningful information to the treating oncologists and considerably less confusion at tumor board.

References:

Sievers P, Bielle F, Göbel K, et.al. Identification of a putative molecular subtype of adult-type diffuse astrocytoma with recurrent MAPK pathway alterations. Acta Neuropathol. 2024 Jul 18;148(1):7.

Singh O, Dampier C, Abdullaev Z, et al. Diffuse astrocytoma, AYA-type, frequently MAPK-altered: report of 45 patients. Acta Neuropathol. 2025 Apr 9;149(1):32.

Ellison DW, Hawkins C, Jones DTW, et al. cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation. Acta Neuropathol. 2019 Apr;137(4):683-687. doi: 10.1007/s00401-019-01987-0. Epub 2019 Mar 8. PMID: 30848347.

Jacques TS, Giannini C, Tabori U, et al. Diffuse low-grade glioma, MAPK pathway-altered. In: WHO Classification of Tumours Editorial Board. Central nervous system tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2021 [cited 2026 May 7]. (WHO classification of tumours series, 5th ed.; vol. 6). Available from: https://tumourclassification.iarc.who.int/chapters/45.