Isocitrate Dehydrogenase (IDH)-Wildtype Glioblastoma With an Unusual EWSR1::RAD51B Gene Fusion: A Case Report and Review of the Literature.

Glioblastoma (GBM) is the most common primary malignant neoplasm of the central nervous system in adults. GBM is defined as an isocitrate dehydrogenase (IDH)-wildtype diffuse astrocytic glioma with characteristic histologic and/or molecular features. The expanding use of integrated histologic, molecular, and epigenetic diagnostics has revealed increasing biological heterogeneity within this category. We report a case of a 73-year-old man with GBM, IDH-wildtype, harboring a novel EWSR1::RAD51B gene fusion identified by next-generation sequencing (NGS). Magnetic resonance imaging revealed a heterogeneous, predominantly peripherally enhancing mass involving the left temporal, parietal, and occipital lobes. Histologic examination demonstrated a diffusely infiltrative high-grade glioma with marked nuclear pleomorphism, brisk mitotic activity, microvascular proliferation, and geographic and pseudopalisading necrosis. Immunohistochemistry was supportive of GBM. Molecular studies revealed MGMT promoter methylation and a truncating PTEN mutation (p.Q214*, c.640C>T). In addition, a previously unreported EWSR1::RAD51B gene fusion was identified by NGS. DNA methylation profiling also classified the tumor as GBM, IDH-wildtype, with high confidence. To our knowledge, this is the first reported case of GBM harboring an EWSR1::RAD51B gene fusion. Although the biological significance of this alteration remains unclear, its identification expands the molecular spectrum of GBM and underscores the value of comprehensive genomic and epigenomic profiling in the diagnostic evaluation of diffuse gliomas, particularly when unexpected or atypical molecular findings are encountered.