Epithelioid Glioblastoma or Anaplastic Pleomorphic Xanthoastrocytoma? Lessons from A Rare High Grade Neuroepithelial Tumor with a Novel Germline FANCA Mutation

Background : Anaplastic pleomorphic xanthoastrocytoma (APXA) and epithelioid glioblastoma (eGBM) are rare central nervous system tumors with overlapping clinical and histopathological features, making their distinction challenging. Accurate classification is clinically important because of their markedly different biological behavior and prognosis. Beyond canonical BRAF alterations, the genetic landscape of these tumors remains incompletely characterized. Methods We report a 46-year-old man presenting with rapidly progressive neurological symptoms, including seizures and cognitive decline. Diagnostic evaluation included magnetic resonance imaging, cerebrospinal fluid analysis, histopathology, immunohistochemistry, and next-generation sequencing of tumor and germline DNA. A focused review of the literature was performed to contextualize the molecular findings within the APXA–eGBM spectrum. Results Integrated clinicopathological assessment identified a high-grade neuroepithelial tumor with overlapping features of APXA and eGBM, precluding definitive classification based on morphology alone. Molecular analysis revealed a novel deleterious germline FANCA frameshift variant (p.Pro615fs), homozygous NF1 inactivation, extensive copy number alterations, including complete deletion of CDKN2A/B , and a mutational signature consistent with homologous recombination deficiency, in the absence of canonical BRAF mutations. While the final diagnostic interpretation was primarily guided by histopathological features and aggressive clinical behavior, the molecular profile provided important biological context for the unusually rapid progression and diffuse leptomeningeal dissemination observed. Conclusion : This case highlights the diagnostic complexity of rare high-grade neuroepithelial tumors at the interface of APXA and eGBM and underscores the value of integrated molecular analysis in biologically aggressive and diagnostically ambiguous cases. Our identification of a deleterious germline FANCA variant suggests a potential role of genetic predisposition like DNA repair defects as biological modifiers that may contribute to genomic instability, tumor aggressiveness, and malignant evolution, particularly in BRAF -negative tumors.