Case Report: The molecular profile of granular cell astrocytoma predicts aggressive clinical behavior, independent of morphology.

Granular cell astrocytoma (GCA) is a rare, morphologically distinct variant of IDH-wildtype glioblastoma that can appear deceptively low-grade yet behave aggressively. Its molecular features remain poorly defined, and no methylation-based classification has previously been reported. Two GCAs diagnosed in our clinical neuropathology department were described with the integration of clinical, intraoperative, histopathological, and molecular data, including DNA methylation profiling, a targeted next-generation sequencing panel, and, in one case, whole genome sequencing (WGS). The patients were aged 63 and 54 years old, respectively, both presenting with supratentorial tumors showing granular cell morphology. Case 1 showed a densely cellular tumor composed entirely of bland-appearing granular cells without a conventional astrocytic component. Case 2 showed low-grade granular cell areas transitioning into high-grade astrocytic regions with mitoses, microvascular proliferation, and necrosis. Despite these morphological differences, both cases matched the methylation class "Glioblastoma, IDH-wildtype, mesenchymal subtype" and shared molecular features typical of glioblastoma, including chromosome +7/-10 and CDKN2A/B deletion. Both patients harbored oncogenic NF1 variants. WGS in Case 2 also revealed homozygous MTAP loss and chromoanasynthesis on chromosome 9. Case 1 received Stupp protocol chemoradiotherapy, recurred after 3 months of treatment, and died 11 months after diagnosis. Case 2 has progressed with a new posterior fossa lesion while on adjuvant temozolomide. These cases demonstrate that GCAs span a morphological spectrum yet molecularly correspond to the mesenchymal subtype of IDH-wildtype glioblastoma. Integrated molecular testing is therefore essential for accurate diagnosis and for guiding clinical management, including consideration for potential clinical trial enrollment.