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

BackgroundGranular 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.MethodsTwo 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).ResultsThe 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.ConclusionThese 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.