Extracranial subcutaneous metastasis of IDH-wildtype glioblastoma with divergent DNA methylation profiles: a case report

Background: Glioblastoma (GBM) typically remains confined to the central nervous system, and extracranial metastasis is exceedingly rare. When extracranial dissemination does occur, the molecular characteristics of extraneural tumor components relative to the parent GBM remain poorly characterized, particularly with respect to its epigenetic characterization. Case presentation: A 51-year-old man, who had undergone resection of a left frontal IDH-wildtype GBM seven months prior, presented with acute neurological deterioration. Imaging revealed a multi-compartment contrast-enhancing lesion involving subdural, subcutaneous, and intramuscular compartments along the previous surgical trajectory, but no recurrence at the site of original resection. Emergency craniotomy with tumor debulking was performed, and tissue samples were obtained from each anatomically distinct site. Histopathology confirmed high-grade glioma at all locations, with the Ki-67 proliferation index increased from approximately 30% to 60–80%. DNA methylation profiling revealed site-dependent epigenetic divergence: the primary tumor at initial diagnosis and all extracranial recurrence sites aligned with pediatric-type diffuse high-grade glioma signatures, whereas the intra-axial frontobasal recurrence shifted to IDH-wildtype GBM, mesenchymal subtype. MYC amplification was detected in the subdural and subcutaneous components but not in the intracranial or muscular compartments. Despite initial postoperative improvement, the patient experienced rapid disease progression and died within 30 days. Conclusion: This case illustrated that extracranial GBM spread along the surgical trajectory may be accompanied by site-dependent epigenetic divergence, with potential implications for the molecular characterization of recurrent glioblastoma.