Glioblastoma beyond the Brain: A Case Series Demonstrating Systemic Metastatic Potential

Glioblastoma (GBM) is an aggressive primary brain tumor that rarely metastasizes outside the central nervous system, with reported rates of extracranial dissemination below 2%. Increasing survival and improved diagnostic capabilities may contribute to more frequent detection of this phenomenon.

We describe a retrospective case series of 3 consecutive patients with histopathologically confirmed IDH-wild-type GBM who developed extracranial metastases at our institution. Clinical, radiological, pathological, and molecular data were extracted from medical records. Histopathological confirmation of metastatic disease was achieved in 2 of three patients, and an independent second-opinion pathology review was obtained for 1 case. Patient 1 (55-year-old man) developed cervical lymph node metastasis within 6 months of initial resection despite MGMT promoter methylation; the recurrent tumor contained a primitive neuroectodermal tumor-like component, immunophenotypically supported by diffuse Ki-67 positivity (∼100%) and expression of synaptophysin, chromogranin, CD56, and NSE. Patient 2 (56-year-old man) developed rapid systemic dissemination to bone, lung, liver, and the interatrial septum approximately 18 months after diagnosis; the metastatic tumor displayed mesenchymal (gliosarcoma-like) differentiation with co-expression of GFAP, SMA, and h-caldesmon, PD-L1 SP263 CPS 10/TPS 10%, retained mismatch-repair proteins, and a clinically significant TP53 c.833C>G (p.Pro278Arg) mutation identified by NGS. Patient 3 (48-year-old woman) survived 61 months despite unfavorable molecular markers, with late leptomeningeal and multiorgan dissemination. Overall survival was 8, 22, and 61 months for patients 1, 2 and 3, respectively.

This series illustrates three distinct biological trajectories of extracranial GBM dissemination and supports the concept that prolonged survival, repeated surgical interventions, and specific molecular features (mesenchymal differentiation, PD-L1 expression, TP53 mutation) may unmask systemic metastatic potential in IDH-wild-type GBM. Clinicians should maintain a high index of suspicion for extracranial dissemination in long-term GBM survivors and in patients with atypical systemic symptoms; targeted use of whole-body 18F-FDG PET/CT and histopathological confirmation of suspicious lesions are essential for accurate diagnosis.