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

Abstract

Introduction: 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.

Case presentation: 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.

Conclusions: 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.