PATH-23. A wolf in sheep’s clothing: molecular glioblastoma defined by p-TERT mutation

Abstract Subsets of glioblastoma (GBM) defined by unique molecular features may affect tumor biology, influence treatment response, and ultimately determine overall survival (OS). While the heterogeneous molecular profile of GBM is well-established, clinical characterization of molecular GBM defined solely by pTERT mutation (pTERT-GBM) has not been well-described. A retrospective chart review of patients diagnosed with pTERT-GBM seen at MGUH between 2021 and 2025 was conducted. Clinical and diagnostic data were reviewed. OS was determined. We reviewed 347 charts. Of the 20 molecular GBM, 9 patients (5 male/4 female) met criteria for pTERT-GBM. Average age at diagnosis was 64 years (range 43-78 years). Eight patients had supratentorial involvement affecting ≥2 lobes. One patient had a brainstem lesion. MRI uniformly showed non-enhancing lesions with infiltrative homogenous FLAIR hyperintensity and mass effect. All patients underwent biopsy. Histopathology revealed diffusely infiltrating astrocytic neoplasms with Ki-67 of 1-30%. All tumors harbored the TERT c.-124C>T pathogenic variant. Common additional mutations included PTEN (4), EGFR (4) and NF1 (3). None harbored PIK3R1, but two had a PIK3CA pathogenic mutation. Out of eight tumors, 6 were MGMT unmethylated. Five patients started concomitant chemoradiation, 2 prematurely discontinued due to side effects. Average time from symptom onset to diagnosis was 7.5 months, and from surgery to start of radiation was 9.5 weeks. Mean OS including 7 patients was 14.3 months (1-33 months). Three patients are still alive. Our small cohort of pTERT-GBM cases demonstrated largely uniform MRI findings without typical high-grade imaging characteristics, along with histopathologic features suggestive of low-grade glioma—despite aggressive clinical behavior and poor prognosis—emphasizing the importance of recognizing this diagnostic consideration. A multidisciplinary approach in a comprehensive brain tumor center can improve access to timely diagnosis and appropriate treatment of glioma patients. Additional research is needed to further define this intriguing GBM subset.