Clinical characterization of patients with molecular glioblastoma.

Abstract

e14074 Background: Glioblastoma (GBM) represents a highly aggressive type of WHO grade 4 intracranial tumor with a median survival of 12-15 months, ranging from 10-24 months. Our understanding of the molecular features of these tumors and their impact on treatment response and overall survival (OS) has been evolving. Here, we describe the clinical characterization of molecular glioblastoma (mol-GBM), a newly described subset of IDH-wildtype and H3-wildtype gliomas that harbor at least one diagnostic molecular alteration (EGFR amplification, pTERT mutation, +7/-10 chromosomal alterations) in the absence of WHO grade 4 histological features (necrosis and/or microvascular proliferation). Methods: A retrospective chart review of patients diagnosed with GBM seen at MedStar Georgetown University Hospital between 2021 and 2025 was conducted. Clinical and diagnostic data were reviewed. OS was determined. Results: Of the 347 charts reviewed, 281 met WHO 2021 GBM criteria. 19 patients (7%; 6 male/13 female) fit criteria for mol-GBM, with average age at diagnosis of 66 years (range 43-80). Thirteen patients had supratentorial involvement affecting ≥ 2 lobes, 3 patients had brainstem lesions, and 3 patients had unilobar tumors. MRI showed non-enhancing (15/19) or minimally enhancing lesions (4/19), with infiltrative homogenous FLAIR hyperintensity and mass effect in 13/19 cases. Thirteen patients underwent biopsy; 6 had resection. Histopathology revealed diffusely infiltrating astrocytic neoplasms of variable cellularity and without grade 4 histologic features. Ki-67 proliferation index ranged from 1-30%. Molecular features diagnostic of mol-GBM were pTERT (17/19), EGFR amplification (2/19), and +7/-10 chromosomal alteration (8/19). Mol-GBM diagnosis was further supported in 4 cases by DNA methylation profiling. Common additional mutations included PTEN (10/19), EGFR (6/19) and NF1 (5/19). No tumors harbored PIK3R1 alterations. Three patients had tumors with PIK3CA pathogenic mutations. Thirteen of 15 patients had unmethylated MGMT. Ten patients started concomitant chemoradiation, 2 discontinued due to side effects. Average time from symptom onset to diagnosis was 4.3 months, and from surgery to start of radiation was 30.9 weeks. Median OS of 14 patients was 15.6 months; mean OS: 18.3 months; range: 1-78 months. Six patients are still alive. Conclusions: Our cohort showed no meaningful difference in OS between patients with mol-GBM and histologically diagnosed GBM. We found that our mol-GBM cases uniformly lacked the typical high-gradeMRI characteristics and had histopathologic features suggestive of low-grade glioma, despite aggressive clinical behavior and poor prognosis, emphasizing the importance of recognizing this diagnostic consideration. Additional research is needed to further define this intriguing GBM subset and to determine the appropriate management of patients with this disease.