Histological grade 2 and non-contrast-enhancing phenotype provide prognostic information complementary to DNA methylation classification in TERTp-mutant molecular glioblastomas

Glioblastoma (GBM), IDH-wildtype, is the most common and aggressive primary brain tumor in adults. According to the 2021 WHO classification, IDH-wildtype diffuse gliomas with a TERT promoter (TERTp) mutation, EGFR amplification, or combined whole-chromosome 7 gain and 10 loss (+ 7/− 10) are designated as GBM, IDH-wildtype, regardless of histological grade, and termed molecular GBM (mol-GBM). Although this redefinition has been widely adopted, the prognostic implications of mol-GBM remain uncertain. To clarify its clinical relevance, we retrospectively analyzed adult patients treated at our institution between 2010 and 2024. We identified 22 cases of TERTp-mutant mol-GBM (grade 2, n = 7; grade 3, n = 15) and compared them with 218 cases of TERTp-mutant histologically confirmed GBM (hist-GBM). Overall survival (OS) was assessed using Kaplan–Meier analysis, log-rank test, and propensity score matching (PSM) adjusted for age, preoperative Karnofsky Performance Status, extent of resection, adjuvant therapy, and MGMT methylation status. Mol-GBM showed significantly longer OS than hist-GBM after PSM (p = 0.019), with grade 2 mol-GBM showing particularly favorable survival (p = 0.008). Cox regression analysis revealed mol-GBM as an independent predictor of good prognosis (hazard ratio: 0.37, 95% confidence interval: 0.22–0.62, p < 0.001). Across all TERTp-mutant GBMs, a non-contrast-enhancing (non-CE) MRI phenotype correlated with significantly longer OS than CE tumors, persisting after PSM (p = 0.004). Within mol-GBM, an isolated TERTp mutation did not stratify OS, whereas CDKN2A/B homozygous deletion predicted worse outcomes (p = 0.026). DNA methylation profiling classified most mol-GBM as GBM, IDH-wildtype methylation class, and all cases clustered with GBM on t-SNE, confirming molecular proximity to GBM. Integrated methylation and RNA-seq analysis revealed WIF-1 promoter hypermethylation with reduced expression in grade 3 cases. These findings suggest that histological grade 2 and the non-CE phenotype may provide exploratory prognostic information in TERTp-mutant mol-GBM, complementary to DNA methylation classification.