Comparison between molecular and histological IDH-wild-type glioblastoma and extensive subgroup analysis of IDH-wild-type astrocytic tumors without genomic glioblastoma-defining alterations

Purpose This study compares clinical characteristics and survival between molecular (MolGBM) and histological IDH -wild-type ( IDH -WT) glioblastoma (HistGBM), and further characterizes histological lower-grade IDH -WT astrocytic tumors without genomic GBM-defining alterations. Methods Adult patients with histologically lower-grade IDH- WT astrocytoma (WHO grade 2–3) and available tumor tissue were included. Tumors were classified according to the 2021 WHO Classification of CNS tumors. Biopsy-only cases were excluded. IDH1 and TERT promoter ( TERT p) mutations were analyzed via Sanger and whole-exome sequencing (WES). TERT p-WT tumors underwent WES and subsequent DNA methylation profiling. Clinical, molecular, and outcome data were collected. Results The cohort comprised 47 surgically resected histologically lower-grade IDH -WT astrocytic tumors. Thirty-nine fulfilled WHO 2021 criteria for MolGBM, mainly based on TERT p mutation ( n = 36), while eight lacked GBM-defining molecular alterations. Compared with HistGBM ( n = 54), MolGBM more frequently presented with seizures and showed a lower Ki-67 index. Median overall survival (OS) was 19.8 months in MolGBM and 14.6 months in HistGBM, without a significant difference in univariable analysis ( p = 0.11). Patients aged ≥ 60 years showed longer overall survival in the MolGBM group (17.9 vs. 12.3 months; p = 0.0079). In multivariable Cox regression adjusted for age, extent of resection, and completion of the Stupp regimen, MolGBM was independently associated with more favorable OS (HR 0.40, 95% CI 0.24–0.67, p = 0.0005). The eight tumors lacking GBM-defining alterations showed longer survival and marked diagnostic heterogeneity. Conclusion MolGBM showed comparable unadjusted OS but more favorable adjusted OS than HistGBM, supporting clinical and biological heterogeneity among molecularly defined IDH -WT diffuse glioma. IDH -WT, TERT p-WT lower-grade astrocytic tumors lacking GBM-defining alterations require comprehensive molecular characterization.