Radiological, clinical, and molecular analyses reveal distinct subtypes of butterfly glioblastomas affecting the prognosis.

Background: Glioblastoma (GB) is known for its highly invasive nature. Images of butterfly GB (bGB) often illustrate this characteristic, but the molecular background and origins of bGB remain unknown.

Methods: We analyzed a cohort of 34 bGB patients from our dataset (K-cohort) and 46 bGB patients from publicly available datasets, including TCGA-GBM, CPTAC-GBM, IvyGAP, and UPENN-GBM.

Results: In the K-cohort, the median age was 66 years, and molecular analyses revealed TERT promoter mutations in 55.9% of cases, with no cases exhibiting H3F3A, HIST1H3B, or BRAF mutations. Sequential radiological imaging from the K-cohort provided unique insights, showing one case originating in the corpus callosum (CC) and 3 cases originating in the cerebral hemisphere before developing into bGB. Multi-regional sampling supported a mutational trajectory from the hemisphere to the CC. These observations indicate the presence of 2 distinct radiological origins for bGB. Consequently, we classified cases into CC-type and Hemispheric-type based on the tumor volume ratio within the CC. This subgrouping was clinically meaningful; the CC-type is an independent poor prognostic factor for overall survival, with a hazard ratio of 1.8 (95% confidence interval 1.1-3.0, P = .033), and is molecularly distinct by a higher frequency of methylated MGMTp (P = .0039) compared to the Hemispheric-type.

Conclusions: Our results highlight that the radiological features of bGB are not homogenous and can indicate 2 potential subtypes based on their origins. Further studies are mandatory, but CC-type and Hemispheric-type exhibit distinct clinical backgrounds, outcomes, and molecular features.