Distinguishing Molecular and Histologic Glioblastomas Using Multiparametric MRI-Based Habitat Analysis

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Abstract
To explore how molecular glioblastoma (mol-GBM) differs from histological glioblastoma (hist-GBM) in tumor heterogeneity using multi-parametric physiologic MRI-based tumor habitat analysis. In this multi-institutional retrospective study, imaging data were collected from two tertiary centers: 13 mol-GBMs and 39 hist-GBMs from institution 1 (2007-2024) for habitat definition, model development, and internal validation and nine mol-GBMs were obtained from institution 2 (2020-2024) for external validation. The apparent diffusion coefficient (ADC; cellularity), relative cerebral blood volume (rCBV; vascularity), and volume transfer constant (Ktrans; permeability) were binarized into high/low categories, which yielded eight spatial habitat clusters to visualize tumor heterogeneity. Habitat proportions and intratumoral heterogeneity features were compared between groups. Multivariable logistic regression models incorporating habitat-derived features were developed to distinguish mol-GBM from hist-GBM, and their performance was evaluated. Fifty-two patients (hist-GBM, n = 39; mol-GBM, n = 13; mean age, 60.0 ± 11.1 years; 22 male) were evaluated. Habitat analysis revealed that mol-GBM had a significantly lower proportion of the most malignant habitat (cluster 3: low-ADC, high rCBV, high Ktrans; 0.80% vs. 7.0%, P < 0.001). The total proportion of high Ktrans habitats was markedly lower in the mol-GBM group (5.7% vs. 21.3%, P < 0.001). A habitat-based multivariable model incorporating tumor volume, cluster 3 proportion, high Ktrans proportion, and Shannon entropy achieved an area under receiver operating characteristic curve (AUC) of 0.87 (95% confidence interval [CI]: 0.73-0.97) at internal validation using a leave-one-out cross-validation, which was substantially greater, albeit nonsignificant, than the AUC for tumor size alone (0.70, 95% CI: 0.51-0.85, P = 0.057), with an external validation accuracy of 88.9% (8/9). Multiparametric physiologic MRI habitat analysis demonstrated differences in the tumor heterogeneity between mol-GBM and hist-GBM. Tumor permeability (Ktrans) was the most discriminating parameter. Incorporating habitat-derived features alongside tumor volume may improve the discrimination of the two subtypes on MRI analysis. Further studies, including more rigorous external validation, are warranted.
Funding Information
  • National Research Foundation of Korea (RS-2023-00251022)
  • Seoul National University Hospital (04-2024-0600)
  • Seoul National University Hospital (04-2025-2060)
  • Korea Health Industry Development Institute (RS-2024-00439549)

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