AI-driven WHO 2021 classification of gliomas based only on H&E-stained slides.

Background: The WHO 2021 classification criteria for adult diffuse glioma integrate histology with molecular profiling for conclusive diagnosis. Since molecular profiling can be expensive and time-consuming, often necessitating outsourcing or leading to the 'not otherwise specified (NOS) label', this study develops an AI-driven WHO 2021 classification of gliomas solely from H&E whole-slide images (WSIs).

Methods: Our pipeline is based on a multi-institutional dataset reclassified per WHO 2021 guidelines. This dataset includes a) Primarily US based TCGA-GBM/TCGA-LGG (n=1,320) for model training, independently evaluated on two hold-out sets, b) Austria-based EBRAINS (n= 794) c) India-based IPD-Brain (n=304). Each WSI undergoes pre-processing followed by quantitative benchmarking across i) eight pathology foundation models, ii) nine aggregation methods, and (iii) 15 combinations of magnification levels through a late fusion approach. Model interpretability conducted through heatmaps highlights distinct, identifiable morphology features.

Results: Our best-performing combination of FM, AM, and multi-magnification achieved an AUC of 97.95% on the training cohort, 96.30% on EBRAINS (set 1), and 92.61% on IPD (set 2). The results yield the following key insights: (1) domain-specific FMs outperform ImageNet-based models, (2) AMs while theoretically promising yield larger performance improvements when used with ImageNet based feature extractor rather than FMs, and (3) Fusion of multiple magnifications adds value in performance.

Conclusion: Determining glioma diagnosis directly from H&E slides can obviate the need for molecular profiling, expedite conclusive diagnosis, and, hence, clinical decision-making. These findings motivate the development of advanced domain-relevant foundation models and the design of more adaptable slide-level aggregation techniques.