Explainable AI for computational pathology identifies model limitations and tissue biomarkers.

Introduction: Deep learning models hold great promise for digital pathology, but their opaque decision-making processes undermine trust and hinder clinical adoption. Explainable AI methods are essential to enhance model transparency and reliability. Methods: We developed HIPPO, an explainable AI framework that systematically modifies tissue regions in whole slide images to generate image counterfactuals, enabling quantitative hypothesis testing, bias detection, and model evaluation beyond traditional performance metrics. HIPPO was applied to a variety of clinically important tasks, including breast metastasis detection in axillary lymph nodes, prognostication in breast cancer and melanoma, and Results: In metastasis detection, HIPPO uncovered critical model limitations that were undetectable by standard performance metrics or attention-based methods. For prognostic prediction, HIPPO outperformed attention by providing more nuanced insights into tissue elements influencing outcomes. In a proof-of-concept study, HIPPO facilitated hypothesis generation for identifying melanoma patients who may benefit from immunotherapy. In Conclusions: HIPPO expands the explainable AI toolkit for computational pathology by enabling deeper insights into model behavior. This framework supports the trustworthy development, deployment, and regulation of weakly-supervised models in clinical and research settings, promoting their broader adoption in digital pathology.