Evaluating Computational Pathology Foundation Models for Prostate Cancer Grading under Distribution Shifts

Abstract

Pathology foundation models (PFMs) have emerged as powerful pretrained encoders for computational pathology, but their robustness under clinically relevant distribution shifts remains insufficiently understood. We benchmark the robustness of recent PFMs in the setting of prostate cancer grading from whole-slide images (WSIs). Using the PANDA dataset, we evaluate PFMs as frozen patch-level feature extractors within weakly supervised slide-level grading models, and assess robustness to two important forms of distribution shift: shifts in WSI image appearance across collection sites, and shifts in the label distribution over cancer grade groups. Across in-distribution settings, PFMs consistently achieve strong performance and clearly outperform a natural-image baseline. Under cross-site transfer from Radboud to Karolinska, however, performance drops substantially for all models, showing that large-scale pretraining alone does not guarantee robust downstream generalization. In contrast, PFMs are less sensitive to label-distribution shift, indicating that visually grounded domain shift is the dominant challenge. Representation analysis further supports these findings by revealing persistent domain separation between sites across all PFMs. While grade-related structure is present, it is comparatively weak, indicating that domain-related variation dominates in the learned feature space. Together, these results provide a comprehensive benchmark of PFMs under distribution shift and highlight an important practical message: although PFMs provide strong representations, generalizability remains constrained by the quality and diversity of the data used to train downstream prediction models.