Cross-Modality Learning for Predicting Immunohistochemistry Biomarkers from Hematoxylin and Eosin–Stained Whole Slide Images

Hematoxylin and eosin (H&E) staining is a cornerstone of pathologic analysis, offering reliable visualization of cellular morphology and tissue architecture for cancer diagnosis, subtyping, and grading. Immunohistochemistry (IHC) staining provides insights by detecting specific proteins within tissues, enhancing diagnostic accuracy, and improving treatment planning. However, IHC staining is costly, time-consuming, and resource intensive, requiring specialized expertise. To address these limitations, this study proposes HistoStainAlign, a novel deep learning framework that predicts IHC staining patterns directly from H&E whole slide images. The framework integrates paired H&E and IHC embeddings through a contrastive training strategy, capturing complementary features across staining modalities without patch-level annotations or tissue registration. The model was evaluated on gastrointestinal and lung tissue whole slide images with three commonly used IHC stains: P53, programmed death ligand-1, and Ki-67. HistoStainAlign achieved weighted F1 scores of 0.735 (95% CI, 0.670-0.799), 0.830 (95% CI, 0.772-0.886), and 0.723 (95% CI, 0.607-0.836), respectively for these three IHC stains. Embedding analyses demonstrated the robustness of the contrastive alignment in capturing meaningful cross-stain relationships. Comparisons with a baseline model further highlight the advantage of incorporating contrastive learning for improved stain pattern prediction. This study demonstrates the potential of computational approaches to serve as a prescreening tool, helping prioritize cases for IHC staining and improving workflow efficiency.