Cross-stain contrastive learning for paired immunohistochemistry and histopathology slide representation learning

Universal, transferable whole-slide image (WSI) representations are central to computational pathology. Incorporating multiple markers (e.g., immunohistochemistry, IHC) alongside H&E enriches H&E-based features with diverse, biologically meaningful information. However, progress is limited by the scarcity of well-aligned multi-stain datasets. Inter-stain Misalignment shifts corresponding tissue across slides, hindering consistent patch-level features and degrading slide-level embeddings. To address this, we curated a slide-level aligned, five-stain dataset (H&E, HER2, KI67, ER, PGR) to enable paired H&E-IHC learning and robust cross-stain representation. Leveraging this dataset, we propose Cross-Stain Contrastive Learning (CSCL), a two-stage pretraining framework: a lightweight adapter trained with patch-wise contrastive alignment to improve the compatibility of H&E features with corresponding IHC-derived contextual cues; and slide-level representation learning with Multiple Instance Learning (MIL), which uses a cross-stain attention fusion module to integrate stain-specific patch features and a crossstain global alignment module to enforce consistency among slide-level embeddings across different stains. Experiments on cancer subtype classification, IHC biomarker status classification, and survival prediction, show consistent gains by yielding high-quality, transferable H&E slide-level representations. The code and data are available at: https://github.com/lily-zyz/CSCL.