# Cross-Stain Contrastive Learning for Paired Immunohistochemistry and Histopathology Slide Representation Learning

arXiv: https://arxiv.org/abs/2512.03577 · HTML: https://mlsanity.com/paper/2512.03577/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 21 of its 41 references that are in the map.
- First posted on arXiv 3 Dec 2025.

## Builds on (most cited first, 21 of 21)

- [SuperGlue: Learning Feature Matching with Graph Neural Networks](https://mlsanity.com/paper/1911.11763/) (2019)
- [SuperPoint: Self-Supervised Interest Point Detection and Description](https://mlsanity.com/paper/1712.07629/) (2017)
- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [TransMIL: Transformer based Correlated Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2106.00908/) (2021)
- [Dual-stream Multiple Instance Learning Network for Whole Slide Image Classification with Self-supervised Contrastive Learning](https://mlsanity.com/paper/2011.08939/) (2020)
- [Scaling Vision Transformers to Gigapixel Images via Hierarchical Self-Supervised Learning](https://mlsanity.com/paper/2206.02647/) (2022)
- [Artificial Intelligence for Digital and Computational Pathology](https://mlsanity.com/paper/2401.06148/) (2023)
- [BCI: Breast Cancer Immunohistochemical Image Generation through Pyramid Pix2pix](https://mlsanity.com/paper/2204.11425/) (2022)
- [Attention-Challenging Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2311.07125/) (2023)
- [Multiple Instance Captioning: Learning Representations from Histopathology Textbooks and Articles](https://mlsanity.com/paper/2103.05121/) (2021)
- [Transcriptomics-guided Slide Representation Learning in Computational Pathology](https://mlsanity.com/paper/2405.11618/) (2024)
- [Predicting Axillary Lymph Node Metastasis in Early Breast Cancer Using Deep Learning on Primary Tumor Biopsy Slides](https://mlsanity.com/paper/2112.02222/) (2021)
- [Multistain Pretraining for Slide Representation Learning in Pathology](https://mlsanity.com/paper/2408.02859/) (2024)
- [Giga-SSL: Self-Supervised Learning for Gigapixel Images](https://mlsanity.com/paper/2212.03273/) (2022)
- [Prototype-Based Image Prompting for Weakly Supervised Histopathological Image Segmentation](https://mlsanity.com/paper/2503.12068/) (2025)
- [Multimodal Cancer Survival Analysis via Hypergraph Learning with Cross-Modality Rebalance](https://mlsanity.com/paper/2505.11997/) (2025)
- [ACROBAT -- a multi-stain breast cancer histological whole-slide-image data set from routine diagnostics for computational pathology](https://mlsanity.com/paper/2211.13621/) (2022)
- [RegWSI: Whole Slide Image Registration using Combined Deep Feature- and Intensity-Based Methods: Winner of the ACROBAT 2023 Challenge](https://mlsanity.com/paper/2404.13108/) (2024)
- [Hypergraph Tversky-Aware Domain Incremental Learning for Brain Tumor Segmentation with Missing Modalities](https://mlsanity.com/paper/2505.16809/) (2025)
- [Feature Re-calibration based Multiple Instance Learning for Whole Slide Image Classification](https://mlsanity.com/paper/2206.10878/) (2022)
- [Memory-Augmented Incomplete Multimodal Survival Prediction via Cross-Slide and Gene-Attentive Hypergraph Learning](https://mlsanity.com/paper/2506.19324/) (2025)

## Abstract (arXiv)

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 with a lightweight adapter trained using 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 cross-stain 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, yielding high-quality, transferable H&E slide-level representations. The code and data are available at https://github.com/lily-zyz/CSCL.