# Biological Spatial Priors Regularize Foundation Model Representations for Cross-Site MSI Generalization in Colorectal Cancer

arXiv: https://arxiv.org/abs/2605.02660 · HTML: https://mlsanity.com/paper/2605.02660/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 10 of its 33 references that are in the map.
- First posted on arXiv 4 May 2026.

## Builds on (most cited first, 10 of 10)

- [Attention-based Deep Multiple Instance Learning](https://mlsanity.com/paper/1802.04712/) (2018)
- [Data Efficient and Weakly Supervised Computational Pathology on Whole Slide Images](https://mlsanity.com/paper/2004.09666/) (2020)
- [Scaling Vision Transformers to Gigapixel Images via Hierarchical Self-Supervised Learning](https://mlsanity.com/paper/2206.02647/) (2022)
- [DTFD-MIL: Double-Tier Feature Distillation Multiple Instance Learning for Histopathology Whole Slide Image Classification](https://mlsanity.com/paper/2203.12081/) (2022)
- [Quantifying the effects of data augmentation and stain color normalization in convolutional neural networks for computational pathology](https://mlsanity.com/paper/1902.06543/) (2019)
- [Deep neural network models for computational histopathology: A survey](https://mlsanity.com/paper/1912.12378/) (2019)
- [PanNuke Dataset Extension, Insights and Baselines](https://mlsanity.com/paper/2003.10778/) (2020)
- [Automated Gleason Grading of Prostate Biopsies using Deep Learning](https://mlsanity.com/paper/1907.07980/) (2019)
- [Deep learning-based survival prediction for multiple cancer types using histopathology images](https://mlsanity.com/paper/1912.07354/) (2019)
- [A General-Purpose Self-Supervised Model for Computational Pathology](https://mlsanity.com/paper/2308.15474/) (2023)

## Abstract (arXiv)

Predicting microsatellite instability (MSI) status from routine hematoxylin and eosin (H&E) whole slide images (WSIs) offers a practical alternative to molecular testing, but models trained at one institution tend to generalize poorly to slides acquired at a different site. Foundation model representations, despite their generality, still encode site-specific texture alongside the conserved biological morphology underlying MSI. We investigate whether tile-level spatial priors derived from known MSI histology can guide these representations toward more site-invariant features. We introduce a biologically motivated spatial prior based on peripheral distance encoding, reflecting the Crohn's-like peripheral lymphocytic reaction at the tumor invasive margin, and evaluate a secondary local immune neighborhood encoding reflecting the lymphocyte-to-tumor ratio in each tile's immediate spatial neighborhood. Both priors are injected into a TransMIL aggregator before self-attention, allowing the transformer to integrate spatial biological context with UNI2-h or Virchow2 features across all attention layers. We evaluate six foundation model and MIL aggregator combinations as a reference, then assess the effect of each spatial prior. Training on TCGA-COAD (137 slides) and evaluating externally on TCGA-READ (50 slides) without retraining, peripheral distance encoding achieves MSI AUC 0.959 +/- 0.012 on COAD and MSS specificity 1.000 on READ, compared to 0.957 and 0.939 for the strongest reference configuration. Local immune neighborhood encoding achieves comparable internal AUC but lower cross-site specificity, suggesting margin proximity encodes a more site-invariant biological signal than local immune density. Results suggest biologically grounded spatial priors act as regularizers that reduce reliance on site-specific imaging patterns.