Predicting Metastatic Risk from Primary Tissue Architecture via Distance-Aware Spatial Modeling

Sandesh Pokhrel, Hamid Manoochehri, Bodong Zhang, Beatrice S Knudsen, Tolga Tasdizen

Predicting the risk of distant metastasis from primary tumor tissue histology is a critical yet challenging task in computational pathology. Multiple Instance Learning (MIL) approaches can attend to subdomains in tumor regions that harbor features of metastatic cancer progression. However MIL models treat tissue patches as unordered bags, discarding the spatial layout that defines the metastatic potential. We propose that metastatic risk is inherently dictated by the geometric arrangement of the tumor microenvironment at the interface with tumor cells. Our model is designed to explicitly capture the spatial relationships between tumor cells, tumor associated fibroblasts and infiltrating lymphocytes. For this purpose, we propose Distance aware Tissue Modeling for Multiple Instance Learning(DTMf-MIL), a novel method that reinforces visual features with explicit spatial priors. By computing signed distance functions (SDF) relative to tissue phenotypes, our model learns to recognize structural signatures of metastatic risk. This geometric awareness translates directly to superior clinical performance as DTMf-MIL significantly outperforms state-of-the-art methods that ignore spatial layout on metastasis prediction from tissue in the primary tumor. We further validate our approach on public benchmarks, demonstrating that spatial awareness consistently improves diagnostic accuracy across diverse clinical tasks.