Histomorphology-Guided Prototypical Multi-Instance Learning for Breast Cancer WSI Classification

Histomorphology is crucial in cancer diagnosis. However, existing whole slide image (WSI) classification methods struggle to effectively incorporate histomorphology information, limiting their ability to capture key pathological features. Particularly when the number of instances within a bag is large and their features are complex, it becomes challenging to accurately identify instances decisive for the bag label, making these methods prone to interference from ambiguous instances. To address this limitation, we propose a novel Histomorphology-Guided Prototypical Multi-Instance Learning (HGPMIL) framework that explicitly learns histomorphology-guided prototypical representations by incorporating tumor cellularity, cellular morphology, and tissue architecture. Specifically, our approach consists of three key components: (1) estimating the importance of tumor-related histomorphology information at patch-level based on medical prior knowledge; (2) generating representative prototypes through histomorphology-prototypical clustering; and (3) enabling WSI classification through histomorphology-guided prototypical aggregation. HGPMIL adjusts the decision boundary by incorporating histomorphological importance to reduce instance label uncertainty, thereby reversely optimizing the bag-level boundary. Experimental results demonstrate its effectiveness, achieving high diagnostic accuracy for molecular subtyping, cancer subtyping and survival analysis. The code will be made available at https://github.com/Badgewho/HMDMIL.