Prototype Instance-semantic Disentanglement with Low-rank Regularized Subspace Clustering for WSIs Explainable Recognition

Digital pathology has fundamentally altered diagnostic workflows by enabling the computational analysis of gigapixel Whole Slide Images (WSIs), yet effectively deciphering their complex tumor microenvironments remains a formidable challenge. Existing Multiple Instance Learning (MIL) frameworks typically treat Whole Slide Images as unstructured bags of patches, discarding critical morphological semantics and spatial geometry. This lack of inductive bias often leads to overfitting on background noise and fails to align visual features with high-level diagnostic knowledge. To overcome these limitations, we propose the Hierarchical Prototype-based Domain Priors (HPDP) framework, a unified multimodal approach for joint histopathology diagnosis and prognosis. HPDP mitigates the data-driven "black box" issue by introducing a Morphologically Anchored Prototype System (MAPS), which anchors learning to interpretable morphological clusters, and a Sinusoidal Positional Encoder (SPE) to explicitly model tissue architecture. Furthermore, we bridge the semantic gap via a Hierarchical Cross-Modal Alignment (HCMA) module, using Large Language Model (LLM)-generated descriptions to contextually refine visual representations. Extensive experiments across seven cancer cohorts demonstrate that HPDP consistently achieves state-of-the-art performance with superior robustness and interpretability.

Whole slide images (WSIs) are the gold standard for pathological diagnosis and sub-typing. Current main-stream two-step frameworks employ offline feature encoders trained without domain-specific knowledge. Among them, attention-based multiple instance learning (MIL) methods are outcome-oriented and offer limited interpretability. Clustering-based approaches can provide explainable decision-making process but suffer from high dimension features and semantically ambiguous centroids. To this end, we propose an end-to-end MIL framework that integrates Grassmann re-embedding and manifold adaptive clustering, where the manifold geometric structure facilitates robust clustering results. Furthermore, we design a prior knowledge guiding proxy instance labeling and aggregation strategy to approximate patch labels and focus on pathologically relevant tumor regions. Experiments on multicentre WSI datasets demonstrate that: 1) our cluster-incorporated model achieves superior performance in both grading accuracy and interpretability; 2) end-to-end learning refines better feature representations and it requires acceptable computation resources.

Multiple instance learning (MIL) has become a standard paradigm for whole slide image (WSI) analysis in digital pathology, as it enables slide-level prediction without dense annotations. Existing MIL methods typically rely on exhaustive extraction and encoding of high-resolution patches. However, this practice suffers from two critical limitations in real-world clinical settings: it struggles to capture global visual cues at lower magnifications, and incurs substantial computational overhead due to the massive number of high-resolution patches per slide. To address these limitations, we propose an efficient low-resolution multiple instance learning (LRMIL) framework that transfers high-resolution knowledge to low-resolution representations. LRMIL adopts a two-stage distillation strategy. First, patch-level cross-resolution distillation aligns low-resolution patch embeddings with high-resolution representations. Second, slide-level knowledge distillation trains a low-resolution student MIL model under both slide-level supervision and teacher guidance. At inference time, LRMIL operates exclusively on low-resolution patches, substantially reducing data preprocessing and computational cost. Extensive experiments on multiple WSI benchmarks demonstrate that LRMIL consistently outperforms state-of-the-art MIL methods while achieving more efficient inference. These results highlight LRMIL as a practical and scalable solution for WSI analysis in clinical pathology.