DeCo-MIL: Debiased Counterfactual Reasoning for Long-Tailed Whole Slide Image Analysis

Multiple instance learning (MIL) is widely used for weakly supervised whole slide image (WSI) analysis. However, under long-tailed distributions, MIL-based WSI analysis faces a nested dual long-tail: an inter-slide class long tail and an intra-slide long tail of instance-level discriminative evidence. The two long tails are coupled: tail classes have few training slides, while their limited diagnostic evidence is concentrated in a few patches and obscured by abundant within-bag redundancy. This coupling biases models toward head classes and degrades rare-class recognition. To address this, we propose DeCo-MIL for long-tailed WSI analysis, which jointly alleviates the nested dual long-tail through frequency-debiased counterfactual reasoning. For the inner long tail, DeCo-MIL clusters patches into tissue-morphology anchors, replaces each anchor with its matched normal prototype to perform a counterfactual intervention, and estimates its counterfactual contribution to the ground-truth class using class-frequency-corrected predictions. These contributions guide redundancy masking to preserve scarce discriminative instances. For the outer long tail, DeCo-MIL constructs anchor-stratified pseudo-bags from redundancy-reduced bags and combines tail-aware oversampling with consistency regularization, increasing effective supervision for tail classes while preserving tissue-morphology composition. Extensive experiments on three long-tailed WSI benchmarks demonstrate that DeCo-MIL achieves state-of-the-art performance in both tail-class recognition and overall classification.

ALICE: Learning a General-Purpose Pathology Foundation Model from Vision, Vision-Language, and Slide-Level Experts

Foundation models are reshaping computational pathology, yet their capabilities remain shaped by pretraining objectives, data sources, and spatial scales, fragmenting complementary expertise across separate backbones. Here we present ALICE, a unified foundation model trained through multi-stage agglomerative distillation that sequentially distills eight vision-only, vision-language, and slide-level teacher models into dedicated modules of a single backbone. ALICE is pretrained on 24,985,184 tile-level pathology images and 155,604 high-resolution images, and evaluated across 21 task scenarios, 96 downstream tasks, and 48 data sources, spanning region-of-interest tissue analysis, vision-language multimodal evaluation, and whole-slide clinical assessment. In all three evaluation settings, ALICE achieved the best average rank among task-matched pathology foundation models. These results demonstrate that agglomerative distillation can consolidate complementary capabilities from specialized models into a unified backbone for broad computational pathology applications. The model is available at https://github.com/WonderLandxD/ALICE.

To What Extent Do Token-Level Representations from Pathology Foundation Models Improve Dense Prediction?

Pathology foundation models (PFMs) have rapidly advanced and are becoming a common backbone for downstream clinical tasks, offering strong transferability across tissues and institutions. However, for dense prediction (e.g., segmentation), practical deployment still lacks a clear, reproducible understanding of how different PFMs behave across datasets and how adaptation choices affect performance and stability. We present PFM-DenseBench, a large-scale benchmark for dense pathology prediction, evaluating 17 PFMs across 18 public segmentation datasets. Under a unified protocol, we systematically assess PFMs with multiple adaptation and fine-tuning strategies, and derive insightful, practice-oriented findings on when and why different PFMs and tuning choices succeed or fail across heterogeneous datasets. We release containers, configs, and dataset cards to enable reproducible evaluation and informed PFM selection for real-world dense pathology tasks. Project Website: https://m4a1tastegood.github.io/PFM-DenseBench

HookMIL: Revisiting Context Modeling in Multiple Instance Learning for Computational Pathology

Multiple Instance Learning (MIL) has enabled weakly supervised analysis of whole-slide images (WSIs) in computational pathology. However, traditional MIL approaches often lose crucial contextual information, while transformer-based variants, though more expressive, suffer from quadratic complexity and redundant computations. To address these limitations, we propose HookMIL, a context-aware and computationally efficient MIL framework that leverages compact, learnable hook tokens for structured contextual aggregation. These tokens can be initialized from (i) key-patch visual features, (ii) text embeddings from vision-language pathology models, and (iii) spatially grounded features from spatial transcriptomics-vision models. This multimodal initialization enables Hook Tokens to incorporate rich textual and spatial priors, accelerating convergence and enhancing representation quality. During training, Hook tokens interact with instances through bidirectional attention with linear complexity. To further promote specialization, we introduce a Hook Diversity Loss that encourages each token to focus on distinct histopathological patterns. Additionally, a hook-to-hook communication mechanism refines contextual interactions while minimizing redundancy. Extensive experiments on four public pathology datasets demonstrate that HookMIL achieves state-of-the-art performance, with improved computational efficiency and interpretability. Codes are available at https://github.com/lingxitong/HookMIL.

StainNet: A Special Staining Self-Supervised Vision Transformer for Computational Pathology

Foundation models trained with self-supervised learning (SSL) on large-scale histological images have significantly accelerated the development of computational pathology. These models can serve as backbones for region-of-interest (ROI) image analysis or patch-level feature extractors in whole-slide images (WSIs) based on multiple instance learning (MIL). Existing pathology foundation models (PFMs) are typically pre-trained on Hematoxylin-Eosin (H&E) stained pathology images. However, images with special stains, such as immunohistochemistry, are also frequently used in clinical practice. PFMs pre-trained mainly on H\&E-stained images may be limited in clinical applications involving special stains. To address this issue, we propose StainNet, a specialized foundation model for special stains based on the vision transformer (ViT) architecture. StainNet adopts a self-distillation SSL approach and is trained on over 1.4 million patch images cropping from 20,231 publicly available special staining WSIs in the HISTAI database. To evaluate StainNet, we conduct experiments on an in-house slide-level liver malignancy classification task and two public ROI-level datasets to demonstrate its strong ability. We also perform few-ratio learning and retrieval evaluations, and compare StainNet with recently larger PFMs to further highlight its strengths. We have released the StainNet model weights at: https://huggingface.co/JWonderLand/StainNet.

Deep Pathomic Learning Defines Prognostic Subtypes and Molecular Drivers in Colorectal Cancer

Precise prognostic stratification of colorectal cancer (CRC) remains a major clinical challenge due to its high heterogeneity. The conventional TNM staging system is inadequate for personalized medicine. We aimed to develop and validate a novel multiple instance learning model TDAM-CRC using histopathological whole-slide images for accurate prognostic prediction and to uncover its underlying molecular mechanisms. We trained the model on the TCGA discovery cohort (n=581), validated it in an independent external cohort (n=1031), and further we integrated multi-omics data to improve model interpretability and identify novel prognostic biomarkers. The results demonstrated that the TDAM-CRC achieved robust risk stratification in both cohorts. Its predictive performance significantly outperformed the conventional clinical staging system and multiple state-of-the-art models. The TDAM-CRC risk score was confirmed as an independent prognostic factor in multivariable analysis. Multi-omics analysis revealed that the high-risk subtype is closely associated with metabolic reprogramming and an immunosuppressive tumor microenvironment. Through interaction network analysis, we identified and validated Mitochondrial Ribosomal Protein L37 (MRPL37) as a key hub gene linking deep pathomic features to clinical prognosis. We found that high expression of MRPL37, driven by promoter hypomethylation, serves as an independent biomarker of favorable prognosis. Finally, we constructed a nomogram incorporating the TDAM-CRC risk score and clinical factors to provide a precise and interpretable clinical decision-making tool for CRC patients. Our AI-driven pathological model TDAM-CRC provides a robust tool for improved CRC risk stratification, reveals new molecular targets, and facilitates personalized clinical decision-making.

SAC-MIL: Spatial-Aware Correlated Multiple Instance Learning for Histopathology Whole Slide Image Classification

We propose Spatial-Aware Correlated Multiple Instance Learning (SAC-MIL) for performing WSI classification. SAC-MIL consists of a positional encoding module to encode position information and a SAC block to perform full instance correlations. The positional encoding module utilizes the instance coordinates within the slide to encode the spatial relationships instead of the instance index in the input WSI sequence. The positional encoding module can also handle the length extrapolation issue where the training and testing sequences have different lengths. The SAC block is an MLP-based method that performs full instance correlation in linear time complexity with respect to the sequence length. Due to the simple structure of MLP, it is easy to deploy since it does not require custom CUDA kernels, compared to Transformer-based methods for WSI classification. SAC-MIL has achieved state-of-the-art performance on the CAMELYON-16, TCGA-LUNG, and TCGA-BRAC datasets. The code will be released upon acceptance.

Multimodal Prototype Alignment for Semi-supervised Pathology Image Segmentation

Pathological image segmentation faces numerous challenges, particularly due to ambiguous semantic boundaries and the high cost of pixel-level annotations. Although recent semi-supervised methods based on consistency regularization (e.g., UniMatch) have made notable progress, they mainly rely on perturbation-based consistency within the image modality, making it difficult to capture high-level semantic priors, especially in structurally complex pathology images. To address these limitations, we propose MPAMatch - a novel segmentation framework that performs pixel-level contrastive learning under a multimodal prototype-guided supervision paradigm. The core innovation of MPAMatch lies in the dual contrastive learning scheme between image prototypes and pixel labels, and between text prototypes and pixel labels, providing supervision at both structural and semantic levels. This coarse-to-fine supervisory strategy not only enhances the discriminative capability on unlabeled samples but also introduces the text prototype supervision into segmentation for the first time, significantly improving semantic boundary modeling. In addition, we reconstruct the classic segmentation architecture (TransUNet) by replacing its ViT backbone with a pathology-pretrained foundation model (Uni), enabling more effective extraction of pathology-relevant features. Extensive experiments on GLAS, EBHI-SEG-GLAND, EBHI-SEG-CANCER, and KPI show MPAMatch's superiority over state-of-the-art methods, validating its dual advantages in structural and semantic modeling.

Deformable Attention Graph Representation Learning for Histopathology Whole Slide Image Analysis

Accurate classification of Whole Slide Images (WSIs) and Regions of Interest (ROIs) is a fundamental challenge in computational pathology. While mainstream approaches often adopt Multiple Instance Learning (MIL), they struggle to capture the spatial dependencies among tissue structures. Graph Neural Networks (GNNs) have emerged as a solution to model inter-instance relationships, yet most rely on static graph topologies and overlook the physical spatial positions of tissue patches. Moreover, conventional attention mechanisms lack specificity, limiting their ability to focus on structurally relevant regions. In this work, we propose a novel GNN framework with deformable attention for pathology image analysis. We construct a dynamic weighted directed graph based on patch features, where each node aggregates contextual information from its neighbors via attention-weighted edges. Specifically, we incorporate learnable spatial offsets informed by the real coordinates of each patch, enabling the model to adaptively attend to morphologically relevant regions across the slide. This design significantly enhances the contextual field while preserving spatial specificity. Our framework achieves state-of-the-art performance on four benchmark datasets (TCGA-COAD, BRACS, gastric intestinal metaplasia grading, and intestinal ROI classification), demonstrating the power of deformable attention in capturing complex spatial structures in WSIs and ROIs.

Subspecialty-Specific Foundation Model for Intelligent Gastrointestinal Pathology

Gastrointestinal (GI) diseases represent a clinically significant burden, necessitating precise diagnostic approaches to optimize patient outcomes. Conventional histopathological diagnosis, heavily reliant on the subjective interpretation of pathologists, suffers from limited reproducibility and diagnostic variability. To overcome these limitations and address the lack of pathology-specific foundation models for GI diseases, we develop Digepath, a specialized foundation model for GI pathology. Our framework introduces a dual-phase iterative optimization strategy combining pretraining with fine-screening, specifically designed to address the detection of sparsely distributed lesion areas in whole-slide images. Digepath is pretrained on more than 353 million image patches from over 200,000 hematoxylin and eosin-stained slides of GI diseases. It attains state-of-the-art performance on 33 out of 34 tasks related to GI pathology, including pathological diagnosis, molecular prediction, gene mutation prediction, and prognosis evaluation, particularly in diagnostically ambiguous cases and resolution-agnostic tissue classification.We further translate the intelligent screening module for early GI cancer and achieve near-perfect 99.6% sensitivity across 9 independent medical institutions nationwide. The outstanding performance of Digepath highlights its potential to bridge critical gaps in histopathological practice. This work not only advances AI-driven precision pathology for GI diseases but also establishes a transferable paradigm for other pathology subspecialties.