Xitong Ling

Xitong Ling, Minxi Ouyang, Yizhi Wang et al. · tsinghua

Histopathology analysis is the gold standard for medical diagnosis. Accurate classification of whole slide images (WSIs) and region-of-interests (ROIs) localization can assist pathologists in diagnosis. The gigapixel resolution of WSI and the absence of fine-grained annotations make direct classification and analysis challenging. In weakly supervised learning, multiple instance learning (MIL) presents a promising approach for WSI classification. The prevailing strategy is to use attention mechanisms to measure instance importance for classification. However, attention mechanisms fail to capture inter-instance information, and self-attention causes quadratic computational complexity. To address these challenges, we propose AMD-MIL, an agent aggregator with a mask denoise mechanism. The agent token acts as an intermediate variable between the query and key for computing instance importance. Mask and denoising matrices, mapped from agents-aggregated value, dynamically mask low-contribution representations and eliminate noise. AMD-MIL achieves better attention allocation by adjusting feature representations, capturing micro-metastases in cancer, and improving interpretability. Extensive experiments on CAMELYON-16, CAMELYON-17, TCGA-KIDNEY, and TCGA-LUNG show AMD-MIL's superiority over state-of-the-art methods.

Mingxi Ouyang, Yuqiu Fu, Renao Yan et al. · tsinghua

Recent advancements in computational pathology and artificial intelligence have significantly improved whole slide image (WSI) classification. However, the gigapixel resolution of WSIs and the scarcity of manual annotations present substantial challenges. Multiple instance learning (MIL) is a promising weakly supervised learning approach for WSI classification. Recently research revealed employing pseudo bag augmentation can encourage models to learn various data, thus bolstering models' performance. While directly inheriting the parents' labels can introduce more noise by mislabeling in training. To address this issue, we translate the WSI classification task from weakly supervised learning to semi-weakly supervised learning, termed SWS-MIL, where adaptive pseudo bag augmentation (AdaPse) is employed to assign labeled and unlabeled data based on a threshold strategy. Using the "student-teacher" pattern, we introduce a feature augmentation technique, MergeUp, which merges bags with low-priority bags to enhance inter-category information, increasing training data diversity. Experimental results on the CAMELYON-16, BRACS, and TCGA-LUNG datasets demonstrate the superiority of our method over existing state-of-the-art approaches, affirming its efficacy in WSI classification.

Xitong Ling, Yuanyuan Lei, Jiawen Li et al.

Advances in optical microscopy scanning have significantly contributed to computational pathology (CPath) by converting traditional histopathological slides into whole slide images (WSIs). This development enables comprehensive digital reviews by pathologists and accelerates AI-driven diagnostic support for WSI analysis. Recent advances in foundational pathology models have increased the need for benchmarking tasks. The Camelyon series is one of the most widely used open-source datasets in computational pathology. However, the quality, accessibility, and clinical relevance of the labels have not been comprehensively evaluated. In this study, we reprocessed 1,399 WSIs and labels from the Camelyon-16 and Camelyon-17 datasets, removing low-quality slides, correcting erroneous labels, and providing expert pixel annotations for tumor regions in the previously unreleased test set. Based on the sizes of re-annotated tumor regions, we upgraded the binary cancer screening task to a four-class task: negative, micro-metastasis, macro-metastasis, and Isolated Tumor Cells (ITC). We reevaluated pre-trained pathology feature extractors and multiple instance learning (MIL) methods using the cleaned dataset, providing a benchmark that advances AI development in histopathology.

Jiawen Li, Jiali Hu, Xitong Ling et al.

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 such as immunohistochemistry (IHC) and special stains are also frequently used in clinical practice. PFMs pre-trained mainly on H\&E-stained images may be limited in clinical applications involving these non-H\&E images. To address this issue, we propose StainNet, a collection of self-supervised foundation models specifically trained for IHC and special stains in pathology images based on the vision transformer (ViT) architecture. StainNet contains a ViT-Small and a ViT-Base model, both of which are trained using a self-distillation SSL approach on over 1.4 million patch images extracted from 20,231 publicly available IHC and special staining WSIs in the HISTAI database. To evaluate StainNet models, we conduct experiments on three in-house slide-level IHC classification tasks, three in-house ROI-level special stain and two public ROI-level IHC classification tasks to demonstrate their strong ability. We also perform ablation studies such as few-ratio learning and retrieval evaluations, and compare StainNet models with recent larger PFMs to further highlight their strengths. The StainNet model weights are available at https://github.com/WonderLandxD/StainNet.

Minxi Ouyang, Lianghui Zhu, Yaqing Bao et al.

Multimodal large models have shown great potential in automating pathology image analysis. However, current multimodal models for gastrointestinal pathology are constrained by both data quality and reasoning transparency: pervasive noise and incomplete annotations in public datasets predispose vision language models to factual hallucinations when generating diagnostic text, while the absence of explicit intermediate reasoning chains renders the outputs difficult to audit and thus less trustworthy in clinical practice. To address these issues, we construct a large scale gastrointestinal pathology dataset containing both microscopic descriptions and diagnostic conclusions, and propose a prompt argumentation strategy that incorporates lesion classification and anatomical site information. This design guides the model to better capture image specific features and maintain semantic consistency in generation. Furthermore, we employ a post training pipeline that combines supervised fine tuning with Group Relative Policy Optimization (GRPO) to improve reasoning quality and output structure. Experimental results on real world pathology report generation tasks demonstrate that our approach significantly outperforms state of the art open source and proprietary baselines in terms of generation quality, structural completeness, and clinical relevance. Our solution outperforms state of the art models with 18.7% higher clinical relevance, 32.4% improved structural completeness, and 41.2% fewer diagnostic errors, demonstrating superior accuracy and clinical utility compared to existing solutions.

Chen Zhang, Yilu An, Ying Chen et al.

Spatial Transcriptomics (ST) merges the benefits of pathology images and gene expression, linking molecular profiles with tissue structure to analyze spot-level function comprehensively. Predicting gene expression from histology images is a cost-effective alternative to expensive ST technologies. However, existing methods mainly focus on spot-level image-to-gene matching but fail to leverage the full hierarchical structure of ST data, especially on the gene expression side, leading to incomplete image-gene alignment. Moreover, a challenge arises from the inherent information asymmetry: gene expression profiles contain more molecular details that may lack salient visual correlates in histological images, demanding a sophisticated representation learning approach to bridge this modality gap. We propose HyperST, a framework for ST prediction that learns multi-level image-gene representations by modeling the data's inherent hierarchy within hyperbolic space, a natural geometric setting for such structures. First, we design a Multi-Level Representation Extractors to capture both spot-level and niche-level representations from each modality, providing context-aware information beyond individual spot-level image-gene pairs. Second, a Hierarchical Hyperbolic Alignment module is introduced to unify these representations, performing spatial alignment while hierarchically structuring image and gene embeddings. This alignment strategy enriches the image representations with molecular semantics, significantly improving cross-modal prediction. HyperST achieves state-of-the-art performance on four public datasets from different tissues, paving the way for more scalable and accurate spatial transcriptomics prediction.

Yizhi Wang, Li Chen, Qiang Huang et al.

Cervical cancer remains a major malignancy, necessitating extensive and complex histopathological assessments and comprehensive support tools. Although deep learning shows promise, these models still lack accuracy and generalizability. General foundation models offer a broader reach but remain limited in capturing subspecialty-specific features and task adaptability. We introduce the Cervical Subspecialty Pathology (CerS-Path) diagnostic system, developed through two synergistic pretraining stages: self-supervised learning on approximately 190 million tissue patches from 140,000 slides to build a cervical-specific feature extractor, and multimodal enhancement with 2.5 million image-text pairs, followed by integration with multiple downstream diagnostic functions. Supporting eight diagnostic functions, including rare cancer classification and multimodal Q&A, CerS-Path surpasses prior foundation models in scope and clinical applicability. Comprehensive evaluations demonstrate a significant advance in cervical pathology, with prospective testing on 3,173 cases across five centers maintaining 99.38% screening sensitivity and excellent generalizability, highlighting its potential for subspecialty diagnostic translation and cervical cancer screening.

Lianghui Zhu, Xitong Ling, Minxi Ouyang et al.

Gastrointestinal (GI) diseases represent a clinically significant burden, necessitating precise diagnostic approaches to optimize patient outcomes. Conventional histopathological diagnosis suffers from limited reproducibility and diagnostic variability. To overcome these limitations, 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 over 353 million multi-scale images from 210,043 H&E-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, protein expression status prediction, gene mutation prediction, and prognosis evaluation. We further translate the intelligent screening module for early GI cancer and achieve near-perfect 99.70% sensitivity across nine independent medical institutions. This work not only advances AI-driven precision pathology for GI diseases but also bridge critical gaps in histopathological practice.

Xitong Ling, Yifeng Ping, Jiawen Li et al.

Multiple Instance Learning (MIL) plays a significant role in computational pathology, enabling weakly supervised analysis of Whole Slide Image (WSI) datasets. The field of WSI analysis is confronted with a severe long-tailed distribution problem, which significantly impacts the performance of classifiers. Long-tailed distributions lead to class imbalance, where some classes have sparse samples while others are abundant, making it difficult for classifiers to accurately identify minority class samples. To address this issue, we propose an ensemble learning method based on MIL, which employs expert decoders with shared aggregators and consistency constraints to learn diverse distributions and reduce the impact of class imbalance on classifier performance. Moreover, we introduce a multimodal distillation framework that leverages text encoders pre-trained on pathology-text pairs to distill knowledge and guide the MIL aggregator in capturing stronger semantic features relevant to class information. To ensure flexibility, we use learnable prompts to guide the distillation process of the pre-trained text encoder, avoiding limitations imposed by specific prompts. Our method, MDE-MIL, integrates multiple expert branches focusing on specific data distributions to address long-tailed issues. Consistency control ensures generalization across classes. Multimodal distillation enhances feature extraction. Experiments on Camelyon+-LT and PANDA-LT datasets show it outperforms state-of-the-art methods.

Jiawen Li, Tian Guan, Qingxin Xia et al.

Foundation models have revolutionized the paradigm of digital pathology, as they leverage general-purpose features to emulate real-world pathological practices, enabling the quantitative analysis of critical histological patterns and the dissection of cancer-specific signals. However, these static general features constrain the flexibility and pathological relevance in the ever-evolving needs of clinical applications, hindering the broad use of the current models. Here we introduce PathFiT, a dynamic feature learning method that can be effortlessly plugged into various pathology foundation models to unlock their adaptability. Meanwhile, PathFiT performs seamless implementation across diverse pathology applications regardless of downstream specificity. To validate PathFiT, we construct a digital pathology benchmark with over 20 terabytes of Internet and real-world data comprising 28 H\&E-stained tasks and 7 specialized imaging tasks including Masson's Trichrome staining and immunofluorescence images. By applying PathFiT to the representative pathology foundation models, we demonstrate state-of-the-art performance on 34 out of 35 tasks, with significant improvements on 23 tasks and outperforming by 10.20% on specialized imaging tasks. The superior performance and versatility of PathFiT open up new avenues in computational pathology.