Tian Guan

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.

Jiawen Li, Yuxuan Chen, Hongbo Chu et al.

Histopathological whole slide images (WSIs) classification has become a foundation task in medical microscopic imaging processing. Prevailing approaches involve learning WSIs as instance-bag representations, emphasizing significant instances but struggling to capture the interactions between instances. Additionally, conventional graph representation methods utilize explicit spatial positions to construct topological structures but restrict the flexible interaction capabilities between instances at arbitrary locations, particularly when spatially distant. In response, we propose a novel dynamic graph representation algorithm that conceptualizes WSIs as a form of the knowledge graph structure. Specifically, we dynamically construct neighbors and directed edge embeddings based on the head and tail relationships between instances. Then, we devise a knowledge-aware attention mechanism that can update the head node features by learning the joint attention score of each neighbor and edge. Finally, we obtain a graph-level embedding through the global pooling process of the updated head, serving as an implicit representation for the WSI classification. Our end-to-end graph representation learning approach has outperformed the state-of-the-art WSI analysis methods on three TCGA benchmark datasets and in-house test sets. Our code is available at https://github.com/WonderLandxD/WiKG.

Renao Yan, Qiehe Sun, Cheng Jin et al. · tsinghua

In computational pathology, whole-slide image (WSI) classification presents a formidable challenge due to its gigapixel resolution and limited fine-grained annotations. Multiple-instance learning (MIL) offers a weakly supervised solution, yet refining instance-level information from bag-level labels remains challenging. While most of the conventional MIL methods use attention scores to estimate instance importance scores (IIS) which contribute to the prediction of the slide labels, these often lead to skewed attention distributions and inaccuracies in identifying crucial instances. To address these issues, we propose a new approach inspired by cooperative game theory: employing Shapley values to assess each instance's contribution, thereby improving IIS estimation. The computation of the Shapley value is then accelerated using attention, meanwhile retaining the enhanced instance identification and prioritization. We further introduce a framework for the progressive assignment of pseudo bags based on estimated IIS, encouraging more balanced attention distributions in MIL models. Our extensive experiments on CAMELYON-16, BRACS, TCGA-LUNG, and TCGA-BRCA datasets show our method's superiority over existing state-of-the-art approaches, offering enhanced interpretability and class-wise insights. Our source code is available at https://github.com/RenaoYan/PMIL.

Qiehe Sun, Jiawen Li, Jin Xu et al.

Due to its superior efficiency in utilizing annotations and addressing gigapixel-sized images, multiple instance learning (MIL) has shown great promise as a framework for whole slide image (WSI) classification in digital pathology diagnosis. However, existing methods tend to focus on advanced aggregators with different structures, often overlooking the intrinsic features of H\&E pathological slides. To address this limitation, we introduced two pathological priors: nuclear heterogeneity of diseased cells and spatial correlation of pathological tiles. Leveraging the former, we proposed a data augmentation method that utilizes stain separation during extractor training via a contrastive learning strategy to obtain instance-level representations. We then described the spatial relationships between the tiles using an adjacency matrix. By integrating these two views, we designed a multi-instance framework for analyzing H\&E-stained tissue images based on pathological inductive bias, encompassing feature extraction, filtering, and aggregation. Extensive experiments on the Camelyon16 breast dataset and TCGA-NSCLC Lung dataset demonstrate that our proposed framework can effectively handle tasks related to cancer detection and differentiation of subtypes, outperforming state-of-the-art medical image classification methods based on MIL. The code will be released later.

Hongbo Chu, Qiehe Sun, Jiawen Li et al.

Histopathological whole slide image (WSI) analysis with deep learning has become a research focus in computational pathology. The current paradigm is mainly based on multiple instance learning (MIL), in which approaches with Transformer as the backbone are well discussed. These methods convert WSI tasks into sequence tasks by representing patches as tokens in the WSI sequence. However, the feature complexity brought by high heterogeneity and the ultra-long sequences brought by gigapixel size makes Transformer-based MIL suffer from the challenges of high memory consumption, slow inference speed, and lack of performance. To this end, we propose a retentive MIL method called RetMIL, which processes WSI sequences through hierarchical feature propagation structure. At the local level, the WSI sequence is divided into multiple subsequences. Tokens of each subsequence are updated through a parallel linear retention mechanism and aggregated utilizing an attention layer. At the global level, subsequences are fused into a global sequence, then updated through a serial retention mechanism, and finally the slide-level representation is obtained through a global attention pooling. We conduct experiments on two public CAMELYON and BRACS datasets and an public-internal LUNG dataset, confirming that RetMIL not only achieves state-of-the-art performance but also significantly reduces computational overhead. Our code will be accessed shortly.

Xinrui Chen, Haoli Bai, Tao Yuan et al.

Layer pruning has emerged as a widely used technique for compressing large language models (LLMs). However, existing layer pruning approaches often incur substantial performance degradation. We identify the majority of this degradation to a single yet previously overlooked issue: \textit{the mismatch of activation magnitudes at the pruning interface}. The pre-interface activations exhibit significantly different scales from the post-interface ones, causing the distributional shift as it propagates through the remaining layers. To address this issue, we introduce \textsc{LinearPatch}, a lightweight and plug-and-play technique that fuses two operations into one matrix multiply at the pruning interface: (i) a Hadamard transformation that suppresses massive outliers at particular tokens and (ii) a channel-wise scaling that aligns activation statistics. On LLaMA-3-8B, \textsc{LinearPatch} preserves up to \textbf{94.15\%} of the original model's performance when pruning 5 out of 32 layers, outperforming the previous state of the art by \textbf{4\%}. The patch can be further refined with 5K unlabeled samples via memory-efficient offline distillation, pushing the retention to 95.16\% within only 30 minutes on a single GPU. Code is available at https://github.com/chenxinrui-tsinghua/LinearPatch.

Qilai Zhang, Jiawen Li, Peiran Liao et al.

The two primary types of Hematoxylin and Eosin (H&E) slides in histopathology are Formalin-Fixed Paraffin-Embedded (FFPE) and Fresh Frozen (FF). FFPE slides offer high quality histopathological images but require a labor-intensive acquisition process. In contrast, FF slides can be prepared quickly, but the image quality is relatively poor. Our task is to translate FF images into FFPE style, thereby improving the image quality for diagnostic purposes. In this paper, we propose Diffusion-FFPE, a method for FF-to-FFPE histopathological image translation using a pre-trained diffusion model. Specifically, we utilize a one-step diffusion model as the generator, which we fine-tune using LoRA adapters within an adversarial learning framework. To enable the model to effectively capture both global structural patterns and local details, we introduce a multi-scale feature fusion module that leverages two VAE encoders to extract features at different image resolutions, performing feature fusion before inputting them into the UNet. Additionally, a pre-trained vision-language model for histopathology serves as the backbone for the discriminator, enhancing model performance. Our FF-to-FFPE translation experiments on the TCGA-NSCLC dataset demonstrate that the proposed approach outperforms existing methods. The code and models are released at https://github.com/QilaiZhang/Diffusion-FFPE.

Jiawen Li, Qiehe Sun, Renao Yan et al. · tsinghua

With the development of digital imaging in medical microscopy, artificial intelligent-based analysis of pathological whole slide images (WSIs) provides a powerful tool for cancer diagnosis. Limited by the expensive cost of pixel-level annotation, current research primarily focuses on representation learning with slide-level labels, showing success in various downstream tasks. However, given the diversity of lesion types and the complex relationships between each other, these techniques still deserve further exploration in addressing advanced pathology tasks. To this end, we introduce the concept of hierarchical pathological image classification and propose a representation learning called PathTree. PathTree considers the multi-classification of diseases as a binary tree structure. Each category is represented as a professional pathological text description, which messages information with a tree-like encoder. The interactive text features are then used to guide the aggregation of hierarchical multiple representations. PathTree uses slide-text similarity to obtain probability scores and introduces two extra tree specific losses to further constrain the association between texts and slides. Through extensive experiments on three challenging hierarchical classification datasets: in-house cryosectioned lung tissue lesion identification, public prostate cancer grade assessment, and public breast cancer subtyping, our proposed PathTree is consistently competitive compared to the state-of-the-art methods and provides a new perspective on the deep learning-assisted solution for more complex WSI classification.

Xiuyuan Chen, Tao Sun, Dexin Su et al.

Current benchmarks for AI clinician systems, often based on multiple-choice exams or manual rubrics, fail to capture the depth, robustness, and safety required for real-world clinical practice. To address this, we introduce the GAPS framework, a multidimensional paradigm for evaluating \textbf{G}rounding (cognitive depth), \textbf{A}dequacy (answer completeness), \textbf{P}erturbation (robustness), and \textbf{S}afety. Critically, we developed a fully automated, guideline-anchored pipeline to construct a GAPS-aligned benchmark end-to-end, overcoming the scalability and subjectivity limitations of prior work. Our pipeline assembles an evidence neighborhood, creates dual graph and tree representations, and automatically generates questions across G-levels. Rubrics are synthesized by a DeepResearch agent that mimics GRADE-consistent, PICO-driven evidence review in a ReAct loop. Scoring is performed by an ensemble of large language model (LLM) judges. Validation confirmed our automated questions are high-quality and align with clinician judgment. Evaluating state-of-the-art models on the benchmark revealed key failure modes: performance degrades sharply with increased reasoning depth (G-axis), models struggle with answer completeness (A-axis), and they are highly vulnerable to adversarial perturbations (P-axis) as well as certain safety issues (S-axis). This automated, clinically-grounded approach provides a reproducible and scalable method for rigorously evaluating AI clinician systems and guiding their development toward safer, more reliable clinical practice.

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.

Deshui Yu, Yizhi Wang, Saihui Jin et al.

Large language models (LLMs) excel on general tasks yet still hallucinate in high-barrier domains such as pathology. Prior work often relies on domain fine-tuning, which neither expands the knowledge boundary nor enforces evidence-grounded constraints. We therefore build a pathology vector database covering 28 subfields and 1.53 million paragraphs, and present YpathRAG, a pathology-oriented RAG framework with dual-channel hybrid retrieval (BGE-M3 dense retrieval coupled with vocabulary-guided sparse retrieval) and an LLM-based supportive-evidence judgment module that closes the retrieval-judgment-generation loop. We also release two evaluation benchmarks, YpathR and YpathQA-M. On YpathR, YpathRAG attains Recall@5 of 98.64%, a gain of 23 percentage points over the baseline; on YpathQA-M, a set of the 300 most challenging questions, it increases the accuracies of both general and medical LLMs by 9.0% on average and up to 15.6%. These results demonstrate improved retrieval quality and factual reliability, providing a scalable construction paradigm and interpretable evaluation for pathology-oriented RAG.

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.

Xuenian Wang, Shanshan Shi, Renao Yan et al.

In the field of whole slide image (WSI) classification, multiple instance learning (MIL) serves as a promising approach, commonly decoupled into feature extraction and aggregation. In this paradigm, our observation reveals that discriminative embeddings are crucial for aggregation to the final prediction. Among all feature updating strategies, task-oriented ones can capture characteristics specifically for certain tasks. However, they can be prone to overfitting and contaminated by samples assigned with noisy labels. To address this issue, we propose a heuristic clustering-driven feature fine-tuning method (HC-FT) to enhance the performance of multiple instance learning by providing purified positive and hard negative samples. Our method first employs a well-trained MIL model to evaluate the confidence of patches. Then, patches with high confidence are marked as positive samples, while the remaining patches are used to identify crucial negative samples. After two rounds of heuristic clustering and selection, purified positive and hard negative samples are obtained to facilitate feature fine-tuning. The proposed method is evaluated on both CAMELYON16 and BRACS datasets, achieving an AUC of 97.13% and 85.85%, respectively, consistently outperforming all compared methods.