Anjia Han

Yingxue Xu, Yihui Wang, Fengtao Zhou et al.

Remarkable strides in computational pathology have been made in the task-agnostic foundation model that advances the performance of a wide array of downstream clinical tasks. Despite the promising performance, there are still several challenges. First, prior works have resorted to either vision-only or image-caption data, disregarding pathology reports with more clinically authentic information from pathologists and gene expression profiles which respectively offer distinct knowledge for versatile clinical applications. Second, the current progress in pathology FMs predominantly concentrates on the patch level, where the restricted context of patch-level pretraining fails to capture whole-slide patterns. Even recent slide-level FMs still struggle to provide whole-slide context for patch representation. In this study, for the first time, we develop a pathology foundation model incorporating three levels of modalities: pathology slides, pathology reports, and gene expression data, which resulted in 26,169 slide-level modality pairs from 10,275 patients across 32 cancer types, amounting to over 116 million pathological patch images. To leverage these data for CPath, we propose a novel whole-slide pretraining paradigm that injects the multimodal whole-slide context into the patch representation, called Multimodal Self-TAught PRetraining (mSTAR). The proposed paradigm revolutionizes the pretraining workflow for CPath, enabling the pathology FM to acquire the whole-slide context. To the best of our knowledge, this is the first attempt to incorporate three modalities at the whole-slide context for enhancing pathology FMs. To systematically evaluate the capabilities of mSTAR, we built the largest spectrum of oncological benchmark, spanning 7 categories of oncological applications in 15 types of 97 practical oncological tasks.

Jiabo Ma, Zhengrui Guo, Fengtao Zhou et al.

Foundation models pretrained on large-scale datasets are revolutionizing the field of computational pathology (CPath). The generalization ability of foundation models is crucial for the success in various downstream clinical tasks. However, current foundation models have only been evaluated on a limited type and number of tasks, leaving their generalization ability and overall performance unclear. To address this gap, we established a most comprehensive benchmark to evaluate the performance of off-the-shelf foundation models across six distinct clinical task types, encompassing a total of 72 specific tasks, including slide-level classification, survival prediction, ROI-tissue classification, ROI retrieval, visual question answering, and report generation. Our findings reveal that existing foundation models excel at certain task types but struggle to effectively handle the full breadth of clinical tasks. To improve the generalization of pathology foundation models, we propose a unified knowledge distillation framework consisting of both expert and self-knowledge distillation, where the former allows the model to learn from the knowledge of multiple expert models, while the latter leverages self-distillation to enable image representation learning via local-global alignment. Based on this framework, we curated a dataset of 96,000 whole slide images (WSIs) and developed a Generalizable Pathology Foundation Model (GPFM). This advanced model was trained on a substantial dataset comprising 190 million images extracted from approximately 72,000 publicly available slides, encompassing 34 major tissue types. Evaluated on the established benchmark, GPFM achieves an impressive average rank of 1.6, with 42 tasks ranked 1st, while the second-best model, UNI, attains an average rank of 3.7, with only 6 tasks ranked 1st.

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.

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.

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.

Yuxuan Chen, Jiawen Li, Huijuan Shi et al.

Bone metastasis analysis is a significant challenge in pathology and plays a critical role in determining patient quality of life and treatment strategies. The microenvironment and specific tissue structures are essential for pathologists to predict the primary bone cancer origins and primary bone cancer subtyping. By digitizing bone tissue sections into whole slide images (WSIs) and leveraging deep learning to model slide embeddings, this analysis can be enhanced. However, tumor metastasis involves complex multivariate interactions with diverse bone tissue structures, which traditional WSI analysis methods such as multiple instance learning (MIL) fail to capture. Moreover, graph neural networks (GNNs), limited to modeling pairwise relationships, are hard to represent high-order biological associations. To address these challenges, we propose a dynamic hypergraph neural network (DyHG) that overcomes the edge construction limitations of traditional graph representations by connecting multiple nodes via hyperedges. A low-rank strategy is used to reduce the complexity of parameters in learning hypergraph structures, while a Gumbel-Softmax-based sampling strategy optimizes the patch distribution across hyperedges. An MIL aggregator is then used to derive a graph-level embedding for comprehensive WSI analysis. To evaluate the effectiveness of DyHG, we construct two large-scale datasets for primary bone cancer origins and subtyping classification based on real-world bone metastasis scenarios. Extensive experiments demonstrate that DyHG significantly outperforms state-of-the-art (SOTA) baselines, showcasing its ability to model complex biological interactions and improve the accuracy of bone metastasis analysis.

Hao Jiang, Cheng Jin, Huangjing Lin et al.

Cervical cancer is a leading malignancy in female reproductive system. While AI-assisted cytology offers a cost-effective and non-invasive screening solution, current systems struggle with generalizability in complex clinical scenarios. To address this issue, we introduced Smart-CCS, a generalizable Cervical Cancer Screening paradigm based on pretraining and adaptation to create robust and generalizable screening systems. To develop and validate Smart-CCS, we first curated a large-scale, multi-center dataset named CCS-127K, which comprises a total of 127,471 cervical cytology whole-slide images collected from 48 medical centers. By leveraging large-scale self-supervised pretraining, our CCS models are equipped with strong generalization capability, potentially generalizing across diverse scenarios. Then, we incorporated test-time adaptation to specifically optimize the trained CCS model for complex clinical settings, which adapts and refines predictions, improving real-world applicability. We conducted large-scale system evaluation among various cohorts. In retrospective cohorts, Smart-CCS achieved an overall area under the curve (AUC) value of 0.965 and sensitivity of 0.913 for cancer screening on 11 internal test datasets. In external testing, system performance maintained high at 0.950 AUC across 6 independent test datasets. In prospective cohorts, our Smart-CCS achieved AUCs of 0.947, 0.924, and 0.986 in three prospective centers, respectively. Moreover, the system demonstrated superior sensitivity in diagnosing cervical cancer, confirming the accuracy of our cancer screening results by using histology findings for validation. Interpretability analysis with cell and slide predictions further indicated that the system's decision-making aligns with clinical practice. Smart-CCS represents a significant advancement in cancer screening across diverse clinical contexts.

Yuxuan Chen, Jiawen Li, Jiali Hu et al.

With the rapid advancement of pathology foundation models (FMs), the representation learning of whole slide images (WSIs) attracts increasing attention. Existing studies develop high-quality patch feature extractors and employ carefully designed aggregation schemes to derive slide-level representations. However, mainstream weakly supervised slide representation learning methods, primarily based on multiple instance learning (MIL), are tailored to specific downstream tasks, which limits their generalizability. To address this issue, some studies explore unsupervised slide representation learning. However, these approaches focus solely on the visual modality of patches, neglecting the rich semantic information embedded in textual data. In this work, we propose ProAlign, a cross-modal unsupervised slide representation learning framework. Specifically, we leverage a large language model (LLM) to generate descriptive text for the prototype types present in a WSI, introducing patch-text contrast to construct initial prototype embeddings. Furthermore, we propose a parameter-free attention aggregation strategy that utilizes the similarity between patches and these prototypes to form unsupervised slide embeddings applicable to a wide range of downstream tasks. Extensive experiments on four public datasets show that ProAlign outperforms existing unsupervised frameworks and achieves performance comparable to some weakly supervised models.

Jiawen Li, Jiali Hu, Qiehe Sun et al. · tsinghua

The emergence of foundation models in computational pathology has transformed histopathological image analysis, with whole slide imaging (WSI) diagnosis being a core application. Traditionally, weakly supervised fine-tuning via multiple instance learning (MIL) has been the primary method for adapting foundation models to WSIs. However, in this work we present a key experimental finding: a simple nonlinear mapping strategy combining mean pooling and a multilayer perceptron, called SiMLP, can effectively adapt patch-level foundation models to slide-level tasks without complex MIL-based learning. Through extensive experiments across diverse downstream tasks, we demonstrate the superior performance of SiMLP with state-of-the-art methods. For instance, on a large-scale pan-cancer classification task, SiMLP surpasses popular MIL-based methods by 3.52%. Furthermore, SiMLP shows strong learning ability in few-shot classification and remaining highly competitive with slide-level foundation models pretrained on tens of thousands of slides. Finally, SiMLP exhibits remarkable robustness and transferability in lung cancer subtyping. Overall, our findings challenge the conventional MIL-based fine-tuning paradigm, demonstrating that a task-agnostic representation strategy alone can effectively adapt foundation models to WSI analysis. These insights offer a unique and meaningful perspective for future research in digital pathology, paving the way for more efficient and broadly applicable methodologies.