Towards a Comprehensive Benchmark for Pathological Lymph Node Metastasis in Breast Cancer Sections

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.

Agent Aggregator with Mask Denoise Mechanism for Histopathology Whole Slide Image Analysis

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.

MergeUp-augmented Semi-Weakly Supervised Learning for WSI Classification

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.

Leveraging Pre-trained Models for FF-to-FFPE Histopathological Image Translation

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 employ a one-step diffusion model as the generator and fine-tune it with LoRA adapters using adversarial learning objectives. To ensure that the model effectively captures both global structural information and local details, we propose a multi-scale feature fusion (MFF) module. This module utilizes two VAE encoders to extract features of varying image sizes and performs feature fusion before feeding them into the UNet. Furthermore, we utilize a pre-trained vision-language model for histopathology as the backbone for the discriminator to further improve performance We conducted FF-to-FFPE translation experiments on the TCGA-NSCLC datasets, and our method achieved better performance compared to other methods. The code and models are released at https://github.com/QilaiZhang/Diffusion-FFPE.

Task-oriented Embedding Counts: Heuristic Clustering-driven Feature Fine-tuning for Whole Slide Image Classification

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.

ProtFAD: Introducing function-aware domains as implicit modality towards protein function perception

Protein function prediction is currently achieved by encoding its sequence or structure, where the sequence-to-function transcendence and high-quality structural data scarcity lead to obvious performance bottlenecks. Protein domains are "building blocks" of proteins that are functionally independent, and their combinations determine the diverse biological functions. However, most existing studies have yet to thoroughly explore the intricate functional information contained in the protein domains. To fill this gap, we propose a synergistic integration approach for a function-aware domain representation, and a domain-joint contrastive learning strategy to distinguish different protein functions while aligning the modalities. Specifically, we associate domains with the GO terms as function priors to pre-train domain embeddings. Furthermore, we partition proteins into multiple sub-views based on continuous joint domains for contrastive training under the supervision of a novel triplet InfoNCE loss. Our approach significantly and comprehensively outperforms the state-of-the-art methods on various benchmarks, and clearly differentiates proteins carrying distinct functions compared to the competitor.

RetMIL: Retentive Multiple Instance Learning for Histopathological Whole Slide Image Classification

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.

Dynamic Graph Representation with Knowledge-aware Attention for Histopathology Whole Slide Image Analysis

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.

Shapley Values-enabled Progressive Pseudo Bag Augmentation for Whole Slide Image Classification

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 complex. 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, and TCGA-LUNG datasets show our method's superiority over existing state-of-the-art approaches, offering enhanced interpretability and class-wise insights. We will release the code upon acceptance.

The Whole Pathological Slide Classification via Weakly Supervised Learning

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.