Context-aware Multiple Instance Learning (MIL) is gaining popularity in Whole Slide Image (WSI) classification. Existing methods typically convert instances in a WSI into one-dimensional sequences and learn the long-range contextual dependencies among instances. However, due to the extremely large size of WSIs and the morphological similarities within tissue structures, the enormous number of redundant instances significantly increases computational overhead in the context learning paradigm. Additionally, the rearrangement of instances into one dimension loses the inherent spatial information involved in image patches, further compromising the classification performance of pathological images. Consequently, efficiently modeling contextual dependencies in WSIs remains a crucial challenge. In this paper, we propose a novel Semantic Anchor-based Context-aware Multiple Instance Learning (SeCoMIL) framework. This framework partitions the WSI into a series of regions and encodes the coordinates of instances within these regions to preserve their spatial relationships. Subsequently, SeCoMIL identifies the most representative instances from each region as semantic anchors. By capturing both the local context around these anchors and the global context across different anchors, the framework efficiently summarizes the critical pathological information of the WSI, enabling precise classification. Extensive experiments on four public datasets (CAMELYON16, CAMELYON17, TCGA-NSCLC, and TCGA-RCC) demonstrate the robustness of our method, with superior performance compared to state-of-the-art methods.

Multiple instance learning (MIL) is a powerful approach for whole-slide pathological image (WSI) analysis, particularly suited for processing gigapixel-resolution images with slide-level labels. Recent attention-based MIL architectures have significantly advanced weakly supervised WSI classification, facilitating both clinical diagnosis and localization of disease-positive regions. However, these methods often face challenges in differentiating between instances, leading to tissue misidentification and a potential degradation in classification performance. To address these limitations, we propose AttriMIL, an attribute-aware multiple instance learning framework. By dissecting the computational flow of attention-based MIL models, we introduce a multi-branch attribute scoring mechanism that quantifies the pathological attributes of individual instances. Leveraging these quantified attributes, we further establish region-wise and slide-wise attribute constraints to dynamically model instance correlations both within and across slides during training. These constraints encourage the network to capture intrinsic spatial patterns and semantic similarities between image patches, thereby enhancing its ability to distinguish subtle tissue variations and sensitivity to challenging instances. To fully exploit the two constraints, we further develop a pathology adaptive learning technique to optimize pre-trained feature extractors, enabling the model to efficiently gather task-specific features. Extensive experiments on five public datasets demonstrate that AttriMIL consistently outperforms state-of-the-art methods across various dimensions, including bag classification accuracy, generalization ability, and disease-positive region localization. The implementation code is available at https://github.com/MedCAI/AttriMIL.

Computer-aided pathology diagnosis based on whole slide images, which is often formulated as a weakly supervised multiple instance learning (MIL) paradigm. Current approaches generally employ attention mechanisms to aggregate instance-level features. However, the weakly supervised signal and the imbalanced instance distribution often lead to inaccurate attention localization, compromising the performance and generalization capability of the MIL framework. To address these problems, this paper presents a novel MIL framework called FAMIL that focuses on inaccurate attention and refines them. FAMIL adopts a dual-branch structure and incorporates two innovative online data augmentation strategies: attention-based Mixup (ABMix) and attention-based Masking (ABMask). ABMix emphasizes the significance of positive instances, generalizing Mixup in the MIL scenarios, while ABMask flexibly identifies challenging positive instances to optimize the feature representation. Moreover, these two methods are plug-and-play and can be easily embedded into attention-based MIL methods. Extensive experiments on three public benchmarks demonstrate the superiority of our FAMIL, outperforming current state-of-the-art methods. The test AUC for the binary tumor classification can be up to 92.61% over CAMELYON16. And the AUC over the cancer subtype classification can be up to 93.81% and 98.41% on TCGA-NSCLC and TCGA-RCC datasets, respectively.

Recently, virtual staining technology has greatly promoted the advancement of histopathology. Despite the practical successes achieved, the outstanding performance of most virtual staining methods relies on hard-to-obtain paired images in training. In this paper, we propose a method for virtual immunohistochemistry (IHC) staining, named confusion-GAN, which does not require paired images and can achieve comparable performance to supervised algorithms. Specifically, we propose a multi-branch discriminator, which judges if the features of generated images can be embedded into the feature pool of target domain images, to improve the visual quality of generated images. Meanwhile, we also propose a novel patch-level pathology information extractor, which is assisted by multiple instance learning, to ensure pathological consistency during virtual staining. Extensive experiments were conducted on three types of IHC images, including a high-resolution hepatocel-lular carcinoma immunohistochemical dataset proposed by us. The results demonstrated that our proposed confusion-GAN can generate highly realistic images that are capable of deceiving even experienced pathologists. Furthermore, compared to using H&E images directly, the downstream diagnosis achieved higher accuracy when using images generated by confusion-GAN. Our dataset and codes will be available at https://github.com/jiahanli2022/confusion-GAN.