Pathology Transport: Optimal-Transport Explanations for Clinical Data, and When Their Heatmaps (Fail to) Localize Disease

Multiple instance learning (MIL) has enabled substantial progress in computational histopathology, where a large amount of patches from gigapixel whole slide images are aggregated into slide-level predictions. Heatmaps are widely used to validate MIL models and to discover tissue biomarkers. Yet, the validity of these heatmaps has barely been investigated. In this work, we introduce a general framework for evaluating the quality of MIL heatmaps without requiring additional labels. We conduct a large-scale benchmark experiment to assess six explanation methods across histopathology task types (classification, regression, survival), MIL model architectures (Attention-, Transformer-, Mamba-based), and patch encoder backbones (UNI2, Virchow2). Our results show that explanation quality mostly depends on MIL model architecture and task type, with perturbation ("Single"), layer-wise relevance propagation (LRP), and integrated gradients (IG) consistently outperforming attention-based and gradient-based saliency heatmaps, which often fail to reflect model decision mechanisms. We further demonstrate the advanced capabilities of the best-performing explanation methods: (i) We provide a proof-of-concept that MIL heatmaps of a bulk gene expression prediction model can be correlated with spatial transcriptomics for biological validation, and (ii) showcase the discovery of distinct model strategies for predicting human papillomavirus (HPV) infection from head and neck cancer slides. Our work highlights the importance of validating MIL heatmaps and establishes that improved explainability can enable more reliable model validation and yield biological insights, making a case for a broader adoption of explainable AI in digital pathology. Our code is provided in a public GitHub repository: https://github.com/bifold-pathomics/xMIL/tree/xmil-journal

Reliable and interpretable decision-making is essential in medical imaging, where diagnostic outcomes directly influence patient care. Despite advances in deep learning, most medical AI systems operate as opaque black boxes, providing little insight into why a particular diagnosis was reached. In this paper, we introduce Med-CAM, a framework for generating minimal and sharp maps as evidence-based explanations for Medical decision making via Classifier Activation Matching. Med-CAM trains a segmentation network from scratch to produce a mask that highlights the minimal evidence critical to model's decision for any seen or unseen image. This ensures that the explanation is both faithful to the network's behaviour and interpretable to clinicians. Experiments show, unlike prior spatial explanation methods, such as Grad-CAM and attention maps, which yield only fuzzy regions of relative importance, Med-CAM with its superior spatial awareness to shapes, textures, and boundaries, delivers conclusive, evidence-based explanations that faithfully replicate the model's prediction for any given image. By explicitly constraining explanations to be compact, consistent with model activations, and diagnostic alignment, Med-CAM advances transparent AI to foster clinician understanding and trust in high-stakes medical applications such as pathology and radiology.

Deep learning shows promise for breast cancer diagnosis, but limited interpretability hinders clinical adoption. We benchmark ten ImageNet-pretrained models (ResNet50, VGG19, InceptionV3, DenseNet121, Xception, MobileNetV2, EfficientNet, ConvNeXt, ViT, and Swin Transformer) for benign-versus-malignant classification on the BreakHis histopathology dataset using a patient-level split, and explain their predictions with Grad-CAM, LIME, Integrated Gradients, and LRP. DenseNet121 performed best, with 99.4% test accuracy and an AUC-ROC of 0.999, and significantly outperformed all other models (p < 0.001). Transformer-based models trailed the CNNs. The explanations consistently highlighted nuclei-rich and glandular regions of diagnostic relevance. Combining transfer learning with explainable AI can thus yield accurate, interpretable tools for breast cancer diagnosis.