Class Visualizations and Activation Atlases for Enhancing Interpretability in Deep Learning-Based Computational Pathology

Histopathology remains the gold standard for cancer diagnosis because it provides detailed cellular-level assessment of tissue morphology. However, manual histopathological examination is time-consuming, labour-intensive, and subject to inter-observer variability, creating a demand for reliable computer-assisted diagnostic tools. Recent advances in deep learning, particularly transformer-based architectures, have shown strong potential for modelling complex spatial dependencies in medical images. In this work, we propose DeepHistoViT, a transformer-based framework for automated classification of histopathological images. The model employs a customized Vision Transformer architecture with an integrated attention mechanism designed to capture fine-grained cellular structures while improving interpretability through attention-based localization of diagnostically relevant regions. The framework is evaluated on three publicly available histopathology datasets covering lung cancer, colon cancer, and acute lymphoblastic leukaemia. Experimental results demonstrate state-of-the-art performance across all datasets, with classification accuracy, precision, recall, F1-score, and ROC-AUC reaching 100 percent on the lung and colon cancer datasets, and 99.85 percent, 99.84 percent, 99.86 percent, 99.85 percent, and 99.99 percent respectively on the acute lymphoblastic leukaemia dataset. All performance metrics are reported with 95 percent confidence intervals. These results highlight the effectiveness of transformer-based architectures for histopathological image analysis and demonstrate the potential of DeepHistoViT as an interpretable computer-assisted diagnostic tool to support pathologists in clinical decision-making.

Hematoxylin and eosin (H&E) staining is the cornerstone of histopathology, yet scalable, quantitative analysis of H&E whole-slide images (WSIs) remains a central challenge in computational pathology. We present Atlas H&E-TME, an AI-based system built on the Atlas family of pathology foundation models that predicts tissue quality, tissue region, and cell type labels across multiple cancer types, yielding over 4,500 quantitative readouts per slide at cell-level resolution. A key challenge to validating such systems is overcoming morphological ambiguity inherent to H&E-only ground truth and the limited scalability of more informed references drawing on modalities such as immunohistochemistry (IHC). We address this with a dual validation framework combining biologically grounded depth with technical and morphological breadth. For depth, we propose an IHC-informed multi-pathologist consensus protocol that substantially improves inter-rater agreement over conventional H&E-only annotation. This yields a molecularly grounded reference against which we compare Atlas H&E-TME and pathologists working from H&E alone. For breadth, we benchmark Atlas H&E-TME on over 200,000 high-confidence H&E-only pathologist annotations across 1,500+ cases spanning eight cancer types and their most common metastatic sites, with subtypes covering >90% of clinical cases per cancer type, drawn from 25+ sources and 8+ scanner models. Benchmarked against the IHC-informed consensus, Atlas H&E-TME matches or exceeds pathologist H&E-only performance and generalizes consistently and robustly across this broad morphological and technical scope. In doing so, Atlas H&E-TME turns the H&E slide -- the most ubiquitous data in pathology -- into a scalable, quantitative window into the tumor and its microenvironment, laying a foundation for the next generation of tissue-based biomarkers in translational and clinical research.

Vision Transformers (ViTs) and their hierarchical variants have achieved strong performance in Computational Pathology (CPath). However, most are pre-trained on single-resolution Whole Slide Images (WSIs), limiting their generalization across arbitrary resolutions. Gigapixel WSIs inherently contain diagnostic patterns at multiple scales, including cellular morphologies, tissue architectures, and global context, mirroring how expert pathologists examine WSIs. We introduce Multi-Resolution Pyramid Transformer (MRPT), a model that hierarchically aggregates multi-resolution information from cellular to tissue and WSI levels. MRPT employs a biologically meaningful Consecutive Cross-Resolution Attention (CCRA) mechanism to capture scale-independent interactions and enforces multi-resolution semantic consistency by aligning embeddings across resolutions, yielding robust and generalizable WSI representations. Pre-trained in a multi-resolution self-supervised manner on 624M patches, 2.4M regions, and 36K WSIs, MRPT learns rich coarse-to-fine histopathology features. Extensive experiments on 34 diverse datasets show that MRPT surpasses recent foundation models and Multimodal Large Language Models (MLLMs) in cancer subtype classification, tissue phenotyping, and Visual Question Answering (VQA) for WSI understanding.