Whole-Slide Image Analysis

In computational pathology, Whole Slide Images (WSIs) survival analysis is crucial for patient prognosis assessment, but it faces multiple technical challenges. Although the Transformer captures long-range dependencies through its self-attention mechanism, its $O(N^2)$ time complexity causes a severe computational bottleneck in large-scale WSIs graph structures. The Mamba model breaks through the Transformer's computational bottleneck with linear complexity. But, owing to Mamba's high sensitivity to the order of input data, traditional node sorting methods in Graph Mamba, such as those based on node degree or subgraph size, fail to adequately account for the topological connectivity of graph data. This inadequacy consequently restricts the performance of Mamba's sequential modeling. Moreover, its unidirectional architecture cannot leverage the bidirectional spatial structure of images. To address these challenges, this paper proposes a novel Graph Mamba survival analysis framework based on topology-aware ordering (TopoMamSurv) to adapt to the sequential sensitivity of Mamba. Our visualization experiments further confirmed that the nodes extracted through the topology-aware ordering (TAO) strategy indeed exhibit higher similarity. Furthermore, we designed a bidirectional Mamba module and integrated a Graph Convolutional Network (GCN) to achieve bidirectional spatial context modeling of images, forming a hierarchical feature learning architecture for "local aggregation - global capture." This framework effectively reconciles the contradiction between long-range dependency modeling, computational efficiency, and spatial structure utilization in WSIs analysis through its systematic design of TAO, bidirectional semantic modeling, and hierarchical feature fusion. This framework has been validated for its comprehensive performance advantage on five TCGA datasets.

Digital pathology archives increasingly contain multiple whole-slide images (WSIs) per case, capturing spatially distinct tumor regions and reflecting intrinsic morphological heterogeneity. However, most existing approaches rely on a single pathologist-selected slide, thereby discarding potentially informative evidence distributed across the remaining WSIs. To date, no autonomous framework has been proposed for comprehensive multi-WSI case processing. Here, we present an unsupervised framework for case-level analysis that integrates information from all available slides within a case. Rather than relying on a single designated slide, the proposed approach constructs case-level representations by selectively distilling informative patches across WSIs. We introduce Clustering-Based Redundancy-Reduced Instance Sampling for Pathology (CRISP), a two-stage framework that first reduces redundancy within individual WSIs and subsequently applies clustering-based sampling to select a compact yet representative set of patches for the entire case. The resulting patch set captures case-level heterogeneity while avoiding exhaustive processing of gigapixel images, and directly serves as a retrieval index. Using two Mayo Clinic breast cancer datasets for diagnosis and treatment planning, we demonstrate that CRISP consistently matches or surpasses the current standard practice of combined model and pathologist slide selection for patient/case search and retrieval. By automating case-level processing and eliminating subjective WSI selection, CRISP potentially enables the exploitation of clinically relevant information distributed across multiple WSIs that is currently overlooked.

Whole-slide image visual question answering (WSI-VQA) frames pathology as an extreme-context search problem: to answer a free-form clinical query, a system must first navigate a gigapixel slide under a strict inspection budget to locate sparse, high-resolution evidence. Existing approaches largely fall into two paradigms: i) supervised pathology multimodal large language models (MLLMs) and agents can absorb localization and reasoning into learned modules, but they often couple navigation to task-specific supervision and retraining, limiting their practicality; ii) training-free pathology agents avoid this cost by keeping core models frozen, but often follow a question-first design, constructing the initial candidate set mainly from query-conditioned relevance. This can miss decisive morphology that is not named in the question, and force heavier inference-time scaffolding. To address this challenge, we introduce PathNavigate, a training-free pathology agent built around a scan-search-readout routine. Before question matching, PathNavigate scans the current slide at low magnification with a shared online memory module over frozen pathology features, producing a slide-specific surprise field that marks an abnormal-region pool. It then applies question-conditioned PLIP relevance only within this pool to select high-magnification search targets. Finally, it extracts local high-magnification evidence and answers with a frozen perceptor-adjudicator stack, using the same online memory as slide-level context. Experiments on WSI-VQA and SlideBench-BCNB show that the proposed scan-search-readout design improves answer accuracy and yields more interpretable evidence-selection trajectories with higher efficiency.The code is available online.

We introduce ProtoPathway, an interpretable-by-design multimodal framework for cancer survival prediction that unifies whole slide imaging and transcriptomics through encoders producing biologically grounded representations on both sides of the fusion. On the histopathology side, $K$ learnable morphological prototypes, trained end-to-end with the survival objective, serve as the slide representation itself: patches flow into prototype tokens via soft assignment, compressing variable-length patch sets into fixed task-adaptive tokens. On the genomic side, a bipartite graph neural network encodes gene expression within the Reactome pathway hierarchy, producing pathway embeddings that reflect both constituent genes and their broader biological context through bidirectional message passing over a shared gene--pathway graph. Cross-modal attention then operates over a compact prototype $\times$ pathway matrix in which prototypes query pathways, modeling the biological direction in which molecular programs give rise to tissue morphology. Because both axes carry stable task-learned identity, the attention matrix is itself an interpretability output, yielding native inference-time attribution across the full biological hierarchy, from genes through pathways and prototypes to spatial tissue maps. We evaluate on five TCGA cancer cohorts, demonstrating competitive or superior survival prediction with substantially improved biological interpretability and reduced computational cost, with interpretability claims validated through fold-stratified rank-based population-level analysis. Our source code, model weights, and Reactome pathways, together with a unified codebase reimplementing all multimodal survival baselines under identical preprocessing and evaluation, are available at: https://github.com/AmayaGS/ProtoPathway.

Traditional whole slide image (WSI) analysis methods typically rely on the multiple instance learning (MIL) paradigm, which extracts patch-level features at high magnification and aggregates them for slide-level prediction. However, such exhaustive patch-level processing is computationally expensive, severely limiting the efficiency and scalability of WSI analysis. To address this challenge, we propose PathCTM (a Pathology-oriented Continuous Thought Model) that enables token-efficient scale-space continuous reasoning for gigapixel WSIs. PathCTM formulates diagnostic inference as a dynamic sequential information pursuit. It progressively transitions from low-magnification global to high-magnification local inspection, and adaptively terminates inference when sufficient evidence is gathered to effectively bound decision uncertainty. Specifically, it uses conditional computation for dynamic scale switching with attention-guided region pruning, coupled with confidence-aware early stopping. Extensive experiments demonstrate that, compared with standard MIL-based methods, PathCTM reduces the number of required image patches by 95.95% and shortens inference time by approximately 95.62%, while maintaining AUC without degradation. Code is available at https://github.com/JSGe-AI/PathCTM.

Implementation of digital pathology leads to an increased number of whole slide images (WSIs). The large size of WSIs is challenging. Today, WSIs are compressed with codecs like JPEG resulting in several gigabytes per WSI, and large amounts of space are wasted storing glass. In this study, deep learning-based tissue segmentation for glass removal, and deep learning compression methods were explored and compared with JPEG, JPEG-2000 and JPEG-XL. Image pyramids (N=21) with intact glass, glass replaced by single-colored pixels, and glass replaced by zero-byte tiles were created and compressed with JPEG, JPEG-XL and a deep learning model. Additionally, several compression models were evaluated on a tissue patch dataset and compared with JPEG, JPEG-2000 and JPEG-XL. Removing glass reduced file sizes considerably for JPEG and JPEG-XL. Deep learning-based image compression reduced the WSI size by 43-72% compared to JPEG compression, whereas deep learning-based glass removal reduced the WSI size by 0.3-33%, and 6-62% using only single-colored pixels and removing all-glass tiles, respectively. Combining the two gave a small improvement to a 44-80% total size reduction which indicates that deep learning-based image compression is able to efficiently compress glass tiles, whereas JPEG is not. On the tissue patch dataset, the best deep learning-based compression models saved on average ~35-40% per patch compared to JPEG, while keeping an average SSIM above 0.95, whereas JPEG-XL and JPEG-2000 saved 17% and 14%, respectively while keeping an SSIM of 0.96. However, the deep learning models had higher decompression times than JPEG and JPEG-XL.

Multiple instance learning (MIL) is the standard approach for whole-slide image (WSI) classification and survival prediction, where attention-based models ag gregate patch features into slide-level predictions. These models treat attention weights as evidence for their predictions, but attention is optimized for classi fication, not for identifying which patches actually support the diagnosis. This conflation leads to three failures: selected patches are insufficient (keeping them alone drops Macro-F1 by 0.078), unnecessary (removing them barely changes the prediction), and unrecoverable (continuous attention scores disagree with discrete patch subsets used at inference). The central premise is that evidence quality should be optimized directly through explicit criteria- Sufficiency, Necessity, and Recov erability (S/N/R)- rather than inherited as a byproduct of classification. GCE-MIL is a backbone-agnostic wrapper implemented through three injection modes and three evidence components: a grounding mechanism that aligns selection with domain-specific concepts, noisy-OR coverage that acts as a differentiable proxy for interventional evidence search, and threshold-plus-repair recovery that converts continuous selectors into discrete subsets through marginal-guided repair. Across 9 backbones and 9 datasets (81 configurations), GCE-MIL improves average Macro-F1 by 0.024 and C-index by 0.014, reduces the continuous-discrete gap by 4-7, and increases complement degradation by 2-4. With optional tile prefiltering after discrete recovery, inference runs up to 5 faster while retaining 0.989 full-bag utility.

Whole-slide MIL models are often called context-aware once graphs, Transform ers, or state-space modules are placed above patch embeddings. We show that this label can be deceptive. On pathology tasks where tissue architecture is part of the diagnostic signal, several strong MIL baselines retain nearly unchanged slide level AUC after patch coordinates are permuted. Their predictions are accurate, but largely compositional. We refer to this failure mode as spatial blindness. Our explanation is optimization-based: dense appearance statistics are learned early under slide-level supervision, leaving weak gradients for sparse spatial relations. ResTopoMIL addresses the issue by first fitting a permutation-invariant prototype histogram and then freezing it while a lightweight graph branch learns the residual under a coordinate-shuffling constraint. The architecture is simple by design; the intervention is in how the spatial branch is trained. Across 9 public WSI bench marks, ResTopoMIL improves classification and survival prediction with 1.15M parameters, restores sensitivity to coordinate perturbation, and gives stronger lo calization evidence on CAMELYON-16.

Robust whole-slide image (WSI) analysis under strict data-governance remains challenging due to substantial cross-institutional stain heterogeneity. Domain generalization (DG) mitigates these shifts but typically requires centralized data, conflicting with privacy regulations. Federated learning (FedL) provides a decentralized alternative; however, existing FedL and federated DG (FedDG) approaches rely almost exclusively on low-order statistics, assuming Gaussian-like stain distributions. In contrast, real-world staining processes often produce asymmetric, heavy-tailed color distributions due to biochemical diffusion and scanner nonlinearity. Consequently, current methods fail to model the higher-order, non-Gaussian characteristics dominating real-world stain variability. To address this, we propose FedStain, a stain-aware FedDG framework explicitly incorporating higher-order stain moments--skewness and kurtosis--as compact statistical descriptors exchanged during federated optimization. These descriptors require no pixel-level data transmission, preserving strict privacy and communication efficiency, while enabling the global model to capture stain variability missed by low-order statistics. FedStain also employs a contrastive, cross-site parameter aggregation strategy to promote stain-invariant representations without relaxing data constraints. Extensive experiments on Camelyon17 and our new MvMidog-Fed benchmark show FedStain yields consistent improvements, outperforming state-of-the-art FedL, DG, and FedDG baselines by up to +3.9% absolute accuracy. To our knowledge, FedStain is the first FedDG approach to explicitly model higher-order stain statistics, enabling robust cross-institutional deployment in computational pathology.

Conditional generative adversarial networks (cGANs) have enabled high-fidelity computational staining and destaining of hematoxylin and eosin (H&E) in digital pathology whole-slide images (WSI). However, their ability to generalize to out-of-distribution WSI across institutions without retraining remains insufficiently characterized. Previously developed cGAN models trained on 102 registered prostate core biopsy WSIs from Brigham and Women's Hospital were evaluated on 82 spatially unregistered WSIs acquired at Stanford University. To mitigate domain shift without retraining, a preprocessing pipeline consisting of histogram-based stain normalization for H&E-stained WSIs and channel-wise intensity calibration for unstained WSIs was developed. Because image registration was intentionally omitted for real-world deployment conditions, the reported quantitative results are conservative lower bounds reflecting both model performance and limited spatial alignment. Under these conditions, virtual destaining achieved a Pearson correlation coefficient (PCC) of 0.854, structural similarity index measure (SSIM) of 0.699, and peak signal-to-noise ratio (PSNR) of 18.41 dB. H&E restaining from computationally destained outputs outperformed direct staining from ground-truth unstained inputs across all metrics (PCC: 0.798 vs. 0.715; SSIM: 0.756 vs. 0.718; PSNR: 20.08 vs. 18.51 dB), suggesting that preprocessing quality may be more limiting than model capacity. Qualitative pathological review indicated preservation of benign glandular structures while showing that malignant glands were often rendered with vessel-like morphologies. These findings support the feasibility of applying cGAN-based computational H&E staining and destaining generative models to external WSI datasets using preprocessing-based adaptation alone while defining specific morphological targets for future domain adaptation.

Inferring spatially resolved gene expression from histology images offers a cost-effective complement to spatial transcriptomics (ST). However, existing methods reduce this task to a simple morphology-to-expression mapping, where visual similarity does not guarantee molecular consistency. Meanwhile, single-cell data has amassed rich resources far surpassing the scale of ST data, yet it remains underexplored in vision-omics modeling. Furthermore, current approaches commit to a monolithic paradigm with bottlenecks, unable to balance expressive flexibility with biological fidelity. To bridge these gaps, we propose DUET, a novel dual-paradigm framework that synergizes parametric prediction and memory-based retrieval under cellular inductive priors. DUET implements a parallel regression-retrieval paradigm, adaptively reconciling the outputs of its complementary pathways. To mitigate aleatoric vision ambiguity, we incorporate large-scale single-cell references to impose molecular states as biological constraints for faithful learning. Building upon structural refinement, we further design a lightweight adapter to dynamically assign branch preference across spatial contexts to achieve optimal performance. Extensive experiments on three public datasets across varied gene scales demonstrate that DUET achieves SOTA performance, with consistent gains contributed by each proposed component. Code is available at https://github.com/Junchao-Zhu/DUET

Whole-slide image (WSI) multiple instance learning (MIL) classifiers can achieve strong slide-level AUC while leaving the full-bag prediction opaque. Attention scores are widely reused as post-hoc explanations, but high attention can reflect aggregation preference rather than a compact, model-sufficient rationale. We study post-hoc rationale highlighting for frozen WSI-MIL: given a trained classifier, can its slide-level prediction be recovered from a compact, output-consistent tile subset without retraining the backbone? We instantiate this with Finding Optimal Contextual Instances (FOCI), a lightweight rationale-readout layer over a frozen MIL backbone. FOCI is trained with model-output sufficiency and exclusion objectives over keep/drop tile subsets, evaluated with an insertion-style Sequential Reveal Protocol (SRP) adapted to WSI-MIL, and summarized by the Selection Headroom Index (SHI). Across three WSI benchmarks and seven MIL backbones, FOCI reveals that compact rationales are selection-headroom dependent: transformer and multi-branch attention aggregators can admit compact rationales, near-minimal attention-pooling baselines enter a selection-saturation regime, and hard-selection backbones can conflict with an external readout. For TransMIL, relative to its documented CLS-proxy ranking, FOCI reduces the Minimum Sufficient K (MSK) tile count by 32-56% across benchmarks, while ACMIL+FOCI attains the highest mean SHI (+0.465). Deletion-based perturbation and selected-only downstream evaluation provide complementary checks. These results position FOCI as a model-level interpretability and audit layer: selected tiles are not claims of clinical or pathologist-level diagnostic sufficiency, but candidate rationales that offer a compact, reviewable view of when a frozen MIL prediction can be localized to a small output-consistent subset.

Multiple instance learning (MIL) is the dominant framework for whole-slide image analysis in computational pathology, typically combining a frozen patch encoder, a projection layer, and a slide-level aggregator. While encoders and aggregators have been extensively studied, the projection layer remains a largely morphology-only bottleneck. This limits endpoints such as biomarker status and survival, which are governed by a molecular state that is not fully captured by H&E morphology. We introduce Molecularly Informed Staining Transform (MIST), a plug-in replacement for the MIL projection layer that uses paired spatial transcriptomics only during training to construct virtual molecular stains. MIST clusters gene expression profiles into cross-modal prototypes, anchors them in the frozen foundation model feature space, and uses them to reorganize H&E patch features along molecularly guided axes. It requires no transcriptomics at inference and can be inserted before standard MIL aggregators. We evaluate MIST across 23 downstream tasks and 8 MIL aggregators. MIST improves 240 of 256 configurations over the standard projection layer, with an average gain of +3.5%, observed consistently across endpoint types: +5.2% on survival prediction, +3.3% on tissue subtyping, and +2.6% on biomarker prediction. Ablations confirm that gene-derived prototypes are the primary source of the gains, while spatial, biological, and pathological analyses show that cross-modal prototype affinities capture spatially coherent molecular programs from H&E alone.

Histopathology whole-slide images (WSIs) are routinely acquired in clinical practice and contain rich tissue morphology but lack direct molecular architecture and functional programs defining pathological states, whereas RNA sequencing (RNA-seq) provides genome-wide transcriptional profiles at substantial cost, thereby motivating WSI-based genome-wide transcriptomic prediction. Existing approaches for predicting gene expression from WSIs predominantly rely on deterministic regression with one-to-one mapping, limiting their ability to capture biological heterogeneity and predictive uncertainty. We propose RNA-FM, a flow-matching generative framework for genome-wide bulk RNA-seq prediction from WSIs. RNA-FM formulates transcriptomic prediction as a continuous-time conditional transport problem, learning a velocity field that maps a simple prior to the target gene expression distribution conditioned on morphologies. By integrating pathway-level structure, RNA-FM enables scalable and biologically interpretable genome-wide gene expression imputation. Extensive experiments demonstrate that RNA-FM consistently outperforms state-of-the-art approaches while maintaining biological meaningfulness. Code is available at https://github.com/YXSong000/RNA-FM.

Training AI models for computational pathology currently requires access to expensive whole-slide-image datasets, GPU infrastructure, deep expertise in machine learning, and substantial engineering effort. We present CellDX AI Autopilot, a platform that lets users -- from pathologists with no ML background to ML practitioners running many parallel experiments -- train, evaluate, and deploy whole-slide image classifiers through natural language interaction with an AI agent. The platform provides a structured set of agent skills that guide the user through dataset curation, automated hyperparameter tuning, multi-strategy model comparison, and human-in-the-loop deployment, all on a pre-built dataset of over 32,000 cases and 66,000 H&E-stained whole-slide images with pre-extracted features. We describe the agent skill architecture, the underlying Multiple Instance Learning (MIL) training framework supporting four classification strategies, and an iterative pairwise hyperparameter search (grid or seeded random) that reduces tuning cost by over 30x compared to exhaustive search. CellDX AI Autopilot is, to our knowledge, the first system to expose pathology-specialized agent skills and a pathology-specialized training platform to general-purpose AI agents (e.g. any LLM-based agent runtime), delivering end-to-end automated model training without requiring the agent itself to be domain-specific. The platform addresses both the ML-expertise bottleneck that limits adoption in diagnostic pathology and the engineering bottleneck that limits how many experiments a researcher can run cost-effectively.

Accurate analysis of histopathological images is critical for disease diagnosis and treatment planning. Whole-slide images (WSIs), which digitize tissue specimens at gigapixel resolution, are fundamental to this process but require aggregating thousands of patches for slide-level predictions. Multiple Instance Learning (MIL) tackles this challenge with a two-stage paradigm, decoupling tile-level embedding and slide-level prediction. However, most existing methods implicitly embed patch representations in homogeneous Euclidean spaces, overlooking the hierarchical organization and regional heterogeneity of pathological tissues. This limits current models' ability to capture global tissue architecture and fine-grained cellular morphology. To address this limitation, we introduce a hybrid hyperbolic-Euclidean representation that embeds WSI features in dual geometric spaces, enabling complementary modeling of hierarchical tissue structures and local morphological details. Building on this formulation, we develop BatMIL, a WSI classification framework that leverages both geometric spaces. To model long-range dependencies among thousands of patches, we employ a structured state space sequence model (S4) backbone that encodes patch sequences with linear computational complexity. Furthermore, to account for regional heterogeneity, we introduce a chunk-level mixture-of-experts (MoE) module that groups patches into regions and dynamically routes them to specialized subnetworks, improving representational capacity while reducing redundant computation. Extensive experiments on seven WSI datasets spanning six cancer types demonstrate that BatMIL consistently outperforms state-of-the-art MIL approaches in slide-level classification tasks. These results indicate that geometry-aware representation learning offers a promising direction for next-generation computational pathology.

Pathology foundation models have shown strong retrospective performance, but whether such systems can support clinically relevant use remains unclear. This challenge is particularly important in breast cancer, where pathological assessment serves as the gold standard for diagnosis and guides treatment planning, surgical decision-making and risk stratification across pre-, intra- and post-operative stages. Here we present \textbf{BRAVE}, a breast-adaptive pathology foundation model developed and evaluated using a total resource of 101,638 breast whole-slide images from 32 sources across Asia, Europe and North America. We assessed BRAVE across 34 tasks in 82 cohorts spanning pre-operative biopsy, intra-operative frozen section and post-operative resection, using an evidence chain comprising retrospective benchmarking, clinically challenging scenarios, workflow-oriented clinical impact simulations, prospective observational validation with the thresholds locked in the retrospective cohorts and crossover pathologist-AI interaction studies. Across these settings, BRAVE supported practical roles in the clinical workflow, including safe exclusion of low-risk cases from routine review, AI-assisted second-review rescue of initially missed positives and prioritization of cases for further assessment. In prospective validation across three centres, BRAVE excluded 76.9% of negative biopsy cases (NPV 0.953) and 70.1% of negative frozen-section cases (NPV 0.973), and triaged 78.8% of post-operative subtyping cases as high-confidence clear-cut cases (NPV 1.000). In reader studies, AI assistance improved balanced accuracy from 88.5% to 95.1% (OR 3.14, P<0.001), with better efficiency, confidence and inter-rater agreement. BRAVE-derived scores also independently predicted disease-free survival (adjusted HR 4.79, P<0.001) and overall survival (adjusted HR 8.14, P<0.001).

Whole-slide images (WSIs) present a fundamental challenge for computational pathology due to their extreme resolution, multi-scale heterogeneity, and the requirement for clinically reliable interpretation. Although recent pathology foundation models have enabled fluent report generation, they often lack clinical grounding, failing to accurately represent key diagnostic concepts and relationships observed by pathologists. This limitation arises from the difficulty of integrating heterogeneous visual evidence spanning fine-grained cellular patterns, slide-level tissue architecture, and high-level diagnostic concepts, while maintaining interpretability and clinical coherence. Here we present SCOUT: Semantic Context-aware mOdality fUsion Transformer, a context-aware concept-grounded multimodal framework for pathology report generation that enables progressive conditioning of image representations by global slide information and explicit diagnostic concepts. The method integrates local histological patterns, whole-slide context, and expert-curated semantic descriptors within a unified learning paradigm, allowing visual features to be dynamically refined throughout the encoding process. By combining depth-aware contextual modulation with adaptive multimodal fusion during text generation, the framework produces clinically coherent reports while preserving complementarity across representational scales. Using CONCH1.5 features, we evaluate SCOUT against WSI-Caption, HistGen, and BiGen on TCGA-BRCA, MICCAI REG, and HistAI. SCOUT achieves the best BLEU-1 to BLEU-4 and METEOR scores on all datasets, plus the best ROUGE-L on TCGA-BRCA and MICCAI REG. On TCGA-BRCA, it reaches 0.436/0.303/0.202/0.156 BLEU-1/2/3/4 and 0.204 METEOR; on REG 2025, it achieves 0.865/0.834/0.805/0.780 and 0.568. These results support progressive contextual conditioning for grounded pathology report generation.

Federated learning (FL) offers a promising framework for collaborative digital pathology by enabling model training across institutions. However, real-world deployments face heterogeneity arising from diverse multiple instance learning (MIL) architectures and heterogeneous feature extractors across institutions. We propose FedHD, a novel FL framework that performs local Gaussian-mixture feature alignment tailored for WSI analysis. Instead of exchanging model parameters, each client independently distills semantically rich synthetic feature representations aligned with the distribution of real WSIs. To preserve diagnostic diversity, FedHD adopts a one-to-one distillation strategy, generating a synthetic counterpart for each real slide to avoid over-compression. During federation, a curriculum-based integration strategy progressively incorporates cross-site synthetic features into local training once performance plateaus. Furthermore, an optional interpretation module reconstructs pseudo-patches from synthetic embeddings, enhancing transparency. FedHD is architecture-agnostic, privacy-preserving, and supports personalized yet collaborative training across diverse institutions. Experiments on TCGA-IDH, CAMELYON16, and CAMELYON17 show that FedHD consistently outperforms state-of-the-art federated and distillation baselines.

Foundation models are reshaping computational histopathology, yet their value for whole-slide image retrieval relative to strong patch-based and supervised aggregation baselines remains unclear. We benchmarked ten pipelines on 9,387 diagnostic slides spanning 17 organs and 60 diagnoses from The Cancer Genome Atlas (TCGA) using patient-level leave-one-patient-out evaluation. Methods included four pre-trained slide foundation models, a supervised attention-based multiple instance learning (ABMIL) aggregator on patch embeddings, and patch-level retrieval across five sampling densities. Performance varied more across organs and diagnoses than across architectures. Although the slide foundation model TITAN achieved the strongest overall results, its advantage was modest; ABMIL and patch-based methods reached comparable Top-1 and Top-3 accuracy, with no model consistently dominant. Morphologically distinctive entities approached ceiling performance, while rare, heterogeneous, and closely related subtypes remained challenging. Misclassifications aligned with organs exhibiting known inter-observer variability, suggesting an intrinsic ceiling for morphology-only retrieval. Performance was driven primarily by patch-level feature representations, with limited benefit from slide-level aggregation, indicating aggregation may be unnecessary in many settings. These findings argue against a universally optimal architecture and instead support organ-resolved benchmarking, diagnosis-aware or ensemble strategies, stronger feature representations, and multimodal retrieval frameworks. Notably, even the best model achieved only $\approx 68\% \pm 21\%$ retrieval accuracy on TCGA, and some subtypes showed $0\%$ accuracy across all methods, highlighting fundamental limitations of morphology-based representations and the need for substantial progress before reliable clinical deployment.

Pathology foundation models (PFMs) have recently emerged as powerful pretrained encoders for computational pathology, enabling transfer learning across a wide range of downstream tasks. However, systematic comparisons of these models for clinically meaningful prediction problems remain limited, especially in the context of survival prediction under external validation. In this study, we benchmark widely used and recently proposed PFMs for breast cancer survival prediction from whole-slide histopathology images. Using a standardized pipeline based on patch-level feature extraction and a unified survival modeling framework, we evaluate model representations across three independent clinical cohorts comprising more than 5,400 patients with long-term follow-up. Models are trained on one cohort and evaluated on two independent external cohorts, enabling a rigorous assessment of cross-dataset generalization. Overall, H-optimus-1 achieves the strongest survival prediction performance. More broadly, we observe consistent generational improvements across model families, with second-generation PFMs outperforming their first-generation counterparts. However, absolute performance differences between many recent PFMs remain modest, suggesting diminishing returns from further scaling of pretraining data or model size alone. Notably, the compact distilled model H0-mini slightly outperforms its larger teacher model H-optimus-0, despite using fewer than 8% of the parameters and enabling significantly faster feature extraction. Together, these results provide the first large-scale, externally validated benchmark of PFMs for breast cancer survival prediction, and offer practical guidance for efficient deployment of PFMs in clinical workflows.

Digital pathology has fundamentally altered diagnostic workflows by enabling the computational analysis of gigapixel Whole Slide Images (WSIs), yet effectively deciphering their complex tumor microenvironments remains a formidable challenge. Existing Multiple Instance Learning (MIL) frameworks typically treat Whole Slide Images as unstructured bags of patches, discarding critical morphological semantics and spatial geometry. This lack of inductive bias often leads to overfitting on background noise and fails to align visual features with high-level diagnostic knowledge. To overcome these limitations, we propose the Hierarchical Prototype-based Domain Priors (HPDP) framework, a unified multimodal approach for joint histopathology diagnosis and prognosis. HPDP mitigates the data-driven "black box" issue by introducing a Morphologically Anchored Prototype System (MAPS), which anchors learning to interpretable morphological clusters, and a Sinusoidal Positional Encoder (SPE) to explicitly model tissue architecture. Furthermore, we bridge the semantic gap via a Hierarchical Cross-Modal Alignment (HCMA) module, using Large Language Model (LLM)-generated descriptions to contextually refine visual representations. Extensive experiments across seven cancer cohorts demonstrate that HPDP consistently achieves state-of-the-art performance with superior robustness and interpretability.

Histologic assessment of ulcerative colitis (UC) activity is an important endpoint in clinical trials and routine care, but manual grading with indices such as the Nancy histological index (NHI) is time-consuming and prone to observer variability. While computational pathology methods can automate scoring, many approaches depend on dense region-level annotations, which are costly to obtain, particularly in heterogeneous, multicenter cohorts. We propose a weakly supervised multiple instance learning (MIL) approach for whole-slide images that learns from case- and slide-level NHI labels, leveraging foundation models. Our method targets clinically relevant endpoints, including neutrophilic activity and derived Nancy-low/high groupings, enabling full five-grade NHI prediction. On a multicenter dataset of H&E-stained colon biopsies from three hospitals (2019-2025), we evaluate multiple foundation model encoders and aggregation strategies. We find that foundation model choice and resolution substantially affect performance, with Virchow2 providing the most consistent gains, and that a simple ensembling rule improves five-grade NHI prediction compared to a hierarchical gating baseline. Overall, our results demonstrate that weakly supervised MIL with modern foundation-model representations can provide robust, interpretable UC histology activity assessment in realistic multicenter settings.

Lung adenocarcinoma (LUAD) grading depends on accurately identifying growth patterns, which are indicators of prognosis and can influence treatment decisions. Common deep learning approaches to determine the predominant pattern rely on patch-level classification or segmentation, requiring extensive annotations. This study proposes an attention-based multiple instance learning (ABMIL) framework to predict the predominant LUAD growth pattern at the whole slide level to reduce annotation burden. Our approach integrates pretrained pathology foundation models as patch encoders, used either frozen or fine-tuned on annotated patches, to extract discriminative features that are aggregated through attention mechanisms. Experiments show that fine-tuned encoders improve performance, with Prov-GigaPath achieving the highest agreement (\k{appa} = 0.699) under ABMIL. Compared to simple patch-aggregation baselines, ABMIL yields more robust predictions by leveraging slide-level supervision and spatial attention. Future work will extend this framework to estimate the full distribution of growth patterns and validate performance on external cohorts.

Liver cancer, especially hepatocellular carcinoma (HCC), imposes a substantial global disease burden. Accurate diagnosis and prognostic assessment directly influence treatment selection and patient survival, and pathological examination remains the gold standard for liver cancer diagnosis. Identifying diverse tissue components and pathological subtypes on histopathology slides is crucial for estimating postoperative recurrence risk and overall prognosis. However, most publicly available resources are still provided at the whole-slide image (WSI) level, and well-annotated datasets for fine-grained tissue component identification in liver cancer are scarce, which hinders reproducible model development and the deployment of quantitative analysis tools. To address this gap, we release HepatoBench, a patch-level image database for liver cancer with annotations for seven key tissue categories. Based on HepatoBench, we train and open-source a deep learning classification model as a tissue recognition tool. Furthermore, we train a WSI-level tumor/non-tumor segmentation model to automatically localize lesion regions across entire slides. By integrating the patch-level tissue classifier with the WSI-level segmentation model, we build HepatoQuant, an end-to-end, disease-specific regional quantification tool for liver cancer, enabling a unified workflow from WSIs to tissue composition parsing and quantitative statistics. We also open-source HepatoBench, the benchmarking protocol, and supporting tools, providing a solid foundation for automated regional quantification and fair method comparison in liver cancer pathology.

The expanding ecosystem of pathology foundation models has produced powerful but fragmented tile-level representations, limiting their use in clinical tasks that require unified slide-level reasoning and interpretable linkage to clinically meaningful information. We present ASTRA, a pan-cancer framework that integrates heterogeneous foundation-model representations into a shared slide-level representation space and semantically grounds that space using structured pathology annotation fields, including classification category, cancer type, and anatomic site. ASTRA combines sparse mixture-of-experts contextualization, masked multi-model reconstruction, and contrastive alignment to structured pathology prompts to learn slide representations that support 4-category classification, 3-class solid tumor typing, 16-class cancer typing, and text-guided tumor localization without pixel-level supervision. Developed on a CHTN cohort of 10,359 whole-slide images (WSIs) spanning 16 tumor types, ASTRA consistently improves pan-cancer classification across four pathology foundation-model backbones, achieving up to 97.8% macro-AUC for 4-category classification, 99.7% for 3-class solid tumor typing, and 99.2% for 16-class cancer typing. For tumor localization, ASTRA achieves a mean Dice of 0.897 on an annotated in-domain CHTN subset (n = 380) spanning 16 cancer types and 0.738 on an external TCGA cohort (n = 1,686) spanning four cancer types. These results demonstrate that minimal structured pathology annotation fields derived from slide-level metadata can provide effective semantic supervision for unified slide representation learning, enabling both pan-cancer prediction and weakly supervised tumor localization within a single framework.

Peripheral Blood Smear (PBS) is a critical microscopic examination in hematopathology that yields whole-slide imaging (WSI). Unlike solid tissue pathology, PBS interpretation focuses on individual cell morphologies rather than tissue architecture, making it distinct in both visual characteristics and diagnostic reasoning. However, current multimodal large language models (MLLMs) for pathology are primarily developed on solid-tissue WSIs and struggle to generalize to PBS. To bridge this gap, we construct PBSInstr, the first vision-language dataset for PBS interpretation, comprising 353 PBS WSIs paired with microscopic impression paragraphs and 29k cell-level image crops annotated with cell type labels and morphological descriptions. To facilitate instruction tuning, PBSInstr further includes 27k question-answer (QA) pairs for cell crops and 1,286 QA pairs for PBS slides. Building upon PBSInstr, we develop PBS-VL, a hematopathology-tailored vision-language model for multi-level PBS interpretation at both cell and slide levels. To comprehensively evaluate PBS understanding, we construct PBSBench, a visual question answering (VQA) benchmark featuring four question categories and six PBS interpretation tasks. Experiments show that PBS-VL outperforms existing general-purpose and pathology MLLMs, underscoring the value of PBS-specific data. We release our code, datasets, and model weights to facilitate future research. Our proposed framework lays the foundation for developing practical AI assistants supporting decision-making in hematopathology.

Breast cancer diagnosis demands rapid and precise tools, yet traditional histopathological methods often fall short in intra-operative settings. Deep Ultraviolet (DUV) fluorescence imaging emerges as a transformative approach, offering high-contrast, label-free visualization of whole-slide images (WSIs) with unprecedented detail, surpassing conventional hematoxylin and eosin (H&E) staining in speed and resolution. However, existing deep learning methods for breast cancer classification, predominantly patch-based, fragment spatial context and incur significant preprocessing overhead, limiting their clinical utility. Moreover, standard attention mechanisms, such as Spatial, Squeeze-and-Excitation, Global Context and Guided Context Gating, fail to fully exploit the rich, multi-scale regional relationships inherent in DUV-WSI data, often prioritizing generic feature recalibration over diagnostic specificity. This study introduces a novel Region-Affinity Attention mechanism tailored for DUV-WSI breast cancer classification, processing entire slides without patching to preserve spatial integrity. By modeling local neighbor distances and constructing a full affinity matrix, our method dynamically highlights diagnostically relevant regions, augmented by a contrastive loss to enhance feature discriminability. Evaluated on a dataset of 136 DUV-WSI samples, our approach achieves an accuracy of 92.67 +/- 0.73% and an AUC of 95.97%, outperforming existing attention methods.

Whole Slide Image (WSI) analysis is pivotal in computational pathology, enabling cancer diagnosis by integrating morphological and architectural cues across magnifications. Multiple Instance Learning (MIL) serves as the standard framework for WSI analysis. Recently, Mamba has become a promising backbone for MIL, overtaking Transformers due to its efficiency and global context modeling capabilities originating from Natural Language Processing (NLP). However, existing Mamba-based MIL approaches face three critical challenges: (1) disruption of 2D spatial locality during 1D sequence flattening; (2) sub-optimal modeling of fine-grained local cellular structures; and (3) high memory peaks during inference on resource-constrained edge devices. Studies like MambaOut reveal that Mamba's SSM component is redundant for local feature extraction, where Gated CNNs suffice. Recognizing that WSI analysis demands both fine-grained local feature extraction akin to natural images, and global context modeling akin to NLP, we propose MambaBack, a novel hybrid architecture that harmonizes the strengths of Mamba and MambaOut. First, we propose the Hilbert sampling strategy to preserve the 2D spatial locality of tiles within 1D sequences, enhancing the model's spatial perception. Second, we design a hierarchical structure comprising a 1D Gated CNN block based on MambaOut to capture local cellular features, and a BiMamba2 block to aggregate global context, jointly enhancing multi-scale representation. Finally, we implement an asymmetric chunking design, allowing parallel processing during training and chunking-streaming accumulation during inference, minimizing peak memory usage for deployment. Experimental results on five datasets demonstrate that MambaBack outperforms seven state-of-the-art methods. Source code and datasets are publicly available.

Pathological diagnosis is highly reliant on image analysis, where Regions of Interest (ROIs) serve as the primary basis for diagnostic evidence, while whole-slide image (WSI)-level tasks primarily capture aggregated patterns. To extract these critical morphological features, ROI-level Foundation Models (FMs) based on Vision Transformers (ViTs) and large-scale self-supervised learning (SSL) have been widely adopted. However, three core limitations remain in their application to ROI analysis: (1) cross-magnification domain shift, as fixed-scale pretraining hinders adaptation to diverse clinical settings; (2) inadequate local-global relationship modeling, wherein the ViT backbone of FMs suffers from high computational overhead and imprecise local characterization; (3) insufficient fine-grained sensitivity, as traditional self-attention mechanisms tend to overlook subtle diagnostic cues. To address these challenges, we propose SSMamba, a hybrid SSL framework that enables effective fine-grained feature learning without relying on large external datasets. This framework incorporates three domain-adaptive components: Mamba Masked Image Modeling (MAMIM) for mitigating domain shift, a Directional Multi-scale (DMS) module for balanced local-global modeling, and a Local Perception Residual (LPR) module for enhanced fine-grained sensitivity. Employing a two-stage pipeline, SSL pretraining on target ROI datasets followed by supervised fine-tuning (SFT), SSMamba outperforms 11 state-of-the-art (SOTA) pathological FMs on 10 public ROI datasets and surpasses 8 SOTA methods on 6 public WSI datasets. These results validate the superiority of task-specific architectural designs for pathological image analysis.