Whole-Slide Images

Label-free virtual staining offers a compelling, non-destructive alternative to standard histopathology; however, its clinical adoption is hindered by the computational bottlenecks inherent to processing gigapixel Whole Slide Images (WSIs). Current deep learning approaches require patch-based inference to avoid memory constraints, which disrupts global tissue continuity and introduces tiling artifacts--displaying visible seams and color shifts. To address this, we introduce the Consistency Memory Bank (COMB), a novel label-free virtual staining framework that enforces spatial and channel consistency across tiles without memory bottlenecks. COMB decouples context storage from computation, utilizing a dynamic retrieval mechanism to fetch feature representations from adjacent tiles. This enables a retrieval-based context integration strategy that adopts local padding to resolve spatial discontinuities and neighbor-aware channel attention to stabilize statistical drift. Further optimized with a sliding window schedule to ensure minimal memory overhead, our method demonstrates superior performance over state-of-the-art baselines, achieving significant improvements in both perceptual fidelity and tiling consistency, while suggesting its downstream utility in tumor segmentation. Code is available at https://github.com/dou0000/COMB.

Histopathological subtyping relies on the recognition of characteristic histological patterns. These patterns may be expressed by individual tissue structures or by the spatial distribution and co-occurrence of multiple structures, and they often span irregularly shaped tissue regions, termed semantic units in this work. However, conventional patch-based representations may fragment such units and fail to explicitly preserve their internal spatial organization, while efficiently modeling relationships among numerous spatially separated units remains challenging. To address these limitations, we propose the Semantic-Aware Subgraph State Space Model (SASG-SSM), a flexible and efficient framework for whole slide image (WSI) classification. Semantic-Aware Subgraphs (SASGs) first approximate irregularly shaped semantic units by adaptively grouping spatially connected patches guided by class-agnostic visual-semantic priors. By representing patches as graph nodes with adjacency edges, SASGs preserve their internal spatial organization rather than treating them as an unordered set. A Subgraph State Space Module (SG-SSM) subsequently combines a graph neural network encoder for intra-subgraph topology encoding with a Mamba-based state space encoder for efficient contextualization across large numbers of subgraphs. This module integrates local structural information within semantic units with global contextual information arising from their distribution and co-occurrence across the WSI, while efficiently modeling a large number of spatially distributed regions. Extensive experiments across four WSI subtyping datasets demonstrate consistent advantages over representative state-of-the-art methods. Further evaluations under small-cohort and few-shot settings demonstrate robustness and data efficiency under limited training data. Code will be released at https://github.com/HLSvois/SASG-SSM.

Patient exams in the cancer diagnosis and staging process typically generate several whole slide images (WSIs). One of the initial steps in training models on WSI data is identifying one or a few slides containing tumor or other diagnostic biomarkers necessary for downstream prediction tasks such as estimating recurrence risk or progression-free survival. This step requires tedious manual curation by experienced pathologists. Many published datasets make the artificial assumption of 1 slide per patient. Alternatively, all slides per patient may be used for model training, which may dilute the signal from the few slides containing tumor or other relevant information. In this paper, we present a pipeline to overcome these challenges using publicly available WSI foundation models (FMs). Our evaluations show that ranking WSIs based on predictions from zero-shot classification using WSI FMs accurately identifies slides with the most tumor, indicating that WSI FMs contain sufficient morphology signal to automatically triage slides. We also present a formulation for ranked evaluation to benchmark FM performance in slide triage. We show, on multiple datasets, that tumor slides are identified in the top-2 ranked slides for patients with up to 43 slides.

The rapid advancement of vision-language models (VLMs) has accelerated progress in computational pathology; however, whole-slide image (WSI)-based pathology report generation remains limited by the scarcity of large-scale WSI--report datasets and the complexity of mapping spatially distributed visual patterns to structured clinical text. To address this, we introduce a clinically curated Pan-Asia WSI--report dataset of approximately 10,500 pairs from five institutions and establish the REG 2025 benchmark through a MICCAI challenge for systematic evaluation of multimodal models. We analyze submitted methods spanning pretrained VLMs, multiple-instance learning frameworks, hierarchical expert models, retrieval-augmented generation, and cross-modal Transformers. Rather than indicating that VLM use alone was sufficient for superior performance, the results suggest that top-performing methods benefited from structured report representations, hierarchical diagnostic decomposition, and effective multimodal grounding. We identify key limitations, including instability in quantitative attribute estimation (e.g., numeric hallucination) and a tendency toward diagnostic overspecification, with some errors resembling known diagnostic pitfalls in routine pathology. These findings establish REG 2025 as a benchmark for evaluating WSI-based structured report generation and vision-language understanding in computational pathology, providing insights for the design of clinically grounded multimodal pathology models.

Histopathological whole slide images (WSIs) are central to cancer diagnosis, but their gigapixel scale, tissue heterogeneity, weak slide-level supervision, sparse diagnostic regions, and multi-scale evidence make robust automated analysis challenging. Multiple instance learning (MIL) is widely used to aggregate tile-level features into slide-level predictions, yet existing augmentation strategies often perturb tissue regions without preserving diagnostic relevance, slide context, or cross-scale structure. We propose SlideMix, a model-agnostic multimodal augmentation framework for MIL-based WSI analysis. SlideMix uses a retrieval-augmented vision-language model (VLM)-based Visual-Language Adaptive Region selector to identify diagnostically relevant regions and reduce weak-label noise. It then performs In-place Tile Shuffling within meaningful tissue regions to mix feature embeddings while preserving slide-level context. A VLM-based soft-labeling module supervises mixed samples, while a multi-factor, loss-driven online Curriculum-Learning Feedback scheme adaptively controls shuffle granularity, feature similarity, and shuffle ratio to promote cross-scale representation learning. Across 11 WSI datasets comprising 20,523 slides, 8 diagnostic tasks, and 10 WSI backbones, SlideMix improves accuracy and generalization in most settings and compares favorably with established augmentation baselines, providing a simple plug-and-play approach for more robust and scalable digital pathology models. Source code: https://github.com/Xia-Research-Lab/SlideMix

Whole-slide images (WSIs) are challenging for vision-language reasoning because diagnostically relevant morphology is sparse, heterogeneous, and distributed across gigapixel-scale images and multiple spatial resolutions. Existing WSI models and pathology agents can aggregate slide features or actively acquire evidence, but the information retained after exploration is often difficult to access semantically while preserving its connection to the original visual evidence. We introduce SlideBank, a training-free framework that represents each WSI as a persistent, concept-indexed, and spatially grounded evidence bank. SlideBank performs question-independent coarse-to-fine exploration to identify informative regions and multi-scale views, converts them into explicit morphological observations, and grounds pathology signals to their supporting patches and WSI coordinates. At inference time, questions are routed to relevant signals and evidence scales, and the linked global, regional, and patch evidence is integrated through confidence-based cross-level consensus. Experiments on WSI-VQA and SlideBench-BCNB show that with Patho-R1, SlideBank reaches 52.77% on WSI-VQA and with Quilt-LLaVA, it reaches 50.92% average accuracy on SlideBench-BCNB, while structured signal-guided retrieval consistently outperforms random evidence sampling. Reusing the same bank across repeated queries further achieves over 99% rephrasing consistency and substantially reduces amortized inference cost through persistent evidence reuse.

Background and Objective: Quality control is a prerequisite for whole-slide image analysis, yet the benchmarks on which quality-control methods are compared share four properties that make their reported differences hard to interpret: few independent slides, annotation concentrated in a minority of them, pooled ratio metrics with no closed-form standard error, and a single inherited train/test partition. We propose a reliability protocol for such benchmarks. Methods: The protocol quantifies four sources of variability - test-set sampling, training stochasticity, partition composition, and undocumented preprocessing - a claim is reportable only if it survives all four; three of the four cost minutes of compute. We apply it to an independent reconstruction of a published diffusion-based artifact detector, evaluated on the original 24-slide partition and against a supervised baseline. Results: The method's central mechanism reproduces: the auxiliary contrastive term improves pooled F1 from 0.673 to 0.688 and replicates under a second seed (+0.0156, p = 0.031; +0.0190, p = 0.005), although it acts on pen marking rather than the artifact types cited to motivate it. Its comparative claims do not: differences between design variants, and against the supervised baseline, fall inside the uncertainty of the evaluation. Four of 24 slides carry 70% of scored annotated pixels, giving an effective sample size of 6.2, and the inherited partition sits at the 7th percentile. An unreported tissue-restriction step excludes 41.4% of out-of-focus annotation against 2.6% of air bubble; such a gate is confounded with blur by construction. Conclusions: Small-cohort benchmarks support far weaker conclusions than current reporting implies. The four checks are cheap enough to accompany any evaluation on such a resource and separate reproducible effects from differences the evaluation cannot resolve.

Automating the analysis of whole-slide images has high clinical value, since characterizing cancers requires examining them in detail. Such analysis increasingly relies on vision-language models that provide patch-level zero-shot predictions. However, these predictions remain noisy and must be refined with a few annotations. A promising paradigm for this refinement is few-shot transduction. Rather than treating each patch independently, these methods leverage the relations between patches, together with a few annotations, to refine all predictions jointly. However, current transductive methods are evaluated under conditions that overlook key properties of whole-slide images: (i) datasets consist of independent patches extracted from multiple slides, ignoring the complex tissue organization; (ii) datasets are mostly balanced, whereas a single whole-slide image exhibits severe class imbalance, with several classes absent; and (iii) annotations are sampled at random, without reflecting how a pathologist annotates a limited number of regions. To align the transduction paradigm to realistic whole-slide settings, we introduce the following contributions. First, we propose SlideCRF, which adapts conditional random fields for whole-slide images by combining spatial and biological cues while accounting for classes that may be absent from a given slide. Second, we provide a set of realistic annotation protocols, based on spatially localized clicks and scribbles, modeling different pathologist interactions, such as the iterative correction of model errors. Across four datasets, we show that SlideCRF outperforms current transductive methods in macro F1, improving over the zero-shot predictions by +24.2% and +37.5% with one and 16 clicks per present class, respectively.

Whole-slide visual reasoning requires identifying sparse diagnostic evidence in gigapixel pathology slides and integrating observations across spatial scales. Existing WSI methods either compress densely sampled patches into global representations or use pretrained vision-language models with heuristic region selection, weakening links between predictions and morphology or lacking pathology-trained observation policies. We present AdaptivePath, an active-perception framework that formulates WSI evidence acquisition as sequential decision making. The Navigator learns question-agnostic abnormality-driven navigation from pathologist-reviewed labels to select observation locations and spatial extents, avoiding costly question-specific trajectory annotations. We train this policy through alternating representation learning and proximal policy optimization, followed by fine-tuning with geometric and appearance consistency objectives to stabilize focus trajectories. During inference, the Navigator hierarchically acquires sparse observations from low to high magnification under a limited ROI budget. A Morphology Interpreter converts observations into question-conditioned evidence, while the Deliberator evaluates evidence and revises intermediate answers across magnifications. The Arbiter integrates deliberation history to produce final answers. AdaptivePath achieves state-of-the-art zero-shot performance on WSI and region pathology VQA benchmarks and reaches 80.14% accuracy for cancer subtype classification across six TCGA cohorts. In a blinded diagnostic-utility study, pathologists using AdaptivePath-selected observation sequences achieve 82.9% accuracy. These results demonstrate that learned active perception enables effective and traceable visual reasoning over gigapixel pathology slides.

Transformer models are increasingly used for whole-slide image analysis in computational pathology. Yet, WSIs differ fundamentally from natural images: neighbouring patches often contain highly similar tissue type, stain, texture, and cellular composition. We identify this local spatial redundancy as a pathology-specific failure mode of self-attention, where dominant neighbourhood features can be repeatedly mixed into patch-tokens and weaken subtle diagnostic or prognostic deviations. We propose Gated Spatial Redundancy Projection (Gated SRP), a lightweight drop-in correction module for self-attention layers. For each patch token and attention head, Gated SRP estimates a local redundancy axis from neighbouring value vectors, projects the attention output onto this axis, and applies a learned signed gate to correct the redundancy-aligned component geometrically. Across five TCGA survival cohorts, Gated SRP obtains the highest mean C-index among the compared attention variants in all cohorts, with an average improvement over the base attention, while adding only +0.02% parameters. Across five slide-level classification datasets, it improves the base attention on 12 of 16 reported metrics and achieves the best AUC on three datasets. Code is publicly available at https://github.com/AtlasAnalyticsLab/GatedSRP.

Whole-slide image (WSI) reasoning requires an agent to sequentially acquire visual evidence before answering a diagnostic question. Existing training-free agentic frameworks formulate this process as iterative patch retrieval based on semantic relevance to the question. However, semantic relevance does not necessarily imply diagnostic informativeness in computational pathology, where competing diagnoses often exhibit similar and overlapping morphological patterns, making many patches semantically relevant yet diagnostically non-discriminative. Consequently, relevance-based retrieval may acquire redundant observations and leave diagnostic uncertainty unresolved. We propose BEACON, a plug-and-play agentic framework that reformulates WSI reasoning as a Bayesian evidence acquisition problem. BEACON maintains a probabilistic belief over competing diagnostic hypotheses and sequentially acquires patches by maximizing expected information gain (EIG) to reduce diagnostic uncertainty. An evidence controller then determines whether to answer, acquire additional evidence, or perform higher-resolution inspection. Built entirely from off-the-shelf foundation models, BEACON requires no additional training or fine-tuning. Extensive zero-shot experiments across five WSI-VQA benchmarks demonstrate that BEACON achieves the strongest overall performance among training-free agentic frameworks while substantially improving evidence acquisition efficiency, establishing Bayesian evidence acquisition as a principled paradigm for uncertainty-aware agentic WSI reasoning. The code is available at https://github.com/bryanwong17/BEACON

Spatial mapping of lung adenocarcinoma (LUAD) growth patterns across whole slide images (WSIs) requires resolving architectural context at the region level, yet existing methods operate at the individual tile level and produce generic morphological clusters rather than clinically defined pattern maps. We propose a weakly supervised Bag-of-Visual-Words (BoVW) pipeline that learns a visual vocabulary from frozen foundation model embeddings extracted from a small set of annotated regions of interest (ROIs). Pattern prototypes are constructed as mean BoVW histograms of same-label ROIs and used for nearest-prototype classification of sliding-window regions under Jensen--Shannon divergence. The resulting predictions are projected onto the WSI tile grid to produce interpretable spatial pattern maps. We evaluate the method on 87 CPTAC-LUAD patients using three foundation model encoders and multiple vocabulary sizes on two clinically motivated tasks. For tumour/healthy classification, the best configuration achieves a balanced accuracy of $0.974$ with H-Optimus-1, approaching the $0.987$ obtained by a supervised SVM trained on mean-pooled WSI embeddings. For binary histologic grade classification, the BoVW pipeline achieves higher balanced accuracy than the supervised baseline for all encoders, suggesting that ROI-level pattern decomposition preserves grade-relevant heterogeneity that is attenuated by global mean pooling.

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.

Safe deployment of AI methods in medicine requires robust guardrails that detect when input data deviate from the training distribution to ensure that models provide predictions only within their scope of expertise and abstain otherwise. Out-of-distribution (OOD) detection can provide such safeguards and is extensively studied in general computer vision. Yet, it remains underdeveloped in computational pathology, where gigapixel whole-slide images (WSIs), subtle differences between disease subtypes, and variability in tissue preparation pose unique challenges for conventional OOD methods. We propose ZIO, a training-free, multimodal OOD detector for pathology WSIs that leverages vision--language pathology foundation models (FMs). ZIO constructs text and visual prototypes of in-distribution classes and integrates their complementary information through a prototype shrinkage mechanism to derive OOD scores. We provide the ZIO formulation for both slide- and patch-level FMs. We evaluate ZIO across diverse clinically relevant domain shifts, including rare diseases and near-OOD settings. Extensive evaluation of over 14,700 WSIs from five independent consortia shows that ZIO consistently outperforms both unimodal prototypes and 40 state-of-the-art OOD methods. These results demonstrate the benefits of multimodal representation for OOD detection and pave the way towards safer AI deployment in clinical practice.

Whole slide image (WSI) classification is an evidence-driven task, where diagnostic cues are often sparse, spatially organized, and class-dependent. Existing MIL and vision-language methods aggregate a large pool of patch features into a single global slide representation. Under few-shot supervision, limited slide-level labels make it difficult to learn a reliable aggregation mechanism that organizes sparse local cues into compact and coherent diagnostic evidence. Moreover, a shared slide representation compresses evidence supporting a candidate class and its alternatives into the same feature, limiting class-specific reasoning and interpretability. To address these issues, we propose EviBall, a class-conditioned evidence retrieval framework for few-shot WSI classification. EviBall organizes local patches into Evidence Balls through semantic-spatial assignment and center refinement, yielding compact and spatially coherent evidence units under weak supervision. It then uses task-specific class queries, including language-guided queries for morphology-oriented tasks and molecular-guided queries for molecular endpoint prediction, to retrieve supporting evidence balls and produce class-conditioned evidence representations for direct class-wise prediction. By introducing structured evidence units and task-relevant semantic guidance, EviBall reduces the reliance on learning an unconstrained global aggregation mechanism from scarce slide-level labels. It therefore reformulates few-shot WSI classification as structured evidence retrieval and competition among candidate classes. Extensive experiments across four morphology-oriented and molecular endpoint WSI tasks demonstrate that EviBall consistently outperforms conventional and vision-language MIL baselines under diverse few-shot settings, while providing spatially localized and class-specific evidence for each prediction.

Identifying the Inflamed'' immunophenotype in Gastric Adenocarcinoma predicts immunotherapy response but requires an expensive 10-gene RNA signature. While deep learning on standard H\&E slides offers a scalable alternative, conventional binary classifiers oversimplify continuous RNA data and introduce label noise. To resolve this, we propose VITA (VIrtual Transcriptomic Approximation). By aligning H\&E and RNA into a joint latent space during training, VITA requires only standard H\&E at inference to retrieve morphologically similar historical cases and approximate the continuous RNA signature. Achieving 0.72 classification accuracy and a 0.66 Spearman correlation, VITA provides a cost-effective virtual transcriptomics'' pre-screening tool that preserves the continuous phenotypic spectrum without requiring genomic sequencing.

The allocation of visual attention by pathologists during cancer diagnosis is a highly selective process that critically shapes the information extracted from whole-slide images (WSIs). Human attention helps medical imaging tasks such as classification and segmentation, and becomes a strong semantic cue for identifying diagnostically informative regions for report generation. In this paper, we introduce human attention into the training of pathologist report generation models. To this end, we collected a multimodal human-attention dataset of 121 prostate WSIs annotated with pathologists' multi-scale viewport trajectories synchronized with the pathologists' verbal descriptions and cursor movements for five clinically relevant components (e.g., Gleason patterns). Using this dataset, we finetune two report generation models with an attention-alignment loss that regularizes the model attention over image patches to match the distribution of pathologist attention. We evaluate our approach on prostate cancer report generation and visual question answering using two models with different internal attention mechanisms (i.e., how image tokens are integrated into the language decoder). Experiments show average gains of 10.9% on NLP-based metrics and 19.3% in accuracy across five clinically relevant report components. Further, model attention maps extracted at inference time, with minimal computational overhead, align more closely with pathologist attention, providing stronger visual support for the generated reports by highlighting the regions that most influence the output.

Whole-slide image (WSI) diagnosis requires identifying diagnostically relevant regions, examining them across magnifications, and integrating multi-scale evidence. However, most existing pathology benchmarks evaluate models on pre-cropped patches or pre-extracted slide features, leaving their ability to acquire evidence directly from gigapixel WSIs largely untested. We introduce PathAgentBench, a benchmark for evaluating evidence-seeking vision-language models (VLMs) across four complementary capabilities: image-to-text matching for evidence interpretation, text-to-image retrieval for evidence verification, diagnostic-region localization for evidence acquisition, and multi-scale reasoning for evidence integration. The benchmark is organized as a diagnostic tree that links nested regions across magnifications with scale-specific findings and path-level diagnoses. It contains 1,822 TCGA WSIs and 17,135 diagnostic paths annotated by ten board-certified pathologists. An additional private cohort of 190 breast cancer WSIs with detailed annotations is used to evaluate autonomous whole-slide exploration. We evaluate 20 general-purpose, medical, and pathology-specialized models. Leading open-weight models achieve over 93% accuracy in multi-scale reasoning and over 50% accuracy in both cross-modal matching tasks. In contrast, diagnostic-region localization remains challenging: the best text-guided mean intersection-over-union is below 0.09, underperforming a simple center-based heuristic. During autonomous exploration, the unconditional hit rate decreases from 0.522 at low magnification to 0.185 at intermediate magnification and 0.020 at high magnification. These results reveal a pronounced gap between reasoning over curated evidence and acquiring that evidence directly from WSIs. PathAgentBench provides a unified framework for measuring and improving evidence-seeking pathology models.

Foundation models have emerged as a driving force in computational pathology, with the potential to transform cancer diagnosis, prognosis, and treatment selection by learning transferable representations from large-scale histopathology data. A growing landscape of pathology foundation models now spans diverse data sources, architectures, and downstream applications. However, most pretrained models operate only at the image-tile level, use restrictive licenses, and remain computationally expensive, limiting large-scale slide-level clinical and research use. Here, we introduce GigaPath-Flash and GigaTIME-Flash, efficient models for whole-slide pathology AI and spatial proteomics prediction. GigaPath-Flash combines a 22M-parameter ViT-S tile encoder with a 21M-parameter LongNet slide encoder, both pretrained on large-scale real-world histopathology data. Its compact tile encoder is distilled from the billion-parameter GigaPath (ViT-g) teacher and shared by both models. GigaPath-Flash retains 97% of GigaPath's average slide-level performance with 50x less compute. GigaTIME-Flash extends this backbone to predict the tumor immune microenvironment directly from routine H&E images. It surpasses the original CNN-based GigaTIME in prediction quality while running 6x faster and using 8x less GPU memory. Together with GigaPath and GigaTIME, these models form an open-weight, Apache-2.0-licensed family pretrained on large-scale real-world clinical data. By releasing all models and weights, we provide accessible building blocks for computational pathology, immuno-oncology, and precision health.

Multiple instance learning (MIL) has become the main paradigm for whole-slide image (WSI) analysis in computational pathology. However, existing MIL aggregators are still typically trained from scratch for each downstream task, relying on limited slide-level labels to learn both aggregation mechanisms and downstream discriminative representations simultaneously. As a result, they often suffer from unstable optimization, overfitting, and limited transferability. Similar to pretrained ResNet and Vision Transformer models in natural image learning, MIL also requires reusable pretrained initialization. However, high-quality slide-level pretraining data remain scarce, and MIL models are usually lightweight and weakly supervised, making large-scale pretraining difficult in practice. To address this challenge, we propose a distillation-based pretraining framework for MIL, which leverages two slide-level foundation models, TITAN and CARE, as teachers to transfer their representational knowledge into a diverse set of MIL architectures. To effectively balance supervision from different teachers, we further introduce an angular dispersion normalized distillation loss. The distilled weights are then used as initialization for downstream adaptation. We conduct systematic evaluations on 15 benchmark datasets under both linear probing and full-parameter fine-tuning, and further validate its advantages in few-shot scenarios. Experimental results show that pretraining generally improves MIL aggregators over from scratch training, especially in linear-probing and few-shot settings, while maintaining the computational efficiency of lightweight MIL models. Code is available at https://github.com/fu0201/MIL_Pretrained.

Weakly supervised whole-slide image (WSI) classification is widely used in computational pathology because slide-level labels are easier to obtain than dense region annotations. Existing multiple instance learning (MIL) methods often aggregate large bags of patch embeddings using mainly visual cues, which can retain many non-informative patches and provide weak alignment between instance features and class-level disease semantics. We propose Concept-Guided Pruning and Representation Learning (CGRL), a simple framework that introduces class-level concept prototypes derived from disease prompts into the MIL pipeline. First, concept-relevance pruning ranks patch instances by their similarity to class concepts and retains the top-K concept-relevant patches for downstream MIL aggregation. Second, concept-guided contrastive representation learning constructs class-wise positive and negative patch sets from the same similarity matrix and optimizes target-class, symmetric auxiliary, and cross-class separation objectives, thereby regularizing the projected concept space. We evaluate CGRL on TCGA-BRCA and TCGA-NSCLC using multiple representative MIL methods. Experimental results show that CGRL improves several model-dataset combinations, with gains depending on the downstream MIL model and dataset. It achieves particularly clear improvements in accuracy and macro-F1 while reducing computational cost through concept-relevance pruning. These findings demonstrate that class-level semantic concepts provide an effective and practical prior for patch selection and representation learning in weakly supervised computational pathology.

Recent vision-language models (VLMs) for computational pathology report striking zero-shot performance on whole-slide image (WSI) visual question answering (VQA) benchmarks. We audit these claims and find them fundamentally compromised by data leakage at two hierarchical levels: patient-level leakage, where slides from the same case appear in both training and test folds, and institutional-level leakage, where different cases nonetheless share staining-batch and scanner signatures through a common Tissue Source Site (TSS). By tracing canonical slide, case, and TSS identifiers across major public resources, we document case level train test overlaps of 92.3~100% on TCGA-derived benchmarks, together with near-complete TSS overlap. We further demonstrate that both leakage levels are linearly decodable from foundation-model feature space, that they induce a measurable accuracy gap between leaked and audit-clean cases on a published checkpoint, and that across multiple published WSI VLMs, peak reported accuracies concentrate on the most heavily contaminated benchmarks. Therefore, the current WSI VQA evaluation cannot distinguish genuine multimodal reasoning from nearest-neighbor retrieval over memorized institutional and patient-specific artifacts. Finally, we outline concrete recommendations for contamination-free evaluation. By addressing benchmark construction, provenance disclosure, and automated overlap auditing, we aim to guide future research toward verifiable claims of progress.

Whole-slide images (WSIs) provide rich tissue-level and cellular-level information, but storing and transmitting high-magnification pathology data is resource-intensive. Moreover, annotating WSIs at the pixel level is labor-intensive and time-consuming. Therefore, it is important to investigate whether low-magnification pathology images with limited annotations (i.e., image-level instead of pixel-level labels) can achieve performance comparable to high-magnification images. This paper presents a systematic benchmark study on weakly supervised histopathological image segmentation under different low-resolution storage settings. Starting from high-resolution image patches, we simulate lower-magnification inputs and reconstruct them to the original size using interpolation and deep learning-based reconstruction methods before applying the weakly-supervised segmentation pipeline. This framework enables a quantitative evaluation of how weakly supervised methods respond to different levels of resolution degradation. Experimental results show that reconstruction quality metrics alone are insufficient to predict downstream segmentation performance. In particular, the study identifies a critical degradation point where the localization of small-scale structures declines significantly. These findings provide practical guidance for designing efficient digital pathology storage systems while maintaining reliable automated analysis. Code is available at https://github.com/Dung-Dx/LowMagWSS

Computational pathology foundation models (PFMs) have advanced whole-slide image analysis. However, their size and inference cost hinder local deployment in pathology departments. We propose MuCoDi, a pretraining framework that distills frozen tile embeddings from multiple PFMs into compact edge-oriented encoders. Instead of regressing individual teacher features, MuCoDi trains lightweight MobileOne and RepViT students with a contrastive distillation objective adapted from MoCo v3, where cached Virchow2, UNI2, and H-Optimus-1 embeddings replace momentum-encoder keys. We pretrain students on 14.3M TCGA tiles from only 11.8K WSIs and evaluate frozen encoders on 23 clinically curated downstream classification tasks. RepViT-based MuCoEdge students retain near-teacher performance while reducing model size by orders of magnitude: MuCoEdge-R2.3 and MuCoEdge-R1.5 reach 71.0% external AUROC, within 0.8 percentage points of the best teacher (Virchow2, 71.8%), while MuCoEdge-R2.3 obtains the best external F1 and the second-best AUPRC (51.8% and 53.3%). MuCoEdge-R1.0 reaches 70.9% AUROC with only 6.4M parameters and 1.12 GFLOPs. On a Raspberry Pi 5, sub-million-parameter MobileOne students achieve up to 605-fold single-tile speedup over Virchow2 while retaining 66.5% to 66.9% external AUROC, demonstrating that PFM-quality pathology representations can be moved toward practical edge deployment. Code is available at https://anonymous.4open.science/r/mucodi-6243.

Survival analysis on Whole Slide Images (WSIs) is important in computational pathology for prognosis estimation and treatment planning. However, existing survival models are typically trained independently for each cancer cohort, making continual adaptation computationally expensive for gigapixel-scale WSIs. In this study, we propose MergeSurv, a merging-based continual learning framework for WSI survival analysis. A pathology vision-language foundation model is independently fine-tuned on each task, and the learned parameters are sequentially merged into a unified model without storing previous training data. We further investigate two inference strategies: One-for-All (OFA) and Voting-Expert Aggregation (VEA). Experiments on four TCGA cohorts demonstrate that MergeSurv outperforms naive fine-tuning as well as representative regularization-based and rehearsal-based continual learning methods, while effectively reducing catastrophic forgetting. The results suggest that model merging is a promising direction for scalable and privacy-preserving continual learning in computational pathology.

Uterine diseases represent an important category of gynecologic pathology and require accurate histopathological assessment for diagnosis and treatment planning. Whole-slide images (WSI) have enabled the digital transformation of pathology workflows and provided new opportunities for artificial intelligence (AI) in computational pathology. In particular, multimodal models that jointly analyze histopathology images and pathology reports have shown promising potential for automated pathology report generation and AI-assisted diagnosis. However, the development of such systems remains limited by the scarcity of datasets that pair whole-slide images with clinically meaningful pathology reports. Instead, existing pathology datasets focus on patch- or slide-level annotations of a single endpoint (e.g., disease class), which do not fully capture the rich information in full clinical diagnostic workflow reports. Here, we introduce TUM-Uteria, a uterine pathology dataset comprising WSIs paired with diagnostic pathology reports at both the case and slide levels, collected from a tertiary medical center. The dataset contains 216 clinical cases, comprising 455 slide-level WSI-report pairs. The dataset underwent a structured multi-stage validation procedure involving board-certified pathologists to ensure reliable annotations. TUM-Uteria supports research in computational pathology, including whole-slide image analysis, multimodal learning, and automated pathology report generation.

Whole slide image (WSI) analysis is central to computational pathology, with multiple instance learning (MIL) emerging as the standard pipeline for slide-level diagnosis. However, conventional approaches formulate WSI diagnosis as a flat classification task over discrete labels, contradicting the inherently hierarchical, coarse-to-fine nature of clinical reasoning. Although recent hierarchical classifiers and vision-language models (VLMs) have sought to address this structural gap, they either fail to capture semantic continuity between related diagnoses or suffer from unconstrained text generation that produces taxonomic hallucinations and parent-child label violations. To address these limitations, we propose TaxoMIL, a taxonomy-constrained framework that reformulates WSI diagnosis as a multi-granularity text generation task. TaxoMIL utilizes a dual-head Transformer decoder to generate coarse- and fine-level diagnostic text, and introduces taxonomy-guided objectives that explicitly structure the label embedding space and strictly ground slide-level visual representations within the clinical taxonomy. Extensive experiments across three diverse WSI datasets demonstrate that TaxoMIL consistently outperforms state-of-the-art MIL classifiers and VLM-based generative methods, yielding accurate and hierarchy-aware diagnostic predictions. The code is released at https://github.com/QuIIL/TaxoMIL

Pathology foundation models (PFMs) offer generalizable representations for whole-slide image (WSI) analysis, yet their clinical adoption remains limited. Specifically, their predictions lack reliable confidence estimates, and no single PFM is universally best across tasks, which severely undermines trust in medical settings. To overcome this, we propose $\mathtt{DICE}$, a plug-and-play framework that ensembles $K$ frozen PFMs and models their disagreement as a proxy for uncertainty estimation. To ensure this proxy yields meaningful estimates, we align the ensemble members via deep mutual learning, and theoretically show that this objective upper-bounds the model uncertainty. Additionally, we demonstrate that the ensemble's consensus localizes abnormalities at the patch level without any explicit supervision. We evaluate $\mathtt{DICE}$ on three challenging WSI benchmarks. Notably, our framework provides reliable uncertainty estimates that accurately flag failure-prone cases under in- and out-of-distribution settings, while matching or outperforming SOTA baselines in classification, calibration, and localization. Overall, $\mathtt{DICE}$ takes a crucial step toward translating PFMs into uncertainty-aware decision-support systems.

Recent advances in pathology foundation models have substantially improved patch and slide level representation learning from whole-slide images (WSIs).However, cell-level representations learning remain underexplored, limiting cell resolved interpretability, biological discovery, and clinical translation. We propose CellDETR, a detection-guided framework built on Deformable DETR for scalable cell representation learning from WSIs. By introducing location feature decoupling and box-constrained attention mechanism, CellDETR enables automated extraction of cell-level embeddings, and outperform existing state-of-the-art methods in supervised cell classification on PanNuke data. In addition, by incorporating contrastive learning design, we build a CellDETR-based pretraining model for scalable cell representation learning from unlabeled WSIs, which improves downstream cell classification performance. Furthermore, we show that after pretraining with Xenium spatial transcriptomics-derived cell annotations, CellDETR achieves accurate cross-dataset cell classification, demonstrating the transferability and biological relevance of the learned cell embeddings. Together, CellDETR provides a scalable route toward general cell-level representation learning framework for interpretable computational patholog

The rapid growth of digital pathology has created an urgent need for efficient indexing and retrieval of whole slide images (WSIs). This need is intensified by emerging generative AI workflows, particularly retrieval-augmented generation (RAG), which require dependable similarity search to support high-stakes clinical decision-making. Yet the substantial cost of high-performance storage limits the scalability and accessibility of WSI indexing for many healthcare institutions. Consequently, methods that can reduce storage demands while preserving retrieval accuracy have become a critical research priority. We propose ARReST (Antithetical Redundancy Reduction Strategy), a principled oppositional framework that leverages redundancy across dissimilar tissue classes to markedly decrease the number of patches that must be indexed from each WSI. Instead of eliminating only within-class duplicates, ARReST identifies antithetical patches-those whose representations contribute minimally to cross-class discrimination-and prunes them from the searchable archive. This targeted reduction substantially compresses the index without sacrificing morphological diversity or retrieval fidelity. By minimizing superfluous patch representations, ARReST reduces storage footprint, lowers computational overhead, and accelerates similarity search across large pathology repositories. Extensive experiments on TCGA repository (The Cancer Genome Atlas with 21 organs) demonstrate that ARReST achieves significant index compression while maintaining competitive retrieval performance. The observed storage savings of 3% to 60% (14%$\pm$13%) can be reliably achieved without compromising retrieval performance for many organs. The proposed strategy enables scalable, cost-efficient WSI indexing and is well-suited for next-generation retrieval-driven clinical AI systems.

The high cost of spatial transcriptomics (ST) has driven extensive studies into predicting gene expression directly from H&E histology images. However, this prediction task faces an inherent limitation, as tissue morphology alone provides insufficient information to fully resolve underlying gene expression. To address this limitation, a recent study leverages partial gene expression to guide the prediction process alongside histology images. Building on this paradigm, we approach the prediction task as a spatial imputation problem, employing a Masked Autoencoder (MAE) to utilize a small fraction of gene expression as genetic anchors for inferring whole-slide gene expression profiles. Specifically, we propose a bio-saliency score and a learning-to-rank strategy to adaptively identify the most informative spots within the tissue. Based on these identified spots, our framework selects contiguous regions as genetic anchors to ensure suitability for real-world ST profiling hardware. To effectively leverage these anchors, we design a cross-modal joint encoder that integrates visual and genetic modalities. By aligning the selected anchors with their corresponding visual features via contrastive learning, the encoder generates robust joint representations to accurately predict gene expression across the whole slide. Notably, our framework consistently surpasses existing methods in both histology-only prediction and spatial imputation, achieving superior accuracy even without genetic anchors and further excelling with as little as 10% transcriptomic coverage. Our code is available at https://github.com/Kyyle2114/CAMMST.

Whole-slide images (WSIs) are widely used for computational cancer prognosis. However, most existing methods primarily focus on in-domain performance and fail to generalize across clinical centers. This limitation stems from their reliance on pixel-derived representations that are highly susceptible to domain-specific artifacts caused by staining protocols and scanner hardware. We hypothesize that high-level pathology semantics, such as tumor grade and micro-environmental architecture, provide a domain-invariant semantic representation that mirrors the robust diagnostic logic of human pathologists. Therefore, we propose a Semantic-Anchored Evidential Fusion Survival (SAEFS) framework, where SAEFS derives semantic anchors from WSIs via Visual Question Answering (VQA), employs a dual-stream WSI evidence extraction architecture, uses Dirichlet-based Subjective Logic to model uncertainty, and fuses semantic and visual evidence through a cautious conjunction rule to avoid overconfident fusion from correlated sources. Trained exclusively on one source domain and evaluated zero-shot across four unseen domains, SAEFS consistently outperforms state-of-the-art models both in prediction accuracy and reliability, improving the average C-index by 10.2%. Quantitative analyses further show that VQA-derived semantic features exhibit significantly lower cross-center divergence than pixel-derived features, highlighting their robustness for cross-center clinical applications.

Multiple Instance Learning (MIL) is a standard paradigm for Whole-Slide Image (WSI) analysis and has achieved strong results in computational pathology. However, most MIL pipelines assume a single "gold" label per slide, which conflicts with clinical practice where substantial inter-pathologist variability is common. Existing multi-annotator learning and label-refinement methods typically estimate global annotator reliability or rely on single-instance assumptions, making them poorly suited to MIL and to localized diagnostic contexts where experts disagree. We propose RaLMPH (Reliability-aware Learning for Multi-Pathologist Harmonization), a MIL-based label reconciliation framework for WSIs annotated by multiple pathologists. RaLMPH introduces a reliability field that jointly models (i) local neighborhood structure in WSI feature space and (ii) expert uncertainty (entropy), enabling per-sample identification of trustworthy reference neighborhoods. Leveraging this field, RaLMPH performs sample-wise local annotator ranking to select reliable opinions per slide and applies an adaptive gating mechanism to fuse labels conditioned on local reliability. Experiments on a clinical WSI dataset with labels from six pathologists, as well as controlled simulated benchmarks, show that RaLMPH consistently outperforms existing approaches. Further analyses clarify how our reliability-aware mechanism improves label reconciliation and downstream MIL performance.

The processing of gigapixel whole slide images within vision language models faces a major difficulty due to an excessive number of visual tokens. Existing solutions typically rely on spatial downsampling or heuristic pruning strategies that operate without training, and these methods often discard subtle but clinically meaningful patterns because pathological evidence is scattered irregularly across the tissue. To overcome this limitation, we reformulate token reduction in whole slide images as a trainable sparsification problem, allowing the model to learn an optimal selection strategy instead of following fixed heuristics. We propose a decoupled routing architecture. To enable gradient propagation through the nondifferentiable pruning operation during training, we introduce a component called SparseLearn. This component uses a variance-preserving noise gate that regulates the information flow of each patch via a differentiable Soft Top-K operator, together with a diagonal attention denoiser that recovers perturbed representations without leaking spatial information. At inference time, the SparseLearn module is entirely discarded, and the trained scorer applies a deterministic Hard Top-K operator to keep only the highest scoring 32 tokens, incurring no extra computation. By compressing the visual sequence down to a sparse set of just 32 tokens, which represents as little as 0.78% of the original length, our framework achieves 73.32% overall accuracy on SlideBench (TCGA), consistently surpassing sampling-based baselines and general-purpose vision language models. It also demonstrates strong zero shot generalization on SlideBench (BCNB) and WSI VQA*. By resolving the visual context bottleneck and preventing the dilution of sparse diagnostic evidence, this work provides a highly efficient paradigm for end to end gigapixel whole slide image reasoning.

Multiple instance learning (MIL) has become a standard paradigm for whole slide image (WSI) analysis in digital pathology, as it enables slide-level prediction without dense annotations. Existing MIL methods typically rely on exhaustive extraction and encoding of high-resolution patches. However, this practice suffers from two critical limitations in real-world clinical settings: it struggles to capture global visual cues at lower magnifications, and incurs substantial computational overhead due to the massive number of high-resolution patches per slide. To address these limitations, we propose an efficient low-resolution multiple instance learning (LRMIL) framework that transfers high-resolution knowledge to low-resolution representations. LRMIL adopts a two-stage distillation strategy. First, patch-level cross-resolution distillation aligns low-resolution patch embeddings with high-resolution representations. Second, slide-level knowledge distillation trains a low-resolution student MIL model under both slide-level supervision and teacher guidance. At inference time, LRMIL operates exclusively on low-resolution patches, substantially reducing data preprocessing and computational cost. Extensive experiments on multiple WSI benchmarks demonstrate that LRMIL consistently outperforms state-of-the-art MIL methods while achieving more efficient inference. These results highlight LRMIL as a practical and scalable solution for WSI analysis in clinical pathology.

Generating clinically useful pathology reports for pathology cases from whole-slide images (WSIs) is challenging due to gigapixel resolution, long visual-token sequences, and the complexity of case-level reasoning, where a single case may contain multiple WSIs with heterogeneous tissues and ambiguous findings. We present a simple token-efficient vision--language model for case-level synoptic report generation that remains practical under constrained GPU memory. Our architecture follows a minimal three-component design: a frozen pathology patch encoder, a lightweight two-layer MLP vision-language aligner, and a large language model decoder, with an explicit WSI marker token to separate slides within a case. Training proceeds in two supervised stages: (1) aligner-only WSI captioning using heterogeneous WSI-text pairs, and (2) case-level supervised fine-tuning on case-report pairs for structured report generation. To reduce sequence length, we represent each slide using $512 \times 512$ patches at $5\times$ magnification, which reduces the average sequence length by up to $64\times$ times compared to the commonly used $20\times$ patches. Combined with efficient training techniques, we enable practical training with only half a NVIDIA H100 GPU. Across both training stages, our approach achieves high ROUGE-L/METEOR/BLEU-4 scores while being substantially more efficient in memory and runtime. In AI-based evaluations, our model is consistently preferred over strong baselines. Extensive ablations characterize performance-efficiency trade-offs and identify simple choices that improve robustness in multi-WSI settings. Overall, this work provides a strong, reproducible baseline for efficient pathology report generation, lowering the barrier to multi-WSI VLM research under limited compute.

Weakly-supervised classification of whole-slide images with attention-based multiple instance learning (ABMIL) on top of foundation features now reaches near-saturation on Camelyon16 slide-level performance, but the corresponding attention maps are an imperfect localization signal: in clinical interpretation, a model that classifies correctly without firing on the actual lesion is hard to trust. We address this gap with cellular sheaves, which equip each vertex and edge of a graph with a finite-dimensional vector space and consistent linear maps between them, providing a principled way to detect local disagreement on graph-structured data. We apply cellular sheaves to weakly-supervised tumour localization on whole-slide images, combining a sheaf disagreement field with ABMIL. The natural training objective, encouraging consistency between similar features, produces a disagreement field that tracks tissue-level texture rather than diagnostic content. We propose attention-conditional consistency, which uses the classifier's attention to define which neighbouring patches should agree. Joint training of the classifier and the sheaf under this objective produces a disagreement field with patch-level AUC 0.940 on Camelyon16 and raises the attention head from its ABMIL-alone level of 0.717 to 0.953. Two-stage ablation with the classifier frozen at its ABMIL values reaches only 0.727 on the disagreement field and leaves attention at 0.717, confirming that the gain comes from the projector co-adapting under both objectives, not from the loss change in isolation. The trained model transfers without retraining to annotated slides from Camelyon17, maintaining Delta AUC 0.932 +/- 0.083 and attention AUC 0.955 +/- 0.099. The result is an attention map and a sheaf-disagreement map that fire on the same diagnostic regions, giving clinicians two complementary explanations for each slide-level prediction.

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.

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.

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.

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.

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.

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.

Whole slide image (WSI) analysis heavily relies on multiple instance learning (MIL). While recent methods benefit from large-scale foundation models and advanced sequence modeling to capture long-range dependencies, they still struggle with two critical issues. First, directly applying frozen, task-agnostic features often leads to suboptimal separability due to the domain gap with specific histological tasks. Second, relying solely on global aggregators can cause over-smoothing, where sparse but critical diagnostic signals are overshadowed by the dominant background context. In this paper, we present ReconMIL, a novel framework designed to bridge this domain gap and balance global-local feature aggregation. Our approach introduces a Latent Space Reconstruction module that adaptively projects generic features into a compact, task-specific manifold, improving boundary delineation. To prevent information dilution, we develop a bi-stream architecture combining a Mamba-based global stream for contextual priors and a CNN-based local stream to preserve subtle morphological anomalies. A scale-adaptive selection mechanism dynamically fuses these two streams, determining when to rely on overall architecture versus local saliency. Evaluations across multiple diagnostic and survival prediction benchmarks show that ReconMIL consistently outperforms current state-of-the-art methods, effectively localizing fine-grained diagnostic regions while suppressing background noise. Visualization results confirm the models superior ability to localize diagnostic regions by effectively balancing global structure and local granularity.

Background and Objective: Precise and scalable instance segmentation of cell nuclei is a fundamental prerequisite for computational pathology, yet gigapixel whole-slide images (WSIs) pose significant computational challenges. While patch-based processing is standard during training, existing methods are often limited to small tile sizes during inference due to architectural bottlenecks or reliance on computationally expensive post-processing for instance separation. We introduce a faster, scalable, and end-to-end framework capable of processing large-scale image tiles while accurately modeling biologically realistic overlapping nuclei. Methods: We propose LSP-DETR (Local Star Polygon DEtection TRansformer). The model represents nuclei as star-convex polygons and employs a lightweight transformer with linear complexity, enabling the processing of high-resolution images in a single forward pass. A novel radial distance loss accommodates annotation uncertainty, allowing the segmentation of overlapping nuclei to emerge naturally without explicit overlap labels. Results: LSP-DETR achieves state-of-the-art efficiency, with an inference time of 0.45 s/mm^2, a 3.2x speedup over StarDist, the next-fastest method. On PanNuke, the model achieves competitive accuracy (67.5 bPQ), while yielding an F$_1$-score of 0.964 in polygon overlap when evaluated against consensus annotations from two expert pathologists. Furthermore, it outperforms larger models such as LKCell in generalization robustness, reaching an F1-score of 85.0 on MoNuSeg. Conclusions: LSP-DETR bridges the gap between high-fidelity segmentation and practical clinical requirements by eliminating heuristic post-processing. By providing a scalable, linear-complexity solution that naturally handles overlaps between nuclei, this framework sets a new direction for efficient high-throughput WSI analysis in digital pathology.

While Vision-Language Models (VLMs) have achieved notable progress in computational pathology (CPath), the gigapixel scale and spatial heterogeneity of Whole Slide Images (WSIs) continue to pose challenges for multimodal understanding. Existing alignment methods struggle to capture fine-grained correspondences between textual descriptions and visual cues across thousands of patches from a slide, compromising their performance on downstream tasks. In this paper, we propose PathFLIP (Pathology Fine-grained Language-Image Pretraining), a novel framework for holistic WSI interpretation. PathFLIP decomposes slide-level captions into region-level subcaptions and generates text-conditioned region embeddings to facilitate precise visual-language grounding. By harnessing Large Language Models (LLMs), PathFLIP can seamlessly follow diverse clinical instructions and adapt to varied diagnostic contexts. Furthermore, it exhibits versatile capabilities across multiple paradigms, efficiently handling slide-level classification and retrieval, fine-grained lesion localization, and instruction following. Extensive experiments demonstrate that PathFLIP outperforms existing large-scale pathological VLMs on four representative benchmarks while requiring significantly less training data, paving the way for fine-grained, instruction-aware WSI interpretation in clinical practice.

The rapid digitization of histopathology slides has opened new opportunities for computational tools in clinical and research workflows. Content-based slide retrieval can help pathologists identify morphologically and semantically related precedent cases, supporting expert diagnosis and example-based education. Effective retrieval of whole-slide images (WSIs), however, remains challenging because gigapixel slides contain abundant irrelevant content, focal diagnostic patterns and slide-level semantic information that must be represented at a practicable search cost. Here we present PathSearch, a retrieval framework that combines fine-grained attentive mosaics with slide-level embeddings aligned through vision-language contrastive learning. Trained on 6,926 slide-report pairs, PathSearch captures both fine-grained morphological cues and high-level semantic patterns to enable accurate and flexible retrieval. The framework supports two key functionalities: (1) mosaic-based image-to-image (I2I) retrieval, ensuring accurate and efficient slide search; and (2) multimodal retrieval, where text queries can directly retrieve relevant slides. PathSearch was evaluated on eight tasks comprising 5,021 evaluation slides, spanning malignancy assessment on frozen and hematoxylin and eosin (H&E)-stained slides, lymph-node metastasis detection, tumor subtyping, mixed-gallery rare-cancer retrieval, and hepatocellular carcinoma (HCC) risk stratification. Internal and external experimental results demonstrate that PathSearch consistently outperforms the strongest existing methods without compromising multimodal accuracy. A multi-center reader study further demonstrated increases in task-level mean diagnostic accuracy, confidence, and inter-observer agreement with PathSearch's support. Together, these results support the effectiveness of PathSearch across diverse retrieval tasks and evaluation settings.

Cancer survival prediction from whole slide images (WSIs) is a challenging task in computational pathology due to the large size, irregular shape, and high granularity of the WSIs. These characteristics make it difficult to capture the full spectrum of patterns, from subtle cellular abnormalities to complex tissue interactions, which are crucial for accurate prognosis. To address this, we propose CrossFusion, a novel multi-scale feature integration framework that extracts and fuses information from patches across different magnification levels. By effectively modeling both scale-specific patterns and their interactions, CrossFusion generates a rich feature set that enhances survival prediction accuracy. We validate our approach across six cancer types from public datasets, demonstrating significant improvements over existing state-of-the-art methods. Moreover, when coupled with domain-specific feature extraction backbones, our method shows further gains in prognostic performance compared to general-purpose backbones. The source code is available at: https://github.com/RustinS/CrossFusion