Computational Pathology

Spatial Transcriptomics (ST) has transformed biomedical research by enabling the spatial mapping of gene expression across tissue sections. However, high operational costs, specialized equipment requirements, and sensitivity to experimental noise limit the accessibility and scalability of ST. Recent computer vision approaches aim to overcome these limitations by predicting spatial gene expression directly from histopathology images. While effective, current approaches often suffer from gene expression over-smoothing and overly uniform predictions across tissue regions, suggesting that further progress depends on learning representations that reflect the hierarchical and asymmetric structure of gene regulation and tissue morphology. To address these issues, we propose Hyperbolic Contrastive Learning with Entailment for Spatial Transcriptomics (HyCLoST), a hyperbolic contrastive learning model that captures the intrinsic hierarchical relationships within ST data. By leveraging hyperbolic geometry and a gene-to-image entailment loss, HyCLoST learns structured, biologically grounded representations that improve gene expression prediction accuracy, achieving a 6% reduction in MSE and an 8% increase in PCC across 26 ST datasets, over previous methods. Our source code is publicly available at https://github.com/BCV-Uniandes/HyCLoST

Unpaired cross-modal distillation transfers grade structure from histopathology into a micro-ultrasound (micro-US) encoder by aligning a pooled needle-region embedding to a frozen histopathology teacher under grade-group correspondence alone. A single objective is thereby required to serve two distinct functions: rendering patch features discriminative of tissue state, and selecting which patches enter the pooled representation. We decouple them. Weak spatial supervision derived from percentage involvement, recorded routinely at biopsy, constrains the predicted proportion of malignant tissue within each core, acting on the encoder features independently of the alignment objective. The alignment loss then operates on features that differ across a core, and attention concentrates on a subset of patches rather than remaining near-uniform. On 7,166 biopsy cores from 811 patients across seven centers under patient-level 5-fold cross-validation, the method reaches 67.1 macro AUC and 68.5 csPCa AUC, against 61.2 and 52.8 for the existing unpaired alignment method and 63.1 and 62.6 for the strongest unimodal baselines. Ablation against existing attention regularizers designed to prevent attention-uniformity collapse shows that such regularizers do not substitute for label-derived supervision: they constrain the attention distribution, whereas the signal required acts on the features that attention reads.

Early diagnosis of melanoma is critical for improving patient survival rates. However, accurately distinguishing melanoma from other skin lesions remains a significant clinical challenge due to the high visual similarity among lesion types and variability in image acquisition conditions. Artificial intelligence, particularly machine learning, has emerged as a promising tool to support dermatological diagnosis by automating feature extraction from medical images. Among the available approaches, convolutional neural networks (CNNs) have demonstrated strong performance in image classification tasks, making them well-suited for analyzing both dermatoscopic and histopathological images, given their ability to capture hierarchical visual patterns relevant to lesion characterization. Nevertheless, despite numerous pre-trained CNN architectures having been proposed, selecting the most appropriate one for a given imaging modality remains an open challenge. In this study, we evaluate pre-trained convolutional neural networks (CNNs) for skin lesion classification using dermatoscopic and histopathological image datasets. Experiments were conducted on the HAM10000, ISIC 2018, and CR-AI4SkIN datasets, evaluating the ResNet50, VGG16, VGG19, MobileNet, and InceptionV3 architectures under the same training protocol. The experimental evaluation showed that the models achieved accuracies ranging from 71% (InceptionV3 on ISIC 2018) to 84% (ResNet50 on HAM10000) on dermatoscopic images. For histopathological images, accuracies ranged from 72% (VGG19) to 83% (ResNet50) on the CR-AI4SkIN dataset. The results demonstrate that model performance differs between dermatoscopic and histopathological image modalities, showing that architectures exhibiting similar performance on dermatoscopic images exhibit different performance on histopathological data.

Multiple Instance Learning (MIL) is widely used for weakly supervised learning, particularly in digital pathology, where fine-grained annotations are costly. Most MIL methods aggregate instance features via attention mechanisms. However, attention weights do not always faithfully reflect instance importance and may focus on spuriously correlated regions. In this work, we propose CAR-MIL, a framework that explicitly guides attention learning through a counterfactual attention regularization objective inspired by counterfactual explanations. Built on a standard attention-based MIL architecture, our approach introduces a lightweight counterfactual attention branch trained to produce an alternative prediction while remaining close to the factual attention distribution. This encourages prediction changes to arise from minimal, structured redistributions of attention, leading to more informative evidence allocation. The resulting factual and counterfactual attention maps capture complementary evidence: the former highlights regions supporting the prediction, while the latter reveals regions whose reweighting would challenge it. We evaluate our method on synthetic MIL benchmarks with instance-level ground truth enabling controlled analysis of attention behavior and on five digital pathology datasets across four tasks. CAR-MIL maintains competitive classification performance, with the largest gains observed on more challenging tasks, while improving attention reliability, demonstrating the benefits of integrating counterfactual explainability reasoning into attention learning. Code is available at: https://github.com/ImaneCR/CAR-MIL/.

Pathology foundation models improve transferable representation learning for histopathology, but recent gains often rely on encoders with hundreds of millions of parameters and high inference cost. We propose TAP-Path, a task-adaptive compression framework that directly restructures a pretrained Virchow2 encoder rather than distilling it into a separate student. TAP-Path combines validation-driven transformer-block selection, physical removal of redundant blocks, input-adaptive patch-token pruning, multi-depth feature recovery, and a lightweight gated task head. The final model retains 24 of 32 transformer blocks and 70% of patch tokens after pruning, reducing encoder parameters by 24.96% (631.24M to 473.70M) and analytical encoder compute by 35.20% (340.13G to 220.40G FLOPs). Across three task-head optimization seeds, TAP-Path achieved $87.98 \pm 0.067$ test accuracy, $81.26 \pm 0.49$ balanced accuracy, and $82.38 \pm 0.48$ macro-F1 on a 32-class histopathology benchmark, compared with 86.89% for full Virchow2 and 87.67% for UNI2-h. TAP-Path achieved a Brier score of $0.1800 \pm 0.0005$ and failure-detection AUROC of $0.9047 \pm 0.0060$. A validation-only rare-aware objective improved rare-class balanced accuracy in a secondary operating analysis. Frozen external evaluation on 433 CPTAC samples yielded $91.22 \pm 0.83$ accuracy and $91.10 \pm 0.81$ balanced accuracy. These results show that task-adaptive structural and token sparsification can improve the accuracy-efficiency trade-off of large pathology foundation models while preserving reliability under internal and external evaluation.

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.

Clear cell renal cell carcinoma (CCRCC) grading is essential for treatment planning, yet existing approaches either analyze patch-level images directly or focus solely on nuclei-level classification, without linking to final tumor grading. We propose a semantic-guided multimodal preprocessing method that integrates nuclei classification maps from existing pre-trained models with RGB histopathology images for Vision Transformer (ViT)-based CCRCC grading. Our approach employs classification map channel concatenation and multiplicative modulation, with optimized overlays to leverage nuclei grading information, while preserving RGB textural features. Evaluation of multiple preprocessing strategies demonstrates that semantic-guided enhancement achieves 0.916 balanced accuracy, outperforming RGB-only baseline (0.707) and max-voting aggregation from prior studies (0.427). Sensitivity analysis reveals that this 21 percentage point improvement over baseline persists even under simulated perturbation at rates matching current state-of-the-art nuclei classification model error thresholds, suggesting both effective semantic utilization and practical robustness. These findings show that preprocessing-based multimodal fusion can leverage the diagnostic potential of existing imperfect nuclei classifiers, effectively bridging previously isolated fine-grained nuclear-level analysis with coarse-grained ViT-based patch classification. Per-class recall was consistent across grades (0.93, 0.91, 0.91), indicating that gains are not concentrated in the majority class. Because the sensitivity analysis perturbs ground-truth maps rather than predictions from an actual nuclei model, this result characterizes robustness under simulated error rather than deployment with a real upstream model, which remains for future work.

Stain normalization reduces color variations caused by variations in staining protocols and imaging conditions, thereby enhancing computer-aided diagnostic system performance. Traditional methods derive mapping relationships from individual or limited reference images through pixel-wise transformation, offering style flexibility but suffering from inaccurate color mapping extraction. While existing deep-learning-based approaches achieve accurate dataset-wide color mapping through complex neural networks, they face challenges including computational inefficiency, artifact generation, and fixed normalization directions requiring model retraining for directional changes. To address these limitations, we propose StainPresetNet - a novel framework that combines structural preservation with dataset-level color mapping while maintaining computational efficiency. Our method implements pixel-wise normalization guided by preset reference images, enabling multi-directional adaptability without retraining. Evaluations on cytopathology and histopathology datasets demonstrate that StainPresetNet achieves superior color mapping accuracy compared to conventional methods, effectively improves classifier generalization in diagnostic tasks, and reduces computational overhead by 90% versus existing deep learning approaches. The proposed preset-guided mechanism facilitates flexible adjustment of normalization directions through simple reference image replacement, overcoming the directional rigidity of current deep-learning-based solutions.

Virtual staining aims to computationally generate target-stained histopathological images while reducing the cost and time associated with conventional staining procedures. However, existing methods rely predominantly on strictly paired and accurately registered training data, which are difficult and expensive to obtain in routine practice. To reduce this dependence, we propose a stable semi-supervised virtual staining framework that jointly exploits both limited paired data and abundant unpaired source images. Directly incorporating unpaired images is challenging because their generated results lack corresponding targets for supervision, potentially leading to unrealistic staining, morphological degradation, or even training collapse. To obtain reliable supervision from these images, Hessian-derived morphology preservation extracts structural cues from each source image and constrains the generated output to retain tissue morphology. Histopathological realism constraints further guide the output toward plausible target-stain characteristics, preventing the source-derived structural supervision from degenerating into contour enhancement or simple color transformation. Together, the two components suppress structural and appearance drift, stabilize semi-supervised stain translation, and promote the preservation of diagnostically relevant information. Extensive experiments on H&E-to-IHC translation for Ki67 and HER2, as well as FFPE-to-H&E translation, demonstrate consistent improvements in image quality, morphology preservation, robustness, and downstream diagnostic performance. Code will be available.

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

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.

Whole slide images (WSIs) in digital histopathology are acquired at discrete magnification levels encoding complementary diagnostic information from global tissue architecture to fine-grained cellular morphology. Yet, deep learning models remain sensitive to scale variation. Existing magnification-invariant methods rely on multi-scale architectures at predefined discrete resolutions, while in clinical deployment the acquisition magnification varies continuously, rarely aligns with a model's fixed training resolution, and intermediate scales are common, so robust coverage otherwise demands a costly ensemble of magnification-specific models. We propose Conditional Layer Normalization (CLN), a lightweight mechanism that generates affine normalization parameters from input pixel size via a small MLP, integrated into standard CNN architectures for both WSI classification and segmentation. Trained on patches sampled continuously across a range of pixel sizes, the model decouples inference from scanner-dependent magnification and generalizes to arbitrary, previously unseen scales at test time. On the PANDA prostate cancer dataset, our approach on average matches or exceeds independently trained single-magnification models and ranks among the top three performers at every evaluated magnification, including those unseen during training. This collapses a five-model ensemble into a single network and reduces training, and inference cost roughly 4-5 times, while leaving the multiply-accumulate count unchanged. The code is available at: https://github.com/aflorkowska/OneModelToMagnifyThemAll.

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.

Hierarchical Phase-Contrast Tomography (HiP-CT) is a synchrotron based X-ray imaging technique that enables non-destructive, volumetric imaging of intact organs with multi-resolutions bridging 20 $μm$/voxel for whole organs to near-cellular resolution ($\sim$0.8 $μm$/voxel) in local regions. This offers the opportunity to bring volumetric whole-organ context to histology. However, nonlinear registration between H&E histology and HiP-CT volumes is challenging due to the differences in feature representations of different colour spaces. Synthesis-before-registration methods have shown strong results in histology-to-MRI and histology-to-CT alignment. However, existing approaches either rely on manual anatomical contours or are trained from scratch without semantic constraints, limiting their generalisability to soft tissue organs and novel modalities. We propose LoRCA (LoRA Cycle Adaptation), a cycle consistent style translation framework built on a shared frozen DINOv3 with modality-specific LoRA adapters, learning modality-specific representations that are decoded and adversarially trained. LoRCA enables structure-preserving translation without requiring paired training data. The frozen backbone is intended to be a structural anchor that prevents content drift by preserving pretrained semantic-extraction capability. We evaluate translation quality using Fréchet Inception Distance (FID) and structural fidelity via mutual information and Canny edge preservation. LoRCA outperforms CycleGAN in both translation quality and structural consistency. As a preliminary indicator of downstream registration utility, we find that style-translated images yield increased feature correspondences under MatchAnything on manually aligned HiP-CT and histology test pairs, suggesting that LoRCA-style translation is a promising step towards 2D histological sections to 3D HiP-CT volumes registration.

Test-time adaptation (TTA) has become a practical way to adapt deployed models to unlabeled target data, a setting that is especially relevant in computational pathology where staining, scanner, and cohort shifts are routine. While most TTA methods are evaluated by their effect on accuracy, clinical use also depends on whether the model's explanations remain reliable after adaptation. In this paper, we take a closer look at this largely unmeasured effect. We study explanation stability under TTA across two histopathology benchmarks, Camelyon17 and NCT CRC-HE, using five architectures ranging from convolutional networks to vision transformers and a pathology foundation model, seventeen TTA methods, and four attribution families. Across 2,958 adaptation runs, we observe a clear and systematic pattern: TTA methods differ sharply in how much they move model explanations, with frozen-backbone methods leaving attributions almost unchanged and continual methods such as CoTTA and RoTTA causing the largest drift. This effect is not uniform. Convolutional networks are substantially more sensitive than transformer and foundation-model backbones, and explanation drift increases with adaptation strength while remaining largely insensitive to batch size. Surprisingly, explanation stability is only weakly coupled to adaptation quality. Some methods preserve explanations almost perfectly while degrading calibration or accuracy, producing silent failures that would be missed by accuracy-only or explanation-only evaluation. These findings show that explanation stability is a distinct reliability axis for TTA in computational pathology. We release the metric, protocol, and full benchmark to support future work on adaptation methods that are not only accurate, but also stable and clinically auditable. Code: https://github.com/bahumanyarg11/tta-explanation-stability-pipeline

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

Accurate diagnosis in Digital Pathology (DP) relies on high-resolution whole-slide images, yet clinical deployment is often limited by hardware costs. Super-Resolution (SR) offers a promising alternative by computationally enhancing low-resolution acquisitions. However, existing SR methods frequently struggle to preserve fine-grained cellular morphology, leading to texture oversmoothing and blurred structural boundaries under complex tissue variability. To address this issue, we propose Morph-ISR, a morphology-aware implicit super-resolution framework for DP that restores diagnostically relevant details with sub-pixel precision. Morph-ISR reformulates SR as a continuous coordinate-based reconstruction problem and integrates an Implicit Position-aware Kernel Generator (IPKG) to adaptively model spatially varying tissue morphology. To further enhance structural fidelity, a Morphological Fidelity Prior (MFP) is introduced, leveraging semantic guidance from a pre-trained cell segmentation network to enforce boundary-preserving and region-aware reconstruction, thereby improving the representation of critical cellular boundaries and nuclear textures. Experiments on TCGA and SurGen datasets show that Morph-ISR achieves the best LPIPS and ST-LPIPS among the evaluated methods, reducing them by up to 38.37% and 39.55%, respectively, over the second-best methods while maintaining strong PSNR and SSIM. These results demonstrate superior preservation of diagnostically relevant cellular boundaries and nuclear textures, while compact parameterization and high throughput support efficient edge deployment. Code and trained models will be released upon publication.

Digital pathology relies on high-resolution whole slide images for accurate diagnosis, yet limitations in imaging devices, storage, and transmission often make lower-resolution pathology images more common in clinical workflows. Current super-resolution techniques often tend to smooth diagnostically relevant morphology, leading to over-smoothed textures and semantic drift that compromise downstream clinical interpretation. To this end, we develop the Structural Semantic Synergy Diffusion Model (S3-Diff), a diffusion framework for high-fidelity super-resolution of pathological images. The core of S3-Diff is Specimen-aware Structural Anchoring (SSA), which combines prognosis-aware tissue support extracted by a fixed SAM with LR-HR gradient discrepancies to generate a specimen-specific structural anchor to preserve pathological morphology. Concurrently, we introduce Structure-guided Semantic Fidelity Tuning (SSFT) to adapt DINOv3 representations using SSA-derived structural supervision. SSFT combines the adapted semantic energy with LR-derived edge and grayscale cues. The resulting control guides denoising to suppress stochastic artifacts and maintain structural consistency. Extensive experimental results demonstrate that S3-Diff consistently outperforms state-of-the-art methods in both reconstruction quality and downstream survival analysis performance. The source code will be made public.

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.

Attention-based multiple instance learning (ABMIL) is the predominant approach for slide-level prediction in computational pathology, yet its attention maps provide only local explanations: they indicate where a model focuses but not which histological features drive its predictions or how the model behaves across a patient cohort. We present Semantic Attention Global Explanations (SAGE), a post-hoc framework that extracts global, language-grounded explanations from a frozen ABMIL model. Using a pathology vision-language model, SAGE scores image patches against a dictionary of 25 histological concepts, aggregates these scores according to the model's learned attention, and quantifies how each concept relates to prediction risk across a cohort. Applied to survival prediction using seven TCGA cancer cohorts and three foundation models, SAGE recovered established prognostic features, such as the adverse association of necrosis, while revealing cancer-specific biology, including a favorable angiogenic signature in renal cell carcinoma consistent with known molecular subtypes. Ablation studies demonstrated that these associations depend on the model's learned attention rather than concept prevalence alone, and that the concept dictionary captures much of the prognostic information encoded by the foundation model features. Through semantically-grounded explanations, SAGE provides a scalable, model-agnostic framework for understanding what ABMIL survival models learn, enabling pathologists to interpret model behavior at the cohort level and offering the potential for biomarker identification.

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.

Pathology foundation models (PFMs) provide strong tissue representations and have become central to digital pathology. However, deployment in disease-specific settings is limited by 1) the high computational cost of billion-parameter PFMs and 2) distribution mismatch and non-biological bias inherited from pan-cancer, multi-centre pre-training, including site-specific signatures and imbalanced disease prevalence. These factors can encourage shortcut learning and under-emphasise subtle morphology required for reliable modelling of a specific cancer type. We present SmartStu (a Smart Student), a framework to customise compact, breast-cancer-specific PFMs via distillation whilst mitigating confounding. SmartStu distils representations from multiple teacher PFMs into a lightweight student backbone. Crucially, we introduce adversarial distillation that leverages a dedicated noise model trained to predict nuisance, edge-dominated cues on the distillation set. Using this noise model as a counterexample, the adversarial objective encourages the student to recognise, yet suppress, features predictive of nuisance targets. We further incorporate multi-teacher ensemble distillation and an auxiliary self-supervised objective with artefact injection. We validate SmartStu on three external cohorts (Yale HER2, SLN-Breast, and BRACS) with multiple tiny backbones. SmartStu yields breast-cancer-specific PFMs that are over $30\times$ smaller than general PFMs whilst largely preserving, and sometimes improving, downstream performance measured by balanced accuracy (bAcc) and AUC. Code is available at https://github.com/zwchen03/advDistall.

Predicting spatial gene expression from histopathology images enables large-scale transcriptomic profiling without the cost of direct measurement. Existing methods decode the target gene set as a flat, unstructured vector, ignoring the inter-gene dependencies arising from shared biological pathways and regulatory programs. Without explicit structural guidance, models must infer these dependencies entirely from limited paired data, constraining prediction quality. We propose MSGR (Multi-Scale Gene Refiner), which bridges this gap by incorporating the Gene Ontology (GO), a curated functional hierarchy of genes, as an explicit structural prior. MSGR organizes target genes into a four-level GO tree. Its GO-guided decoder then progressively refines predictions from coarse functional domains to fine individual genes via residual corrections under scale-weighted supervision. Operating solely on the gene side, the GO-guided decoder serves as a seamless plug-in replacement that consistently improves existing architectures without requiring any image-side modifications. Extensive experiments on nine datasets from the HEST-1k benchmark provide empirical evidence for two central claims: GO-structured decoding consistently outperforms flat decoding, even against a state-of-the-art generative baseline, and the gain is attributable to biological ontology structure rather than hierarchical decomposition per se, as confirmed by a +0.027 margin over a structurally equivalent random hierarchy.

Volumetric CT vision-language pretraining learns 3D representations from scan-report pairs, but global and anatomy-aware objectives supervise only correspondence: they establish what is present and leave how much unconstrained. Nothing separates a mild from an extensive case of the same finding along a consistent direction, so the graded burden language in reports collapses into a present/absent signal. Longitudinal supervision would supply this order, but patient-matched CT pairs are scarce at scale; cross-sectional cohorts already encode weak burden cues across different patients. We introduce Spectrum, an anatomy-conditioned framework that represents each study at whole-study and organ scopes. For each organ-mapped pathology, a rule-based scorer mines confidence-filtered lower-to-higher pairs of different patients, and Burden-Direction Alignment (BDA) aligns the pathology-conditioned image delta with the report delta at each scope, separating that direction from its reverse. Because the endpoints are different people, a target-conditioned aligner first makes them comparable, so the delta reflects burden rather than between-patient variation. BDA further separates the selected direction from its reverse, anchors it to the observed higher-burden endpoint, and enforces consistency across ordered triplets. Since every pair is drawn within a single pathology, BDA is designed to constrain intra-class structure that image-report contrast alone never touches. Spectrum attains 85.6 zero-shot AUROC on CT-RATE and 72.7 on external RAD-ChestCT, with consistent gains in linear probing and retrieval. Weak cross-patient order is thus a scalable complement to anatomy-aware correspondence, yielding burden-aware CT representations without longitudinal data.

Multimodal large language models (MLLMs) are increasingly used to analyze pathology images. However, dominant multimodal benchmarks in pathology mainly score final diagnostic answers, captions, or reports. These evaluations provide limited insight into whether a model understands the multiscale visual content needed for pathology reasoning and decision-making. We introduce PathVU, a vision-anchored benchmark for fine-grained and multiscale visual understanding in computational pathology. Built from 23 public pathology imaging datasets with human-supervised labels and spatial annotations, PathVU evaluates MLLM understanding in two fields of view: Region FOV for high-resolution local regions and Slide FOV for macro whole-slide views. By converting raw annotations into deterministic task targets, PathVU enables programmatic scoring of region localization, visual recognition, quantity estimation, spatial reasoning, and insufficient-context judgment. The benchmark contains 14 VQA-style tasks, 61,673 images, and 308,070 samples across 28 organs and 7,253,526 annotations. Evaluating 18 representative general-purpose, medical-domain, and pathology-oriented MLLMs, we observe substantial limitations even in advanced models on fine-grained visual tasks across multiscale pathology images. PathVU provides a reproducible basis for developing and evaluating pathology MLLMs with explicit multiscale visual understanding.

Brain tumor diagnosis is a time-sensitive process in which patients may wait weeks for a finalized pathology report. This problem motivates automated systems that classify tumor subtype from multimodal inputs. This paper details the DS@GT ARC team's work for ImageCLEFmed MEDIQA-CORE 2026 Task~1, Brain Tumor Subtype Classification. The task evaluates three glioma classification problems: Level-1 Molecular Type, LGG vs HGG, and WHO Grade. We combine pre-extracted MRI (NeuroVFM) and histopathology (Prov-GigaPath) embeddings with free-text radiology reports. Our team explored two trimodal fusion architectures, two report encoders (RadBERT and Llama-3.1-8B-Instruct), and a biologically motivated post-processing stage. We achieve a mean macro-F1 of 0.801 under the Fully Multimodal condition, exceeding the organizers' baseline of 0.796 and ranking second among the teams whose code passed verification. Additional evaluation across modality-dropping conditions shows that this advantage depends heavily on the availability of the histopathology modality, and that our system falls behind the baseline when modalities are missing. Our code is available on GitHub at https://github.com/dsgt-arc/imageclef-mediqacore-2026.

Computational cytology on whole-slide images is challenging because malignant cells are rare, heterogeneous, and annotated slides are scarce. Anomaly detection frameworks can be trained on normal slide-negative patches and then applied at test time to flag abnormal patches in held-out slides. Most unsupervised anomaly detection approaches including generative ones (GAN-based and diffusion-based), are tuned to organ-level imaging and require large curated datasets. In cytology the signal is cell-centric: rotating or flipping a single-cell patch does not change its diagnostic class, yet standard diffusion models treat transformed views as distinct inputs, leading to transformation-dependent reconstructions and unstable anomaly scores. We propose a D4-equivariant diffusion framework that enforces rotation and reflection symmetry both architecturally, via a D4-equivariant U-Net, and at inference, via equivariant noise coupling and (optionally) frame averaging. This alignment with biological invariance yields transformation-consistent pseudo-healthy reconstructions and more stable anomaly ranking under symmetry. On two publicly available cytology datasets of bone marrow and peripheral blood smears, our D4-equivariant diffusion models achieve higher AUC and retrieve more abnormal cells in the top K predictions than non-equivariant generative baselines, a deep one-class, and a multiple instance learning based method, while substantially reducing score variance across rotations and flips. Code is available at https://swchmida.github.io/D4diffCyto/.

Histopathological examination primarily relies on hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining. Although IHC provides critical molecular information, it is costly and requires specialized expertise. Stain transfer provides an efficient alternative by computationally generating IHC from H&E images, but remains challenged by unified and interpretable modeling for heterogeneous biomarkers under pixel-unaligned supervision. We propose DMCoStain, a novel Data-Model Co-optimization framework for Stain transfer. It iteratively co-refines training data and model capability, improving staining accuracy and interpretability in both pathological and structural consistency. To refine training data in a clinically meaningful manner, it incorporates the Multimodal Expert-Guided Finer Selection (MEGFS) strategy, built upon a pioneering IHC-positive-expression (IPE) vision-language model (VLM) that emulates pathologist reasoning. To support MEGFS, we construct ImmunoInstruction, the first large-scale IPE instruction-following dataset with 150K VQA samples. Extensive experiments on multiple tissues and biomarkers demonstrate that DMCoStain achieves state-of-the-art (SOTA) accuracy. This paradigm offers strong practical value, and MEGFS also functions as a specialized evaluation tool for future model development. Dataset, code, and more details are in https://github.com/SikangSHU/DMCoStain.

Spatial transcriptomics assays remain costly and technically demanding, restricting transcriptome-wide profiling to specialist settings and preventing routine clinical deployment. Predicting spatially resolved gene expression from H&E histology could close this gap, yet current methods largely ignore the underlying tissue architecture and rarely quantify how their predictions can be trusted. We introduce HierarchicalDAEW, a dual-graph architecture that addresses both gaps. On the spot graph, a Domain-Aware Edge-Weighted convolutional operator learns separate projections for inter-domain, intra-domain, and boundary edges derived from Leiden clustering, allowing the model to treat tissue heterogeneity as an explicit structural signal rather than an implicit one. A second gene-level graph then fuses protein-protein interaction priors from STRING-DB with tissue-specific co-expression through learned attention gating, propagating predictions from a landmark gene set to a broader gene panel. Reliability is handled through evidential uncertainty estimation, which produces far better calibrated confidence intervals than Monte Carlo dropout under identical conditions. Across six human Visium sections spanning breast, colorectal, prostate, and cerebellar tissue, and against thirteen published baselines, HierarchicalDAEW achieves the strongest correlation with ground-truth expression, with gains that hold up under multi-seed reproducibility checks and negative controls that rule out positional shortcuts. Ablations further confirm that both the domain-aware edge typing and the hierarchical depth are necessary to this improvement, and calibrated uncertainty estimates identify low-confidence predictions for pathologist review before clinical action.

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.

Prostate cancer diagnosis with multiparametric MRI (mpMRI) is commonly based on PI-RADS assessment or binary classification, which suffer from subjectivity and fail to capture clinically relevant pathological heterogeneity. To address this limitation, we construct a Prostate Cancer Histopathology Spectrum Dataset (PCa-HSD) and formulate a clinically meaningful four-class classification task, addressing the underrepresentation of benign lesions that are easily confounded with prostate cancer in existing datasets. We propose Language-guided Segmentation-assisted Diagnostic Transformer model (LSDT), which leverages zero-shot segmentation to provide anatomical priors and performs effective multi-modal slice fusion for classification. Our proposed method consistently improves accuracy across backbones, achieving the best average accuracy of 0.633 and JointRecall of 0.768 in five-fold cross-validation on a cohort of 344 patients. These results demonstrate that integrating pathology supervision and anatomical priors significantly enhances fine-grained prostate MRI classification and provides a more clinically relevant paradigm for risk stratification. Code will be made publicly available in a future revision.

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.

Positive margins in head and neck oncologic surgery require mapping specimen-side pathology findings to the patient resection bed. This is challenging because pathologists identify the positive margin on slices of the resected, deformed specimen, while surgeons must relocate the corresponding site on the resection bed using only verbal descriptions and no visual guidance. We present a marker-free augmented reality (AR) workflow for mapping a margin label from a three-dimensional specimen scan to the resection bed. The method combines contour-constrained deformation, residual alignment to a depth scan, surface-based fusion to a head-mounted display, and target projection onto the reconstructed bed. Bead-suture correspondences estimate specimen deformation, whereas patient-to-display fusion does not require external fiducial markers. Following formative experiments, five residents and surgeons performed cadaveric cheek and scalp re-resection tasks under verbal guidance, verbal guidance with specimen examination, and AR guidance. Deformation target errors were $7.63 \pm 3.74$ mm for the cheek and $3.72 \pm 1.02$ mm for the scalp; residual specimen-to-bed distances were $2.43 \pm 2.15$ mm and $2.19 \pm 1.06$ mm, respectively. Fusion error did not differ significantly between marker-free and marker-based methods on either cadaver; overall marker-free fusion error was $2.15 \pm 0.87$ mm. End-to-end margin localization error decreased from $21.40 \pm 3.84$ mm with verbal guidance and $16.09 \pm 4.30$ mm with specimen examination to $6.19 \pm 1.79$ mm with AR guidance ($p < 0.001$). Online fusion required $5.23 \pm 0.34$ s. These results demonstrate effective marker-free AR guidance for positive-margin localization and support more precise tumor resection.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths globally, with approximately 1,926,425 new cases and 904,019 deaths reported in 2022. Accurate histologic grading plays a critical role in prognosis and treatment planning for colorectal adenocarcinoma. In recent years, artificial intelligence and its subcategories, including machine learning and deep learning, have been increasingly employed for automated cancer detection and classification. An appropriate and well-organized dataset is the essential first step to achieve this goal. This paper introduces CRC-HGD, a histopathological microscopy image dataset of 1,914 images obtained from 214 colorectal adenocarcinoma patients (Grade I: 106, Grade II: 75, Grade III: 33). The specimens are H&E-stained colorectal tissue sections acquired at the Poursina Hakim Research Center of Isfahan University of Medical Sciences, Iran, diagnosed between 2014 and 2019, and graded according to the World Health Organization (WHO) criteria into three grades: well-differentiated (Grade I), moderately differentiated (Grade II), and poorly differentiated (Grade III). For each specimen, four magnification levels are provided: 4x, 10x, 20x, and 40x. The dataset is accessible via Mendeley Data (https://doi.org/10.17632/yfp5sfj47m.4) and at http://databiox.com, where the latest version is also available. The distinctive feature of this dataset is the provision of labeled specimens across all three differentiation grades at multiple magnification levels, enabling comprehensive computational analysis of colorectal cancer grading.

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.

Causal inference using front door intervention and multi-instance learning (MIL) has advanced the analysis of Whole Slide Images (WSI) in digital pathology. These methods adjust feature distributions of subtle evidence sub-images to correctly associate them with WSI-level diagnoses. We propose and prove 2 hypotheses for evaluating such methods: 1) Causal inference MIL introduces an independent classification channel that effectively completes WSI classification; 2) Greater difference between features extracted by the new and baseline channels increases effectiveness in eliminating false correlations. This hypothesis describes the core of causal inference MILs: overlaying parallel, independent channels to eliminate false associations between WSI-level diagnostic and non-diagnostic evidence sub-images by increasing deep feature diversity. Based on these hypotheses, we evaluated several causal inference MILs on breast cancer and non-small cell lung cancer datasets. This hypothesis provides a new theoretical perspective for applying causal inference to WSI analysis.

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

Deep learning-based segmentation of histopathology whole-slide images (WSIs) requires large amounts of pixel-level annotations, which are costly and time-consuming to obtain. Active learning (AL) has been proposed to reduce this effort, but existing methods exhibit three key limitations. Uncertainty estimation is unreliable on partially annotated WSIs, patch-level acquisition is inconsistent with slide-level annotation workflows, and class imbalance in multi-class settings is not explicitly addressed. To address these challenges, we propose SHAL (Slide-level Hybrid Active Learning), a patient-level AL framework for annotation-efficient multi-class histopathology segmentation. SHAL integrates three complementary components: a foreground-aware strategy that suppresses bias from unlabeled background regions, a stage-adaptive mechanism that hybridizes predictive entropy and epistemic uncertainty across learning stages, and a class-aware strategy that prioritizes diagnostically relevant tissue classes. SHAL is evaluated on the TCGA colorectal cancer dataset. It achieves the highest Macro Dice at the full annotation budget (0.846) and reaches Dice greater than or equal to 0.80 using only 26 percent of the budget (50 of 190 slides), whereas competing methods reach this threshold only at 37 percent (70 slides). Across five independent external cohorts, SHAL attains the highest mean external Macro Dice (0.815) and the smallest internal-to-external generalization gap among all methods (0.025 at Round 3 and 0.026 at the full budget). The results indicate that patient-level hybrid uncertainty acquisition reduces annotation cost without sacrificing cross-domain generalization in computational pathology.

Whole slide images (WSIs) provide rich diagnostic information for computational pathology, but their gigapixel scale, stain variation, scanner differences, tissue artifacts, and limited expert annotation make robust model training challenging. This paper presents a multi-source Masked Autoencoder (MAE) framework, named ProsMAE, for histopathology representation learning. Tiles from Prostate cANcer graDe Assessment (PANDA), CAncer MEtastases in LYmph nOdes challeNge 2017 (CAMELYON17), and BReAst Carcinoma Subtyping (BRACS) are used for ProsMAE pretraining to expose the encoder to diverse tissue morphology and acquisition conditions. The learned encoder is transferred for International Society of Urological Pathology (ISUP) grade classification through ProsCLS, using a frozen encoder and a linear classification head. ProsMAE achieved a higher mean validation quadratic weighted kappa (QWK) than the vanilla MAE frozen linear-probe baseline under the evaluated disjoint PANDA split. Repeated-split evaluation remains necessary to further establish robustness across split compositions.

Model merging offers a practical alternative to conventional continual learning by integrating independently fine-tuned models without retaining previous training data. Recent state-of-the-art model merging methods employ test-time adaptation (TTA-guided merging) to address distribution shifts by adjusting merging-related variables using unlabeled target data. However, these methods have primarily been studied in multi-task or single-target settings, and their behavior under sequential continual learning remains insufficiently understood. We present a benchmark study that maps this family of methods to rehearsal-free continual Whole Slide Image classification and evaluates them against traditional continual-learning approaches. Experiments on six TCGA cancer-subtyping cohorts cover CLASS-IL and TASK-IL scenarios, in-domain and out-of-domain evaluation, and different task orders. The results show that adapting model merging at test time can provide strong task-specific performance and improve retention of previously acquired knowledge without storing historical WSIs. Nevertheless, performance remains sensitive to task order and to the interaction between adaptation on the current distribution and accumulated knowledge. This benchmark identifies model merging with test-time adaptation as a promising direction for continual computational pathology and motivates future methods that balance adaptation to domain shift with explicit preservation of historical knowledge.

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.

Spatial Transcriptomics (ST) measures gene expression while preserving spatial context, but its high cost and low throughput leave public datasets small. Inferring expression directly from widely available Hematoxylin and Eosin (H&E) stained histology offers a cost-effective alternative. However, existing approaches face several limitations: regression methods over-smooth toward the conditional mean, while generative methods are faithful but require slow multi-step inference; most methods treat genes as independent and equally important, ignoring inter-gene dependencies and heterogeneous gene informativeness; and most are tailored to a single resolution, either spot-level or cell-level. To address these issues, we propose DriftST, a unified framework for inferring spatially resolved gene expression from H&E images. DriftST builds on a Cellular Drifting generative model that learns a direct drift from a histology-conditioned source to the expression distribution, retaining generative expressiveness while enabling efficient one-step generation. To capture gene structure, we introduce the STransformer, which combines a co-expression attention module for inter-gene dependencies with a gene residual gate for differential gene importance. Operating on a generic gene-panel representation, DriftST applies directly to both spot-level and cell-level data in one framework, and extensive experiments across diverse tissues and platforms show that it achieves state-of-the-art performance at both resolutions.

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.

A unified multiplex virtual staining model enables scalable and non-destructive multiplex analysis from H&E slides while promoting parameter efficiency, shared pathological knowledge, and consistent cross-biomarker representations. However, in clinical practice, data for new biomarkers are typically acquired sequentially over time. Fine-tuning on such temporally arriving data leads to severe performance degradation on previously learned biomarkers, as sequential optimization disrupts the structured relationships among biomarker representations in the latent space. To address this issue, we propose ContiStain, an IHC multi-domain relational distillation framework for continual virtual staining. We first (i) construct a domain-aware structured feature space using a mixture-of-experts (MoE) feature extractor to reduce representation interference across biomarker domains. Based on this stabilized feature space, we then (ii) propose a relation-preserving distillation strategy that explicitly enforces the consistency of cross-domain token-level cosine similarity matrices between learned biomarker domains during continual adaptation. By maintaining cross-domain structural coherence, ContiStain mitigates forgetting while retaining adaptability to new domains. Experiments on the MIST dataset under a four-domain sequential virtual IHC staining setting show improved stability, reducing FID and ConchFID by 11.1 and 60.9 compared to sequential fine-tuning, enabling scalable and robust multi-domain virtual staining. Code is released at https://github.com/ccitachi/ContiStain.

As hematoxylin & eosin (H&E) staining constitutes the primary entry point in routine diagnostic workflows, computer-aided diagnosis from whole-slide H&E images is of particular clinical relevance. However, substantial variability in specimen preparation, staining protocols, and scanning conditions, together with inherent uncertainty in expert pixel-level annotations, makes automated analysis of H&E-stained images challenging. In this study, we propose a semantic segmentation-based framework for image-level diagnosis, grounded in the clinically motivated assumption that each histopathological image corresponds to a single cancer type. Image-level predictions are obtained by assigning the class of the dominant pixel-level label in the segmentation output. To ensure clinical relevance, we adopt the nnU-Net architecture and train it on a publicly available dataset collected in our study with pixel-level annotations for three liver cancer types: hepatocellular cacrcinoma (HCC; 55 images from 30 patients), cholangiocellular carcinoma (CCA; 55 images from 29 patients), and colorectal metastatic adenocarcinoma (CMA; 60 images from 30 patients). Annotations were independently provided by four pathologist. We hypothesize that the combination of stain normalization and semantic segmentation mitigates domain shift and reduces sensitivity to annotation noise. Five-fold cross-validation yielded balanced accuracy of 0.975 (HCC), 0.950 (CCA), and 1.000 (CMA), comparable to results obtained with immunohosthochemical staining and superior to several deep learning models trained on patch-level annotations. The proposed framework has the potential to support pathologists in prioritizing immunohistochemical marker selection, thereby reducing diagnostic costs and turnaround time. Integration with immunohistochemical findings improve overall diagnostic reliability.

Autonomous computational pathology (ACP) converts high-level pathology analysis goals into executable, traceable and clinically bounded workflows. Realizing this capability requires adapting general agentic harness systems to pathology-specific tasks, tools, evidence standards and clinical claim boundaries. We contribute ACP-Bench, a framework that adapts existing harness systems from computational pathology support toward ACP workflow capability. ACP-Bench evaluates 41 pathology workflow tasks, including 24 biomarker, 7 morphology and 10 prognosis tasks spanning 6 body-system groups and 9 endpoint families. The benchmark evaluates 9 models and 3 harness groups (Claude Code, Codex and Open Code), yielding 369 complete trajectories. ACP-Bench evaluates each trajectory across workflow execution, diagnostic performance and clinical-boundary alignment, combining expert-adjudicated process audits, diagnostic assessment and pathologist-validated safety review. Across evaluated systems, workflow initiation, task interpretation and diagnostic reporting were more mature than tool-bound execution, result binding and reflective workflow revision, and formal end-to-end completion remained rare. ACP-Bench provides a reusable standard for auditing whether agentic systems can operationalize pathology workflows before claims of reliable clinical autonomy.

Automated pathology report generation from Whole Slide Images (WSIs) has attracted increasing attention in digital pathology. However, existing methods are predominantly developed under single-organ settings, overlooking the multi-organ scenarios encountered in clinical practice, where organ types typically follow a long-tailed distribution. To address this gap, we identify two critical biases: (1) visual representation bias, where the encoder favors head-class patterns over tail-class discriminative features, and (2) textual decoding bias, where the decoder overfits to head-class narrative patterns, yielding diagnostically unreliable outputs for tail-class organs. To mitigate these two biases, we propose a novel Prior-anchored multi-Organ pathology report Generation framework (PriOrGen). Specifically, a Visual-Prototype Anchored Bottleneck module leverages the information bottleneck principle with learnable anchor representations to selectively retain diagnostically relevant visual information while filtering out head-biased redundancy. Secondly, a Meta-Report Anchored Bank module constructs an organ-specific meta-report anchored bank and retrieves organ-faithful textual priors to steer the decoder away from head-class narrative patterns. Extensive experiments on a multi-organ pathology dataset demonstrate that our method effectively mitigates long-tail biases and achieves superior report generation performance across both head and tail organ categories compared to state-of-the-art methods.

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

Micro-ultrasound ($μ$US) is a new, emerging, and promising imaging modality for prostate cancer (PCa) detection, but accurate identification of suspicious tissue remains highly dependent on clinical experience, leading to substantial inter-observer variability. Machine-learning assistance can reduce this variability; however, training reliable deep models is challenging because supervision is sparse and noisy -- typically limited to core-level histopathology outcomes (e.g., cancer grade and its percentage in a biopsy core) without pixel-level lesion annotations and under severe class imbalance. We introduce Prost-RL, which reframes $μ$US PCa detection as a spatially aware, policy-driven inference problem by learning where to look before decoding. Prost-RL integrates a lightweight reinforcement-learning policy into a foundation-model encoder-decoder to generate interpretable spatial attention maps that act as soft prompts for both cancer-likelihood heatmap prediction and image-level classification. We further propose Adaptive Policy Optimization (APO) to stabilize hybrid supervised-RL training and a noise-robust objective combining symmetric cross-entropy with negative-entropy regularization to mitigate weak-label noise and encourage sharp localization. On a cohort of 6,607 biopsy cores from 693 patients across five clinical sites, Prost-RL achieves $79.0\pm3.5$ AUROC with $64.6\pm6.3$% sensitivity at 80% specificity for core-level detection (+2.1 AUROC and +4.5 sensitivity points over the strongest baseline), and $79.3\pm5.8$ AUROC for clinically significant cancer classification. The learned policy highlights biopsy-aligned regions, providing transparent, spatially grounded evidence alongside quantitative risk predictions. Code is available at: https://github.com/DeepRCL/Prost-RL.

H&E-stained whole-slide images offer cohort-scale availability and rich spatial context but lack molecular specificity, whereas bulk RNA-seq provides transcriptome-wide resolution at high cost with limited archival availability. We show that training a lightweight alignment module atop frozen histopathology and RNA-Seq foundation models enables open-vocabulary molecular prompting -- querying H&E slides with gene-set signatures to predict pathway activity without sequencing or end-to-end retraining. Using contrastive learning on a multi-cancer cohort (N=1,720), we achieve a 25-fold improvement in retrieval over baseline methods. Systematic analysis reveals a graduated predictability spectrum: morphologically grounded programs (cell-cycle programs, immune-related) are most reliably predicted (R^2>0.5), while predicting pathways with no morphological footprint remains challenging as expected. We validate clinical utility on the POSEIDON clinical trial: H&E-predicted squamous cell carcinoma scores recapitulate NSCLC subtype identity and predicted IFN-gamma mirror PD-L1 tumor-cell expression groups. Furthermore, genesets describing immune activation and fibrosis predict known tumor microenvironment archetypes from histology alone. We further validate generalization of our approach across unseen cohorts and demonstrate data-efficient domain adaptation, establishing a slide-native framework for molecular analysis on H&E images.

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

Pathology foundation models (PFMs) have demonstrated strong potential across clinical and scientific applications, yet their performance is often hindered by batch effects, which are non-biological variations across tissue source institutions (TSIs) that distort learned feature representations and impair generalization. Conventional mitigation strategies, such as stain normalization, offer limited success in addressing these high-dimensional, complex artifacts. We present GLMP (General-purpose LLM-Mediated Pathology model), a novel framework that generates robust numerical embeddings from histology image patches through an intermediate textual representation. By leveraging pretrained general-purpose multimodal large language models (MLLMs) and text encoders, GLMP effectively prioritizes biologically meaningful signals over TSI-specific artifacts, thereby improving cross-institutional generalization. To our knowledge, GLMP is the first pathology model to use text descriptions of histological features as an intermediate representation for generating numerical embeddings from histology images. Our results highlight the untapped potential of broad-domain, non-specialized MLLMs in computational pathology and introduce a new paradigm for building versatile, generalizable, and robust pathology models.

Deep learning has demonstrated remarkable success in high-throughput histopathology image analysis. However, the performance of learning-based models critically depends on the quality and size of annotations by expert pathologists, which is a resource-intensive and time-consuming process. To address the limitations of data scarcity and annotation burden, several methods have been proposed to synthesize paired histopathology data. Nevertheless, these frameworks typically still require annotation data, albeit in reduced quantities, to impose structural constraints during training. In this work, we present CHIS, a plug-in framework that guides the sampling trajectory of a pretrained diffusion model through two key stages: structural initialization at the start and textural modulation during generation. The initial noise state is refined by fusing the phase information from a prior mask with the amplitude of Gaussian noise in the frequency domain, yielding a structurally informed starting point. During the reverse diffusion process, we adaptively modulate both coarse-grained and fine-grained textures at different wavelet decomposition levels. This enables a diffusion model pretrained solely on unlabeled images to generate outputs that align with prior structural masks while preserving the reference tissue style. We conducted extensive experiments demonstrating the superiority of CHIS in generation fidelity and its substantial benefits for downstream segmentation tasks. Code is available at https://github.com/IBIL-Code/CHIS.

Diffusion MRI (dMRI) tractography enables non-invasive reconstruction of white-matter pathways, but its accuracy is fundamentally limited by indirect, low-resolution measurements of axonal organization. Tracer injection studies in non-human primates provide a gold standard for validating dMRI tractography. This, however, requires time-consuming manual annotation of fiber bundles in histology sections. We propose a synthetic-data augmented framework for automated fiber bundle segmentation in macaque tracer histology. Our approach uses ex vivo dMRI tractography as a generative prior to synthesize 2D image patches for training. This provides us with sufficiently realistic foreground texture, which we compose with backgrounds from blockface photos and diversify via domain randomization. A 2D U-Net is trained on mixed real and synthetic patches. Experiments on held-out brains demonstrate improved generalization across brains and fiber bundle densities compared to training with real data only. Training with synthetic data only leads to poor performance, underscoring the need for real supervision. Overall, our approach achieves performance comparable to the state-of-the-art while requiring 3x less manually annotated data.

Recent studies have shown that spatial properties of tumors are critical for understanding disease biology and predicting patient outcomes. These spatial properties are increasingly uncovered through complementary modalities: spatial transcriptomics (ST) captures spatially-resolved molecular states, while hematoxylin and eosin-stained whole slide images (HE) reveal tissue morphology. While approaches are emerging to fuse these modalities, effective methods that learn not only joint representations but also incorporate spatial context across modalities are lacking. Here, we present JASPR (Joint Spatial Representation learning), a self-supervised deep learning framework that integrates HE images and ST data through a cross-modal reconstruction objective that incorporates spatial context within HE images and ST profiles. It employs shared modules to capture universal spatial properties across modalities, while modality-specific experts encode features unique to morphological and genomic data. We train and validate JASPR on breast cancer datasets, demonstrating that its learned joint representation substantially improves HE-based prediction of 9,248 genes and provides prognostic value for breast cancer outcomes.

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.

Training of neural networks for histopathology classification tasks typically relies on data encoding into latent space, which reduces complexity and improves performance. There are several encoder networks available, either pretrained on general image datasets such as ImageNET, or specifically on histopathological images. Training of encoder networks should be adapted to downstream tasks, allowing encoding of biologic/diagnostic content while rendering networks invariant to label-irrelevant transformations. This paper investigates the effect of classical image transformation on the latent space, using networks provided by Lunit Inc. and Bioptimus, both focusing on pathological images, and by Meta Research Team. We assess variance of embeddings resulting from standard data transformations by comparing original and transformed image embeddings and by contrasting them with random, unrelated embeddings, using image tiles from hematoxylin/eosin-stained sections available in a colorectal tissue dataset and the publicly accessible TCGA dataset. Our findings show that embeddings of original and transformed images are closer to each other than to random embeddings, indicating robustness to transformations. However, they are not fully invariant, revealing that the encoder networks do not completely neutralize transformation effects in latent space, explaining why transformation-mediated augmentation of datasets can improve performance. Significant differences were observed between general and histopathology-specific encoder networks.