Computational Pathology

Ask about this topic

Overview

Computational pathology studies how to extract diagnostic and biological information from digitized tissue and cell images, including whole-slide images, biopsies, and cytology. Common approaches include convolutional and vision-transformer models, weakly supervised multiple-instance learning for slide-level labels, and segmentation or graph methods for cells and tissue structure; benchmarks such as CAMELYON and PANDA test detection and grading. Foundation and vision-language models increasingly align image features with reports, clinical records, and molecular data for retrieval, prognosis, virtual staining, and spatial gene-expression prediction. A central challenge is ensuring that models remain reliable across hospitals, scanners, and stains while producing interpretable evidence and demonstrating benefit in prospective clinical workflows.

Latest papers

CardsList

279 papers33 papers in the last four weeks, up 18% on the four weeks before. 0.2% of all new papers.

Jun 6, 2026

A Multi-modal Agentic Co-pilot for Evidence Grounded Computational Pathology

Pathology is the cornerstone of modern medicine, where accurate decision-making relies heavily on evidence-based practices. While artificial intelligence (AI) has the potential to transform clinical workflows, the intersection of AI and evidence-based medicine remains under-explored, with primitive attempts restricted to text-only general medicine. In this work, we present PathPocket, a multimodal AI agentic co-pilot designed specifically for evidence grounded pathology. We construct the most comprehensive pathology evidence corpus to date, encompassing approximately 110,472 public and authorized documents structured across a rigorous hierarchy of evidence from clinical guideline to expert opinion. From this meticulously graded foundation, we build a large-scale multimodal pathology hypergraph containing over 4.55 million entities and 7.10 million relations. Serving as a robust knowledge engine, this hypergraph provides traceable evidence for a collaborative multi-agent reasoning framework integrating input understanding, evidence retrieval, filtering, and diagnosis generation. This enables PathPocket to seamlessly resolve a wide spectrum of clinical tasks, ranging from text-only queries to complex multimodal diagnostics involving region-of-interest (ROI) and gigapixel whole-slide images (WSIs). We rigorously evaluate the system on a multidimensional benchmark of over 200,000 real-world cases, where it significantly outperforms existing state-of-the-arts. Crucially, extensive user studies demonstrate that PathPocket substantially improves the diagnostic accuracy and confidence of pathologists. By directly grounding pathology interpretations in verifiable literature, PathPocket offers a practical and scalable solution for the future of evidence grounded computational pathology.

Zhe Xu, Zhengyu Zhang, Zhiyuan Cai +12

Department of Computer Science and Engineering, Hong Kong University of Science and Technology, Hong Kong, China · Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China · Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China +7

Computational PathologyClinical Decision SupportMedical QAMultimodal AgentsKnowledge GraphsWhole-Slide Image Analysis+1
AskPDF
Jun 5, 2026

Mitosis Detection in the Wild: Multi-Tumor and Context-Aware Generalization in the MIDOG 2025 Challenge

Automated mitosis detection is a well-established task in computational pathology. While previous benchmarks focused on scanner-induced domain shift, clinical "real-world" application requires models to be robust across the vast variance to be expected in the histological landscape. The MItosis DOmain Generalization (MIDOG) 2025 challenge was designed to evaluate algorithmic performance across unprecedented biological and contextual diversity. We curated a test dataset of 365 cases, encompassing 12 distinct human, canine and feline tumor types, digitized across multiple scanning platforms. Moving beyond hand-selected hotspots, the challenge required detection also in random tissue areas (representative of the whole slide detection situation) and challenging areas (areas rich in hard negatives). In the second track, we introduced the classification of atypical mitotic figures (AMFs). There were 18 teams submitting to the detection track, with F1 scores ranging up to 0.740. In the AMF detection track, we had 21 submissions with balanced accuracy values up to 0.908. Our analysis reveals that while most models perform reliably in traditional hotspots, significant performance degradation occurs in challenging ROIs, where false positive rates tripled. Furthermore, performance varied significantly across the 12 tumor types, highlighting "blind spots" in current state-of-the-art architectures when encountering rare or highly pleomorphic malignancies. Moreover, we evaluated the effectiveness of ensembling and found a mean increases of 1.5 and 1.3 percentage points in F1 score and balanced accuracy, respectively. In contrast, TTA showed no relevant improvement. MIDOG 2025 demonstrates that "in the wild" mitosis detection remains a significant hurdle. The transition from hotspot-only evaluation to a multi-contextual framework provides a more realistic proxy for clinical reliability.

Marc Aubreville, Jonas Ammeling, Sweta Banerjee +64

Computational PathologyDomain GeneralizationMedical Image Anomaly DetectionOncologyMedical Image BenchmarksWhole-Slide Image Analysis
AskPDF
Jun 5, 2026

DualGate-Net: A Prior-Gated Dual-Encoder Framework for Histopathology Cell Detection

Cell detection in histopathology images strongly depends on surrounding tissue context, where visually similar cells may belong to different classes under different microenvironments. Recent tissue-aware methods incorporate contextual priors, but often rely on static fusion strategies that may propagate noisy information. In this work, we propose DualGate-Net, a prior-aware dual-encoder framework that combines a ConvNeXtV2-based local encoder and a SegFormer-based global encoder through a learnable prior-gated fusion mechanism. The proposed module adaptively regulates the influence of tissue priors across spatial locations, while an auxiliary foreground reconstruction branch preserves high-frequency cellular structures during training. In addition, auxiliary cellness-guided cues are incorporated to further improve localization robustness. Experiments on the OCELOT benchmark demonstrate consistent improvements, achieving macro F1-scores of 0.7722 on the validation set and 0.7345 on the test set, highlighting the effectiveness of adaptive prior integration for robust histopathology cell detection.

Bahman Jafari Tabaghsar, Son Tran, K. Devaraja +1

School of Information Technology, Deakin University, Burwood, VIC 3125, Australia · Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India

Computational PathologyMedical Image Localization
AskPDF
Jun 4, 2026

Symb-xMIL: Symbolic Explanations for Multiple Instance Learning in Digital Pathology

Explanations of multiple instance learning (MIL) models are widely used for validation and discovery in digital histopathology. Existing methods primarily rely on heatmaps that highlight influential regions but do not explain how evidence from different tissue regions is combined to produce a prediction. This limits interpretability, especially when decisions depend on interactions between tissue features. We introduce Symbolic explainable MIL (Symb-xMIL), a post-hoc explanation framework that quantifies how a MIL model's behavior aligns with human-readable decision rules, expressed as logical relationships (e.g., AND, OR, NOT) between input features. These alignment scores reveal semantic patterns underlying the model's predictions. We evaluate Symb-xMIL on synthetic and real-world histopathology datasets. On synthetic MIL data, Symb-xMIL reliably recovers ground-truth logical rules. In a clinical tumor detection task, the best-aligned rules uncover heterogeneous decision patterns and expose hidden model errors. On an HPV-prediction task on TCGA-HNSCC, a cohort of head and neck cancer, our framework refines patient survival stratification beyond HPV status with potential clinical relevance. Overall, Symb-xMIL extends MIL explainability beyond visual attribution toward structured, rule-based reasoning, enabling more transparent and semantically grounded interpretation of model predictions.

Yanqing Luo, Julius Hense, Niklas Prenißl +4

Berlin Institute for the Foundations of Learning and Data, Berlin, Germany · Machine Learning Group, Technische Universität Berlin, Berlin, Germany · Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany +10

Computational PathologyExplainable Medical Image AnalysisHistopathology Image ClassificationMultiple Instance Learning
AskPDF
Jun 3, 2026

A Pathology Foundation Model for Gastric Cancer with Real-World Validation

Gastric cancer remains a major cause of cancer mortality, yet its histological and molecular heterogeneity complicates diagnosis and risk stratification. General-purpose pathology foundation models (PFMs) often plateau on fine-grained endpoints central to gastric cancer care, and few have undergone rigorous prospective validation or clinical reader studies. We present GRACE, a Gastric-specific foundation model for Real-world Assessment and Clinical dEcision support. GRACE was developed from multicenter gastric pathology datasets totaling 48,364 primarily HE-stained whole-slide images from 37,493 patients. When evaluated on 28 clinically relevant tasks, GRACE consistently outperformed representative pancancer PFMs, achieving a macro-AUC of 0.9188, with strong performance for precancerous lesion diagnosis (macro-AUC 0.9322), tumor histopathological assessment (macro-AUC 0.9119), molecular profiling (macro-AUC 0.8682), and prognostic prediction. Beyond benchmarking, GRACE's translational value was substantiated through a rigorous evidence chain. Under safety-gated criteria requiring 100% NPV for rule-out and 100% PPV for rule-in, GRACE streamlined review for up to 69.6% of malignancy-diagnosis cases and triaged 46.8% of MMR-IHC follow-up requests. This translational feasibility was further strengthened by a randomized crossover reader study of pathologist-AI collaboration. With GRACE assistance, diagnostic accuracy improved from 82.0% to 89.9%, yielding nearly twofold higher adjusted odds of a correct diagnosis (OR 1.987) alongside concurrent gains in sensitivity and specificity. AI assistance also reduced diagnostic time by 14.9%, elevated diagnostic confidence by 9.0%, and markedly improved inter-rater agreement. When calibrated to maintain non-inferior performance to senior pathologists, the AI-assisted workflow could triage 60.7% of atrophy and 82.7% of intestinal metaplasia cases.

Ling Liang, Jiabo Ma, Zhengyu Zhang +25

Department of Computer Science and Engineering, The Hong Kong University of Science and Technology, Hong Kong SAR, China · Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China · Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China +18

Computational PathologyMedical DiagnosisClinical Decision SupportPathology Foundation ModelsOncologyHistopathology Image Classification
AskPDF
Jun 1, 2026

Pathway-Structured Privileged Distillation for Deployable Computational Pathology

Integrating transcriptomics and histopathology can improve cancer risk modelling, yet practical use is constrained by the limited availability of RNA profiling in routine settings. Here we introduce Mixture of Pathway Experts (MoPE), a knowledge-distillation framework that reframes multimodal learning as privileged distillation for histology-only inference. MoPE is motivated by the partial observability between RNA profiles and whole-slide images: histology can capture morphology-linked consequences of certain molecular programmes, but cannot be expected to reconstruct the full transcriptomic state. MoPE encodes RNA-derived pathways and transfers the molecular supervision to pathway-indexed pathology experts through memory-usage alignment. Across diverse public benchmarks and two independent breast cancer cohorts, MoPE consistently improved WSI-only inference performance relative to baseline methods. Pathway-usage analyses and human-audited visual inspection provide bounded inspection of model behaviour and candidate morphology-linked readouts. These results support pathway-structured privileged distillation as a promising route to using molecular information during training while preserving RNA-free inference.

Yongxin Guo, Hao Lu, Onur Koyun +2

School of Medicine, Wake Forest University, Winston-Salem, NC, USA.

Computational PathologyOncologyMixture-of-Experts ModelsLearning Using Privileged InformationKnowledge DistillationWhole-Slide Image Analysis
AskPDF
Jun 1, 2026

GC-MoE: Genomics-Guided Cell-Type-Specific Mixture of Experts for Histology-Based Single-Cell Spatial Transcriptomics

Histology-based single-cell spatial transcriptomics (ST) estimation aims to predict gene expression for individual cells from histopathological images and cell locations, reducing the need for costly single-cell ST measurements. Unlike existing histology-to-ST methods that mainly predict spot-level profiles for local regions containing multiple cells, this task requires modeling cell-to-cell expression variability, which is strongly structured by cell type. We propose Genomics-Guided Cell-Type-Specific Mixture-of-Experts (GC-MoE), which estimates cell-type probabilities with a routing network and softly combines cell-type-specific experts for gene expression prediction. To further encode cell-type-dependent gene programs, we introduce the Cell-Type-Specific Co-Expression-Aware Predictor (CAP), together with a lightweight Cell-to-Cell Interaction Attention (C2CA) module for neighboring-cell context. Experiments and ablations on public single-cell ST datasets show consistent improvements over existing single-cell and adapted spot-level baselines.

Kaito Shiku, Ahtisham Fazeel Abbasi, Ryoma Bise +4

Kyushu University, Japan · German Research Center for Artificial Intelligence (DFKI GmbH), Germany · RPTU University Kaiserslautern-Landau, Germany +3

Computational PathologySpatial TranscriptomicsSpatial Gene Expression PredictionMixture-of-Experts ModelsGene Expression Prediction from Histopathology ImagesSingle-Cell Transcriptomics
AskPDF
Jun 1, 2026

Deep Learning for Generating Computational PIN-4 Immunohistochemistry Staining from Prostate Biopsy H&E Images

Immunohistochemistry (IHC)is frequently used to resolve diagnostically ambiguous prostate cancer biopsy findings on hematoxylin and eosin (H&E)-stained tissue. However, PIN-4 IHC staining is typically performed on adjacent tissue sections, limiting direct spatial comparison between the H&E morphology and the corresponding immunophenotypic signal. A paired, registered H&E/PIN-4 dataset was constructed from routine clinical prostate biopsy whole-slide images (WSIs), and a conditional generative adversarial network (cGAN) was trained to synthesize PIN-4 staining patterns directly from native H&E image patches. The final dataset comprised 172 paired WSIs from 93 patients and 27,298 registered 1024x1024 patch pairs, spanning adenocarcinoma-positive and benign cases with representation across age, race, and ethnicity groups. The model was evaluated on a held-out test set of 1,814 patch pairs from 17 WSIs, achieving a mean peak signal-to-noise ratio (PSNR) of 21.88 dB, structural similarity index measure (SSIM) of 0.667, Pearson correlation coefficient (PCC) of 0.684, and learned perceptual image patch similarity (LPIPS) of 0.417. Qualitative review by a board-certified pathologist showed that generated images captured diagnostically relevant PIN-4 staining patterns, including AMACR/racemase expression and basal-cell-associated staining, while preserving spatial correspondence with the source H&E morphology. Accuracy of synthesis varied across morphologically complex regions, including high-grade carcinoma and intraductal carcinoma. These results support the feasibility of supervised PIN-4 synthesis from routinely acquired brightfield H&E prostate biopsy images. The approach enables direct interpretation of predicted PIN-4 marker patterns in the context of the source prostate H&E architecture, addressing a current spatial limitation of conventional adjacent-section IHC.

Vietbao Tran, Pratik Shah

Biomedical Engineering University of California, Irvine Irvine, CA, USA · Pathology and Laboratory Medicine Biomedical Engineering Electrical Engineering and Computer Science University of California, Irvine Irvine, CA, USA

Computational PathologyConditional Image GenerationVirtual StainingMedical Image SynthesisWhole-Slide Image Analysis
AskPDF
May 30, 2026

CodeCytos: AI-assisted spatial molecular imaging analysis via code-augmented agent action space

Conventional tissue image analysis software provides foundational capabilities for cellular analysis, including segmentation, basic morphological feature extraction, and spatial organization analysis. However, these tools often require manual intervention and are not well integrated with code-driven automation, limiting efficiency and scalability for complex spatial tissue studies. In addition, they offer limited flexibility for custom analyses, as they typically support only a fixed set of pre-implemented spatial cellular features. To address these limitations, we propose CodeCytos, a coding-based reasoning agent framework that enables dynamic, programmable interaction with spatial molecular imaging data to improve automation and customization. CodeCytos is designed to streamline the exploration of custom spatial cellular features and adapt to diverse research needs. We demonstrate its utility through case studies on four expert-curated datasets from distinct tissue types: frontal cortex, non-small-cell lung cancer, pancreas, and tonsil. We evaluate CodeCytos under a realistic minimal prompt setting, where bioscientists pose simple questions without task-specific instructions or contextual information about spatial cellular analysis, and benchmark multiple LLM backbones with strong coding capabilities. We further show that incorporating tailored, domain-agnostic few-shot in-context coding-reasoning examples (randomly sampled demonstrations outside the spatial analysis domain) can substantially improve performance without requiring costly, expert-crafted in-domain demonstrations. Overall, CodeCytos outperforms baseline approaches, highlighting the potential of code-action agents to assist with custom feature exploration in spatial molecular imaging and to accelerate biomarker discovery.

Hung Q. Vo, Huy Q. Vo, Son T. Ly +6

University of Houston, Department of Electrical and Computer Engineering, Houston, Texas, 77004, USA · Houston Methodist Hospital, Department of Systems Medicine and Biomedical Engineering, Houston, Texas, 77030, USA

Computational PathologySpatial TranscriptomicsAI Agents for Scientific DiscoveryAgentic Code Generation
AskPDF
May 29, 2026

Simple Token-Efficient Vision-Language Model for Case-level Pathology Synoptic Report Generation

Generating clinically useful pathology reports for pathology cases from whole-slide images (WSIs) is challenging due to gigapixel resolution, long visual-token sequences, and the complexity of case-level reasoning, where a single case may contain multiple WSIs with heterogeneous tissues and ambiguous findings. We present a simple token-efficient vision--language model for case-level synoptic report generation that remains practical under constrained GPU memory. Our architecture follows a minimal three-component design: a frozen pathology patch encoder, a lightweight two-layer MLP vision-language aligner, and a large language model decoder, with an explicit WSI marker token to separate slides within a case. Training proceeds in two supervised stages: (1) aligner-only WSI captioning using heterogeneous WSI-text pairs, and (2) case-level supervised fine-tuning on case-report pairs for structured report generation. To reduce sequence length, we represent each slide using 512×512512 \times 512 patches at 5×5\times magnification, which reduces the average sequence length by up to 64×64\times times compared to the commonly used 20×20\times patches. Combined with efficient training techniques, we enable practical training with only half a NVIDIA H100 GPU. Across both training stages, our approach achieves high ROUGE-L/METEOR/BLEU-4 scores while being substantially more efficient in memory and runtime. In AI-based evaluations, our model is consistently preferred over strong baselines. Extensive ablations characterize performance-efficiency trade-offs and identify simple choices that improve robustness in multi-WSI settings. Overall, this work provides a strong, reproducible baseline for efficient pathology report generation, lowering the barrier to multi-WSI VLM research under limited compute.

Zhiyuan Yang, Jiahao Cheng, Vincent Quoc-Huy Trinh +1

Department of Computer Science and Software Engineering (CSSE), Concordia University, Montreal, Canada · Axe Cancer, Centre de recherche du CHUM, Université de Montréal, Montreal, Canada · Institut de recherche en immunologie et cancérologie (IRIC), Université de Montréal

Computational PathologyMedical Report GenerationEfficient VLM InferenceMedical VLMsWhole-Slide Image Analysis
AskPDF
May 28, 2026

Genetically Aligned Patient Representations Improve Hematological Diagnosis

Multimodal alignment of histopathology encoders with transcriptomic and genomic data has been shown to significantly improve performance in downstream diagnostic tasks. Hematological cytology is unique in that visual single-cell evaluation is often paired with cytogenetics and molecular genetics for blood cancer diagnosis. In this study, we present a framework to align single white blood cell images with chromosomal aberrations (karyotype) and somatic mutations from targeted gene panels. Our training strategy follows a two-stage approach: (i) self-supervised, vision-only pretraining of a transformer aggregator using an iBOT head on a cohort of over 1500 patients, and (ii) genetic alignment via supervised contrastive loss on acute myeloid leukemia patients. Our genetically aligned patient encoder improves hematological diagnostic tasks, outperforming slide-level histopathology foundation models. Additionally, the model provides off-the-shelf retrieval capabilities for diseases and genetic alterations. Incorporating genetic data into patient encoders increases the quality of patient representations, providing a framework that aligns with clinical diagnostic workflows and paves the way for future multimodal hematology-specific AI. The code and model weights are available at https://github.com/marrlab/GenBloom.

Muhammed Furkan Dasdelen, Fatih Ozlugedik, Ilaria Looser +3

Institute of AI for Health, Helmholtz Munich, Germany · International School of Medicine, Istanbul Medipol University, Türkiye · Munich Leukemia Laboratory, Germany +4

Computational PathologyHealthcareMedical DiagnosisCross-Modal AlignmentOncologyMedical Image Representation Learning
AskPDF
May 25, 2026

A Clinically Validated Foundation Model for Comprehensive Lung Pathology Interpretation

Pathological assessment guides lung cancer diagnosis, treatment selection, and prognostic evaluation, yet current CPath approaches rely on task-specific models for isolated objectives. Although pan-cancer foundation models offer versatility, they lack subspecialty-level depth and have not been evaluated across clinical workflows or prospectively validated in real-world settings. We introduce PulmoFoundation, a multi-center, prospectively validated, randomized controlled trial (RCT)-evaluated foundation model for comprehensive lung pathology assessment across pre-operative, intra-operative, and post-operative care. Built upon Virchow2 via subspecialty-specific pretraining using ~40,000 diagnostic H&E-stained whole-slide images (WSIs), PulmoFoundation was systematically evaluated on ~26,000 WSIs across 32 clinically relevant tasks. In addition to accurately predicting molecular markers and patient survival, our model achieves clinical-grade performance in core diagnostic tasks across biopsy, frozen section, and surgical resection slides. In a registered prospective study of 1,357 patients across 11 diagnostic tasks, our model achieved an average AUC of 92.3%. Using pre-specified triage thresholds, PulmoFoundation could reduce additional second-review burden for 68.8% of biopsies and 83.0% of frozen sections, and defer 44.5% of IHC stain orders, with PPVs of 1.0, 0.991, and 0.966. Beyond prospective validation, we conducted a crossover RCT with eight pathologists, in which AI assistance improved diagnostic accuracy across 4,928 case-reader pairs (91.7% w/ AI vs. 83.8% w/o AI). AI assistance also reduced median diagnostic time by 19.6%, increased diagnostic confidence by 8.7%, and improved inter-rater agreement from moderate (kappa = 0.56) to substantial (kappa = 0.76). Together, these evaluations support PulmoFoundation as a clinically validated decision-support system for lung pathology.

Zhengrui Guo, Zhengyu Zhang, Jiabo Ma +23

Department of Computer Science and Engineering, Hong Kong University of Science and Technology, Hong Kong, China · Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China · Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China +15

Computational PathologyClinical Decision SupportPathology Foundation ModelsOncologyWhole-Slide Image Analysis
AskPDF
May 24, 2026

Discrepancy Minimization Improves Cross-Hospital Robustness in Digital Pathology

Pathology foundation models (PFMs) have advanced rapidly in recent years and support training classifiers for a range of histopathology tasks. However, their robustness across hospitals remains limited: performance often degrades when training a classifier on data from one hospital and evaluating it on another target hospital. We address this challenge by fine-tuning PFMs with a local maximum mean discrepancy (LMMD) objective that applies to two settings: domain adaptation, where unlabeled target-hospital data is available, and domain generalization, where target-hospital data is unavailable at all. Experiments at both the patch- and slide-level show consistent improvements across multiple PFMs and tasks.

Ben Vardi, Dana Schonberger, Yuval Friedmann +4

Reichman University, Herzliya, Israel · Institute of Pathology, Sheba Medical Center, Ramat-Gan, Israel · Technion - Israel Institute of Technology, Haifa, Israel

Computational PathologyUnsupervised Domain AdaptationHealthcareMaximum Mean DiscrepancyDomain GeneralizationPathology Foundation Models+1
AskPDF
May 23, 2026

ConceptM3^3oE: Concept-Guided Multimodal Mixture of Experts for Interpretable Computational Pathology

Healthcare models are transitioning from unimodal prediction toward multimodal reasoning over heterogeneous diagnostic inputs. In computational pathology, for complex tumor subtypes where morphology alone can be challenging to distinguish, pathology reports and molecular measurements may provide additional diagnostic evidence alongside whole-slide images, yet existing models often fail to clarify how diverse signals assemble into recognizable diagnostic concepts. We propose ConceptM3^3oE (Concept Multimodal MoE), which embeds concept formation directly within interaction-aware mixture-of-experts (MoE) pathways. The architecture decomposes evidence into modality-specific, redundant, and synergistic experts, which are then projected into structured concept bottlenecks mapping latent features to a hierarchy of morphology and biomarker concepts. To prevent the information loss typical of interpretable bottlenecks, we utilize residual pathways within each expert to allow task-relevant signals to flow both through the concepts and directly to the final task prediction, so that high performance is maintained alongside interpretability. Across an institutional pediatric brain tumor cohort and a public glioma cohort, the framework delivers competitive performance to unconstrained models while producing reasoning traces validated by an independent neuropathologist. In data-limited regimes, ConceptM3^3oE improves limited-data performance, increasing macro-F1 from 56.41% to 66.70% at small training sizes compared to non-concept-informed baselines, while also showing faster training convergence consistent with the regularizing effect of concept learning. This work offers a scalable path toward high-performance medical AI that is inherently verifiable and better aligned with the complex decision-making of clinical practice.

Xuan Wang, Zhongling Xu, Gopi Kannedhara +13

University of Texas at Austin, Austin, TX, USA · University of North Carolina at Chapel Hill, NC, USA · Dell Children’s Medical Center, Austin, TX, USA +2

Computational PathologyConcept Bottleneck ModelsHealthcareInterpretable MLMultimodal ClassificationOncology+4
AskPDF
May 22, 2026

CRISP -- Clustering-Based Redundancy-Reduced Instance Sampling for Pathology Case Representation and Retrieval

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

Zahra Rahimi Afzal, Wataru Uegami, Saghir Alfasly +6

Kimia Lab, Department of Artificial Intelligence & Informatics, Mayo Clinic, Rochester, MN, USA · DICE Lab, Department of Electrical and Computer Engineering, University of Illinois Chicago, IL, USA · Division of Computational Pathology and Informatics, Mayo Clinic, Rochester, MN, USA +4

Computational PathologyMedical Image Representation LearningWhole-Slide Image Analysis
AskPDF
May 22, 2026

Discontinuous Galerkin Neural Operator for Pathology Defocus Deblurring

Defocus deblurring in pathological microscopy remains challenging due to the spatially varying and locally discontinuous nature of optical blur induced by a position-dependent integral imaging process. Existing deep learning methods, constrained by shift-invariance assumptions and limited interpretability, are not well suited to such heterogeneous blur patterns. Neural operators provide a principled alternative by modeling defocus formation directly as an integral operator, offering a new perspective on defocus deblurring. However, most existing neural operator architectures for low-level vision rely on globally parameterized kernels that assume smoothness and stationarity, limiting their ability to model heterogeneous and locally discontinuous blur patterns. To address this limitation, we propose the Discontinuous Galerkin Neural Operator (DGNO), which parameterizes the integral kernel using a discontinuous Galerkin formulation with element-local volume operators and interface numerical fluxes. DGNO provides a principled combination of locality, heterogeneity modeling, and global coherence while preserving the underlying physics of optical image formation. Extensive and insightful experiments demonstrate that DGNO surpasses state-of-the-arts, delivering sharper reconstructions, robust handling of spatially varying blur, and scalable high-resolution performance. The code will be released at https://github.com/DeepMed-Lab-ECNU/Single-Image-Deblur.

Shaoqing Duan, Haofei Song, Xintian Mao +2

Shanghai Key Laboratory of Multidimensional Information Processing, East China Normal University, Shanghai, China.

Computational PathologyImage DeblurringPhysics-Informed Neural OperatorsNeural Operators
AskPDF
May 21, 2026

Virtual 3D H&E Staining from Phase-contrast Back-illumination Interference Tomography

Three-dimensional (3D) histopathology of unprocessed tissues has the potential to transform disease management by enabling volumetric characterization of tissue microarchitecture and in-vivo assessment. Back-illumination Interference Tomography (BIT) is a new phase microscopy technology that provides rapid, non-destructive volumetric imaging of unprocessed tissues. However, translating BIT volumes into clinically interpretable H&E images remains challenging, particularly due to shift-variant contrast and the absence of quantitative validation benchmarks. We introduce HistoBIT3D, the first voxel-wise paired BIT and fluorescence-labeled nuclei dataset, enabling quantitative evaluation of structural preservation in unsupervised virtual staining against ground-truth nuclear distributions. Using this dataset, we present a novel virtual staining framework that translates BIT volumes with shift-variant contrast into realistic H&E volumes by leveraging bidirectional multiscale content consistency and cross-domain style reuse to enhance structural fidelity and perceptual realism. Our method achieves state-of-the-art realism metrics while significantly improving 3D nuclei segmentation accuracy and boundary preservation under zero-shot Cellpose evaluation. Together, these contributions establish a quantitatively validated, structurally faithful, and scalable pipeline for 3D virtual H&E staining, advancing the paradigm of slide-free, volumetric computational histopathology. Our data and code are available at: https://github.com/aasong113/HistoBIT3D_VirtualStaining.

Anthony Song, Boyan Zhou, Mayank Golhar +3

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA · Department of Pathology, Johns Hopkins Hospital,2026 Baltimore, MD, USA

Computational PathologyImage-to-Image TranslationVirtual StainingMicroscopy Image Analysis
AskPDF
May 19, 2026

HAPS: Rethinking Image Similarity for Virtual Staining

Virtual staining of histopathology images (e.g., H&E-IHC) is an emerging tool in digital pathology, enabling faster and cheaper workflows by synthesizing target stains from routinely acquired slides. Yet, the quality of virtual staining models is still predominantly assessed with generic metrics such as SSIM, PSNR, and LPIPS. Originally developed for natural images, these metrics are inherently misaligned with the domain-specific characteristics of histological data, failing to capture tissue morphology preservation and biomarker expression patterns. Consequently, a robust, domain-specific standard for quantifying similarity across diverse histological modalities remains a critical gap in the field. In this work, we formalize histology image similarity as a standalone problem and systematically evaluate a broad set of full-reference metrics against a dataset of H&E-IHC patch pairs annotated with expert similarity scores. We further analyze metrics sensitivity to controlled geometric distortions (shifts, rotations and non-rigid deformations) that mimic realistic registration errors between serial sections. Guided by these observations, we propose the Histology-Aware Perceptual Similarity (HAPS) metric. HAPS computes distances in the feature space of a frozen encoder pretrained on histopathology data, adding a linear head to aggregate feature-level differences into a final score that aligns with expert assessments. Finally, we demonstrate the practical value of HAPS for quality control of training data. By quantifying the similarity of training pairs in the MIST dataset and filtering low-scoring samples, we create a cleaner training set. Virtual staining models trained on this refined data outperform those trained on the original, unfiltered dataset.

Fedor Gubanov, Svetlana Illarionova, Vlad Kozlovskiy +6

1*Skolkovo Institute of Science and Technology, Moscow, 121205, Russia. · 2BIMAI-Lab, Biomedically Informed Artificial Intelligence Laboratory,2026 University of Sharjah, Sharjah, United Arab Emirates. · 3National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Moscow, Russia.

Computational PathologyMedical Image AnalysisVirtual StainingImage Quality Assessment
AskPDF
May 19, 2026

Thinking in Scales: Accelerating Gigapixel Pathology Image Analysis via Adaptive Continuous Reasoning

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

Jiusong Ge, Yingkang Zhan, Wenjie Zhao +13

School of Computer Science and Technology, Xi’an Jiao-tong University, Xi’an, China · Department of Transmedia Art, Xi’an Academy of Fine Arts, Xi’an, China · Language Technology Lab, University of Cambridge, Cambridge, U.K. +3

Computational PathologyAdaptive InferenceHistopathology Image ClassificationWhole-Slide Image Analysis
AskPDF
May 18, 2026

Beyond Morphology: Quantifying the Diagnostic Power of Color Features in Cancer Classification

In histopathology, human experts primarily rely on color as a means of enhancing contrast to interpret tissue morphology, whereas machine vision models process color as raw statistical information. This distinction raises a fundamental question: to what extent can pixel intensity alone, independent of structural and morphological cues, support cancer classification? To address this question, we systematically evaluated the standalone discriminative power of global color features while deliberately excluding all morphological information. Specifically, we extracted statistical color moments and discretized RGB and HSV color histograms, and assessed their performance across ten diverse experimental settings using classical machine learning classifiers. Our results demonstrate that color features alone can achieve strong performance in binary diagnostic tasks (e.g., benign versus malignant), with classification accuracies reaching up to 89%. This performance is likely attributable to global chromatic shifts associated with malignancy. Importantly, these simple color-based representations consistently outperformed random baselines by a substantial margin, indicating that raw color distributions encode a non-random and diagnostically relevant signal for cancer detection. Consequently, this study suggests that simple, computationally efficient color features can serve as an effective pre-screening tool. By identifying samples with strong chromatic indicators of malignancy, these lightweight models could function as a first-pass triage system, reducing the computational burden on complex deep learning architectures.

Farnaz Kheiri, Shahryar Rahnamayan, Masoud Makrehchi

Dept. of Electrical, Computer and Software Engineering Ontario Tech University Oshawa, Ontario, Canada · Dept. of Engineering Brock University St. Catharines, Ontario, Canada

Computational PathologyOncologyHistopathology Image Classification
AskPDF
May 18, 2026

PathoSage: Towards Multi-Source Evidence Adjudication in Pathology via Experience-Aware Agentic Workflow

Recent advances in Multimodal Large Language Models (MLLMs) and agent workflows have shown strong promise for computational pathology, yet reliable patch-level reasoning remains challenging. End-to-end pathology MLLMs often hallucinate morphological features, while recent agentic systems usually merge tool outputs and retrieved knowledge into a shared context, making decisions vulnerable to conflicting evidence and context contamination. We propose PathoSage, a three-stage framework that explicitly separates knowledge retrieval, evidence collection, and evidence adjudication for patch-level pathology multimodal reasoning. Its core component, Structured Evidence Deliberation, independently evaluates heterogeneous evidence from tools, performs conflict analysis, and generates the final judgment in a fresh context to reduce anchoring bias. We further introduce a training-free Beta-Bernoulli experience system with continuous credit assignment to model long-term tool reliability and construct similarity-weighted priors for future tool use. Experiments show that PathoSage effectively mitigates VQA hallucinations and classifier disagreement, outperforming strong pathology MLLM and agentic baselines. Our results highlight explicit evidence adjudication and reliability-aware tool modeling as key ingredients for robust pathology agents.

Chengyang Zhang, Wenchuan Zhang, Bo Li +5

College of Computer Science, Sichuan University · Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University · Department of Computer and Information Science, University of Macau +1

Computational PathologyEvidence-Grounded ReasoningMultimodal QAMultimodal Agents
AskPDF
May 15, 2026

Diffusion Attention Expert Model for Predicting and Semi-automatic Localizing STAS in Lung Cancer Histopathological Images

Accurate intraoperative and postoperative diagnosis of spread through air spaces (STAS) is essential for guiding surgical decisions and postoperative management in lung cancer. However, histopathological assessment is labor-intensive and is prone to missed or incorrect diagnoses. We propose a Diffusion Attention Expert Model (DAEM) to detect STAS in frozen sections (FSs) and paraffin sections (PSs). Its diffusion attention expert module leverages full attention aggregation to learn multi-scale features from histopathological images, while a dual-branch architecture strengthens multi-scale feature representation. On an internal dataset, DAEM achieves AUCs of 0.8946 for FSs and 0.9112 for PSs. Validation on external multi-center datasets from eight institutions demonstrates strong generalizability and interpretability. Using tumor microenvironment (TME) features in PSs, we further enable semi-automatic measurement of STAS location and its distance from the primary tumor. Several quantitative TME metrics are identified as potential biomarkers for STAS, including micropapillary-type STAS. Overall, DAEM offers a clinically actionable framework for STAS assessment by enabling accurate and interpretable detection on FSs and PSs, supporting postoperative risk stratification through quantitative TME-based analysis.

Liangrui Pan, Jiadi Luo, Yuxuan Xiao +13

College of Computer Science and Electronic Engineering, Hunan University, Changsha, 410082, China · Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China · Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China +8

Computational PathologyOncologyExplainable Medical Image AnalysisHistopathology Image ClassificationMedical Image Localization
AskPDF
May 14, 2026

FedStain: Modeling Higher-Order Stain Statistics for Federated Domain Generalization in Computational Pathology

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

Fengyi Zhang, Junya Zhang, Wenzhuo Sun

School of Electronic Science and Technology, Hainan University, Haikou, China, 570228 · School of Computer Science and Technology, Xidian University, Xi’an, China, 710126 · Xiangjiang College of Elite Engineers, Hunan University, Changsha, China, 410082

Computational PathologyFederated Domain GeneralizationWhole-Slide Image AnalysisFederated Learning
AskPDF
May 14, 2026

Generative Deep Learning for Computational Destaining and Restaining of Unregistered Digital Pathology Images

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

Aarushi Kulkarni, Alarice Lowe, Pratik Shah

Department of Computer Science University of California Irvine, CA, USA · Department of Pathology Stanford University Stanford, CA, USA · Department of Pathology and Laboratory Medicine Biomedical Engineering Electrical Engineering and Computer Science University of California Irvine, CA, USA

Computational PathologyDomain GeneralizationVirtual StainingGenerative Adversarial NetworksWhole-Slide Image Analysis
AskPDF
May 13, 2026

PRISM: Perinuclear Ring-based Image Segmentation Method for Acute Lymphoblastic Leukemia Classification

Automated analysis of peripheral blood smears for Acute Lymphoblastic Leukemia (ALL) is hindered by low contrast and substantial variability in cytoplasmic appearance, which complicate conventional membrane-based segmentation. We found that many recent approaches rely on heavy neural architectures and extensive training, but still struggle to generalize across staining and acquisition variability. To address these limitations, we propose the Perinuclear Ring-based Image Segmentation Method (PRISM), which replaces explicit cytoplasmic delineation with adaptive concentric zones constructed around the nucleus. These perinuclear regions enable the extraction of robust cytoplasmic descriptors by integrating color information with texture statistics derived from grey-level co-occurrence patterns, without requiring accurate cell-boundary detection. A calibrated stacking ensemble of traditional classifiers leverages these descriptors to achieve a high performance, with an accuracy of 98.46% and a precision-recall AUC of 0.9937.

Larissa Ferreira Rodrigues Moreira, Leonardo Gabriel Ferreira Rodrigues, Rodrigo Moreira +1

Institute of Exact and Technological Sciences – Federal University of Viçosa (UFV) Rio Paranaíba – MG – Brazil · School of Computer Science – Federal University of Uberlândia (UFU) Uberlândia – MG – Brazil · Departament of Computing – Federal University of São Carlos (UFSCar) São Carlos – SP – Brazil

Computational PathologyMedical Image Classification
AskPDF
May 12, 2026

Bridging the Modality Bottleneck in Pathology MIL through Virtual Molecular Staining

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

Yucheng Xing, Pei Liu, Jingying Ma +6

National University of Singapore, Singapore · Hunan University, China · Peking Union Medical College Hospital (PUMCH), China +1

Computational PathologyCross-Modal Representation LearningVirtual StainingMultiple Instance LearningWhole-Slide Image Analysis
AskPDF
May 12, 2026

RNA-FM: Flow-Matching Generative Model for Genome-wide RNA-Seq Prediction

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

Yaxuan Song, Jianan Fan, Tianyi Wang +4

School of Computer Science, The University of Sydney, Australia · Biological Systems and Engineering Division, Lawrence Berkeley National Lab, USA · Berkeley Biomedical Data Science Center, Lawrence Berkeley National Lab, USA +1

Computational PathologyGenomicsGene Expression Prediction from Histopathology ImagesWhole-Slide Image Analysis
AskPDF
May 11, 2026

CellDX AI Autopilot: Agent-Guided Training and Deployment of Pathology Classifiers

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

Alexey Pchelnikov, Aleksei Pchelnikov

1HistAI

Computational PathologyHealthcareHistopathology Image ClassificationAutomated Machine LearningWhole-Slide Image Analysis
AskPDF
May 8, 2026

Beyond ViT Tokens: Masked-Diffusion Pretrained Convolutional Pathology Foundation Model for Cell-Level Dense Prediction

Cell-level dense prediction is central to computational pathology, but remains challenging due to fine-grained histological structures, strong domain shifts, and costly dense annotations. Existing ViT-based pathology foundation models rely on patch tokenization, which can disrupt spatial continuity and weaken local morphological details needed for cell-level prediction. To address this, we propose Masked-Diffusion Convolutional Foundation Models, termed ConvNeXt Masked-Diffusion (CMD), a self-supervised convolutional generative pretraining framework for dense pathology representation learning. CMD uses a fully convolutional ConvNeXt-UNet backbone, performs masked-diffusion pretraining in pixel space, and incorporates frozen pathology foundation model features through adaptive normalization. Experimental results demonstrate that CMD consistently outperforms existing ViT-based pathology foundation models and even surpasses state-of-the-art end-to-end segmentation methods while fine-tuning only a small number of task-specific parameters across multiple pathology dense prediction tasks. The advantage is particularly pronounced under limited annotation settings, where CMD exhibits stronger robustness and generalization ability. Our findings suggest that purely convolutional architectures can also serve as competitive pathology foundation models for cell-level dense prediction, achieving leading performance within the current ViT-dominated paradigm and providing a scalable, high-performance solution that better preserves histological structural priors for fine-grained pathology understanding.

Weiming Chen, Xitong Ling, Zhenyang Cai +5

1Tsinghua Shenzhen International Graduate School, Tsinghua University · 3Research Institute of Tsinghua, Pearl River Delta · 2The Chinese University of Hong Kong, ShenZhen

Computational PathologyHistopathology Image SegmentationPathology Foundation ModelsMedical Image SegmentationConvolutional Neural NetworksMedical Image Representation Learning+1
AskPDF
May 6, 2026

HEXST: Hexagonal Shifted-Window Transformer for Spatial Transcriptomics Gene Expression Prediction

Spatial transcriptomics offers spatially resolved gene expression profiling within tissue sections, but its cost and limited throughput hinder large-scale deployment. To extend this capability to routine practice, recent computational methods aim to infer spatial gene expression directly from ubiquitous hematoxylin and eosin-stained histology slides. However, most existing models assume Cartesian or geometry-agnostic locality, despite the hexagonal sampling of widely used spot-array platforms, and point-wise regression objectives often yield over-smoothed gene expression profiles, obscuring gene-specific spatial heterogeneity. To address these, we propose HEXST, a geometry-aligned Transformer for spatial gene expression prediction from histology. HEXST operates directly on hexagonal spot coordinates to enable efficient local-to-global contextual modeling via tailored shifted-window attention mechanism and hexagonal rotary positional encoding. To enhance gene-wise spatial contrast, HEXST complements point-wise regression with a contrast-sensitive differential objective and transcriptomic priors from a pretrained single-cell foundation model during training. Across seven spatial transcriptomics datasets, HEXST consistently outperforms state-of-the-art models, providing accurate and robust spatial gene expression predictions while preserving gene-wise contrast and spatial heterogeneity.

Keunho Byeon, Jin Tae Kwak

School of Electrical Engineering, Korea University, Seoul

Computational PathologySpatial TranscriptomicsTransformer AttentionSpatial Gene Expression Prediction
AskPDF