Computational Pathology

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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

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

Aug 2, 2026

Training-Free Out-of-Distribution Detection for Pathology Whole-Slide Images

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.

Sabri Mustafa Kahya, Richard R. Chen, Muhammet Sami Yavuz +4

Computational PathologyOOD DetectionWhole-Slide Image Analysis
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Aug 2, 2026

Understanding Synergistic Interactions among Pathology Foundation Models via Adaptive Fusion

Pathology foundation models (PFMs) provide strong tile-level representations via self-supervised pre-training on large-scale pathology images. Yet, PFMs are developed under diverse and often opaque data, architecture, and objective choices, inducing latent representational biases that limit robustness and obscure what each model specialises in. We present AdaFusion, a lightweight adaptive fusion framework that integrates complementary signals from multiple frozen PFMs through (1) low-dimensional feature compression and (2) a sample-conditioned gating module that reweights model-wise (and optionally channel-wise) contributions. Beyond improving predictive accuracy, AdaFusion provides contribution-driven interpretation that offers evidence consistent with model-specific preferences and synergistic interactions across tissue phenotypes. We evaluate AdaFusion on three public benchmarks spanning treatment response prediction, prostate cancer grading, and spatial gene expression inference. AdaFusion consistently outperforms individual PFMs and other fusion baselines, while providing interpretable tissue visualisation which aligns model preferences with morphological patterns. Code is available at: https://github.com/xyx-98/PathoOracle.

Yuxiang Xiao, Yang Hu, Bin Li +5

School of Computer Science and Engineering, South China University of Technology, China · School of Computing and Mathematical Sciences, University of Leicester, UK · Leicester Cancer Research Centre, University of Leicester, UK +4

Computational PathologyPathology Foundation ModelsExplainable Medical Image AnalysisFeature Fusion
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Aug 2, 2026

Harnessing Adversarial Distillation to Customise Debiased, Disease-Specific Pathology Foundation Models for Breast Cancer

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 30×30\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.

Zhiwei Chen, Yang Hu, Yuxiang Xiao +7

School of Computer Science and Engineering, South China University of Technology, China · School of Computing and Mathematical Sciences, University of Leicester, UK · Leicester Cancer Research Centre, University of Leicester, UK +4

Computational PathologyPathology Foundation ModelsOncologyShortcut LearningKnowledge DistillationAdversarial Knowledge Distillation
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Aug 1, 2026

Zero-Cost Virtual RNA: Approximating Immunotherapy Signatures via Cross-Modal WSI Retrieval

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

Sigrid Vila-Bagaria, Mar Teixidó, Miquel Piñol +3

Image Processing Group, Universitat Politècnica de Catalunya, Spain · Research group of Cancer Biomarkers & Oncological Pathology, IRB Lleida, Spain

Computational PathologyCross-Modal RetrievalOncologyGene Expression Prediction from Histopathology ImagesWhole-Slide Image Analysis
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Aug 1, 2026

Gene Ontology-Guided Hierarchical Spatial Gene Expression Prediction from Histopathology Images

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.

Zhiwen Xu, Xiaoming Yan, Chengkun Wu +3

National University of Defense Technology Changsha, China

Computational PathologySpatial TranscriptomicsHierarchical Representation LearningSpatial Gene Expression PredictionGenomicsGene Expression Prediction from Histopathology Images
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Jul 31, 2026

What Carries the Signal in Pathology Foundation-Model Atlases? A Patient-Level Controlled Benchmark in Breast Cancer

Pathology foundation models are reported to encode molecular programmes in tissue morphology, but the evidence is usually a cohort-wide ranked gene list rather than a prediction for a held-out patient. We rebuild such an analysis with the patient as the unit of evidence and ask which pipeline component carries signal. Across 11 frozen backbones, four pre-specified gene programmes and 285 TCGA-BRCA patients with paired slides and RNA-seq (44 cells; GroupKFold by patient, all preprocessing fitted inside the fold), ridge regression on mean-pooled embeddings predicts held-out programme scores at Spearman rho = 0.25-0.56, UNI2 strongest on all four (immune 0.556). A matched permutation null gives raw p ~ 1e-4 at 10,000 permutations for every cell; Holm-adjusted p = 0.0044. The signal is real but not uniformly morphological. Against competing models on the same patients and folds, embeddings beat tissue composition for ER/luminal, proliferation and immune (+0.280, +0.284, +0.479; p <= 0.003) but not basal, where compartment fractions alone reach 0.469 against the embedding's 0.493 (p = 0.77). Fifty-four interpretable cell-count features come within 0.043-0.085 on every programme. The geometric machinery contributes nothing measurable, and we identify why: the geodesic graph selects neighbours by Euclidean nearest-neighbour search and only reweights edges already chosen, so the topology is Euclidean by construction (Riemannian minus Euclidean = +0.0010, 95% CI [-0.0007, +0.0029]). Applied consistently the geometry is worse (-0.0117). Ridge regression beats the graph-and-metric decoder by +0.097 (CI [+0.069, +0.127]). The driver-count metric common in this literature is near-uninformative here: 91.8% of random six-gene panels recover >=5/6 drivers.

Chimdi Walter Ndubuisi

Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO 65211, USA

Breast CancerComputational PathologyPathology Foundation ModelsManifold LearningOncologyMedical Image Representation Learning+1
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Jul 30, 2026

PathView-Bench: Can Multimodal Large Language Models Achieve Fine-grained Multiscale Understanding of Pathology Images?

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.

Zongyi Chen, Yu Liang, Jie Lin +1

National Institute for Data Science in Health and Medicine, Xiamen University · Institute of Artificial Intelligence Xiamen University, Xiamen, China · Department of Computer Science School of Informatics Xiamen University, Xiamen, China

Computational PathologyMedical VQAMultimodal Model EvaluationMedical Image BenchmarksPathology VQA
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Jul 30, 2026

Beyond Classification: Pathology Foundation Models as Detection Encoders for Mitotic Figures

Pathology foundation models (FMs) are models trained on vast amounts of typically unlabeled data and have been shown to yield regularized latent spaces that can be used effectively in downstream classification tasks. This is also true for the classification of mitotic figures vs. other cells. However, it is so far unclear if the latent space of current FMs provides features that are discriminant and spatially suitably resolved to also serve as a backbone for dense object detection paradigms. In this work, we investigate this question for common current pathology FMs (UNI, UNI2-h, Virchow, Virchow2, H-optimus-0, H-optimus-1) and compare their performance against a fully end-to-end trained baseline based on a ResNet50 architecture. We combine FM backbones with representatives of single stage, dual stage and self-attention-based detectors (RetinaNet, Faster R-CNN, Deformable DETR respectively) on the multi-domain MIDOG++ dataset, and on the TUPAC16 dataset as an out-of-domain case. We show that the H-optimus-0 and Virchow models yielded competitive performance, indicating that the latent spaces of current FMs, all trained on image-level self-supervision, are suitable for direct mitotic figure detection and may be slightly more robust on our out-of-domain test case. All code is made available publicly at https://github.com/DeepMicroscopy/FM4MFdet.

Sweta Banerjee, Alireza Teimoury, Nils Porsche +11

Flensburg University of Applied Sciences, Flensburg, Germany · Julius-Maximilians-Universität Würzburg, Würzburg, Germany · Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany +4

Computational PathologyPathology Foundation ModelsObject DetectionWhole-Slide Image Analysis
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Jul 28, 2026

Group Equivariant Diffusion for Anomaly Detection in Computational Cytology

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/.

Swarnadip Chatterjee, Ssharvien Kumar Sivakumar, Anirban Mukhopadhyay

Uppsala University, Uppsala, Sweden · Technical University of Darmstadt, Darmstadt, Germany

Computational PathologyMedical Image Anomaly DetectionReconstruction-Based Anomaly DetectionDiffusion Models
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Jul 28, 2026

Towards Reliable Stain Transfer: An Iterative Data-Model Co-Optimization Framework Based on Multimodal Expert-Guided Assessment

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.

Siyuan Xu, Yan Wang, Haofei Song +7

East China Normal University Shanghai, China · Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China · Hangzhou Hyperspectral Imaging Technology Co., Ltd. Hangzhou, China +1

Computational PathologyImage Style TransferVirtual StainingMedical VLMsExplainable Medical Image Analysis
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Jul 27, 2026

HistoGPA: A Context-Conditioned Gene-Prior Attention Framework for Histology-Based Spatial Gene Expression Prediction

Predicting spatial gene expression from routine hematoxylin and eosin (H&E) images provides a practical complement to experimental spatial transcriptomics. Existing approaches focus on local or multi-scale visual features and often treat pretrained gene representations as fixed priors, although the interpretation of local morphology and the relevance of gene priors depend on tissue context. We propose HistoGPA, a context-conditioned gene-prior attention framework that uses a shared slide-level representation in two parallel pathways: one modulates local morphological features, whereas the other conditions pretrained gene embeddings and retrieves gene-prior information through cross-attention. This design enables each spatial location to retrieve context-adapted gene-prior information using its local morphology, position, and slide context. Across ten cancer types in HEST-1k, HistoGPA achieves the highest macro-averaged gene-wise Pearson correlation coefficient among the compared methods under the same evaluation protocol for both the top-50 and top-1,500 highly variable gene sets. Additional analyses show that HistoGPA better recovers the spatial expression patterns of cancer-associated genes and yields greater agreement between clusters derived independently from predicted and ground-truth expression profiles. Together, these findings motivate a context-dependent view of histology-to-expression prediction, in which local morphological representations and gene priors are jointly adapted to the broader tissue context.

Ziang Liu, Xinhai Chen, Yigui Feng +3

Laboratory of Digitizing Software for Frontier Equipment, National University of Defense Technology · National Key Laboratory of Parallel and Distributed Computing, National University of Defense Technology · College of Computer Science and Technology, National University of Defense Technology, Changsha 410073, China

Computational PathologySpatial TranscriptomicsSpatial Gene Expression PredictionGenomicsGene Expression Prediction from Histopathology Images
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Jul 26, 2026

PathScale-R1: Cross-scale Reasoning for Pathological Image Analysis

Pathological diagnosis is inherently multi-scale, requiring the integration of global tissue architecture at low magnification with cellular morphology at higher magnification. However, existing pathology benchmarks and vision-language models (VLMs) are still largely developed under single-scale settings, limiting their ability to learn clinically meaningful multi-magnification reasoning. Moreover, naively constructed visual question answering (VQA) tasks may be susceptible to text-only or superficial visual shortcuts, leading to unreliable assessments of visual understanding. To address these limitations, we introduce a benchmark and training framework for shortcut-resistant cross-scale pathology reasoning. We design an Adversarial Text-only Screening strategy for semantic reasoning questions and a Structure-controlled Distractor Sampling strategy for visual grounding questions, encouraging models to rely on cross-scale visual evidence. Based on this pipeline, we construct PathScale-VQA, a high-quality cross-scale pathology VQA benchmark with 10,373 multiple-choice questions grounded in 1,368 diagnostic paths across multiple magnification levels. Building on the semantic reasoning set, PathScale-R1 is optimized through Difficulty-driven Reasoning Distillation supervised fine-tuning followed by reinforcement learning with a Scale-aware Reasoning Structure reward, which encourages the use of evidence across magnifications. Extensive experiments demonstrate state-of-the-art performance of PathScale-R1 on cross-scale reasoning tasks and effective transfer to conventional single-scale pathology VQA. Our code is available at https://github.com/iMVR-PL/PathScale-R1.

Chi Phan, Tianyi Zhang, Yufeng Wu +7

Department of Electrical and Computer Engineering, National University of Singapore, Singapore 117417 · Department of Biomedical Engineering, National University of Singapore, Singapore 117417, Singapore · Department of Pathology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, China +1

Computational PathologyMedical VQAVLM ReasoningShortcut LearningPathology VQAMedical Image Benchmarks
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Jul 24, 2026

Robustifying pathology foundation models via fine-tuning

Pathology foundation models (FMs) produce powerful tile-level representations which remain sensitive to scanner and staining variability, undermining deployment across laboratories. We develop a novel fine-tuning recipe that improves the robustness of pathology FMs to acquisition factors. Applied to ten different FMs, our fine-tuning strategy consistently improves robustness for every model as well as downstream performance, with no observed trade-off. On average, it raises the PathoROB robustness index by 23% (from 0.72 to 0.87) and increases the overall cross-benchmark performance by 43% on Patho-Bench, HEST and THUNDER combined, with individual gains reaching up to 72% in robustness (Phikon-v2) and 76% in performance (Midnight-12k). We publicly release the fine-tuned versions of Phikon-v2 (Phaet) and Midnight-12k (Mascaret) at https://huggingface.co/wearewaiv/models.

Alexandre Filiot, Oskar Thaeter, Benoit Schmauch +1

1Waiv · Institute of Pathology, Technical University of Munich · School of Computation, Information and Technology, Technical University of Munich

Computational PathologyFine-TuningPathology Foundation Models
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Jul 23, 2026

Agent-Guided Relational Concept Discovery: Toward Interpretable Surgical Margin Assessment

Deep learning models can effectively use Rapid Evaporative Ionization Mass Spectrometry (REIMS) data for surgical margin assessment. However, their clinical adoption remains challenging due to limited generalization to operating room conditions. This difficulty arises because models are typically trained on labeled spectra collected from resected tissue samples, while they must operate on noisy, unlabeled data acquired directly during surgery. In addition, the black-box nature of deep learning models makes it difficult to understand and systematically improve their behavior. Concept-based learning offers a promising way to address these challenges by mapping raw measurements to human-understandable concepts. However, supervised concept-based approaches rely on concept annotations, which are difficult to obtain in complex mass spectrometry workflows. We propose Agent-Guided Concept Discovery, a framework that learns meaningful concepts directly from data without requiring predefined concept labels. During training, a reasoning agent refines semantic descriptions of the learned concepts and adaptively adjusts their weight based on diagnostic relevance. These concepts are further grounded using a biochemical knowledge graph to ensure consistency with known metabolic relationships. Across Skin and Breast Cancer datasets, our model improves balanced accuracy and sensitivity over the baseline. In a representative intraoperative case, it shows fewer false positives, indicating better generalization to surgical conditions.

Nooshin Maghsoodi, Amoon Jamzad, Robert Policelli +11

Queen’s University, Kingston, ON, Canada

Computational PathologyMass Spectrometry
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Jul 23, 2026

A Multi-Cohort Validation of Censoring-Aware Conformal Lower Predictive Bounds for Pathology Survival Models

Whole-slide survival models commonly provide risk rankings without calibrated statements about individual event times. We evaluate fixed-cutoff drcosarc, a post-hoc conformal wrapper for discrete-time multiple-instance learning survival heads using frozen UNI2-h representations, in an internal 18-configuration sweep across five TCGA cohorts and an external five-configuration evaluation across three CPTAC cohorts. We distinguish configuration--fold--split summaries of the inverse-probability-of-censoring-weighted (IPCW) estimate and median lower predictive bound (LPB) from a hierarchy-aware patient-ensemble estimand of the mean drcosarc--naive LPB difference. At α=0.1α=0.1, the drcosarc IPCW estimate was nearest 0.90 in KIRC, LUAD, and STAD. Patient-ensemble drcosarc--naive intervals excluded zero in KIRC, KIRP, STAD, UCEC, and CPTAC-CCRCC, but included zero in internal LUAD, CPTAC-LUAD, CPTAC-UCEC, and the internal LUSC extension. In a 20-replicate low-censoring semi-synthetic setting with known event times, drcosarc empirical coverage was 0.9129 [0.9053, 0.9207]. An exploratory analysis supported a head-error-by-censoring interaction within that data-generating process. In a two-cohort ABMIL sensitivity analysis, increasing the hazard grid to K=16K=16 raised localized marginal IPCW estimates above the prespecified 0.87 threshold and yielded positive paired LPB differences, although worst-group estimates remained below 0.87. Overall, performance was cohort dependent, and its interpretation changed with the patient-level unit, estimand, and censoring assumptions.

Mingi Hong

Independent Researcher

Computational PathologyCancer Survival PredictionSurvival AnalysisConformal PredictionOncologyRegression Prediction Intervals
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Jul 23, 2026

Do Pathology Vision-Language Models Truly See Pathology?

Pathology vision-language models (VLMs) have recently progressed rapidly and are commonly evaluated by answer accuracy on pathology VQA benchmarks. However, we dig into current evaluations and identify three overlooked issues: 1) Visual evidence is not always necessary. For instance, Gemini-3-Pro achieves 53.5% average accuracy across 5 VQA benchmarks without any visual input. 2) Domain training can improve accuracy without proportional gains in visual binding. Compared with Qwen2.5-VL-7B, Patho-R1-7B exhibits a 5.8-point lower multimodal gain and a 3.7-point lower attention IoU. 3) Entity-level attention is diffuse and weakly query-specific. On PathVG, attention maps remain highly correlated across different entity queries. These issues can lead to substantial misjudgments of pathology VLMs' actual multimodal capabilities. To this end, we present PathBind, a benchmark comprising 2,600 samples: PathBind-VQA with 1,500 questions across six dimensions, PathBind-PTA with 600 questions from a private pathology teaching atlas, and PathBind-Grounding with 500 expert-curated region-level samples. Each component undergoes task-specific automated filtering and expert review to reduce textual shortcuts and improve entity-region correspondence. We evaluate 18 representative VLMs on VQA samples of PathBind and five existing pathology VQA benchmarks, and further evaluate 10 VLMs on PathBind-Grounding and PathVG. Results show that current pathology VLMs still exhibit a substantial gap between answer-side performance and visual-semantic binding.

Chengyang Zhang, Wenchuan Zhang, Bo Li +10

College of Computer Science, Sichuan University · Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University · Department of Computer Science, School of Computing, National University of Singapore +2

VLM EvaluationComputational PathologyMedical VQAVision-Language GroundingMedical VLMsPathology VQA
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Jul 23, 2026

HierarchicalDAEW: Domain-Aware Edge-Weighted Graph Convolution with Evidential Uncertainty for Multi-Section Spatial Gene Expression Prediction from H&E Histology

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.

Kritanu Chattopadhyay, Soumya Chatterjee, Ondrej Krejcar +1

Department of Mechanical Engineering, National Institute of Technology Durgapur,, Durgapur, 713209, West Bengal, India · Department of Electrical Engineering, National Institute of Technology Durgapur,, Durgapur, 713209, West Bengal, India · Research Center, Skoda Auto University, Na Karmeli 1457, Mlada Boleslav, 293 01,, Czech Republic +1

Computational PathologySpatial TranscriptomicsConvolutional Neural NetworksSpatial Gene Expression PredictionGene Expression Prediction from Histopathology Images
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Jul 21, 2026

Pathologist Attention-Aligned Report Generation for Prostate Histopathology

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

Ruoyu Xue, Suryakant Singh, Souradeep Chakraborty +12

Department of Computer Science, Stony Brook University, USA · Department of Biomedical Informatics, Stony Brook University, USA · Université Paris-Saclay, CentraleSupélec, Gustave Roussy, INSERM, IHU PRISM, Cancer Data Science Unit, France +4

Computational PathologyMedical Report GenerationMedical VQAOncologyWhole-Slide Image Analysis
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Jul 14, 2026

C-Norm: Cell-Distribution Normalization Enables Precision Recognition of Medical-Cell Image

ThinPrep Cytologic Test (TCT) enables early cervical cancer screening, but manual reading is time-consuming and yields inconsistent diagnostic results among cytopathologists. Existing AI detection models perform poorly under real clinical conditions, primarily restricted by two key constraints: unbalanced spatial distribution of cell populations in TCT slides, and limited high-quality annotated cytology data relying on professional pathologist labeling. To address these limitations, we propose a Cell-Distribution Normalization (C-Norm) method. By decoupling abnormal and normal cells from the original TCT images and re-synthesizing them, this method ensures a uniform distribution of cell populations, thereby mitigating generalization degradation caused by distribution bias. Building upon this, we integrate the YOLOv12 framework with a DINOv3 module. This hybrid architecture leverages the advanced detection capability of YOLO models and the superior feature representations of DINOv3 to capture subtle morphological nuances essential for precise recognition of TCT images. Extensive experiments demonstrate that our proposed method achieves state-of-the-art performance, significantly outperforming mainstream detection algorithms. The complete implementation is available at: https://github.com/ddw2AIGROUP2CQUPT/Cell-Norm

Yang Qianl, Liu Xiany, Dai Daw +5

Chongqing University Cancer Hospital, Chongqing, China · Chongqing University of Posts and Telecommunications, Chongqing, China · Shanghai First Maternity and Infant Hospital, Tongji University, Shanghai, China

Computational PathologyMedical Image AnalysisObject Detection
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Jul 14, 2026

CRC-HGD: A Histopathological Image Dataset for Grading Colorectal Cancer

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.

Elham Amjadi, Amin Bahreini, Sayed Mohammad Hasan Emami +4

Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran · Division of Transplant Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York, USA · Cancer Prevention Research Center, Isfahan University of Medical Sciences, Isfahan, Iran +1

Computational PathologyHistopathology Image ClassificationMedical Image Benchmarks
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Jul 14, 2026

CGRL: Concept-Guided Pruning and Representation Learning for Whole-Slide Image Classification

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.

Thuc Huynh, Tuan Le, Doanh C. Bui

University of Information Technology, Ho Chi Minh City, Vietnam · Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Vietnam

Computational PathologyContrastive LearningWeakly Supervised LearningMultiple Instance LearningWhole-Slide Image Analysis
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Jul 13, 2026

LaGuadia: Language-Guided Adaptive Distillation from Pathology Foundation Models

Pathology Foundation Models (PFMs) offer powerful Whole Slide Image (WSI) representations but suffer from massive computational costs. While Knowledge Distillation (KD) can create efficient student models, existing multi-teacher methods often use suboptimal uniform weighting that ignores tissue heterogeneity. We propose LaGuadia (Language-Guided Adaptive DistillAtion), a framework that develops a compact pathology image encoder by dynamically integrating expertise from multiple PFMs under clinical linguistic guidance. Our approach utilizes a multi-stage pipeline: first, extracting visually observable clinical keywords from pathology reports; second, aligning visual features with these keywords via a Vision-Language meta-teacher (MedSigLIP) to provide dense semantic guidance; and finally, performing adaptive KD where teacher contributions are weighted based on their semantic alignment with the clinical narrative. Experiments on WSI captioning, visual question answering, and slide-level classification tasks demonstrate that an 87M parameter LaGuadia student model matches or exceeds foundation-scale models such as GigaPath and UNI, achieving strong factual consistency and robust generalization. These results highlight clinical language as an effective semantic anchor for building efficient and reliable digital pathology systems. Code is available at https://github.com/hvcl/LaGuadia.

Gangsu Kim, Won-Ki Jeong

Department of Computer Science and Engineering, College of Informatics, Korea University, Republic of Korea

Computational PathologyAdaptive Knowledge DistillationPathology Foundation ModelsMedical VLMsMultimodal Foundation ModelsKnowledge Distillation
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Jul 11, 2026

Geometry-aware Gaussian Prior and Axial Attention for Cervical Cytology Image Classification

Accurate cervical cytology image classification is a key component of automated cervical cancer screening, where reliable recognition of normal, precancerous, and cancer-associated cellular patterns from Pap smear images can improve screening efficiency and diagnostic consistency. However, this task remains challenging because cervical cells exhibit complex morphology, subtle intra-class variations, and strong inter-class similarities. Existing convolution-based models capture local texture well but have limited ability to model long-range relationships, whereas attention-based models provide broader context but often lack explicit structural guidance. To address these limitations, we propose a geometry-aware classification framework for cervical cancer screening-oriented cytology image analysis, incorporating semantic abstraction and structural priors learned from pre-trained vision-language features. The method uses Gaussian expert modules to generate axis-wise priors from global semantic information, capturing structural regularities such as nuclear alignment and cellular spatial organization. These priors are embedded into an axial self-attention module to modulate similarity computation along horizontal and vertical directions, improving long-range dependency modeling and structure-sensitive feature interaction. Experiments on the Mendeley liquid-based cytology and SIPaKMeD datasets show that the proposed method achieves 99.48% accuracy on the former and 96.08% on the latter, with balanced gains in recall, precision, and overall classification performance. Visual analysis further shows that the learned priors highlight diagnostically relevant cellular regions, demonstrating the potential of the proposed framework as a screening-oriented decision-support tool for cervical cytology.

Yating Li, Cheng Ye, Nenan Lyu +2

School of Cyber Science and Technology, University of Science and Technology of China, Hefei 230026, China · School of Information Science and Technology, University of Science and Technology of China, Hefei 230026, China · Department of Gynecologic Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

Computational PathologyMedical Image ClassificationAttention Mechanisms
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Jul 10, 2026

Reliability-Aware Ensemble Classification Under Class Imbalance: A Calibration Study on Liquid-Based Cervical Cytology

Cervical cytology classification models are typically evaluated on curated, class-balanced benchmarks, but real-world liquid-based cytology (LBC) collections are often small and class-imbalanced. This paper presents a class-imbalance-aware and calibration-aware ensemble classification study on the Mendeley LBC dataset, using its native four-class Bethesda taxonomy (NILM, LSIL, HSIL, SCC) rather than a collapsed binary formulation. Three lightweight architectures (Swin-Tiny, TinyViT-5M, DenseNet121) are trained directly on Mendeley LBC using weighted random sampling to counteract class imbalance, and compared against two soft-voting ensembles (Hybrid-2, Hybrid-3). Post-hoc temperature scaling is fit on a held-out calibration subset carved out of the training portion of each cross-validation fold, distinct from both the training data used to fit model weights and the evaluation fold used for final metrics, avoiding the optimistic calibration estimates that result when the same data is used for both purposes. Calibration substantially reduces expected calibration error, Brier score, and negative log-likelihood for every model and ensemble configuration tested, while discrimination metrics (accuracy, macro-F1, macro-AUROC) remain essentially unchanged. Ensemble size shows no consistent additional reliability benefit over the best individual model once all configurations are properly calibrated. Confusion matrices show that all classification errors, across every configuration, are confined to the boundary between high-grade lesions (HSIL) and carcinoma (SCC); no errors involve the negative (NILM) or low-grade (LSIL) categories. These results suggest that, for this dataset, calibration is the dominant lever for reliability, not ensemble size, though this conclusion should be read in light of the dataset's modest size.

Nisreen Albzour, Sarah S. Lam

School of Systems Science and Industrial Engineering, Binghamton University, Binghamton, NY 13902, USA

Class-Imbalanced LearningComputational PathologyProbability CalibrationEnsemble LearningMedical Image ClassificationMulticlass Classification
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Jul 10, 2026

ALICE: Learning a General-Purpose Pathology Foundation Model from Vision, Vision-Language, and Slide-Level Experts

Foundation models are reshaping computational pathology, yet their capabilities remain shaped by pretraining objectives, data sources, and spatial scales, fragmenting complementary expertise across separate backbones. Here we present ALICE, a unified foundation model trained through multi-stage agglomerative distillation that sequentially distills eight vision-only, vision-language, and slide-level teacher models into dedicated modules of a single backbone. ALICE is pretrained on 24,985,184 tile-level pathology images and 155,604 high-resolution images, and evaluated across 21 task scenarios, 96 downstream tasks, and 48 data sources, spanning region-of-interest tissue analysis, vision-language multimodal evaluation, and whole-slide clinical assessment. In all three evaluation settings, ALICE achieved the best average rank among task-matched pathology foundation models. These results demonstrate that agglomerative distillation can consolidate complementary capabilities from specialized models into a unified backbone for broad computational pathology applications. The model is available at https://github.com/WonderLandxD/ALICE.

Jiawen Li, Tian Guan, Huijuan Shi +5

Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China · Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China · Department of Engineering Science, University of Oxford, Oxford, UK +1

Computational PathologyUnified Multimodal ModelsPathology Foundation ModelsMulti-Teacher Knowledge DistillationMultimodal Foundation ModelsWhole-Slide Image Analysis
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Jul 10, 2026

Slide-Level Active Learning Reduces Annotation Burden in H&E images

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.

Mahsa Vali, Zhilong Weng, Noémie Moreaua +2

Institute for Biomedical Informatics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany · Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany · Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany +3

Computational PathologyHistopathology Image SegmentationMedical Image SegmentationWhole-Slide Image Analysis
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Jul 9, 2026

ProsMAE: Multi-Source MAE Pretraining for ISUP Grade Classification

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.

Anna Jung, Kyeonghun Kim, Youngung Han +6

SNU · OUTTA · GIST +1

Computational PathologyMasked AutoencodersOncologyHistopathology Image ClassificationProstate Cancer GradingMedical Image Representation Learning+1
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Jul 7, 2026

Finding H. pylori in the Fine Print: Evidence-Linked Multi-Agent Case Finding from Gastric Biopsy Reports

Data from Singapore indicated that about 31% of the population had evidence of Helicobacter pylori infection. Persistent H. pylori infection is associated with chronic active gastritis and peptic ulcer disease, and its eradication is key to gastric cancer prevention. However, evidence supporting H. pylori positivity and H. pylori-associated gastritis may be distributed across heterogeneous coded and free-text report fields and may require contextual interpretation of assertion and negation, limiting keyword search, and making manual review difficult to scale. We conducted a retrospective pilot evaluation of the Nimblemind Multi-Agent System (nMAS), a field-name-driven, evidence-linked extraction workflow, using 54 de-identified gastric biopsy pathology reports from a large healthcare system in Singapore. Four clinician-scoped binary fields were evaluated: gastric/stomach biopsy, biopsy status, H. pylori positivity, and H. pylori-associated gastritis. Across 216 feature-case decisions, nMAS correctly classified 213, corresponding to 98.61% overall accuracy. A separately implemented UMA-style MiniMax M2.5 comparator produced similar aggregate and per-field classification metrics. Although predictive performance was similar, nMAS maintained unified report-level outputs with supporting source sentences; the demonstrated contribution is therefore workflow integration and traceability rather than predictive superiority. Under an illustrative, unmeasured scenario, reviewing 1,000 reports at five minutes per manual review versus five seconds per evidence-linked verification would reduce review time from 83.3 to 1.4 staff-hours, corresponding to 81.9 staff-hours and about USD~6,100 in potential staff-time value. Larger multi-institutional studies should evaluate evidence-span correctness, clinician verification time, and generalizability.

Yufan Wang, Anit Kumar Sahu, Yan Fei Ng +8

Nimblemind.ai, USA · Independent Researcher · Department of Anatomical Pathology, Singapore General Hospital, Singapore +2

Computational PathologyClinical Information ExtractionMulti-Agent Systems
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Jul 6, 2026

Multi-Teacher Contrastive Distillation for Edge-Efficient Pathology Foundation Models

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

Tim Lenz, Maurice Heide, Marco Gustav +2

EKFZ for Digital Health, TU Dresden, Dresden, Germany · Pathology, University of Augsburg, Augsburg, Germany · Bavarian Cancer Research Center (BZKF), Augsburg, Germany +3

Computational PathologyPathology Foundation ModelsHistopathology Image ClassificationEdge MLKnowledge Distillation
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Jul 6, 2026

DriftST: One-Step Generative Inference of Spatial Transcriptomics from H&E Histology

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.

Yuhang Yang, Yonggan Bu, Shengyuan Zhou +2

University of Science and Technology of China, Hefei, China · Peking University Cancer Hospital, Beijing, China

Computational PathologySpatial TranscriptomicsOne-Step Generative ModelingSpatial Gene Expression PredictionGene Expression Prediction from Histopathology Images
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