Pathology Foundation Models

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Overview

Pathology foundation models learn visual patterns from digital tissue slides, often using self-supervised learning on image patches and whole-slide images, or aligning images with text and molecular data. Researchers adapt these representations with frozen-feature probes, fine-tuning, and multiple-instance learning for tasks such as tumor classification, cell segmentation, biomarker prediction, and survival analysis. Evaluation spans benchmarks such as HEST and TCGA, external hospital cohorts, and increasingly prospective studies and pathologist reader evaluations. Models can transfer across many tasks, but performance may shift with tissue type, staining, or institution, while biological interpretability and the trade-off between model size, efficiency, and clinical reliability remain open challenges.

Latest papers

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93 papers11 papers in the last four weeks, up 57% on the four weeks before. 0.1% of all new papers.

Nov 2, 2026

CellPlex: Benchmarking Single-Cell Spatial Proteomics Prediction from H&E

Spatial proteomics measures tens of proteins in every cell of a tissue section, but its cost confines it to small research cohorts, whereas hematoxylin and eosin (H&E) slides exist for nearly every patient. Inferring single-cell spatial proteomics from H&E would bring its analyses to routine pathology, and a growing number of virtual staining models pursue this goal. Each is evaluated on its own cohort, panel and pixel-level metric, and released models transfer poorly to new cohorts, leaving open which approach to build on and which proteins H&E can reveal. We introduce CellPlex, a benchmark that poses the task at the level of the cell: seven cohorts with same-section H&E and multiplexed immunofluorescence, from colorectal and breast cancer to lymph-node metastases, bone marrow and glioma, with 717 samples, 44.8 million cells and 149 proteins, processed by one pipeline into per-cell targets. Pathology foundation models (PFMs) are adapted with one cell-level protocol, specialist models are fine-tuned under a matched budget, and all are scored on the same cells. Adapted PFMs are the most accurate models on every cohort, ahead of the specialists even after fine-tuning, but keep less than half of their accuracy on cohorts they were not trained on. Which proteins can be predicted depends on the tissue, not on how many cells were measured for them. By fixing the cells, targets and splits on which predictions are judged, CellPlex sets a common standard for inferring costly molecular measurements from routine H&E and shows how far H&E can stand in for spatial proteomics. We will release the data, splits, evaluation code and baselines as a testbed for developing and comparing future pathology foundation models and virtual staining methods.

Zijun Gao, Yijiang Chen, Xiangde Luo +1

The Chinese University of Hong Kong · Stanford University School of Medicine

Virtual StainingMedical Image BenchmarksPathology Foundation Models
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Oct 29, 2026

Sparse Autoencoders for Expert-Assisted Interpretation of Histopathology Foundation Model Embeddings

Histopathology foundation models learn rich embedding representations, but their internal structure remains difficult to inspect. Concept-level interpretability is particularly relevant in computational pathology because pathologists reason through recurring morphological and tissue-level patterns, including tissue architecture, cellular morphology, staining variation, and artifacts. In this work, we investigate whether sparse autoencoders (SAEs) can decompose embeddings from histopathology foundation models into sparse latent features suitable for expert-assisted interpretation. We train vanilla and Batch-TopK SAE variants on NCT-CRC embeddings, using CONCH as the primary foundation model and UNI2-h as an additional robustness evaluation, and characterize the resulting latent features through reconstruction fidelity, sparsity, coherence, label enrichment, and downstream class-signal preservation. The learned sparse representations preserve most downstream tissue-class information, and their latent features retrieve more coherent and label-concentrated patch groups than raw embedding dimensions or PCA components. Discussions with pathology experts further motivated a WSI-level latent visualization workflow that places feature activations into larger tissue context. Overall, the additional UNI2-h evaluation suggests that the observed behavior is not specific to CONCH, supporting the use of sparse autoencoders for expert-assisted analysis of histopathology foundation-model embeddings, while emphasizing that latent features should be treated as candidate concepts requiring pathological assessment rather than automatically validated histopathological concepts.

Šimon Šmída, Wanda Benesova

Czech Technical University, Prague, Czech Republic

Explainable Medical Image AnalysisComputational PathologyConcept-Based ExplanationsSparse AutoencodersPathology Foundation Models
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Oct 28, 2026

Knowledge-structured and evidence-aware semantic self-distillation for glomerular pathology foundation model

Visual foundation models learn rich pathological morphology but lack explicit concept-level supervision. Vision--language pretraining can provide this supervision but requires costly image--text pairs. Here, we introduce GloSAGE, a semantic self-distillation framework that uses lesion profiles predicted by a pretrained visual teacher to construct structured pathology descriptions. Reliability-guided selection identifies image--text anchors, while Knowledge-Structured Pathology Text Synthesis and Evidence-Guided Negative-pair Construction account for partially observed lesions. Image--text alignment trains projection layers while retaining the frozen visual encoder; an intermediate Semantic Transfer Layer supplies features for downstream tasks. Developed on GloMillion and evaluated across seven glomerulus- and case-level cohorts, GloSAGE supported zero-shot lesion recognition, image--text retrieval, hard-negative discrimination and concept-intervention analyses. It outperformed its source visual model in most lesion-recognition tasks and improved lesion grading, while supporting competitive case-level disease classification, injury grading and baseline renal function estimation. Ablations supported the combined contributions of knowledge-structured text and evidence-guided negatives, and the intermediate transfer layer improved mean lesion-recognition ROC-AUC relative to the complete projection output. A frozen language model conditioned on GloSAGE features generated glomerular descriptions. These findings suggest that teacher-derived lesion profiles can provide annotation-efficient semantic supervision for extending a glomerular visual foundation model.

Qiming He, Jing Li, Zihan Wang +24

Fuzhou University Affiliated Provincial Hospital, Interdisciplinary Institute for Medical Engineering, Fuzhou University, Fuzhou, China. · Medical Optical Technology R&D Center, Research Institute of Tsinghua, Pearl River Delta, Guangzhou, China. · Department of Pathology, School of Basic Medicine and Xijing Hospital, Fourth Military Medical University, Xi’an, China. +5

Pathology Foundation ModelsMedical VLMsSelf-Distillation
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Oct 27, 2026

PRISM: Pathology Reliability In Scarce-label Medicine. A Tile-level Benchmark of Pathology Foundation Models

Pathology foundation models are typically benchmarked on classification performance at full label availability and on in-distribution test sets, while calibration, behavior at low label budgets, and robustness under cross-institutional shift are seldom evaluated jointly. We introduce PRISM, a tile-level benchmark that measures the reliability of pathology foundation models along four axes: model choice, label fraction, calibration, and out-of-distribution transfer. PRISM evaluates eight foundation models (CLIP, PLIP, CONCH, UNI, Virchow2, GigaPath, H-Optimus-0, Midnight) on six tile-level datasets at six label fractions (1% to 100%) with three seeds (864 linear probe runs), extended with a five-hospital Camelyon17 study of 20 directed transfer pairs. Four phenomena emerge. (i) Under full supervision, AUROC rank predicts post-temperature calibration rank consistently across datasets (Spearman rho = 0.52, I^2 = 0%), whereas at 1% labels the relationship becomes dataset-specific (rho = -0.24, I^2 = 67%). (ii) On harder datasets the linear probe collapses to a single predicted class below a dataset-specific label fraction. (iii) Whether additional source-domain labels help or harm target calibration tracks how well the probe transfers: below a transfer AUROC of roughly 0.85, more labels worsen target ECE in 86-88% of combinations. (iv) Temperature scaling fails to reduce ECE in 49 of 288 cells, miscalibration is predominantly under-confidence, and a source-fitted temperature is harmful under failing transfer. PRISM is released as a pip-installable package with reference results for all 288 cells. Code and data: https://github.com/alicemkyn/prism-benchmark

Alicem Koyun

Westcliff University

Computational PathologyPathology Foundation ModelsMedical Image BenchmarksHistopathology Image ClassificationMedical Image ClassificationOOD Generalization
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Oct 20, 2026

AdaptMIL: Domain Adaptation for Multiple Instance Learning in Digital Pathology

Pathology foundation models (PFMs) support a wide range of histopathology tasks on whole-slide images through multiple instance learning (MIL). Despite recent progress, these models remain sensitive to cross-hospital distribution shifts: performance often degrades when a task head (e.g., classification) is trained on data from one hospital and then used on data from another hospital. To address this challenge, we propose AdaptMIL, a training strategy for integrating domain adaptation into MIL training. AdaptMIL is motivated by our finding that directly applying domain adaptation objectives during MIL training can interfere with MIL aggregation learning, often resulting in performance degradation over standard training. AdaptMIL resolves this by decoupling representation-level domain alignment learning from MIL aggregation learning through a two-stage training procedure. We show that AdaptMIL improves cross-hospital performance and outperforms alternative adaptation methods across experiments spanning multiple WSI datasets, tasks, PFMs, MIL architectures, and domain adaptation objectives. AdaptMIL's code will be released upon publication.

Ben Vardi, Dana Schonberger, Yuval Friedmann +4

Reichman University · Institute of Pathology, Sheba Medical Center · Technion – Israel Institute of Technology +1

Domain AdaptationComputational PathologyMultiple Instance LearningPathology Foundation Models
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Oct 19, 2026

Scaling Vision Foundation Models for Toxicologic Pathology

Here, we present TOX-FM, a family of non-clinical PFMs trained on large-scale diverse histopathology datasets of over one million whole slide images consisting of over 60 organs across six animal species from over 14,000 toxicology studies across six decades. We introduce a comprehensive benchmark of 18 non-clinical downstream tasks, incorporate an established benchmark of 9 clinical downstream tasks, and evaluate TOX-FM against state-of-the-art clinical PFMs across both non-clinical and clinical domains. Notably, we explore open questions surrounding domain-specific training and cross-domain generalization, offering insights into the opportunities and challenges of applying PFMs in the non-clinical domain.

Jessica Loo, Theodoros Pissas, Byunghak Kang +7

Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA · Novartis Pharma AG, Basel, Switzerland · Novartis Ireland Limited, Dublin, Ireland

Pathology Foundation ModelsComputational PathologyWhole-Slide Image AnalysisCross-Domain GeneralizationMedical Image Benchmarks
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Oct 19, 2026

Multi-scale Fusion of Fast Vision Mamba and Foundation Model Features for Patch-Level Gleason Grading in Computational Pathology

Automated Gleason grading of prostate whole slide images (WSIs) enables faster and more consistent cancer risk stratification. However, it remains a challenging task due to the subtle morphological differences between grades, the severe class imbalance arising from rare patterns, and the diagnostic features that span multiple spatial scales. Pathology foundation models (FMs) extract strong patch representations but often operate at a single-scale, which limits spatial context and disproportionately affects classes that depend on broader context. The challenge of fusing multiple scales and complementary models, with minimal data and computational resources, remains unresolved. We propose a multi-scale classifier built on state-space models. Our method combines two complementary feature sources: a frozen foundation model, and a lightweight FastVim, pre-trained on ImageNet and distilled from the foundation model, that reads the raw image crops. At each scale, a Mamba model encodes the features from both sources with linear-time spatial context, and a jointly trained head fuses the encoded representations into one prediction. On the PANDA dataset, our method reaches macro F1 of 0.894 and Gleason 5 F1 of 0.802 under 5-fold cross-validation, a 12% and 21% relative improvement over the best single-scale model. A controlled study over 5 foundation models, 5 base classifiers and 3 scales confirms that the gain holds across encoders, with larger improvements observed at smaller scales.

Zihe Zhang, Weimiao Yu, Piumi Don Simonge

Nanyang Technological University, Singapore · Bioinformatics institute, Agency for Science Technology and Research, Singapore

Histopathology Image ClassificationProstate Cancer GradingMulti-Scale Feature FusionPathology Foundation Models
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Oct 15, 2026

Input- and Feature-Space Correction for Cross-Hospital IHC Grading

Pathology foundation models (FMs) are trained predominantly on hematoxylin and eosin (H&E) images but are increasingly used as frozen feature extractors for immunohistochemistry (IHC), where cross-hospital differences can impair grading. However, systematic comparisons of correction methods for cross-hospital IHC grading remain limited. To address this gap, we benchmark label-free transformations applied to input images before frozen-FM encoding and to features after frozen-FM encoding using UNI and Virchow2, three IHC markers, and six directed cross-hospital transfers, yielding 12 settings. Among the evaluated input-space methods, our proposed method FIX achieved the largest macro-F1 improvement over no correction, outperforming well-known stain normalization techniques. Among feature-space methods, a simple feature-wise standardization achieved the best improvement over no correction, outperforming CORAL. Under patient-averaged tile-level evaluation, combining FIX with feature-wise standardization improved macro-F1 and quadratic weighted kappa (QWK) by 0.181 and 0.208, respectively, and reduced ordinal error by 0.209 relative to no correction. These results show that input- and feature-space transformations can provide complementary benefits for cross-hospital IHC grading with frozen pathology FMs.

Jongwoon Lee, Jhair Gallardo, Christopher Kanan

Department of Computer Science, University of Rochester, Rochester, NY · Rochester Institute of Technology, Rochester, NY

Domain AdaptationHistopathology Image ClassificationPathology Foundation Models
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Oct 15, 2026

Pathology foundation models for training-free case retrieval in salivary gland tumors

In pathology, pattern recognition relies on a frame of reference built through extensive training and experience, which may still fall short when encountering rare cancer subtypes. Archives of previously diagnosed tumors often contain relevant precedents, yet identifying the most relevant cases remains challenging. Here we explore whether content-based retrieval with current pathology foundation models facilitates rare cancer diagnostics without any task-specific training. Pathologists can query a digitized archive using a region of interest (ROI) from a whole slide image (WSI) and retrieve morphologically similar cases, along with their ICD-O codes and corresponding WSIs. The ROI can be selected manually or automatically using a gated attention-based multiple instance learning model. We evaluate our approach by leave-one-case-out on an imbalanced dataset of 137 salivary gland tumor cases spanning 12 ICD-O morphology categories, comparing four pathology foundation models (Atlas2, Atlas2-B, Atlas2-S, and UNI2h). Top-1/3/5 retrieval was 62.5%/76.7%/81.3% for Atlas2, 50.2/66.6/72.9% for UNI2h, 52.3%/71.5%/77.6% for Atlas2-B and 54.4/65.2/73.7% for Atlas2-S. Macro-averaged F1 ranged from 69.0% for the smallest model Atlas2-S to 76.6% for the largest model Atlas2 across the five classes with at least ten cases. Our modified Chamfer similarity separated correct from incorrect matches among the Top-5 more reliably for Atlas2 (AUC 0.754) than for Atlas2-B (0.679, p = 0.020) and Atlas2-S (0.653, p = 0.003), but not UNI2h (0.697, p = 0.196). Requiring no additional training or manual annotation, this approach makes departmental archives searchable with pathology foundation models, providing a low-barrier route to case-based differential diagnosis and extending the individual frame of reference to the collective experience of the department.

Maximilian J. Roesel, Niklas Kiermeyer, Philipp Keyl +1

Institute of Pathology, Ludwig-Maximilians-Universität München · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Munich partner site · Institute of Pathology, Charité-Universitätsmedizin Berlin +1

Computational PathologyMedical Image RetrievalPathology Foundation ModelsWhole-Slide Image AnalysisFine-Grained Image RetrievalOncology
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Oct 12, 2026

FOCUS: A Subspecialty Foundation Model for Intraoperative Central Nervous System Pathology

Intraoperative frozen-section diagnosis of central nervous system (CNS) lesions guides surgical decisions but is challenged by artefacts, diagnostic complexity and time constraints. Most pathology foundation models have limited exposure to CNS frozen tissue. Here we present FOCUS, a subspecialty foundation model pretrained on 27,930 frozen-section whole-slide images enriched for CNS tissue. FOCUS ranked first across all 11 diagnostic and 12 biomarker-prediction tasks in the internal test cohort, achieving mean AUCs of 0.969 and 0.877, respectively. This advantage was retained in the temporal and external test cohorts. We further organized a WHO-aligned diagnostic hierarchy, where FOCUS also outperformed comparator models. In a reader study, FOCUS assistance enabled junior readers to approach or exceed unassisted senior readers in hierarchical diagnostic accuracy and granularity. More importantly, FOCUS assistance enabled readers to correctly identify a mean of 63.0% of initially missed lymphoma cases (73.2% among junior readers), potentially avoiding unnecessary extensive resection. These findings highlight the potential of FOCUS to provide clinically actionable support for intraoperative CNS pathology and inform surgical decisions.

Xing Liu, Yifan Guo, Hongtai Lv +18

Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing,100070, P.R.China. · CAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No. 95 Zhongguancun East Road, Haidian District, Beijing, 100190, P.R. China. · School of Artificial Intelligence, University of Chinese Academy of Sciences, No. 1 Yanqihu East Road, Huairou District, Beijing, 101408, P.R. China. +5

Pathology Foundation ModelsComputational PathologyHistopathology Image ClassificationClinical Decision Support
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Oct 8, 2026

Scaling Multi-Teacher Distillation for Digital Pathology

Multi-teacher distillation allows transferring knowledge from multiple "teacher" networks to a single "student" network. This method is promising in fields such as digital pathology, where many powerful foundation models were proposed recently. However, as we show in this paper, the standard multi-teacher distillation approach reacts poorly to an increase in the number of teachers used to train a student encoder. We demonstrate that learning teacher-specific representations is a key to scaling in MTD. Importantly, different design choices, such as learnable teacher tokens, a tailored attention scheme, additional mixture-of-experts layers and a contrastive loss, are proposed to better learn such teacher-specific representations. We show that our method better scales with respect to the number of considered teachers, allowing us to train compact student encoders, up to 10x more efficient than larger teacher foundation models, while matching their performance and even outperforming them on a large set of tile-level and slide-level tasks. We conduct a thorough empirical validation, evaluating more than 10 foundation models on 39 tasks spanning tile and slide levels. As a result, we release a new collection of strong and efficient foundation models, named OMNI, trained from the knowledge of 10 state-of-the-art foundation models. We finally conduct an analysis of the learned teacher-specific representations, highlighting their complementarity and explaining why they can be easily aggregated at downstream time.

Sofiène Boutaj, Pierre Marza, Varun Belagali +3

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

Multi-Teacher Knowledge DistillationPathology Foundation ModelsComputational Pathology
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Oct 6, 2026

One-Slide Calibration of Pathology Foundation Models

Scanner variation changes how pathology foundation models represent the same tissue. We introduce SlideRuler, which uses other regions within a slide as internal controls to predict a query region's scanner-induced shift. A transfer map learned from paired rescans enables calibration from a single scan at inference while keeping the foundation model fixed. Across two encoders and five SCORPION scanners, learned transfer reduces mean target-to-source embedding distance by 16.3-38.5% relative to raw embeddings. Replacing controls with unrelated same-scanner regions reveals a positive same-slide contribution in all four evaluation settings, including scanner holdout. A source-anchored variant reduces source-feature displacement by 47.7-83.6% relative to learned transfer while retaining most of its alignment gain. By drawing calibration information from the slide itself, SlideRuler offers a path toward more consistent use of frozen pathology models across imaging systems.

Ming Ren Hou, Tianyi Huang

Ryquo

Computational PathologyPathology Foundation Models
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Sep 30, 2026

SCALE: Synthetic Calibration via Agreement Labeling in Embedding Space

Foundation models for computational pathology are usually evaluated using AUC and accuracy, while calibration is often left untested. This matters because a model can be accurate on average but still assign overly confident probabilities to cases that are difficult even for pathologists. We study calibration across eight pathology foundation models. Using pathologist agreement as a measure of diagnostic difficulty, we find that calibration error is consistently higher on low-agreement cases than on high-agreement cases. This pattern is not apparent from aggregate expected calibration error (ECE) alone. We then propose synthetic agreement calibration, a method for improving calibration without collecting multi-annotator labels. Given a trained linear probe, we select high-confidence embeddings as class anchors and interpolate between anchors from opposite classes. The interpolation weights encode a continuous notion of diagnostic ambiguity, which we use as a synthetic agreement signal to retrain the probe with agreement-aware label smoothing. On MHIST, which includes annotations from seven pathologists, synthetic agreement calibration recovers most of the calibration improvement obtained by label smoothing based on real pathologist agreement, while substantially reducing low-agreement ECE relative to the uncalibrated baseline. Discrimination metrics are preserved. On PatchCamelyon and BreakHis, public histopathology datasets without multi-annotator labels, the method improves calibration across the evaluated foundation models, whereas annotator-dependent approaches cannot be used without additional expert annotation.

Wenjun Liu, Saeed Hassanpour

Department of Computer Science Dartmouth College Hanover, NH, USA · Departments of Biomedical Data Science, Computer Science, and Epidemiology Dartmouth College, Hanover, NH, USA

Computational PathologyPathology Foundation ModelsModel CalibrationHistopathology Image Classification
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Sep 28, 2026

HERO: Histology Encoder for Robust Representation in Oncology

Foundation models trained on large pathology image corpora now provide strong, transferable representations for computational pathology. Over the past few years a series of such models has been released, each trained on more slides than the last; on standard classification and segmentation benchmarks, the leading models are now separated by small margins. In clinical use, however, the foundation model is applied to images from hospitals, scanners, and staining protocols outside its training data. Encoders generally embed these acquisition factors alongside biological information, which may introduce downstream errors and hinder safe clinical adoption. A pathology foundation model should therefore be robust to acquisition shift without giving up representation quality, yet robustness is seldom the axis along which models are compared. In this report, we introduce HERO (Histology Encoder for Robust Representation in Oncology), a ViT-G/14 pathology foundation model trained with the DINO and iBOT objectives and refined with high-resolution Gram anchoring on a morphology-balanced corpus of 500 million tiles from approximately 575,000 clinical whole-slide images. Across the evaluated public benchmarks, HERO shows the strongest robustness to center, scanner, and stain variation among the compared state-of-the-art foundation models, performs comparably on tile-level classification, segmentation, and gene-expression prediction, ranks first on average across 39 evaluated slide-level clinical tasks, and, under an equal-weighted framework-level analysis, has the best average rank across the six benchmark frameworks.

Zhi Li, Eghbal Amidi, Yating Cheng +11

Caris Life Sciences, Irving, TX, United States

Computational PathologyDomain GeneralizationPathology Foundation ModelsMedical Image Representation LearningWhole-Slide Image Analysis
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Sep 28, 2026

Role-Guided MOE for Encoder-Level Pathology Representation Learning in WSI Classification

Whole slide image classification is a fundamental task in computational pathology, where patch representation quality directly affects downstream aggregation and slide-level discriminability. Pathology foundation models are widely adopted as frozen feature extractors for WSI classification; however, their fixed encoders may produce representations insufficiently adapted to target-specific tissue patterns and discriminative cues. Fine-tuning can improve target adaptation, but introduces a trade-off between pathology-specific representation capacity and adaptation efficiency, particularly in data-scarce settings. To address this, we propose a pathology role-guided mixture-of-experts feed-forward network (MoE-FFN) framework for efficient encoder-level representation learning. We design a two-stage training paradigm to establish and adapt pathology-aware expert specialization. In source-domain expert initialization, pathology-specific priors are distilled from a frozen Virchow2 teacher into a lightweight DINOv2-small student, while role prototypes serve as weak pathological anchors to encourage distinct expert functions. MoE-FFN blocks are introduced into selected high-level transformer layers to provide transformation diversity for heterogeneous pathological patterns. In target-domain adaptation, the initialized experts are refined through asymmetric prototype-guided optimization, enhancing task-relevant positive evidence and separating confusable hard negatives. The resulting encoder extracts offline patch representations that can be directly integrated with standard MIL aggregators. Experiments on the public BRACS dataset and a private PAROTID WSI dataset across five representative backbones demonstrate consistent improvements over the strongest baseline.

Xinyu Ma, Xing Yang, Hongtao Jin +4

Artificial Intelligence Research Institute, Shenzhen MSU-BIT University, Shenzhen 518172, China · Shenzhen People’s Hospital, Shenzhen 518020, China

Pathology Foundation ModelsMixture-of-Experts ModelsMedical Image Representation LearningWhole-Slide Image Analysis
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Sep 27, 2026

Can Protein-Derived Knowledge Improve Pathology Foundation Models?

Molecularly guided pathology foundation models (PFMs) exploit transcriptomic or proteomic information to enrich whole-slide image (WSI) representations, yet effectively leveraging large standalone molecular corpora remains challenging. First, existing molecular foundation models encode protein sequences or single-cell states, not the patient-level bulk expression profiles paired with WSIs. Second, because cross-modal supervision is restricted to paired WSI-omics samples, knowledge from standalone molecular corpora reaches the pathology encoder only indirectly, creating a paired-support bottleneck. To address these challenges, we propose a three-stage framework that decouples proteomic knowledge acquisition from cross-modal transfer, yielding ProSlide, a slide-level hierarchical pathology foundation model. First, to close the modality gap, we pretrain a Proteomic Foundation Encoder (PFE) on 12,695 sample-level bulk protein profiles using virtual profile generation and expression-space multi-view pretraining. Second, we pretrain ProSlide, a patch-region-slide encoder, to predict protein expression from paired WSI-protein samples. Third, to relax the paired-support bottleneck, we introduce Prot2Path, a cross-modal relational distillation objective. For each paired sample, it aligns the similarity distributions of the WSI and its protein profile over a shared, frozen bank of PFE-encoded paired and standalone profiles. We evaluate ProSlide on 12 downstream tasks across breast, lung, and renal cancers. Despite being pretrained with only 2,229 WSIs and 12,695 sample-level protein profiles, ProSlide achieves the highest mean accuracy and AUC within each cancer group.

Di Zhang, Zhangpeng Gong, Jiashuai Liu +10

School of Computer Science and Technology, Xi’an Jiaotong University · Tsinghua Shenzhen International Graduate School, Tsinghua University · University of Cambridge +4

Pathology Foundation ModelsComputational PathologyWhole-Slide Image AnalysisMolecular Representation LearningCross-Modal Knowledge Distillation
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Sep 26, 2026

Multimodal LLMs Outperform Pathology Foundation Models in Cross-Domain Histological Similarity

State-of-the-art pathology foundation models, trained on millions of histology tiles, can fail to preserve tissue similarity when comparisons cross slide or institution boundaries. We show that general-purpose multimodal LLMs, without being trained as pathology foundation models, consistently outperform these specialized models in cross-domain histological similarity judgments. Using a relative similarity framework that we release as the MOSAIC (Model Similarity Assessment across Institutions and Cohorts) benchmark, we evaluate 17 models across 6 datasets and find that pathology encoders often rank same-institution, different-disease tiles as more similar than same-disease, different-institution tiles, a clinically dangerous failure mode invisible to standard within-domain evaluations. LLMs appear less susceptible to this failure, likely because they perform semantic visual comparison of morphology and tissue architecture rather than relying on shortcut features tied to acquisition context. Scaling training data does not resolve the problem for pathology encoders, implicating the learning objective rather than data coverage. Our results expose a fundamental robustness gap in current pathology foundation models and establish multimodal LLMs as a viable alternative for cross-institutional retrieval, dataset harmonization, and multi-site quality control. Code and data will be released upon acceptance.

Yishu Zhang, Yun Li, Daiwei Zhang

University of North Carolina at Chapel Hill

Multimodal RobustnessMultimodal Large Language ModelsPathology Foundation ModelsMultimodal Model EvaluationMedical Image Benchmarks
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Sep 23, 2026

Do Center Biases Propagate? Robustness of Pathology Foundation Models in Whole-Slide Image Classification

Pathology foundation models (PFMs) have transformed computational pathology through powerful representation learning from histopathological images. PFMs provide rich, discriminative representations for whole slide image (WSI) analysis, enabling tasks such as slide-level classification under multiple instance learning (MIL). However, these representations may also encode non-biological signals associated with acquisition centers, potentially introducing spurious shortcuts into downstream predictions. In this work, we evaluate center-associated robustness in WSI classification using a controlled training setting with increasing class-center correlations quantified by Cramér's V. We benchmark six PFMs across four datasets and two MIL aggregators, while evaluating ComBat as a robustification strategy. We further introduce the Area Under the Cramér's V Curve (AUCC) to jointly capture absolute classification performance and its degradation as spurious correlation increases. Results show that center-related information encoded by PFMs propagates to WSI-level predictions, with robustness depending on both the PFM representation and MIL aggregation strategy. Additionally, ComBat harmonization does not provide consistent robustness gains across datasets.

Ilán Carretero, Pablo Meseguer, Rocío del Amor +1

CVBLab, HumanTech, Universitat Politècnica de València (UPV), Valencia, Spain · Artikode Intelligence S.L., Valencia, Spain

Batch Effect CorrectionPathology Foundation ModelsSpurious Correlation RobustnessHistopathology Image ClassificationWhole-Slide Image Analysis
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Sep 20, 2026

WILSON - Multi-magnification composites as a foundation for patient-level pathology analysis and diagnostic text generation

Pathologists examine tissue sections across multiple magnifications and slides, integrating morphological information to establish a diagnosis. In contrast, most pathology foundation models encode thousands of image patches from a single representative ("best") slide and aggregate their features, limiting multiscale and patient-level contextual integration. Here we introduce WILSON, a vision-language foundation model that represents whole-slide images and multi-slide cases through multi-magnification composites. Trained on approximately 189,000 slides spanning 42 organs and 838 diagnostic entities, WILSON enables patient-level analysis, multimodal retrieval and diagnostic text generation. Without task-specific training, WILSON outperformed a dedicated case-level model (macro-F1, 0.52 versus 0.38) and matched substantially larger slide-level models while requiring 400-1,350 times fewer computational operations. End-to-end fine-tuning improved breast cancer subtyping and stromal lymphocyte grading. WILSON also surpassed PRISM in image-text retrieval (recall@1, 75.6% versus 58.1%) and generated diagnostic descriptions that received higher ratings from five board-certified pathologists than competing models. These findings demonstrate that compact, multiscale representations can support computationally efficient, clinically grounded pathology foundation models.

Saghir Alfasly, Wataru Uegami, Sobhan Hemati +17

KIMIA Lab, Department of AI & Informatics, Mayo Clinic, Rochester, MN, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. · Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. +3

Pathology Foundation ModelsComputational PathologyMedical VLMsWhole-Slide Image AnalysisHistopathology Image ClassificationMedical Report Generation
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Sep 4, 2026

Conserved Immune Topology Improves Pathology Foundation Model Generalization for Cross-Cancer MSI-H Prediction

Pathology foundation models integrated with multiple instance learning achieve competitive accuracy within single-cancer cohorts, yet cross-cancer generalization remains unresolved due to organ-specific histological and architectural differences. In this paper, we propose Conserved Immune Topology (CIT), a lightweight spatial representation for cross-cancer MSI-H prediction that augments foundation-model embeddings with biologically motivated immune descriptors. CIT uses unsupervised clustering to identify immune-associated tiles, then encodes tertiary lymphoid structures, peritumoral immune reactions, multi-scale tumor-infiltrating lymphocyte density, and immune-tumor mixing from frozen foundation-model embeddings and tile coordinates without requiring annotations or target-domain data. The proposed method was evaluated under cross-site and cross-cancer settings using CPTAC-COAD and TCGA-STAD cohorts, which introduce scanner variability, distribution shifts, and organ-specific architectural variations. Zero-shot cross-cancer transfer with CIT increased TransMIL AUC from 0.6627 to 0.7161, an absolute gain of 0.0534 (p=0.003), with consistent improvements across all three MIL aggregators. These results suggest that spatial immune topology provides potentially an organ-invariant representation for MSI-H prediction, supporting cross-cancer generalization of pathology foundation models.

Dasari Naga Raju

Independent Researcher, Andhra Pradesh, India

Cross-Domain GeneralizationPathology Foundation ModelsHistopathology Image ClassificationClinical Prediction
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Sep 3, 2026

TAP-Path: Task-Adaptive Structural and Token Pruning for Efficient and Trustworthy Pathology Foundation Models

Pathology foundation models improve transferable representation learning for histopathology, but recent gains often rely on encoders with hundreds of millions of parameters and high inference cost. We propose TAP-Path, a task-adaptive compression framework that directly restructures a pretrained Virchow2 encoder rather than distilling it into a separate student. TAP-Path combines validation-driven transformer-block selection, physical removal of redundant blocks, input-adaptive patch-token pruning, multi-depth feature recovery, and a lightweight gated task head. The final model retains 24 of 32 transformer blocks and 70% of patch tokens after pruning, reducing encoder parameters by 24.96% (631.24M to 473.70M) and analytical encoder compute by 35.20% (340.13G to 220.40G FLOPs). Across three task-head optimization seeds, TAP-Path achieved 87.98±0.06787.98 \pm 0.067% test accuracy, 81.26±0.4981.26 \pm 0.49% balanced accuracy, and 82.38±0.4882.38 \pm 0.48% macro-F1 on a 32-class histopathology benchmark, compared with 86.89% for full Virchow2 and 87.67% for UNI2-h. TAP-Path achieved a Brier score of 0.1800±0.00050.1800 \pm 0.0005 and failure-detection AUROC of 0.9047±0.00600.9047 \pm 0.0060. A validation-only rare-aware objective improved rare-class balanced accuracy in a secondary operating analysis. Frozen external evaluation on 433 CPTAC samples yielded 91.22±0.8391.22 \pm 0.83% accuracy and 91.10±0.8191.10 \pm 0.81% balanced accuracy. These results show that task-adaptive structural and token sparsification can improve the accuracy-efficiency trade-off of large pathology foundation models while preserving reliability under internal and external evaluation.

Mehedi Hasan, Ashfak Yeafi, Md Khairul Islam

Department of Computer Science and Engineering, Brac University, Dhaka, Bangladesh · EEE, Khulna University of Engineering & Technology, Khulna, Bangladesh · Mathematics and Computer Science, Hobart and William Smith Colleges, Geneva, NY, USA

Computational PathologyPathology Foundation ModelsTransformer PruningHistopathology Image ClassificationVisual Token PruningNeural Network Compression+1
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Sep 2, 2026

Seeing Beyond the Lesion: Disease Recognition from Reactive CNS Tissue

Sampling error yields exclusively reactive, non-lesional brain parenchyma in a significant proportion of intracranial biopsies, leaving the underlying disease undiagnosed. We benchmark four pathology foundation models (UNI2-h, Virchow2, Prov-GigaPath, H-optimus-0) as frozen patch encoders within a shared attention-based multiple-instance learning framework using 245 whole-slide images from 186 patients with confirmed downstream diagnoses. We first show that coarse disease-category prediction can be reproduced largely from slide size alone. After restricting classification to three finer diagnostic distinctions within common tissue categories, this confound no longer explains performance, yet disease labels remain predictable above chance under permutation testing (p ≤10−4\le 10^{-4} throughout). Surprisingly, performance is statistically indistinguishable across all foundation-model encoders, suggesting that recovering these weak morphological signatures is not limited by current patch representations. Signed instance-contribution maps and expert review further test whether predictive evidence localizes to reactive parenchyma rather than sampling-induced bias like blood introduced during tissue sampling. These results position acquisition-shortcut auditing via a provenance-only baseline as a necessary control in computational-pathology benchmarks, and show, once that confound is removed, that weakly supervised models still recover disease signal from tissue conventionally regarded as non-diagnostic.

Jan Schnorrenberg, Jan Ernsting, Enrico Küllenberg +3

Institute of Neuropathology, University Hospital Münster, Münster, Germany · Institute for Geoinformatics, University of Münster, Münster, Germany · Faculty of Mathematics and Computer Science, University of Münster, Münster, Germany +2

Computational PathologyPathology Foundation ModelsShortcut Learning
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Sep 2, 2026

Morphology signal in whole slide image foundation models can automatically triage slides

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

Ayushi Sinha, Shashank Yadav, Benjamin Holmes +9

Department of Radiology, Mayo Clinic, Rochester MN · Department of Radiation Oncology, Mayo Clinic, Rochester MN · AI Program, Mayo Clinic, Rochester MN +4

Computational PathologyPathology Foundation ModelsOncologyWhole-Slide Image Analysis
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Aug 28, 2026

EXPOSE: Explainable and Domain-Robust Embeddings from Pathology Vision Foundation Models using Sparse Autoencoders

Vision Foundation Models (VFMs) are widely used in computational pathology but remain sensitive to domain shifts arising from variations in staining, tissue preparation, and scanner hardware. A key limitation is that VFM embeddings entangle biological with domain-specific information, hindering cross-domain generalization. We propose Explainable Probing of Cross-Domain Sparse Embeddings (EXPOSE), a framework that uses Sparse Autoencoders (SAEs) as an explainable bottleneck to identify and suppress domain-specific components in VFM embeddings. We train a sparse representation of VFM features, use a linear classifier to identify domain-specific latent dimensions, and mask these features prior to downstream relapse prediction without retraining the backbone model. Experiments on a large prostate cancer dataset with multiple acquisition domains show that SAE features capture both domain- and task-specific information, which are partially disentangled in the latent space. Removing domain-specific features improves cross-domain performance and increases embedding robustness as measured by the Domain Robustness Index (DoRI). Code is available at https://github.com/imsb-uke/expose .

Anja Witte, Maximilian Lennartz, Jan Baumbach +4

Institute of Medical Systems Bioinformatics, Center for Biomedical AI (bAIome), Center for Molecular Neurobiology Hamburg (ZMNH), Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany · Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany · Institute of Computational Systems Biology, University of Hamburg, Hamburg, Germany +2

Computational PathologyPathology Foundation ModelsExplainable Medical Image AnalysisSparse Autoencoders
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Aug 26, 2026

VIPER: An Expert-Curated Benchmark for Vision-Language Models in Veterinary Pathology

Pathology vision-language models are advancing rapidly, yet existing benchmarks remain focused on human tissue, particularly oncology, leaving non-human pathology largely unaddressed. This gap is especially important in toxicologic pathology, where microscopic tissue examination of laboratory animals is a core component of preclinical drug safety assessment. To address it, we introduce VIPER, the first expert-curated benchmark for vision-language model evaluation in toxicologic pathology. VIPER contains 1,251 questions associated with 419 H&E-stained rat histology images across seven organ systems, covering multiple-choice, KPrim, and free-text formats. All questions were curated and validated by board-certified veterinary pathologists. In total, we benchmarked 16 models, including two newly introduced veterinary-pathology models, seven human pathology-specialized models, and seven general-purpose frontier models. The results identify a substantial domain gap between veterinary and human pathology, expose the risk of over-diagnosis of normal tissue in frontier models, and show that domain-specific training remains critical for visually grounded predictions. VIPER data and evaluation code are available at https://github.com/mahmoodlab/viper.

Luca L. Weishaupt, Simone de Brot, Javier Asin +9

Harvard-MIT HST · Mass General Brigham · Harvard Medical School +6

VLM EvaluationPathology Visual Question AnsweringComputational PathologyMedical VLMsPathology Foundation Models
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Aug 25, 2026

Towards Trustworthy Biological Alignment in TabPFN-Probed Pathology Foundation Models

Histology and transcriptomics provide complementary views of tissue biology, capturing spatial morphology and molecular activity, respectively. Pathology foundation models (PFMs) learn rich morphological representations from H&E images, yet strong downstream performance alone does not establish whether these representations encode biologically meaningful and robust molecular information. We present a training-free framework for auditing biological alignment in frozen PFMs using spatially paired histology and transcriptomics from HEST-1k, evaluated on 240 samples spanning three organs. Multiple frozen PFMs are used to extract H&E representations, while gene expression is aggregated into biologically interpretable pathway-level programs. We use TabPFN as a pretrained probe to quantify the extent to which these molecular programs can be decoded from frozen image representations without task-specific gradient updates. Beyond predictive performance, our audit examines whether pathway decodability generalizes across tissue sections, patient groups, and tissue types; whether representations exhibit section-level or other shortcut dependencies; and whether predictions remain stable under small image perturbations and context resampling. This multi-tissue evaluation distinguishes molecular programs that are consistently encoded from those that are tissue-specific, unstable, or shortcut-sensitive. Our framework therefore provides a systematic approach for assessing not only what biological information pathology foundation models encode, but also how reliably that information persists under clinically relevant sources of variation.

Ushashi Bhattacharjee, Alloy Das, Saria Hannan +3

Pathology Foundation ModelsGene Expression Prediction from Histopathology ImagesShortcut LearningSpatial Gene Expression Prediction
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Aug 21, 2026

CellPath-Bench: A Multidimensional Benchmark for Whole-Slide Cellular Representations in Pathology Foundation Models

Pathology foundation models (PFMs) are increasingly used as general-purpose backbones, yet existing benchmarks cannot systematically diagnose their whole-slide cellular representation capabilities, including the decodability of cell-type information and the transferability of such information across tissue sections, datasets, and anatomical organs. We introduce CellPath-Bench, a cellular-resolution benchmark that evaluates frozen PFMs themselves. Following quality control of 52 candidate Xenium datasets, we construct a panel of 25 spatially aligned H&E--Xenium tissue sections spanning 11 organs and 7,079,283 cells, harmonized into fine- and coarse-grained taxonomies. CellPath-Bench samples frozen WSI feature maps at registered nuclear coordinates and evaluates them using standardized multiclass linear probes. Cell Representation Advantage (CRA) measures the within-section advantage of nucleus-anchored representations over patch-level mean pooling, while Cell Representation Transferability (CRT) characterizes the generalization of cell-type decodability across tissue sections, datasets, and organs. We benchmark 30 pathology-specific and general-purpose foundation models through 304,920 runs across spatial readouts, magnifications, taxonomic granularities, and evaluation protocols. The results reveal substantial model-dependent differences in cell-type decodability and its cross-domain generalization, yielding distinct multidimensional capability profiles. CellPath-Bench provides a standardized framework for auditing cellular information in frozen PFM representations.

Bokai Zhao, Yiyang Zhang, Hanqing Chao +6

School of Artificial Intelligence, University of Chinese Academy of Sciences. · Brainnetome Center, Institute of Automation, Chinese Academy of Sciences. · DAMO Academy, Alibaba Group. +1

Computational PathologyPathology Foundation ModelsWhole-Slide Image Analysis
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Aug 18, 2026

DistillPath: An Efficient 22M Distilled Pathology Encoder Approaching Large Foundation Model Performance

Many high-performing pathology tile encoders are now foundation models with hundreds of millions to over a billion parameters. Encoding and storing the thousands of tiles in each whole-slide image with such models is costly on commodity hardware, so compact encoders that retain useful downstream performance are a valuable alternative. We present DistillPath-KS16, which starts from the existing 22M kaiko ViT-S/16 encoder and improves it by distilling from released pathology encoders used as frozen teachers. The recipe reads only the teachers' final class and patch tokens and trains on 6,000 public slides, needing neither their DINO nor iBOT pretraining heads nor a billion-tile corpus, so it applies to any released encoder that exposes backbone tokens. We distill four teachers spanning 86M to 1.1B parameters into the same student. Every variant improves the kaiko baseline on all three benchmarks we use, EVA, HEST, and PLISM, and the strongest teacher is task-dependent. On the seven-task EVA mean, DistillPath-KS16-Virchow2 reaches 0.7950.795, within 0.0150.015 points of Virchow2, the top-scoring model in our evaluation, at about 29×29\times fewer parameters; it also scores above H0-mini and GPFM on this aggregate metric, though that advantage is task-concentrated rather than uniform. Because it remains a 22M ViT-S/16 with 384-dimensional features, DistillPath-KS16 runs more than 25×25\times faster than Virchow2. Code is available at https://github.com/RamonKaspar/DistillPath, and released model weights are available at https://huggingface.co/collections/RamonK/distillpath.

Ramon Kaspar, Andrey Ignatov, Valentina Boeva

Department of Computer Science, ETH Zürich, Switzerland

Pathology Foundation ModelsEfficient ViTsKnowledge DistillationVision Transformer
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Aug 17, 2026

Lymphocyte Mimicry Correction via Region-Level Tissue Reasoning and Unbalanced Optimal Transport

Cell mimicry arises when different cell types appear morphologically similar. Human pathologists resolve this ambiguity using surrounding tissue context, whereas current vision models either lack contextual reasoning (cell foundation models) or cannot operate at the cell level (pathology MLLMs). We present Loki-OT, which propagates region-level tissue reasoning to individual cell predictions via Unbalanced Optimal Transport, using MLLM-derived density priors as soft guidance for ambiguous cell reassignment. Loki-OT is motivated by the observation that pretrained cell foundation model features already encode discriminative information, including tissue context, but standard cell-level supervision fails to use tissue context effectively. The resulting transport plan is distilled into a lightweight student MLP classifier that learns context-aware decision boundaries within the pretrained feature space. On the independent TCGA-BRCA cohort, Loki-OT achieved lower patient-level MAE than the fully supervised in-domain PanopTILs classifier and improved F1 in epithelium-rich mimicry tissues, using 278 weak region-level MLLM estimates built on a general-domain cell foundation model. Code: https://github.com/xiangli980/Lymphocyte_Mimicry_Correction_via_Loki_OT

Xiang Li, Yuqi Wang, Casey C. Heirman +2

Department of Electrical and Computer Engineering, Duke University, US · Medical Physics Graduate Program, Duke University, US · Department of Biomedical Engineering, Duke University, US +3

Computational PathologyHistopathology Image ClassificationWeakly Supervised LearningPathology Foundation Models
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Aug 17, 2026

CytoFormer: A Molecularly Supervised Cell Foundation Model for Histopathology Cell Classification

Identifying cell types directly from routine haematoxylin and eosin (H&E) histology would enable single-cell analysis at scale, but training such models has relied on manual pathologist annotations, which are slow, expensive and unreliable for many cell types. We instead supervise morphology with molecules. Imaging-based spatial transcriptomics profiles individual cells in situ on a section that can afterwards be stained with H&E, so that molecular identity and morphology are observed for the same physical cell. We assembled 81 such paired Xenium sections spanning 16 organs, derived per-cell labels by clustering, marker-gene annotation, organ-wise human review and quality control, and mapped them onto the cell types commonly reported in each organ. This yielded 15.4 million cells, each with a paired H&E image patch and one of 23 cell types, on which we trained CytoFormer, a cell foundation model with a multi-task, per-organ classification head. On spatially held-out tissue CytoFormer reached an accuracy of 0.85 and a macro-F1 of 0.78 across all 16 organs, and its predictions reproduced the tissue architecture of an entire held-out section. The representation also transfers: with the encoder frozen, a linear head on CytoFormer features performed better than six pathology foundation models on four expert-annotated benchmarks, including on organs and cell types that were not part of pretraining. Finally, in an interactive active-learning setting, CytoFormer's embeddings are markedly more label-efficient than existing pathology foundation models, detecting normal epithelium amid look-alike tumour with an F1 of 0.82 from only a few annotations and leading the strongest baseline by 0.13 in F1. CytoFormer turns paired H&E and spatial transcriptomics into a reusable, label-efficient representation for cell-level analysis of routine histology.

Jialu Yao, Songhao Li, Alina Yu +1

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA · Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, PA, USA · Germantown Friends School, Philadelphia, PA, USA +1

Histopathology Image ClassificationPathology Foundation Models
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