Histopathology Image Classification

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Histopathology image classification studies how to recognize disease and clinically relevant tissue patterns in microscope images, from small patches and cells to whole-slide images (WSIs). Common approaches include convolutional and vision-transformer models, pathology foundation models, and multiple-instance learning (MIL), which uses slide-level labels to combine evidence from many patches; newer methods also model spatial structure, multiple magnifications, and clinical or molecular data. These systems are evaluated on tasks such as tumor detection, cancer subtyping, grading, and biomarker prediction, using public benchmarks and increasingly external, multicenter, or prospective clinical settings. A central challenge is maintaining reliable performance across sites, stains, scanners, and patient groups while ensuring models use meaningful diagnostic evidence and provide calibrated, interpretable predictions at feasible computational cost.

Latest papers

146 papers18 papers in the last four weeks, up 20% on the four weeks before. 0.1% of all new papers.

Apr 26, 2026

Leveraging Cell-level Spatial Transcriptomics as Weak Supervision for Nuclei Classification

Deep learning-based nuclei analysis in histopathology relies heavily on large-scale, expert-curated datasets that are costly and difficult to scale across organs. To address this, we propose a scalable framework leveraging cell-level spatial transcriptomics (ST) as an alternative supervision source for nuclei classification. Cell-level ST provides both gene expression profiles and nucleus masks, enabling automatic generation of image-label pairs without manual annotation. We convert gene expression into cell-type labels and introduce an image-oriented classification strategy to effectively transfer these identities to histopathology images. Evaluated on unseen tissues, our framework achieves comparable segmentation and classification performance compared with conventional supervised approaches, despite using fewer manually annotated datasets.

Kazuya Nishimura, Ryoma Bise, Haruka Hirose +1

The University of Osaka, Osaka, Japan · National Cancer Center Tokyo, Japan · Kyushu University, Fukuoka, Japan

Computational Pathology Histopathology Image Segmentation Medical Image Segmentation Histopathology Image Classification

Apr 22, 2026

Clinically-Informed Modeling for Pediatric Brain Tumor Classification from Whole-Slide Histopathology Images

Accurate diagnosis of pediatric brain tumors, starting with histopathology, presents unique challenges for deep learning, including severe data scarcity, class imbalance, and fine-grained morphologic overlap across diagnostically distinct subtypes. While pathology foundation models have advanced patch-level representation learning, their effective adaptation to weakly supervised pediatric brain tumor classification under limited data remains underexplored. In this work, we introduce an expert-guided contrastive fine-tuning framework for pediatric brain tumor diagnosis from whole-slide images (WSI). Our approach integrates contrastive learning into slide-level multiple instance learning (MIL) to explicitly regularize the geometry of slide-level representations during downstream fine-tuning. We propose both a general supervised contrastive setting and an expert-guided variant that incorporates clinically informed hard negatives targeting diagnostically confusable subtypes. Through comprehensive experiments on pediatric brain tumor WSI classification under realistic low-sample and class-imbalanced conditions, we demonstrate that contrastive fine-tuning yields measurable improvements in fine-grained diagnostic distinctions. Our experimental analyses reveal complementary strengths across different contrastive strategies, with expert-guided hard negatives promoting more compact intra-class representations and improved inter-class separation. This work highlights the importance of explicitly shaping slide-level representations for robust fine-grained classification in data-scarce pediatric pathology settings.

Joakim Nguyen, Jian Yu, Jinrui Fang +7

Dept. of Computer Science University of Texas at Austin Austin, TX, USA · School of Information University of Texas at Austin Austin, TX, USA · Dept. of Computer Science UNC at Chapel Hill Chapel Hill, NC, USA +3

Pathology Foundation Models Medical Image Classification Histopathology Image Classification Brain Tumor Classification Supervised Contrastive Learning Multiple Instance Learning

Apr 22, 2026

A Digital Pathology Resource for Liver Cancer Quantification with Datasets, Benchmarks, and Tools

Liver cancer, especially hepatocellular carcinoma (HCC), imposes a substantial global disease burden. Accurate diagnosis and prognostic assessment directly influence treatment selection and patient survival, and pathological examination remains the gold standard for liver cancer diagnosis. Identifying diverse tissue components and pathological subtypes on histopathology slides is crucial for estimating postoperative recurrence risk and overall prognosis. However, most publicly available resources are still provided at the whole-slide image (WSI) level, and well-annotated datasets for fine-grained tissue component identification in liver cancer are scarce, which hinders reproducible model development and the deployment of quantitative analysis tools. To address this gap, we release HepatoBench, a patch-level image database for liver cancer with annotations for seven key tissue categories. Based on HepatoBench, we train and open-source a deep learning classification model as a tissue recognition tool. Furthermore, we train a WSI-level tumor/non-tumor segmentation model to automatically localize lesion regions across entire slides. By integrating the patch-level tissue classifier with the WSI-level segmentation model, we build HepatoQuant, an end-to-end, disease-specific regional quantification tool for liver cancer, enabling a unified workflow from WSIs to tissue composition parsing and quantitative statistics. We also open-source HepatoBench, the benchmarking protocol, and supporting tools, providing a solid foundation for automated regional quantification and fair method comparison in liver cancer pathology.

Ying Xiao, Shimiao Tang, Xitong Ling +11

Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China · Shenzhen International Graduate School, Tsinghua University, Shenzhen, China

Computational Pathology Image Segmentation Histopathology Image Segmentation Oncology Histopathology Image Classification Medical Image Benchmarks+1

Apr 21, 2026

Unified Multi-Foundation-Model Slide Representation for Pan-Cancer Recognition and Text-Guided Tumor Localization

The expanding ecosystem of pathology foundation models has produced powerful but fragmented tile-level representations, limiting their use in clinical tasks that require unified slide-level reasoning and interpretable linkage to clinically meaningful information. We present ASTRA, a pan-cancer framework that integrates heterogeneous foundation-model representations into a shared slide-level representation space and semantically grounds that space using structured pathology annotation fields, including classification category, cancer type, and anatomic site. ASTRA combines sparse mixture-of-experts contextualization, masked multi-model reconstruction, and contrastive alignment to structured pathology prompts to learn slide representations that support 4-category classification, 3-class solid tumor typing, 16-class cancer typing, and text-guided tumor localization without pixel-level supervision. Developed on a CHTN cohort of 10,359 whole-slide images (WSIs) spanning 16 tumor types, ASTRA consistently improves pan-cancer classification across four pathology foundation-model backbones, achieving up to 97.8% macro-AUC for 4-category classification, 99.7% for 3-class solid tumor typing, and 99.2% for 16-class cancer typing. For tumor localization, ASTRA achieves a mean Dice of 0.897 on an annotated in-domain CHTN subset (n = 380) spanning 16 cancer types and 0.738 on an external TCGA cohort (n = 1,686) spanning four cancer types. These results demonstrate that minimal structured pathology annotation fields derived from slide-level metadata can provide effective semantic supervision for unified slide representation learning, enabling both pan-cancer prediction and weakly supervised tumor localization within a single framework.

Tianyang Wang, Ziyu Su, Abdul Rehman Akbar +6

Department of Pathology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA · Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA

Pathology Foundation Models Oncology Histopathology Image Classification Medical Image Representation Learning Whole-Slide Image Analysis

Apr 19, 2026

Region-Affinity Attention for Whole-Slide Breast Cancer Classification in Deep Ultraviolet Imaging

Breast cancer diagnosis demands rapid and precise tools, yet traditional histopathological methods often fall short in intra-operative settings. Deep Ultraviolet (DUV) fluorescence imaging emerges as a transformative approach, offering high-contrast, label-free visualization of whole-slide images (WSIs) with unprecedented detail, surpassing conventional hematoxylin and eosin (H&E) staining in speed and resolution. However, existing deep learning methods for breast cancer classification, predominantly patch-based, fragment spatial context and incur significant preprocessing overhead, limiting their clinical utility. Moreover, standard attention mechanisms, such as Spatial, Squeeze-and-Excitation, Global Context and Guided Context Gating, fail to fully exploit the rich, multi-scale regional relationships inherent in DUV-WSI data, often prioritizing generic feature recalibration over diagnostic specificity. This study introduces a novel Region-Affinity Attention mechanism tailored for DUV-WSI breast cancer classification, processing entire slides without patching to preserve spatial integrity. By modeling local neighbor distances and constructing a full affinity matrix, our method dynamically highlights diagnostically relevant regions, augmented by a contrastive loss to enhance feature discriminability. Evaluated on a dataset of 136 DUV-WSI samples, our approach achieves an accuracy of 92.67 +/- 0.73% and an AUC of 95.97%, outperforming existing attention methods.

Nagur Shareef Shaik, Teja Krishna Cherukuri, Dong Hye Ye

Department of Computer Science, Georgia State University, Atlanta, GA USA

Medical Image Classification Histopathology Image Classification Whole-Slide Image Analysis

Apr 18, 2026

Multimodal Fusion of Histopathology Images and Electronic Health Records for Early Breast Cancer Diagnosis

Breast cancer is a leading cause of cancer-related mortality worldwide, and timely accurate diagnosis is critical to improving survival outcomes. While convolutional neural networks (CNNs) have demonstrated strong performance on histopathology image classification, and machine learning models on structured electronic health records (EHR) have shown utility for clinical risk stratification, most existing work treats these modalities in isolation. This paper presents a systematic multimodal framework that integrates patch-level histopathology features from the BreCaHAD dataset with structured clinical data from MIMIC-IV. We train and evaluate unimodal image models (a simple CNN baseline and ResNet-18 with transfer learning), unimodal tabular models (XGBoost and a multilayer perceptron), and an intermediate-fusion model that concatenates latent representations from both modalities. ResNet-18 achieves near-perfect accuracy (1.000) and AUC (1.000) on three-class patch-level classification, while XGBoost achieves 98% accuracy on the EHR prediction task. The intermediate fusion model yields a macro-average AUC of 0.997, outperforming all unimodal baselines and delivering the largest improvements on the diagnostically critical but class-imbalanced mitosis category (AUC 0.994). Grad-CAM and SHAP interpretability analyses validate that model decisions align with established pathological and clinical criteria. Our results demonstrate that multimodal integration delivers meaningful improvements in both predictive performance and clinical transparency.

Aditya Shribhagwan Khandelwal, Mohammad Samar Ansari, Asra Aslam

University of Sheffield, UK · University of Chester, UK

Breast Cancer Computational Pathology Multimodal Classification Oncology Histopathology Image Classification Multimodal Fusion

Apr 17, 2026

Dual-Modal Lung Cancer AI: Interpretable Radiology and Microscopy with Clinical Risk Integration

Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Conventional computed tomography (CT) imaging, while essential for detection and staging, has limitations in distinguishing benign from malignant lesions and providing interpretable diagnostic insights. To address this challenge, this study proposes a dual-modal artificial intelligence framework that integrates CT radiology with hematoxylin and eosin (H&E) histopathology for lung cancer diagnosis and subtype classification. The system employs convolutional neural networks to extract radiologic and histopathologic features and incorporates clinical metadata to improve robustness. Predictions from both modalities are fused using a weighted decision-level integration mechanism to classify adenocarcinoma, squamous cell carcinoma, large cell carcinoma, small cell lung cancer, and normal tissue. Explainable AI techniques including Grad-CAM, Grad-CAM++, Integrated Gradients, Occlusion, Saliency Maps, and SmoothGrad are applied to provide visual interpretability. Experimental results show strong performance with accuracy up to 0.87, AUROC above 0.97, and macro F1-score of 0.88. Grad-CAM++ achieved the highest faithfulness and localization accuracy, demonstrating strong correspondence with expert-annotated tumor regions. These results indicate that multimodal fusion of radiology and histopathology can improve diagnostic performance while maintaining model transparency, suggesting potential for future clinical decision support systems in precision oncology.

Baramee Sukumal, Aueaphum Aueawatthanaphisut

Hatyaiwittayalai School, Hat Yai, Songkhla, Thailand, 90110 · School of Information, Computer, and Communication Technology,2026 Sirindhorn International Institute of Technology, Thammasat University, Pathum Thani, Thailand

Medical Image Classification Explainable Medical Image Analysis Histopathology Image Classification Multimodal Fusion

Apr 17, 2026

SSMamba: A Self-Supervised Hybrid State Space Model for Pathological Image Classification

Pathological diagnosis is highly reliant on image analysis, where Regions of Interest (ROIs) serve as the primary basis for diagnostic evidence, while whole-slide image (WSI)-level tasks primarily capture aggregated patterns. To extract these critical morphological features, ROI-level Foundation Models (FMs) based on Vision Transformers (ViTs) and large-scale self-supervised learning (SSL) have been widely adopted. However, three core limitations remain in their application to ROI analysis: (1) cross-magnification domain shift, as fixed-scale pretraining hinders adaptation to diverse clinical settings; (2) inadequate local-global relationship modeling, wherein the ViT backbone of FMs suffers from high computational overhead and imprecise local characterization; (3) insufficient fine-grained sensitivity, as traditional self-attention mechanisms tend to overlook subtle diagnostic cues. To address these challenges, we propose SSMamba, a hybrid SSL framework that enables effective fine-grained feature learning without relying on large external datasets. This framework incorporates three domain-adaptive components: Mamba Masked Image Modeling (MAMIM) for mitigating domain shift, a Directional Multi-scale (DMS) module for balanced local-global modeling, and a Local Perception Residual (LPR) module for enhanced fine-grained sensitivity. Employing a two-stage pipeline, SSL pretraining on target ROI datasets followed by supervised fine-tuning (SFT), SSMamba outperforms 11 state-of-the-art (SOTA) pathological FMs on 10 public ROI datasets and surpasses 8 SOTA methods on 6 public WSI datasets. These results validate the superiority of task-specific architectural designs for pathological image analysis.

Enhui Chai, Sicheng Chen, Tianyi Zhang +2

School of Computer Science, Northwest University · PuzzleLogic Pte Ltd, Singapore 229594, Singapore · Department of Electrical & Computer Engineering, National University of Singapore +1

Self-Supervised Learning Pathology Foundation Models Histopathology Image Classification Medical Image Representation Learning Whole-Slide Image Analysis State Space Models

Apr 15, 2026

Artificial intelligence application in lymphoma diagnosis with Vision Transformer using weakly supervised training

Vision transformers (ViT) have been shown to allow for more flexible feature detection and can outperform convolutional neural network (CNN) when pre-trained on sufficient data. Due to their promising feature detection capabilities, we deployed ViTs for morphological classification of anaplastic large cell lymphoma (ALCL) versus classic Hodgkin lymphoma (cHL). We had previously designed a ViT model which was trained on a small dataset of 1,200 image patches in fully supervised training. That model achieved a diagnostic accuracy of 100% and an F1 score of 1.0 on the independent test set. Since fully supervised training is not a practical method due to lack of expertise resources in both the training and testing phases, we conducted a recent study on a modified approach to training data (weakly supervised training) and show that labeling training image patch automatically at the slide level of each whole-slide-image is a more practical solution for clinical use of Vision Transformer. Our ViT model, trained on a larger dataset of 100,000 image patches, yields evaluation metrics with significant accuracy, F1 score, and area under the curve (AUC) at 91.85%, 0.92, and 0.98, respectively. These are respectable values that qualify this ViT model, with weakly supervised training, as a suitable tool for a deep learning module in clinical model development using automated image patch extraction.

Nghia, Nguyen, Amer Wahed +9

Andy · Department of Pathology and Laboratory Medicine, The University of Texas McGovern Medical School, Houston, Texas · Department of Hematopathology, The University of Texas MD Anderson Cancer, Houston, Texas

Histopathology Image Classification Oncology Vision Transformer Whole-Slide Image Analysis

Apr 13, 2026

PC-MIL: Decoupling Feature Resolution from Supervision Scale in Whole-Slide Learning

Whole-slide image (WSI) classification in computational pathology is commonly formulated as slide-level Multiple Instance Learning (MIL) with a single global bag representation. However, slide-level MIL is fundamentally underconstrained: optimizing only global labels encourages models to aggregate features without learning anatomically meaningful localization. This creates a mismatch between the scale of supervision and the scale of clinical reasoning. Clinicians assess tumor burden, focal lesions, and architectural patterns within millimeter-scale regions, whereas standard MIL is trained only to predict whether "somewhere in the slide there is cancer." As a result, the model's inductive bias effectively erases anatomical structure. We propose Progressive-Context MIL (PC-MIL), a framework that treats the spatial extent of supervision as a first-class design dimension. Rather than altering magnification, patch size, or introducing pixel-level segmentation, we decouple feature resolution from supervision scale. Using fixed 20x features, we vary MIL bag extent in millimeter units and anchor supervision at a clinically motivated 2mm scale to preserve comparable tumor burden and avoid confounding scale with lesion density. PC-MIL progressively mixes slide- and region-level supervision in controlled proportions, enabling explicit train-context x test-context analysis. On 1,476 prostate WSIs from five public datasets for binary cancer detection, we show that anatomical context is an independent axis of generalization in MIL, orthogonal to feature resolution: modest regional supervision improves cross-context performance, and balanced multi-context training stabilizes accuracy across slide and regional evaluation without sacrificing global performance. These results demonstrate that supervision extent shapes MIL inductive bias and support anatomically grounded WSI generalization.

Syed Fahim Ahmed, Gnanesh Rasineni, Florian Koehler +7

Kahlert School of Computing, University of Utah, Salt Lake City, UT 84112, USA · Scientific Computing & Imaging Institute, University of Utah, Salt Lake City, UT 84112, USA · Instapath Inc., Houston, TX 77021, USA +1

Whole-Slide Image Analysis Histopathology Image Classification Multiple Instance Learning Weakly Supervised Learning

Apr 10, 2026

DSVTLA: Deep Swin Vision Transformer-Based Transfer Learning Architecture for Multi-Type Cancer Histopathological Cancer Image Classification

In this study, we proposed a deep Swin-Vision Transformer-based transfer learning architecture for robust multi-cancer histopathological image classification. The proposed framework integrates a hierarchical Swin Transformer with ResNet50-based convolution features extraction, enabling the model to capture both long-range contextual dependencies and fine-grained local morphological patterns within histopathological images. To validate the efficiency of the proposed architecture, an extensive experiment was executed on a comprehensive multi-cancer dataset including Breast Cancer, Oral Cancer, Lung and Colon Cancer, Kidney Cancer, and Acute Lymphocytic Leukemia (ALL), including both original and segmented images were analyzed to assess model robustness across heterogeneous clinical imaging conditions. Our approach is benchmarked alongside several state-of-the-art CNN and transfer models, including DenseNet121, DenseNet201, InceptionV3, ResNet50, EfficientNetB3, multiple ViT variants, and Swin Transformer models. However, all models were trained and validated using a unified pipeline, incorporating balanced data preprocessing, transfer learning, and fine-tuning strategies. The experimental results demonstrated that our proposed architecture consistently gained superior performance, reaching 100% test accuracy for lung-colon cancer, segmented leukemia datasets, and up to 99.23% accuracy for breast cancer classification. The model also achieved near-perfect precision, f1 score, and recall, indicating highly stable scores across divers cancer types. Overall, the proposed model establishes a highly accurate, interpretable, and also robust multi-cancer classification system, demonstrating strong benchmark for future research and provides a unified comparative assessment useful for designing reliable AI-assisted histopathological diagnosis and clinical decision-making.

Muazzem Hussain Khan, Tasdid Hasnain, Md. Jamil khan +4

Department of Computer Science and Engineering, Metropolitan University, Sylhet-3104 · Department of Statistics, Pabna University of Science and Technology, Pabna-6600, Bangladesh · Department of Computer Science and Engineering, Rajshahi University of Engineering and Technology, Rajshahi-6204, Bangladesh +1

Histopathology Image Classification Hybrid CNN-Transformer Architectures Vision Transformer Transfer Learning

Apr 9, 2026

Shortcut Learning in Glomerular AI: Adversarial Penalties Hurt, Entropy Helps

Stain variability is a pervasive source of distribution shift and potential shortcut learning in renal pathology AI. We ask whether lupus nephritis glomerular lesion classifiers exploit stain as a shortcut, and how to mitigate such bias without stain or site labels. We curate a multi-center, multi-stain dataset of 9,674 glomerular patches (224

\times

224) from 365 WSIs across three centers and four stains (PAS, H&E, Jones, Trichrome), labeled as proliferative vs. non-proliferative. We evaluate Bayesian CNN and ViT backbones with Monte Carlo dropout in three settings: (1) stain-only classification; (2) a dual-head model jointly predicting lesion and stain with supervised stain loss; and (3) a dual-head model with label-free stain regularization via entropy maximization on the stain head. In (1), stain identity is trivially learnable, confirming a strong candidate shortcut. In (2), varying the strength and sign of stain supervision strongly modulates stain performance but leaves lesion metrics essentially unchanged, indicating no measurable stain-driven shortcut learning on this multi-stain, multi-center dataset, while overly adversarial stain penalties inflate predictive uncertainty. In (3), entropy-based regularization holds stain predictions near chance without degrading lesion accuracy or calibration. Overall, a carefully curated multi-stain dataset can be inherently robust to stain shortcuts, and a Bayesian dual-head architecture with label-free entropy regularization offers a simple, deployment-friendly safeguard against potential stain-related drift in glomerular AI.

Mohammad Daouk, Jan Ulrich Becker, Neeraja Kambham +3

University of Houston, Houston, TX, USA · University Hospital Cologne, Cologne, Germany · Stanford University, Stanford, CA, USA +1

Shortcut Learning Histopathology Image Classification Domain-Adversarial Learning

Apr 9, 2026

Plug-and-Play Logit Fusion for Heterogeneous Pathology Foundation Models

Pathology foundation models (FMs) have become central to computational histopathology, offering strong transfer performance across a wide range of diagnostic and prognostic tasks. The rapid proliferation of pathology foundation models creates a model-selection bottleneck: no single model is uniformly best, yet exhaustively adapting and validating many candidates for each downstream endpoint is prohibitively expensive. We address this challenge with a lightweight and novel model fusion strategy, LogitProd, which treats independently trained FM-based predictors as fixed experts and learns sample-adaptive fusion weights over their slide-level outputs. The fusion operates purely on logits, requiring no encoder retraining and no feature-space alignment across heterogeneous backbones. We further provide a theoretical analysis showing that the optimal weighted product fusion is guaranteed to perform at least as well as the best individual expert under the training objective. We systematically evaluate LogitProd on 22 benchmarks spanning WSI-level classification, tile-level classification, gene mutation prediction, and discrete-time survival modeling. LogitProd ranks first on 20/22 tasks and improves the average performance across all tasks by ~3% over the strongest single expert. LogitProd enables practitioners to upgrade heterogeneous FM-based pipelines in a plug-and-play manner, achieving multi-expert gains with

\sim

12

\times

lower training cost than feature-fusion alternatives.

Gexin Huang, Anqi Li, Yusheng Tan +4

University of British Columbia, Vancouver, BC, Canada · Vector Institute, Toronto, ON, Canada · Washington University in St. Louis, St. Louis, MO, USA

Computational Pathology Ensemble Learning Data Fusion Pathology Foundation Models Histopathology Image Classification

Apr 8, 2026

Region-Graph Optimal Transport Routing for Mixture-of-Experts Whole-Slide Image Classification

Multiple Instance Learning (MIL) is the dominant framework for gigapixel whole-slide image (WSI) classification in computational pathology. However, current MIL aggregators route all instances through a shared pathway, constraining their capacity to specialise across the pathological heterogeneity inherent in each slide. Mixture-of-Experts (MoE) methods offer a natural remedy by partitioning instances across specialised expert subnetworks; yet unconstrained softmax routing may yield highly imbalanced utilisation, where one or a few experts absorb most routing mass, collapsing the mixture back to a near-single-pathway solution. To address these limitations, we propose ROAM (Region-graph OptimAl-transport Mixture-of-experts), a spatially aware MoE-MIL aggregator that routes region tokens to expert poolers via capacity-constrained entropic optimal transport, promoting balanced expert utilisation by construction. ROAM operates on spatial region tokens, obtained by compressing dense patch bags into spatially binned units that align routing with local tissue neighbourhoods and introduces two key mechanisms: (i) region-to-expert assignment formulated as entropic optimal transport (Sinkhorn) with explicit per slide capacity marginals, enforcing balanced expert utilisation without auxiliary load-balancing losses; and (ii) graph-regularised Sinkhorn iterations that diffuse routing assignments over the spatial region graph, encouraging neighbouring regions to coherently route to the same experts. Evaluated on four WSI benchmarks with frozen foundation-model patch embeddings, ROAM achieves performance competitive against strong MIL and MoE baselines, and on NSCLC generalisation (TCGA-CPTAC) reaches external AUC 0.845 +- 0.019.

Xin Tian, Jiuliu Lu, Ephraim Tsalik +3

Centre for Human Genetics, University of Oxford, Oxford, UK · Beckman Coulter Diagnostics, Brea, CA, USA · Danaher Corporation, Washington, DC, USA

Histopathology Image Classification Whole-Slide Image Analysis Mixture-of-Experts Models Multiple Instance Learning Optimal Transport

Apr 6, 2026

MedGemma 1.5 Technical Report

We introduce MedGemma 1.5 4B, the latest model in the MedGemma collection. MedGemma 1.5 expands on MedGemma 1 by integrating additional capabilities: high-dimensional medical imaging (CT/MRI volumes and histopathology whole slide images), anatomical localization via bounding boxes, multi-timepoint chest X-ray analysis, and improved medical document understanding (lab reports, electronic health records). We detail the innovations required to enable these modalities within a single architecture, including new training data, long-context 3D volume slicing, and whole-slide pathology sampling. Compared to MedGemma 1 4B, MedGemma 1.5 4B demonstrates significant gains in these new areas, improving 3D MRI condition classification accuracy by 11% and 3D CT condition classification by 3% (absolute improvements). In whole slide pathology imaging, MedGemma 1.5 4B achieves a 47% macro F1 gain. Additionally, it improves anatomical localization with a 35% increase in Intersection over Union on chest X-rays and achieves a 4% macro accuracy for longitudinal (multi-timepoint) chest x-ray analysis. Beyond its improved multimodal performance over MedGemma 1, MedGemma 1.5 improves on text-based clinical knowledge and reasoning, improving by 5% on MedQA accuracy and 22% on EHRQA accuracy. It also achieves an average of 18% macro F1 on 4 different lab report information extraction datasets (EHR Datasets 2, 3, 4, and Mendeley Clinical Laboratory Test Reports). Taken together, MedGemma 1.5 serves as a robust, open resource for the community, designed as an improved foundation on which developers can create the next generation of medical AI systems. Resources and tutorials for building upon MedGemma 1.5 can be found at https://goo.gle/medgemma.

Andrew Sellergren, Chufan Gao, Fereshteh Mahvar +39

Medical Imaging Foundation Models 3D Medical Imaging Medical Image Localization Histopathology Image Classification Longitudinal Medical Image Analysis

Apr 2, 2026

A deep learning pipeline for PAM50 subtype classification using histopathology images and multi-objective patch selection

Breast cancer is a highly heterogeneous disease with diverse molecular profiles. The PAM50 gene signature is widely recognized as a standard for classifying breast cancer into intrinsic subtypes, enabling more personalized treatment strategies. In this study, we introduce a novel optimization-driven deep learning framework that aims to reduce reliance on costly molecular assays by directly predicting PAM50 subtypes from H&E-stained whole-slide images (WSIs). Our method jointly optimizes patch informativeness, spatial diversity, uncertainty, and patch count by combining the non-dominated sorting genetic algorithm II (NSGA-II) with Monte Carlo dropout-based uncertainty estimation. The proposed method can identify a small but highly informative patch subset for classification. We used a ResNet18 backbone for feature extraction and a custom CNN head for classification. For evaluation, we used the internal TCGA-BRCA dataset as the training cohort and the external CPTAC-BRCA dataset as the test cohort. On the internal dataset, an F1-score of 0.8812 and an AUC of 0.9841 using 627 WSIs from the TCGA-BRCA cohort were achieved. The performance of the proposed approach on the external validation dataset showed an F1-score of 0.7952 and an AUC of 0.9512. These findings indicate that the proposed optimization-guided, uncertainty-aware patch selection can achieve high performance and improve the computational efficiency of histopathology-based PAM50 classification compared to existing methods, suggesting a scalable imaging-based replacement that has the potential to support clinical decision-making.

Arezoo Borji, Gernot Kronreif, Bernhard Angermayr +6

Austrian Center for Medical Innovation and Technology, Wiener Neustadt, Austria · Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems an der Donau, Austria. · Department of Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria +3

Monte Carlo Dropout Histopathology Image Classification Whole-Slide Image Analysis

Mar 26, 2026

Dictionary-based Pathology Mining with Hard-instance-assisted Classifier Debiasing for Genetic Biomarker Prediction from WSIs

Prediction of genetic biomarkers, e.g., microsatellite instability in colorectal cancer is crucial for clinical decision making. But, two primary challenges hamper accurate prediction: (1) It is difficult to construct a pathology-aware representation involving the complex interconnections among pathological components. (2) WSIs contain a large proportion of areas unrelated to genetic biomarkers, which make the model easily overfit simple but irrelative instances. We hereby propose a Dictionary-based hierarchical pathology mining with hard-instance-assisted classifier Debiasing framework to address these challenges, dubbed as D2Bio. Our first module, dictionary-based hierarchical pathology mining, is able to mine diverse and very fine-grained pathological contextual interaction without the limit to the distances between patches. The second module, hard-instance-assisted classfier debiasing, learns a debiased classifier via focusing on hard but task-related features, without any additional annotations. Experimental results on five cohorts show the superiority of our method, with over 4% improvement in AUROC compared with the second best on the TCGA-CRC-MSI cohort. Our analysis further shows the clinical interpretability of D2Bio in genetic biomarker diagnosis and potential clinical utility in survival analysis. Code will be available at https://github.com/DeepMed-Lab-ECNU/D2Bio.

Ling Zhang, Boxiang Yun, Ting Jin +3

Shanghai Key Laboratory of Multidimensional Information Processing, East China Normal University, Shanghai, China · Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China

Computational Pathology Histopathology Image Classification Cancer Genomics

Mar 23, 2026

Mixture of Mini Experts: Overcoming the Linear Layer Bottleneck in Multiple Instance Learning

Multiple Instance Learning (MIL) is the predominant framework for classifying gigapixel whole-slide images in computational pathology. MIL follows a sequence of 1) extracting patch features, 2) applying a linear layer to obtain task-specific patch features, and 3) aggregating the patches into a slide feature for classification. While substantial efforts have been devoted to optimizing patch feature extraction and aggregation, none have yet addressed the second point, the critical layer which transforms general-purpose features into task-specific features. We hypothesize that this layer constitutes an overlooked performance bottleneck and that stronger representations can be achieved with a low-rank transformation tailored to each patch's phenotype, yielding synergistic effects with any of the existing MIL approaches. To this end, we introduce MAMMOTH, a parameter-efficient, multi-head mixture of experts module designed to improve the performance of any MIL model with minimal alterations to the total number of parameters. Across eight MIL methods and 19 different classification tasks, we find that such task-specific transformation has a larger effect on performance than the choice of aggregation method. For instance, when equipped with MAMMOTH, even simple methods such as max or mean pooling attain higher average performance than any method with the standard linear layer. Overall, MAMMOTH improves performance in 130 of the 152 examined configurations, with an average

+3.8\%

change in performance. Code is available at https://github.com/mahmoodlab/mammoth.

Daniel Shao, Joel Runevic, Richard J. Chen +4

Massachusetts Institute of Technology, Cambridge MA · Harvard University, Cambridge MA · Emory University, Atlanta GA +1

Multiple Instance Learning Histopathology Image Classification Whole-Slide Image Analysis Mixture-of-Experts Models Computational Pathology

Mar 20, 2026

Jigsaw Regularization in Whole-Slide Image Classification

Computational pathology involves the digitization of stained tissues into whole-slide images (WSIs) that contain billions of pixels arranged as contiguous patches. Statistical analysis of WSIs largely focuses on classification via multiple instance learning (MIL), in which slide-level labels are inferred from unlabeled patches. Most MIL methods treat patches as exchangeable, overlooking the rich spatial and topological structure that underlies tissue images. This work builds on recent graph-based methods that aim to incorporate spatial awareness into MIL. Our approach is new in two regards: (1) we deploy vision foundation-model embeddings to incorporate local spatial structure within each patch, and (2) achieve across-patch spatial awareness using graph neural networks together with a novel {\em jigsaw regularization}. We find that a combination of these two features markedly improves classification over state-of-the-art attention-based MIL approaches on benchmark datasets in breast, head-and-neck, and colon cancer.

So Won Jeong, Veronika Ročková

Booth School of Business, The University of Chicago, IL, USA.

Histopathology Image Classification Whole-Slide Image Analysis Multiple Instance Learning

Mar 20, 2026

ReconMIL: Synergizing Latent Space Reconstruction with Bi-Stream Mamba for Whole Slide Image Analysis

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

Lubin Gan, Jing Zhang, Heng Zhang +4

USTC, Anhui, China · Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Anhui, China · SCNU, Guangdong, China +2

Histopathology Image Classification Medical Image Localization Multiple Instance Learning Whole-Slide Image Analysis

Mar 16, 2026

Domain Adaptation Without the Compute Burden for Efficient Whole Slide Image Analysis

Computational methods on analyzing Whole Slide Images (WSIs) enable early diagnosis and treatments by supporting pathologists in detection and classification of tumors. However, the extremely high resolution of WSIs makes end-to-end training impractical compared to typical image analysis tasks. To address this, most approaches use pre-trained feature extractors to obtain fixed representations of whole slides, which are then combined with Multiple Instance Learning (MIL) for downstream tasks. These feature extractors are typically pre-trained on natural image datasets such as ImageNet, which fail to capture domain-specific characteristics. Although domain-specific pre-training on histopathology data yields more relevant feature representations, it remains computationally expensive and fail to capture task-specific characteristics within the domain. To address the computational cost and lack of task-specificity in domain-specific pre-training, we propose EfficientWSI (eWSI), a careful integration of Parameter-Efficient-Fine-Tuning (PEFT) and Multiple Instance Learning (MIL) that enables end-to-end training on WSI tasks. We evaluate eWSI on seven WSI-level tasks over Camelyon16, TCGA and BRACS datasets. Our results show that eWSI when applied with ImageNet feature extractors yields strong classification performance, matching or outperforming MILs with in-domain feature extractors, alleviating the need for extensive in-domain pre-training. Furthermore, when eWSI is applied with in-domain feature extractors, it further improves classification performance in most cases, demonstrating its ability to capture task-specific information where beneficial. Our findings suggest that eWSI provides a task-targeted, computationally efficient path for WSI tasks, offering a promising direction for task-specific learning in computational pathology.

Umar Marikkar, Muhammad Awais, Sara Atito

Institute for People-Centered AI, University of Surrey · Centre of Vision, Speech and Signal Processing, University of Surrey

Whole-Slide Image Analysis Computational Pathology Histopathology Image Classification Multiple Instance Learning

Mar 15, 2026

Histo-MExNet: A Unified Framework for Real-World, Cross-Magnification, and Trustworthy Breast Cancer Histopathology

Accurate and reliable histopathological image classification is essential for breast cancer diagnosis. However, many deep learning models remain sensitive to magnification variability and lack interpretability. To address these challenges, we propose Histo-MExNet, a unified framework designed for scaleinvariant and uncertainty-aware classification. The model integrates DenseNet, ConvNeXt, and EfficientNet backbones within a gated multi-expert architecture, incorporates a prototype learning module for example-driven interpretability, and applies physics-informed regularization to enforce morphology preservation and spatial coherence during feature learning. Monte Carlo Dropout is used to quantify predictive uncertainty. On the BreaKHis dataset, Histo-MExNet achieves 96.97% accuracy under multi-magnification training and demonstrates improved generalization to unseen magnification levels compared to single-expert models, while uncertainty estimation helps identify out-of-distribution samples and reduce overconfident errors, supporting a balanced combination of accuracy, robustness, and interpretability for clinical decision support.

Enam Ahmed Taufika, Md Ahasanul Arafatha, Abhijit Kumar Ghoshb +2

European University of Bangladesh, Department of Computer Science and Engineering, Dhaka, Bangladesh · BRAC University, Department of Computer Science and Engineering, Dhaka, Bangladesh · Ochsner Center for Outcomes Research, Ochsner Research, Ochsner Clinic Foundation, New Orleans, LA, 70121, USA

Histopathology Image Classification Explainable Medical Image Analysis

Mar 14, 2026

Every Error has Its Magnitude: Asymmetric Mistake Severity Training for Multiclass Multiple Instance Learning

Multiple Instance Learning (MIL) has emerged as a promising paradigm for Whole Slide Image (WSI) diagnosis, offering effective learning with limited annotations. However, existing MIL frameworks overlook diagnostic priorities and fail to differentiate the severity of misclassifications in multiclass, leaving clinically critical errors unaddressed. We propose a mistake-severity-aware training strategy that organizes diagnostic classes into a hierarchical structure, with each level optimized using a severity-weighted cross-entropy loss that penalizes high-severity misclassifications more strongly. Additionally, hierarchical consistency is enforced through probabilistic alignment, a semantic feature remix applied to the instance bag to robustly train class priority and accommodate clinical cases involving multiple symptoms. An asymmetric Mikel's Wheel-based metric is also introduced to quantify the severity of errors specific to medical fields. Experiments on challenging public and real-world in-house datasets demonstrate that our approach significantly mitigates critical errors in MIL diagnosis compared to existing methods. We present additional experimental results on natural domain data to demonstrate the generalizability of our proposed method beyond medical contexts.

Sungrae Hong, Jiwon Jeong, Jisu Shin +4

Korea Advanced Institute of Science and Technology, Daejeon, South Korea · Seegene Medical Foundation, Seoul, South Korea

Multiple Instance Learning Cost-Sensitive Learning Histopathology Image Classification Hierarchical Classification

Mar 13, 2026

A protocol for evaluating robustness to H&E staining variation in computational pathology models

Sensitivity to staining variation remains a major barrier to deploying computational pathology (CPath) models as hematoxylin and eosin (H&E) staining varies across laboratories, requiring systematic assessment of how this variability affects model prediction. In this work, we developed a three-step protocol for evaluating robustness to H&E staining variation in CPath models. Step 1: Select reference staining conditions, Step 2: Characterize test set staining properties, Step 3: Apply CPath model(s) under simulated reference staining conditions. Here, we first created a new reference staining library based on the PLISM dataset. As an exemplary use case, we applied the protocol to assess the robustness properties of 306 microsatellite instability (MSI) classification models on the unseen SurGen colorectal cancer dataset (n=738), including 300 attention-based multiple instance learning models trained on the TCGA-COAD/READ datasets across three feature extractors (UNI2-h, H-Optimus-1, Virchow2), alongside six public MSI classification models. Classification performance was measured as AUC, and robustness as the min-max AUC range across four simulated staining conditions (low/high H&E intensity, low/high H&E color similarity). Across models and staining conditions, classification performance ranged from AUC 0.769-0.911 (

Δ

= 0.142). Robustness ranged from 0.007-0.079 (

Δ

= 0.072), and showed a weak inverse correlation with classification performance (Pearson r=-0.22, 95% CI [-0.34, -0.11]). Thus, we show that the proposed evaluation protocol enables robustness-informed CPath model selection and provides insight into performance shifts across H&E staining conditions, supporting the identification of operational ranges for reliable model deployment. Code is available at https://github.com/CTPLab/staining-robustness-evaluation .

Lydia A. Schönpflug, Nikki van den Berg, Sonali Andani +5

Computational Pathology Microscopy Image Analysis Histopathology Image Classification

Mar 12, 2026

Selective Prediction Forgetting for Adaptation of Weakly Supervised Localization of Histology Images

Under strong cross-domain shifts, weakly supervised object localization (WSOL) models often lose their capacity to discriminate and develop a strong prediction bias toward a subset of classes. As a result, the majority of target samples are assigned to these dominant classes. Since source-free (unsupervised) domain adaptation (SFDA) methods typically rely on pseudo-labels, inaccurate pseudo-label estimation causes suboptimal adaptation and poor classification and localization performance. This issue is particularly challenging in computational histopathology, where shifts in organ-specific morphology, staining protocols, and acquisition conditions can significantly impact class-discriminative visual cues. This paper introduces SFDA with selective prediction forgetting (SFDA-SPF), a method designed to mitigate excessive concentration of predictions for dominant classes during target-domain adaptation. SFDA-SPF identifies prediction-dominant classes based on the model's target predictions and selectively revises uncertain samples assigned to them. Importantly, this procedure does not require knowledge of the true target class distribution. In contrast with previous SFDA methods, SFDA-SPF introduces a 'forget set' composed of uncertain samples from dominant classes near their decision boundaries, enabling the classification boundaries to shift away from biased predictions. A second 'retain set' is used to anchor certain and accurate samples. To forget the predictions of dominant classes, SFDA-SPF introduces a complementary optimization objective that reduces their probability while allowing alternative class assignments to emerge. This iterative optimization process reassesses target images for forget and retain sets at regular intervals. In addition to improving image-level pseudo-label estimation, the pixel-level classifier is jointly optimized, further enhancing localization.

Alexis Guichemerre, Banafsheh Karimian, Soufiane Belharbi +6

ÉTS Montréal, Montreal, Canada · Sorbonne Université, Paris, France · University of York, York, United Kingdom +1

Source-Free Domain Adaptation Weakly Supervised Learning Computational Pathology Histopathology Image Classification

Mar 12, 2026

Unmasking Biases and Reliability Concerns in Convolutional Neural Networks Analysis of Cancer Pathology Images

Convolutional Neural Networks have shown promising effectiveness in identifying different types of cancer from radiographs. However, the opaque nature of CNNs makes it difficult to fully understand the way they operate, limiting their assessment to empirical evaluation. Here we study the soundness of the standard practices by which CNNs are evaluated for the purpose of cancer pathology. Thirteen highly used cancer benchmark datasets were analyzed, using four common CNN architectures and different types of cancer, such as melanoma, carcinoma, colorectal cancer, and lung cancer. We compared the accuracy of each model with that of datasets made of cropped segments from the background of the original images that do not contain clinically relevant content. Because the rendered datasets contain no clinical information, the null hypothesis is that the CNNs should provide mere chance-based accuracy when classifying these datasets. The results show that the CNN models provided high accuracy when using the cropped segments, sometimes as high as 93%, even though they lacked biomedical information. These results show that some CNN architectures are more sensitive to bias than others. The analysis shows that the common practices of machine learning evaluation might lead to unreliable results when applied to cancer pathology. These biases are very difficult to identify, and might mislead researchers as they use available benchmark datasets to test the efficacy of CNN methods.

Michael Okonoda, Eder Martinez, Abhilekha Dalal +1

Department of Computer Science, Kansas State University, Manhattan, KS 66506, USA

Dataset Bias Convolutional Neural Networks Algorithmic Bias Medical Image Benchmarks Histopathology Image Classification Shortcut Learning

Mar 12, 2026

Automated Detection of Malignant Lesions in the Ovary Using Deep Learning Models and XAI

The unrestrained proliferation of cells that are malignant in nature is cancer. In recent times, medical professionals are constantly acquiring enhanced diagnostic and treatment abilities by implementing deep learning models to analyze medical data for better clinical decision, disease diagnosis and drug discovery. A majority of cancers are studied and treated by incorporating these technologies. However, ovarian cancer remains a dilemma as it has inaccurate non-invasive detection procedures and a time consuming, invasive procedure for accurate detection. Thus, in this research, several Convolutional Neural Networks such as LeNet-5, ResNet, VGGNet and GoogLeNet/Inception have been utilized to develop 15 variants and choose a model that accurately detects and identifies ovarian cancer. For effective model training, the dataset OvarianCancer&SubtypesDatasetHistopathology from Mendeley has been used. After constructing a model, we utilized Explainable Artificial Intelligence (XAI) models such as LIME, Integrated Gradients and SHAP to explain the black box outcome of the selected model. For evaluating the performance of the model, Accuracy, Precision, Recall, F1-Score, ROC Curve and AUC have been used. From the evaluation, it was seen that the slightly compact InceptionV3 model with ReLu had the overall best result achieving an average score of 94% across all the performance metrics in the augmented dataset. Lastly for XAI, the three aforementioned XAI have been used for an overall comparative analysis. It is the aim of this research that the contributions of the study will help in achieving a better detection method for ovarian cancer.

Md. Hasin Sarwar Ifty, Nisharga Nirjan, Labib Islam +4

Dept. of Computer Science and Engr. BRAC University Dhaka, Bangladesh

Histopathology Image Classification Computational Pathology Convolutional Neural Networks Explainable Medical Image Analysis

Mar 12, 2026

DeepHistoViT: An Interpretable Vision Transformer Framework for Histopathological Cancer Classification

Histopathology remains the gold standard for cancer diagnosis because it provides detailed cellular-level assessment of tissue morphology. However, manual histopathological examination is time-consuming, labour-intensive, and subject to inter-observer variability, creating a demand for reliable computer-assisted diagnostic tools. Recent advances in deep learning, particularly transformer-based architectures, have shown strong potential for modelling complex spatial dependencies in medical images. In this work, we propose DeepHistoViT, a transformer-based framework for automated classification of histopathological images. The model employs a customized Vision Transformer architecture with an integrated attention mechanism designed to capture fine-grained cellular structures while improving interpretability through attention-based localization of diagnostically relevant regions. The framework is evaluated on three publicly available histopathology datasets covering lung cancer, colon cancer, and acute lymphoblastic leukaemia. Experimental results demonstrate state-of-the-art performance across all datasets, with classification accuracy, precision, recall, F1-score, and ROC-AUC reaching 100 percent on the lung and colon cancer datasets, and 99.85 percent, 99.84 percent, 99.86 percent, 99.85 percent, and 99.99 percent respectively on the acute lymphoblastic leukaemia dataset. All performance metrics are reported with 95 percent confidence intervals. These results highlight the effectiveness of transformer-based architectures for histopathological image analysis and demonstrate the potential of DeepHistoViT as an interpretable computer-assisted diagnostic tool to support pathologists in clinical decision-making.

Ravi Mosalpuri, Mohammed Abdelsamea, Ahmed Karam Eldaly

Histopathology Image Classification Computational Pathology Vision Transformer Explainable Medical Image Analysis

Mar 10, 2026

Leveraging whole slide difficulty in Multiple Instance Learning to improve prostate cancer grading

Multiple Instance Learning (MIL) has been widely applied in histopathology to classify Whole Slide Images (WSIs) with slide-level diagnoses. While the ground truth is established by expert pathologists, the slides can be difficult to diagnose for non-experts and lead to disagreements between the annotators. In this paper, we introduce the notion of Whole Slide Difficulty (WSD), based on the disagreement between an expert and a non-expert pathologist. We propose two different methods to leverage WSD, a multi-task approach and a weighted classification loss approach, and we apply them to Gleason grading of prostate cancer slides. Results show that integrating WSD during training consistently improves the classification performance across different feature encoders and MIL methods, particularly for higher Gleason grades (i.e. worse diagnosis).

Marie Arrivat, Rémy Peyret, Elsa Angelini +1

Primaa, Paris, France · LTCI, Telecom Paris, Institut Polytechnique de Paris, France

Prostate Cancer Grading Histopathology Image Classification Whole-Slide Image Analysis Computational Pathology Multiple Instance Learning

Mar 7, 2026

Class Visualizations and Activation Atlases for Enhancing Interpretability in Deep Learning-Based Computational Pathology

The rapid adoption of transformer-based models in computational pathology has enabled prediction of molecular and clinical biomarkers from H&E whole-slide images, yet interpretability has not kept pace with model complexity. While attribution- and generative-based methods are common, feature visualization approaches such as class visualizations (CVs) and activation atlases (AAs) have not been systematically evaluated for these models. We developed a visualization framework and assessed CVs and AAs for a transformer-based foundation model across tissue and multi-organ cancer classification tasks with increasing label granularity. Four pathologists annotated real and generated images to quantify inter-observer agreement, complemented by attribution and similarity metrics. CVs preserved recognizability for morphologically distinct tissues but showed reduced separability for overlapping cancer subclasses. In tissue classification, agreement decreased from Fleiss k = 0.75 (scans) to k = 0.31 (CVs), with similar trends in cancer subclass tasks. AAs revealed layer-dependent organization: coarse tissue-level concepts formed coherent regions, whereas finer subclasses exhibited dispersion and overlap. Agreement was moderate for tissue classification (k = 0.58), high for coarse cancer groupings (k = 0.82), and low at subclass level (k = 0.11). Atlas separability closely tracked expert agreement on real images, indicating that representational ambiguity reflects intrinsic pathological complexity. Attribution-based metrics approximated expert variability in low-complexity settings, whereas perceptual and distributional metrics showed limited alignment. Overall, concept-level feature visualization reveals structured morphological manifolds in transformer-based pathology models and provides a framework for expert-centered interrogation of learned representations across label granularities.

Marco Gustav, Fabian Wolf, Christina Glasner +6

Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany · Institute of Pathology, University Medical Center Mainz, Mainz, Germany · Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany +4

Feature Visualization Explainable Medical Image Analysis Computational Pathology Transformer Interpretability Histopathology Image Classification