Computational Pathology

Recent breakthroughs in artificial intelligence through foundation models and agents have accelerated the evolution of computational pathology. Demonstrated performance gains reported across academia in benchmarking datasets in predictive tasks such as diagnosis, prognosis, and treatment response have ignited substantial enthusiasm for clinical application. Despite this development momentum, real world adoption has lagged, as implementation faces economic, technical, and administrative challenges. Beyond existing discussions of technical architectures and comparative performance, this review considers how these emerging AI systems can be responsibly integrated into medical practice by connecting deployable clinical relevance with downstream analytical capabilities and their technical maturity, operational readiness, and economic and regulatory context. Drawing on perspectives from an international group, we provide a practical assessment of current capabilities and barriers to adoption in patient care settings.

Prostate cancer being one of the frequently diagnosed malignancy in men, the rising demand for biopsies places a severe workload on pathologists. The grading procedure is tedious and subjective, motivating the development of automated systems. Although deep learning has made inroads in terms of performance, its limited interpretability poses challenges for widespread adoption in high-stake applications like medicine. Existing interpretability techniques for prostate cancer classifiers provide a coarse explanation but do not reveal why the highlighted regions matter. In this scenario, we propose a novel prototype-based weakly-supervised framework for an interpretable grading of prostate cancer from histopathology images. These networks can prove to be more trustworthy since their explicit reasoning procedure mirrors the workflow of a pathologist in comparing suspicious regions with clinically validated examples. The network is initially pre-trained at patch-level to learn robust prototypical features associated with each grade. In order to adapt it to a weakly-supervised setup for prostate cancer grading, the network is fine-tuned with a new prototype-aware loss function. Finally, a new attention-based dynamic pruning mechanism is introduced to handle inter-sample heterogeneity, while selectively emphasizing relevant prototypes for optimal performance. Extensive validation on the benchmark PANDA and SICAP datasets confirms that the framework can serve as a reliable assistive tool for pathologists in their routine diagnostic workflows.

Background and objective: Cell-level pathological image analysis requires working with extremely small image patches (40x40 pixels), far below standard ImageNet resolutions. It remains unclear whether modern deep learning architectures and foundation models can learn robust and scalable representations under this constraint. We systematically evaluated architectural suitability and data-scale effects for small-patch cell classification. Methods: We analyzed 303 colorectal cancer specimens with CD103/CD8 immunostaining, generating 185,432 annotated cell images. Eight task-specific architectures were trained from scratch at multiple data scales (FlagLimit: 256--16,384 samples per class), and three foundation models were evaluated via linear probing and fine-tuning after resizing inputs to 224x224 pixels. Robustness to blur was assessed using pre- and post-resize Gaussian perturbations. Results: Task-specific models improved consistently with increasing data scale, whereas foundation models saturated at moderate sample sizes. A Vision Transformer optimized for small patches (CustomViT) achieved the highest accuracy, outperforming all foundation models with substantially lower inference cost. Blur robustness was comparable across architectures, with no qualitative advantage observed for foundation models. Conclusion: For cell-level classification under extreme spatial constraints, task-specific architectures are more effective and efficient than foundation models once sufficient training data are available. Higher clean accuracy does not imply superior robustness, and large pre-trained models offer limited benefit in the small-patch regime.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus that affects pediatric patients with significantly greater severity and worse renal outcomes compared to adults. Despite the urgent clinical need, predicting pediatric LN prognosis remains unexplored in computational pathology. Furthermore, the only existing histopathology-based approach for LN relies on multiple costly staining protocols and fails to integrate complementary clinical data. To address these gaps, we propose the first multimodal computational pathology framework for three-class treatment response prediction (complete remission, partial response, and no response) in pediatric LN, utilizing only routine PAS-stained biopsies and structured clinical data. Our framework introduces two key methodological innovations. First, a Clinical-Injection Transformer (CIT) embeds clinical features as condition tokens into patch-level self-attention, facilitating implicit and bidirectional cross-modal interactions within a unified attention space. Second, we design a decoupled representation-knowledge adaptation strategy using a domain-adapted Masked Autoencoder (MAE). This strategy explicitly separates self-supervised morphological feature learning from pathological knowledge extraction. Additionally, we introduce a multi-granularity morphological type injection mechanism to bridge distilled classification knowledge with downstream prognostic predictions at both the instance and patient levels. Evaluated on a cohort of 71 pediatric LN patients with KDIGO-standardized labels, our method achieves a three-class accuracy of 90.1% and an AUC of 89.4%, demonstrating its potential as a highly accurate and cost-effective prognostic tool.

Foundation models are changing the way we develop medical artificial intelligence. By learning broadly generalizable features across diverse data modalities, a single model can be rapidly adapted to address multiple modalities and tasks with minimal supervision. This potential comes with the urgent need to reliably benchmark, understand and compare the performance and clinical impact of foundation models across data modalities and clinical tasks. We introduce UNICORN, a fundamentally new benchmarking concept for medical foundation models. UNICORN brings four main contributions to medical artificial intelligence. First, a framework that enables a one-to-many benchmarking approach, where a single foundation model is tested across multiple tasks and data modalities. Here, we populate it with 20 tasks across radiology, pathology, and clinical text, covering classification, detection, segmentation, regression, and vision-language generation. Second, a publicly available evaluation platform that implements, for the first time, a two-step approach to run foundation models for data encoding followed by custom task-specific adaptation via few-shot learning and linear probing mechanisms. Third, we create a meta-model that combines state-of-the-art foundation models in pathology, radiology and language with novel task-specific adapters that address all UNICORN tasks, which we refer to as Unicorn Model-0 (UM-0). Finally, we design a novel UNICORN score to benchmark and compare model performance across all tasks. We present the results of UM-0 using sequestered test data from over 2,400 patients, 3,700 vision cases, and 2,400 clinical reports from 17 institutions across eight countries, spanning eight anatomical regions and four imaging modalities. Data, baselines, and evaluation platform are publicly accessible at unicorn.grand-challenge.org.

The pathological diagnosis of gestational trophoblastic disease(GTD) takes a long time, relies heavily on the experience of pathologists, and the consistency of initial diagnosis is low, which seriously threatens maternal health and reproductive outcomes. We developed an expert model for GTD pathological diagnosis, named GTDoctor. GTDoctor can perform pixel-based lesion segmentation on pathological slides, and output diagnostic conclusions and personalized pathological analysis results. We developed a software system, GTDiagnosis, based on this technology and conducted clinical trials. The retrospective results demonstrated that GTDiagnosis achieved a mean precision of over 0.91 for lesion detection in pathological slides (n=679 slides). In prospective studies, pathologists using GTDiagnosis attained a Positive Predictive Value of 95.59% (n=68 patients). The tool reduced average diagnostic time from 56 to 16 seconds per case (n=285 patients). GTDoctor and GTDiagnosis offer a novel solution for GTD pathological diagnosis, enhancing diagnostic performance and efficiency while maintaining clinical interpretability.

While multimodal survival prediction models are increasingly more accurate, their complexity often reduces interpretability, limiting insight into how different data sources influence predictions. To address this, we introduce DIMAFx, an explainable multimodal framework for cancer survival prediction that produces disentangled, interpretable modality-specific and modality-shared representations from histopathology whole-slide images and transcriptomics data. Across multiple cancer cohorts, DIMAFx achieves state-of-the-art performance and improved representation disentanglement. Leveraging its interpretable design and SHapley Additive exPlanations, DIMAFx systematically reveals key multimodal interactions and the biological information encoded in the disentangled representations. In breast cancer survival prediction, the most predictive features contain modality-shared information, including one capturing solid tumor morphology contextualized primarily by late estrogen response, where higher-grade morphology aligned with pathway upregulation and increased risk, consistent with known breast cancer biology. Key modality-specific features capture microenvironmental signals from interacting adipose and stromal morphologies. These results show that multimodal models can overcome the traditional trade-off between performance and explainability, supporting their application in precision medicine.

Recent AI navigation approaches aim to improve Whole-Slide Image (WSI) diagnosis by modeling spatial exploration and selecting diagnostically relevant regions, yet most operate at a single fixed magnification or rely on predefined magnification traversal. In clinical practice, pathologists examine slides across multiple magnifications and selectively inspect only necessary scales, dynamically integrating global and cellular evidence in a sequential manner. This mismatch prevents existing methods from modeling cross-magnification interactions and adaptive magnification selection inherent to real diagnostic workflows. To these, we propose a clinically consistent Multi-Magnification WSI Navigation Agent (MMNavAgent) that explicitly models multi magnification interaction and adaptive magnification selection. Specifically, we introduce a Cross-Magnification navigation Tool (CMT) that aggregates contextual information from adjacent magnifications to enhance discriminative representations along the navigation path. We further introduce a Magnification Selection Tool (MST) that leverages memory-driven reasoning within the agent framework to enable interactive and adaptive magnification selection, mimicking the sequential decision process of pathologists. Extensive experiments on a public dataset demonstrate improved diagnostic performance, with 1.45% gain of AUC and 2.93% gain of BACC over a non-agent baseline. Code will be public upon acceptance.

Recent methods for pathology report generation from whole-slide image (WSI) are capable of producing slide-level diagnostic descriptions but fail to ground fine-grained statements in localized visual evidence. Furthermore, they lack control over which diagnostic details to include and how to verify them. Inspired by emerging agentic analysis paradigms and the diagnostic workflow of pathologists,who selectively examine multiple fields of view, we propose QCAgent, an agentic framework for quality-controllable WSI report generation. The core innovations of this framework are as follows: (i) it incorporates a customized critique mechanism guided by a user-defined checklist specifying required diagnostic details and constraints; (ii) it re-identifies informative regions in the WSI based on the critique feedback and text-patch semantic retrieval, a process that iteratively enriches and reconciles the report. Experiments demonstrate that by making report requirements explicitly prompt-defined, constraint-aware, and verifiable through evidence-grounded refinement, QCAgent enables controllable generation of clinically meaningful and high-coverage pathology reports from WSI.

Accurate classification of pediatric central nervous system tumors remains challenging due to histological complexity and limited training data. While pathology foundation models have advanced whole-slide image (WSI) analysis, they often fail to leverage the rich, complementary information found in clinical text and tissue microarchitecture. To this end, we propose PathMoE, an interpretable multimodal framework that integrates H&E slides, pathology reports, and nuclei-level cell graphs via an interaction-aware mixture-of-experts architecture built on state-of-the-art foundation models for each modality. By training specialized experts to capture modality uniqueness, redundancy, and synergy, PathMoE employs an input-dependent gating mechanism that dynamically weights these interactions, providing sample-level interpretability. We evaluate our framework on two dataset-specific classification tasks on an internal pediatric brain tumor dataset (PBT) and external TCGA datasets. PathMoE improves macro-F1 from 0.762 to 0.799 (+0.037) on PBT when integrating WSI, text, and graph modalities; on TCGA, augmenting WSI with graph knowledge improves macro-F1 from 0.668 to 0.709 (+0.041). These results demonstrate significant performance gains over state-of-the-art image-only baselines while revealing the specific modality interactions driving individual predictions. This interpretability is particularly critical for rare tumor subtypes, where transparent model reasoning is essential for clinical trust and diagnostic validation.

The application of large vision-language models to computational pathology holds great promise for diagnostic assistants but faces a critical computational bottleneck: the gigapixel scale of Whole Slide Images (WSIs). A single WSI typically contains over 105 patches, creating sequence lengths that exceed the constraints of standard Transformer architectures. Existing solutions often resort to spatial sampling, which risks discarding diagnostically critical evidence. To address this, we propose TC-SSA (Token Compression via Semantic Slot Aggregation), a learnable token compression framework that aggregates patch features into a fixed number of semantic slots. A gated routing module assigns patches to slots using sparse Top-2 routing, followed by weighted aggregation, enabling global slide coverage under a strict token budget. The resulting representation retains diagnostically relevant information while reducing the number of visual tokens to 1.7% of the original sequence. On the SlideBench(TCGA), our model achieves 78.34% overall accuracy and 77.14% on the diagnosis subset, outperforming sampling-based baselines under comparable token budgets. The method also generalizes to MIL classification, reaching AUC of 95.83% on TCGA-BRCA, 98.27% on TCGA-NSCLC and 79.80% on PANDA. These results suggest that learnable semantic aggregation provides an effective trade-off between efficiency and diagnostic performance for gigapixel pathology reasoning.

Whole-slide image classification for invasive lung adenocarcinoma subtyping remains vulnerable to real-world imaging perturbations that undermine model reliability at the decision boundary. We propose a margin consistency framework evaluated on 203,226 patches from 143 whole-slide images spanning five adenocarcinoma subtypes in the BMIRDS-LUAD dataset. By combining attention-weighted patch aggregation with margin-aware training, our approach achieves robust feature-logit space alignment measured by Kendall correlations of 0.88 during training and 0.64 during validation. Contrastive regularization, while effective at improving class separation, tends to over-cluster features and suppress fine-grained morphological variation; to counteract this, we introduce Perturbation Fidelity (PF) scoring, which imposes structured perturbations through Bayesian-optimized parameters. Vision Transformer-Large achieves 95.20 +/- 4.65% accuracy, representing a 40% error reduction from the 92.00 +/- 5.36% baseline, while ResNet101 with an attention mechanism reaches 95.89 +/- 5.37% from 91.73 +/- 9.23%, a 50% error reduction. All five subtypes exceed an area under the receiver operating characteristic curve (AUC) of 0.99. On the WSSS4LUAD external benchmark, ResNet50 with an attention mechanism attains 80.1% accuracy, demonstrating cross-institutional generalizability despite approximately 15-20% domain-shift-related degradation and identifying opportunities for future adaptation research.

Batch effects arising from technical variations in histopathology staining protocols, scanners, and acquisition pipelines pose a persistent challenge for computational pathology, hindering cross-batch generalization and limiting reliable deployment of models across clinical sites. In this work, we introduce Latent Manifold Compaction (LMC), an unsupervised representation learning framework that performs image harmonization by learning batch-invariant embeddings from a single source dataset through explicit compaction of stain-induced latent manifolds. This allows LMC to generalize to target domain data unseen during training. Evaluated on three challenging public and in-house benchmarks, LMC substantially reduces batch-induced separations across multiple datasets and consistently outperforms state-of-the-art normalization methods in downstream cross-batch classification and detection tasks, enabling superior generalization.

We propose a Hierarchical Multi-scale Knowledge-aware Graph Network (HMKGN) that models multi-scale interactions and spatially hierarchical relationships within whole-slide images (WSIs) for cancer prognostication. Unlike conventional attention-based MIL, which ignores spatial organization, or graph-based MIL, which relies on static handcrafted graphs, HMKGN enforces a hierarchical structure with spatial locality constraints, wherein local cellular-level dynamic graphs aggregate spatially proximate patches within each region of interest (ROI) and a global slide-level dynamic graph integrates ROI-level features into WSI-level representations. Moreover, multi-scale integration at the ROI level combines coarse contextual features from broader views with fine-grained structural representations from local patch-graph aggregation. We evaluate HMKGN on four TCGA cohorts (KIRC, LGG, PAAD, and STAD; N=513, 487, 138, and 370) for survival prediction. It consistently outperforms existing MIL-based models, yielding improved concordance indices (10.85% better) and statistically significant stratification of patient survival risk (log-rank p < 0.05).

Immunohistochemical (IHC) staining enables precise molecular profiling of protein expression, with over 200 clinically available antibody-based tests in modern pathology. However, comprehensive IHC analysis is frequently limited by insufficient tissue quantities in small biopsies. Therefore, virtual multiplex staining emerges as an innovative solution to digitally transform H&E images into multiple IHC representations, yet current methods still face three critical challenges: (1) inadequate semantic guidance for multi-staining, (2) inconsistent distribution of immunochemistry staining, and (3) spatial misalignment across different stain modalities. To overcome these limitations, we present a prompt-guided framework for virtual multiplex IHC staining using only uniplex training data (PGVMS). Our framework introduces three key innovations corresponding to each challenge: First, an adaptive prompt guidance mechanism employing a pathological visual language model dynamically adjusts staining prompts to resolve semantic guidance limitations (Challenge 1). Second, our protein-aware learning strategy (PALS) maintains precise protein expression patterns by direct quantification and constraint of protein distributions (Challenge 2). Third, the prototype-consistent learning strategy (PCLS) establishes cross-image semantic interaction to correct spatial misalignments (Challenge 3).

Foundation models for computational pathology are expected to facilitate the development of high-performing, generalisable deep learning systems. However, in addition to biologically relevant features, current foundation models also capture pre-analytic and scanner-specific variation that bias the predictions made by downstream task-specific models trained on these features. Here we show that introducing novel robustness losses during downstream model training reduces sensitivity to technical variability. A purpose-designed comprehensive experimentation setup with 27,042 whole-slide images from 6,155 patients is used to train thousands of models from the features of eight well-known foundation models for computational pathology. In addition to a substantial improvement in robustness, our approach improves classification accuracy by focusing on biologically relevant features. It mitigates robustness limitations of foundation models for computational pathology without retraining the foundation models themselves, enabling development of models that are more suitable in real-world clinical use.

In recent years, a standard computational pathology workflow has emerged where whole slide images are cropped into tiles, these tiles are processed using a foundation model, and task-specific models are built using the resulting representations. At least 15 different foundation models have been proposed, and the vast majority are trained exclusively with tiles using the 20$\times$ magnification. However, it is well known that certain histologic features can only be discerned with larger context windows and requires a pathologist to zoom in and out when analyzing a whole slide image. Furthermore, creating 224$\times$224 pixel crops at 20$\times$ leads to a large number of tiles per slide, which can be gigapixel in size. To more accurately capture multi-resolution features and investigate the possibility of reducing the number of representations per slide, we propose a region-level mixing encoder. Our approach jointly fuses image tile representations of a mixed magnification foundation model using a masked embedding modeling pretraining step. We explore a design space for pretraining the proposed mixed-magnification region aggregators and evaluate our models on transfer to biomarker prediction tasks representing various cancer types. Results demonstrate cancer dependent improvements in predictive performance, highlighting the importance of spatial context and understanding.

Multimodal learning that integrates genomics and histopathology has shown strong potential in cancer diagnosis, yet its clinical translation is hindered by the limited availability of paired histology-genomics data. Knowledge distillation (KD) offers a practical solution by transferring genomic supervision into histopathology models, enabling accurate inference using histology alone. However, existing KD methods rely on batch-local alignment, which introduces instability due to limited within-batch comparisons and ultimately degrades performance. To address these limitations, we propose Momentum Memory Knowledge Distillation (MoMKD), a cross-modal distillation framework driven by a momentum-updated memory. This memory aggregates genomic and histopathology information across batches, effectively enlarging the supervisory context available to each mini-batch. Furthermore, we decouple the gradients of the genomics and histology branches, preventing genomic signals from dominating histology feature learning during training and eliminating the modality-gap issue at inference time. Extensive experiments on the TCGA-BRCA benchmark (HER2, PR, and ODX classification tasks) and an independent in-house testing dataset demonstrate that MoMKD consistently outperforms state-of-the-art MIL and multimodal KD baselines, delivering strong performance and generalization under histology-only inference. Overall, MoMKD establishes a robust and generalizable knowledge distillation paradigm for computational pathology.

In computational pathology, few-shot whole slide image classification is primarily driven by the extreme scarcity of expert-labeled slides. Recent vision-language methods incorporate textual semantics generated by large language models, but treat these descriptions as static class-level priors that are shared across all samples and lack sample-wise refinement. This limits both the diversity and precision of visual-semantic alignment, hindering generalization under limited supervision. To overcome this, we propose the stochastic MUlti-view Semantic Enhancement (MUSE), a framework that first refines semantic precision via sample-wise adaptation and then enhances semantic richness through retrieval-augmented multi-view generation. Specifically, MUSE introduces Sample-wise Fine-grained Semantic Enhancement (SFSE), which yields a fine-grained semantic prior for each sample through MoE-based adaptive visual-semantic interaction. Guided by this prior, Stochastic Multi-view Model Optimization (SMMO) constructs an LLM-generated knowledge base of diverse pathological descriptions per class, then retrieves and stochastically integrates multiple matched textual views during training. These dynamically selected texts serve as enriched semantic supervisions to stochastically optimize the vision-language model, promoting robustness and mitigating overfitting. Experiments on three benchmark WSI datasets show that MUSE consistently outperforms existing vision-language baselines in few-shot settings, demonstrating that effective few-shot pathology learning requires not only richer semantic sources but also their active and sample-aware semantic optimization. Our code is available at: https://github.com/JiahaoXu-god/CVPR2026_MUSE.

Self-supervised vision models have achieved notable success in digital pathology. However, their domain-agnostic transformer architectures are not originally designed to account for fundamental biological elements of histopathology images, namely cells and their complex interactions. In this work, we hypothesize that a biologically-informed modeling of tissues as cell graphs offers a more efficient representation learning. Thus, we introduce GrapHist, a novel graph-based self-supervised learning framework for histopathology, which learns generalizable and structurally-informed embeddings that enable diverse downstream tasks. GrapHist integrates masked autoencoders and heterophilic graph neural networks that are explicitly designed to capture the heterogeneity of tumor microenvironments. We pre-train GrapHist on a large collection of 11 million cell graphs derived from breast tissues and evaluate its transferability across in- and out-of-domain benchmarks. Our results show that GrapHist achieves competitive performance compared to its vision-based counterparts in slide-, region-, and cell-level tasks, while requiring four times fewer parameters. It also drastically outperforms fully-supervised graph models on cancer subtyping tasks. Finally, we also release five graph-based digital pathology datasets used in our study at https://huggingface.co/ogutsevda/datasets , establishing the first large-scale graph benchmark in this field. Our code is available at https://github.com/ogutsevda/graphist .

The emergence of tool-calling-based agent systems introduces a more evidence-driven paradigm for pathology image analysis in contrast to the coarse-grained text-image diagnostic approaches. With the recent large-scale experimental adoption of spatial transcriptomics technologies, molecularly validated pathological diagnosis is becoming increasingly open and accessible. In this work, we propose LAMMI-Pathology (LVLM-Agent System for Molecularly Informed Medical Intelligence in Pathology), a scalable agent framework for domain-specific agent tool-calling. LAMMI-Pathology adopts a tool-centric, bottom-up architecture in which customized domain-adaptive tools serve as the foundation. These tools are clustered by domain style to form component agents, which are then coordinated through a top-level planner hierarchically, avoiding excessively long context lengths that could induce task drift. Based on that, we introduce a novel trajectory construction mechanism based on Atomic Execution Nodes (AENs), which serve as reliable and composable units for building semi-simulated reasoning trajectories that capture credible agent-tool interactions. Building on this foundation, we develop a trajectory-aware fine-tuning strategy that aligns the planner's decision-making process with these multi-step reasoning trajectories, thereby enhancing inference robustness in pathology understanding and its adaptive use of the customized toolset.

In recent years, foundation models such as CLIP, DINO,and CONCH have demonstrated remarkable domain generalization and unsupervised feature extraction capabilities across diverse imaging tasks. However, systematic and independent evaluations of these models for pixel-level semantic segmentation in histopathology remain scarce. In this study, we propose a robust benchmarking approach to asses 10 foundational models on four histopathological datasets covering both morphological tissue-region and cellular/nuclear segmentation tasks. Our method leverages attention maps of foundation models as pixel-wise features, which are then classified using a machine learning algorithm, XGBoost, enabling fast, interpretable, and model-agnostic evaluation without finetuning. We show that the vision language foundation model, CONCH performed the best across datasets when compared to vision-only foundation models, with PathDino as close second. Further analysis shows that models trained on distinct histopathology cohorts capture complementary morphological representations, and concatenating their features yields superior segmentation performance. Concatenating features from CONCH, PathDino and CellViT outperformed individual models across all the datasets by 7.95% (averaged across the datasets), suggesting that ensembles of foundation models can better generalize to diverse histopathological segmentation tasks.

It is a critical task to evalaute HER2 expression level accurately for breast cancer evaluation and targeted treatment therapy selection. However, the standard multi-step Immunohistochemistry (IHC) staining is resource-intensive, expensive, and time-consuming, which is also often unavailable in many areas. Consequently, predicting HER2 levels directly from H&E slides has emerged as a potential alternative solution. It has been shown to be effective to use virtual IHC images from H&E images for automatic HER2 scoring. However, the pixel-level virtual staining methods are computationally expensive and prone to reconstruction artifacts that can propagate diagnostic errors. To address these limitations, we propose the Latent-Guided Dual-Stream Network (LGD-Net), a novel framework that employes cross-modal feature hallucination instead of explicit pixel-level image generation. LGD-Net learns to map morphological H&E features directly to the molecular latent space, guided by a teacher IHC encoder during training. To ensure the hallucinated features capture clinically relevant phenotypes, we explicitly regularize the model training with task-specific domain knowledge, specifically nuclei distribution and membrane staining intensity, via lightweight auxiliary regularization tasks. Extensive experiments on the public BCI dataset demonstrate that LGD-Net achieves state-of-the-art performance, significantly outperforming baseline methods while enabling efficient inference using single-modality H&E inputs.

Whole-slide images (WSIs) from cancer patients contain rich information that can be used for medical diagnosis or to follow treatment progress. To automate their analysis, numerous deep learning methods based on convolutional neural networks and Vision Transformers have been developed and have achieved strong performance in segmentation and classification tasks. However, due to the large size and complex cellular organization of WSIs, these models rely on patch-based representations, losing vital tissue-level context. We propose using scalable Graph Transformers on a full-WSI cell graph for classification. We evaluate this methodology on a challenging task: the classification of healthy versus tumor epithelial cells in cutaneous squamous cell carcinoma (cSCC), where both cell types exhibit very similar morphologies and are therefore difficult to differentiate for image-based approaches. We first compared image-based and graph-based methods on a single WSI. Graph Transformer models SGFormer and DIFFormer achieved balanced accuracies of $85.2 \pm 1.5$ ($\pm$ standard error) and $85.1 \pm 2.5$ in 3-fold cross-validation, respectively, whereas the best image-based method reached $81.2 \pm 3.0$. By evaluating several node feature configurations, we found that the most informative representation combined morphological and texture features as well as the cell classes of non-epithelial cells, highlighting the importance of the surrounding cellular context. We then extended our work to train on several WSIs from several patients. To address the computational constraints of image-based models, we extracted four $2560 \times 2560$ pixel patches from each image and converted them into graphs. In this setting, DIFFormer achieved a balanced accuracy of $83.6 \pm 1.9$ (3-fold cross-validation), while the state-of-the-art image-based model CellViT256 reached $78.1 \pm 0.5$.

Whole-slide image (WSI) preprocessing, including tissue detection and patch extraction, is critical computational pathology, yet remains a major bottleneck for large-scale workflows. Existing methods often rely either on threshold-based heuristics that are sensitive to staining variations, tissue fragmentation, and artifacts, or on patch-wise deep learning pipelines with substantially higher computational cost. We present AtlasPatch, a scalable high-throughput WSI preprocessing method built around a foundation-model-based tissue detector that operates at thumbnail resolution: a single thumbnail-level forward pass yields a tissue mask that directly guides patch coordinate generation at the target desired magnification, avoiding repeated patch-level inference. The proposed detector's robustness and efficiency is driven by two coupled contributions: (i) a parameter-efficient adaptation of the SAM2 foundation model that updates only its layer-normalization parameters (0.076% of model weights), and (ii) a curated and semi-manually annotated multi-cohort dataset of 30,000 WSI thumbnail-mask pairs deliberately spanning multiple organs, scanners, tissue appearances, and artifacts. The detector is coupled with pyramid-aware contour mapping from thumbnail to full-resolution slide coordinates, enabling direct patch coordinate generation at the target magnification and parallelized high-throughput patch extraction. AtlasPatch's tissue detection achieves a precision of 0.986 and remains robust across slide variations. Compared with widely used deep-learning preprocessing methods, AtlasPatch is up to 16x faster while preserving downstream multiple-instance learning performance across six slide-level classification tasks. These results position AtlasPatch as a frontier of efficient preprocessing in large-scale computational pathology and pathology foundation models.

Deep learning models in computational pathology often fail to generalize across cohorts and institutions due to domain shift. Existing approaches either fail to leverage unlabeled data from the target domain or rely on image-to-image translation, which can distort tissue structures and compromise model accuracy. In this work, we propose a semi-supervised domain adaptation (SSDA) framework that utilizes a latent diffusion model trained on unlabeled data from both the source and target domains to generate morphology-preserving and target-aware synthetic images. By conditioning the diffusion model on foundation model features, cohort identity, and tissue preparation method, we preserve tissue structure in the source domain while introducing target-domain appearance characteristics. The target-aware synthetic images, combined with real, labeled images from the source cohort, are subsequently used to train a downstream classifier, which is then tested on the target cohort. The effectiveness of the proposed SSDA framework is demonstrated on the task of lung adenocarcinoma prognostication. The proposed augmentation yielded substantially better performance on the held-out test set from the target cohort, without degrading source-cohort performance. The approach improved the weighted F1 score on the target-cohort held-out test set from 0.611 to 0.706 and the macro F1 score from 0.641 to 0.716. Our results demonstrate that target-aware diffusion-based synthetic data augmentation provides a promising and effective approach for improving domain generalization in computational pathology.

Expert-annotated training data remains the critical bottleneck for AI in histopathology, particularly for rare pathologies where even dozens of cases may be unavailable. While data augmentation offers a solution, existing methods fail to generate sufficiently realistic lesion morphologies that preserve tissue-specific architectures. Here we present PathoGen, a diffusion-based generative model enabling controllable, high-fidelity lesion inpainting into benign histopathology images. We validate PathoGen across four datasets representing kidney, skin, breast, and prostate pathology. Quantitative assessment confirms PathoGen outperforms state-of-the-art baselines in image fidelity and distributional similarity. Evaluation by six expert pathologists revealed that synthetic images by PathoGen were only marginally distinguished from real tissue image slightly above chance (57.75% accuracy), demonstrating strong perceptual realism of PathoGen-generated lesions. PathoGen achieved the highest win rate (35.4%) when pathologists ranked generation quality against all baselines. Crucially, augmenting training sets with PathoGen-synthesized lesions improves segmentation Dice scores by up to 0.18 compared to traditional augmentations, with maximum benefit in data-scarce regimes. By simultaneously generating realistic morphology and pixel-level annotations, PathoGen effectively addresses both data scarcity and annotation cost, two critical bottlenecks in computational pathology development.

Background and Objective: Precise and scalable instance segmentation of cell nuclei is a fundamental prerequisite for computational pathology, yet gigapixel whole-slide images (WSIs) pose significant computational challenges. While patch-based processing is standard during training, existing methods are often limited to small tile sizes during inference due to architectural bottlenecks or reliance on computationally expensive post-processing for instance separation. We introduce a faster, scalable, and end-to-end framework capable of processing large-scale image tiles while accurately modeling biologically realistic overlapping nuclei. Methods: We propose LSP-DETR (Local Star Polygon DEtection TRansformer). The model represents nuclei as star-convex polygons and employs a lightweight transformer with linear complexity, enabling the processing of high-resolution images in a single forward pass. A novel radial distance loss accommodates annotation uncertainty, allowing the segmentation of overlapping nuclei to emerge naturally without explicit overlap labels. Results: LSP-DETR achieves state-of-the-art efficiency, with an inference time of 0.45 s/mm^2, a 3.2x speedup over StarDist, the next-fastest method. On PanNuke, the model achieves competitive accuracy (67.5 bPQ), while yielding an F$_1$-score of 0.964 in polygon overlap when evaluated against consensus annotations from two expert pathologists. Furthermore, it outperforms larger models such as LKCell in generalization robustness, reaching an F1-score of 85.0 on MoNuSeg. Conclusions: LSP-DETR bridges the gap between high-fidelity segmentation and practical clinical requirements by eliminating heuristic post-processing. By providing a scalable, linear-complexity solution that naturally handles overlaps between nuclei, this framework sets a new direction for efficient high-throughput WSI analysis in digital pathology.

While Vision-Language Models (VLMs) have achieved notable progress in computational pathology (CPath), the gigapixel scale and spatial heterogeneity of Whole Slide Images (WSIs) continue to pose challenges for multimodal understanding. Existing alignment methods struggle to capture fine-grained correspondences between textual descriptions and visual cues across thousands of patches from a slide, compromising their performance on downstream tasks. In this paper, we propose PathFLIP (Pathology Fine-grained Language-Image Pretraining), a novel framework for holistic WSI interpretation. PathFLIP decomposes slide-level captions into region-level subcaptions and generates text-conditioned region embeddings to facilitate precise visual-language grounding. By harnessing Large Language Models (LLMs), PathFLIP can seamlessly follow diverse clinical instructions and adapt to varied diagnostic contexts. Furthermore, it exhibits versatile capabilities across multiple paradigms, efficiently handling slide-level classification and retrieval, fine-grained lesion localization, and instruction following. Extensive experiments demonstrate that PathFLIP outperforms existing large-scale pathological VLMs on four representative benchmarks while requiring significantly less training data, paving the way for fine-grained, instruction-aware WSI interpretation in clinical practice.

Molecular biomarker testing in pathology is often costly and tissue-consuming, limiting scalable clinical deployment. Artificial intelligence applied to hematoxylin and eosin (HE)-stained histology could enable rapid biomarker screening, but clinical translation requires models that are both accurate and interpretable. Here we introduce Hireca, a biomarker-focused pathology foundation model pretrained on more than 80,000 whole-slide images spanning 38 organ types from three medical centers, together with CytoMap, an interpretability module that localizes cellular-scale evidence underlying predictions. Across 10 biomarker tasks encompassing morphological, molecular, genetic, and spatial-transcriptomic-proxy readouts, Hireca ranked first in five tasks and outperformed comparable models overall. In evaluation by eight pathologists from two countries, CytoMap was consistently preferred over alternative visualization approaches and revealed error patterns in difficult cases. These results position Hireca and CytoMap as a transparent framework for clinically reviewable biomarker assessment directly from routine HE histology.