Computational Pathology

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.

A key challenge in segmentation in digital histopathology is inter- and intra-stain variations as it reduces model performance. Labelling each stain is expensive and time-consuming so methods using stain transfer via CycleGAN, have been developed for training multi-stain segmentation models using labels from a single stain. Nevertheless, CycleGAN tends to introduce noise during translation because of the one-to-many nature of some stain pairs, which conflicts with its cycle consistency loss. To address this, we propose the Domain Shift Aware CycleGAN, which reduces the presence of such noise. Furthermore, we evaluate several advances from the field of machine learning aimed at resolving similar problems and compare their effectiveness against DSA-CycleGAN in the context of multi-stain glomeruli segmentation. Experiments demonstrate that DSA-CycleGAN not only improves segmentation performance in glomeruli segmentation but also outperforms other methods in reducing noise. This is particularly evident when translating between biologically distinct stains. The code is publicly available at https://github.com/zeeshannisar/DSA-CycleGAN.

Peripheral Blood Smear (PBS) is a critical microscopic examination in hematopathology that yields whole-slide imaging (WSI). Unlike solid tissue pathology, PBS interpretation focuses on individual cell morphologies rather than tissue architecture, making it distinct in both visual characteristics and diagnostic reasoning. However, current multimodal large language models (MLLMs) for pathology are primarily developed on solid-tissue WSIs and struggle to generalize to PBS. To bridge this gap, we construct PBSInstr, the first vision-language dataset for PBS interpretation, comprising 353 PBS WSIs paired with microscopic impression paragraphs and 29k cell-level image crops annotated with cell type labels and morphological descriptions. To facilitate instruction tuning, PBSInstr further includes 27k question-answer (QA) pairs for cell crops and 1,286 QA pairs for PBS slides. Building upon PBSInstr, we develop PBS-VL, a hematopathology-tailored vision-language model for multi-level PBS interpretation at both cell and slide levels. To comprehensively evaluate PBS understanding, we construct PBSBench, a visual question answering (VQA) benchmark featuring four question categories and six PBS interpretation tasks. Experiments show that PBS-VL outperforms existing general-purpose and pathology MLLMs, underscoring the value of PBS-specific data. We release our code, datasets, and model weights to facilitate future research. Our proposed framework lays the foundation for developing practical AI assistants supporting decision-making in hematopathology.

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.

Segmentation is a critical task in computational pathology, as it identifies areas affected by disease or abnormal growth and is essential for diagnosis and treatment. However, acquiring high-quality pixel-level supervised segmentation data requires significant workload demands from experienced pathologists, limiting the application of deep learning. To overcome this challenge, relaxing the label conditions to image-level classification labels allows for more data to be used and more scenarios to be enabled. One approach is to leverage Class Activation Map (CAM) to generate pseudo pixel-level annotations for semantic segmentation with only image-level labels. However, this method fails to thoroughly explore the essential characteristics of pathology images, thus identifying only small areas that are insufficient for pseudo masking. In this paper, we propose a novel shuffle-based feedback learning method inspired by curriculum learning to generate higher-quality pseudo-semantic segmentation masks. Specifically, we perform patch level shuffle of pathology images, with the model adaptively adjusting the shuffle strategy based on feedback from previous learning. Experimental results demonstrate that our proposed approach outperforms state-of-the-arts on three different datasets.

In NLP classification tasks where little labeled data exists, domain fine-tuning of transformer models on unlabeled data is an established approach. In this paper we have two aims. (1) We describe our observations from fine-tuning the Finnish BERT model on Finnish medical text data. (2) We report on our attempts to predict the benefit of domain-specific pre-training of Finnish BERT from observing the geometry of embedding changes due to domain fine-tuning. Our driving motivation is the common\situation in healthcare AI where we might experience long delays in acquiring datasets, especially with respect to labels.

Objective. Standard Magnetic Resonance Imaging (MRI) reconstruction pipelines discard phase information captured during acquisition, despite evidence that it encodes tissue properties relevant to tumor diagnosis. Current machine learning approaches inherit this limitation by operating exclusively on reconstructed magnitude images. The aim of this study is to build a generative framework which is capable of jointly modeling magnitude and phase information of complex-valued MRI scans. Approach. The proposed generative framework combines a conditional variational autoencoder, which compresses complex-valued MRI scans into compact latent representations while preserving phase coherence, with a flow-matching-based generative model. Synthetic sample quality is assessed via a real-versus-synthetic classifier and by training downstream classifiers on synthetic data for abnormal tissue detection. Main results. The autoencoder preserves phase coherence above 0.997. Real-versus-synthetic classification yields low AUROC values between 0.50 and 0.66 across all acquisition sequences, indicating generated samples are nearly indistinguishable from real data. In downstream normal-versus-abnormal classification, classifiers trained entirely on synthetic data achieve an AUROC of 0.880, surpassing the real-data baseline of 0.842 on a publicly available dataset (fastMRI). This advantage persists on an independent external test set from a different institution with biopsy-confirmed labels. Significance. The proposed framework demonstrates the feasibility of jointly modeling magnitude and phase information for normal and abnormal complex-valued brain MRI data. Beyond synthetic data generation, it establishes a foundation for the usage of complete brain MRI information in future diagnostic applications and enables systematic investigation of how magnitude and phase jointly encode pathology-specific features.

Computational pathology needs whole-slide image (WSI) foundation models that transfer across diverse clinical tasks, yet current approaches remain largely slide-centric, often depend on private data and expensive paired-report supervision, and do not explicitly model relationships among multiple slides from the same patient. We present MOOZY, a patient-first pathology foundation model in which the patient case, not the individual slide, is the core unit of representation. MOOZY explicitly models dependencies across all slides from the same patient via a case transformer during pretraining, combining multi-stage self-supervision with scaled low-cost task supervision. In Stage 1, we pretrain a vision-only slide encoder on 77,134 public slide feature grids using masked self-distillation. In Stage 2, we align these representations with clinical semantics using a case transformer and multi-task supervision over 333 tasks from 56 public datasets, including 205 classification and 128 survival tasks across four endpoints. Across sixteen held-out tasks, MOOZY improves macro weighted F1, balanced accuracy, and macro weighted ROC-AUC relative to PRISM by +4.19%, +7.93%, and +6.95%, respectively. MOOZY is also parameter efficient with 85.77M parameters, 14$\times$ smaller than GigaPath. These results suggest that patient-level pretraining yields transferable embeddings, providing a path toward scalable patient-first histopathology foundation models.

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.

Drug-induced toxicity is a leading cause of preclinical and early-clinical failure, making early detection critical. Histopathology is the gold standard for toxicity assessment but relies on expert pathologists, creating a bottleneck for large-scale screening. We introduce an AI-based anomaly detection framework for whole-slide images (WSIs) of rodent liver that identifies healthy tissue and known pathologies (anomalies) and flags samples without training data as out-of-distribution (OOD). We evaluate OOD detection on two held-out categories: apoptosis (single-cell, near-OOD) and staining/processing artifacts (heterogeneous, far-OOD). We build a novel pixelwise-annotated dataset and fine-tune a pre-trained Vision Transformer (DINOv2) via Low-Rank Adaptation (LoRA) for segmentation, then use the Mahalanobis distance for OOD detection with class-specific thresholds. Optimizing the false positive rate subject to a predefined constraint on the false negative rate yields only 0.16% of pathological tissue classified as healthy and 0.35% of healthy tissue classified as pathological. Our false negative rate does not penalise cross-type errors, reflecting the safety-first objective of never overlooking a lesion; under the stricter correct-class criterion our method assigns 93.93% of ID and 89.38% of OOD findings to their own class. The study demonstrates technical feasibility of pixel-level anomaly detection for mouse liver histopathology, indicating possible applications in improving preclinical workflows and drug development efficiency.

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.

The rapid digitization of histopathology slides has opened new opportunities for computational tools in clinical and research workflows. Content-based slide retrieval can help pathologists identify morphologically and semantically related precedent cases, supporting expert diagnosis and example-based education. Effective retrieval of whole-slide images (WSIs), however, remains challenging because gigapixel slides contain abundant irrelevant content, focal diagnostic patterns and slide-level semantic information that must be represented at a practicable search cost. Here we present PathSearch, a retrieval framework that combines fine-grained attentive mosaics with slide-level embeddings aligned through vision-language contrastive learning. Trained on 6,926 slide-report pairs, PathSearch captures both fine-grained morphological cues and high-level semantic patterns to enable accurate and flexible retrieval. The framework supports two key functionalities: (1) mosaic-based image-to-image (I2I) retrieval, ensuring accurate and efficient slide search; and (2) multimodal retrieval, where text queries can directly retrieve relevant slides. PathSearch was evaluated on eight tasks comprising 5,021 evaluation slides, spanning malignancy assessment on frozen and hematoxylin and eosin (H&E)-stained slides, lymph-node metastasis detection, tumor subtyping, mixed-gallery rare-cancer retrieval, and hepatocellular carcinoma (HCC) risk stratification. Internal and external experimental results demonstrate that PathSearch consistently outperforms the strongest existing methods without compromising multimodal accuracy. A multi-center reader study further demonstrated increases in task-level mean diagnostic accuracy, confidence, and inter-observer agreement with PathSearch's support. Together, these results support the effectiveness of PathSearch across diverse retrieval tasks and evaluation settings.

Peripheral neuroblastic tumors (pNTs) are among the most common extracranial solid tumors in children, and accurate pathological subtyping is important for risk stratification and treatment planning. However, pNT subtyping on hematoxylin-eosin whole-slide images (WSIs) remains challenging because of limited pediatric tumor cohorts, marked histological heterogeneity, inter-observer variability, and the computational burden of existing WSI classifiers. To address these challenges, we propose CoPath, a framework consisting of CoHisNet and PathVote. CoHisNet is a lightweight multi-scale feature-fusion network for patch-level histopathological classification. By replacing the multilayer perceptron components in Swin Transformer blocks and the classification head with Kolmogorov-Arnold Network layers, CoHisNet improves nonlinear feature modeling under a compact architecture. Its multi-scale interaction and contrast-driven feature-enhancement design enables the model to capture both tissue-level structures and fine-grained cellular morphology. PathVote further incorporates pathology-informed tissue-component priors to aggregate patch-level predictions into WSI-level decisions. We validated CoPath on a private two-branch PpNTs cohort and the public BreakHis breast cancer histopathology dataset. Experimental results show that CoPath achieves competitive or superior performance compared with general image classifiers, pathology foundation models under linear probing, and pathology-specific classification models, while maintaining substantially lower computational complexity. The source code is available at https://github.com/JSLiam94/CoPath.

Cancer survival prediction from whole slide images (WSIs) is a challenging task in computational pathology due to the large size, irregular shape, and high granularity of the WSIs. These characteristics make it difficult to capture the full spectrum of patterns, from subtle cellular abnormalities to complex tissue interactions, which are crucial for accurate prognosis. To address this, we propose CrossFusion, a novel multi-scale feature integration framework that extracts and fuses information from patches across different magnification levels. By effectively modeling both scale-specific patterns and their interactions, CrossFusion generates a rich feature set that enhances survival prediction accuracy. We validate our approach across six cancer types from public datasets, demonstrating significant improvements over existing state-of-the-art methods. Moreover, when coupled with domain-specific feature extraction backbones, our method shows further gains in prognostic performance compared to general-purpose backbones. The source code is available at: https://github.com/RustinS/CrossFusion

To overcome the black-box nature of predictive AI and the hallucination risks of generative models, retrieval-based models offer an interpretable, evidence-based paradigm for pathology clinical workflow. However, real-world clinical queries are inherently interleaved (e.g., pathology images and text). Current dual-encoders suffer from an \textbf{Architectural Mismatch}, lacking the mechanism to fuse such composed queries. To address this, we formalize the task of Pathology Composed Retrieval (PCR). While Multimodal Large Language Models (MLLMs) offer deep-fusion capabilities, directly applying them exposes a \textbf{Task Mismatch} and a \textbf{Domain Mismatch}. To resolve these challenges, we propose HOMIE, a model-agnostic adaptation framework that transforms any generative MLLM into a specialized pathology retrieval expert. Evaluated on our newly introduced PCR Benchmark, a lightweight 2B-parameter HOMIE variant substantially outperforms existing paradigms, surpassing specialized 7B pathology MLLMs and dual-encoders by large margins on composed retrieval, while maintaining strong performance on traditional simple retrieval. The project page is available at https://qfchou.github.io/HOMIE_page/.

Deploying deep learning-based imaging tools across various clinical sites poses significant challenges due to inherent domain shifts and regulatory hurdles associated with site-specific fine-tuning. For histopathology, stain normalization techniques can mitigate discrepancies, but they often fall short of eliminating inter-site variations. Therefore, we present Data Alchemy, an explainable stain normalization method combined with test time data calibration via a template learning framework to overcome barriers in cross-site analysis. Data Alchemy handles shifts inherent to multi-site data and minimizes them without needing to change the weights of the normalization or classifier networks. Our approach extends to unseen sites in various clinical settings where data domain discrepancies are unknown. Extensive experiments highlight the efficacy of our framework in tumor classification in hematoxylin and eosin-stained patches. Our explainable normalization method boosts classification tasks' area under the precision-recall curve(AUPR) by 0.165, 0.545 to 0.710. Additionally, Data Alchemy further reduces the multisite classification domain gap, by improving the 0.710 AUPR an additional 0.142, elevating classification performance further to 0.852, from 0.545. Our Data Alchemy framework can popularize precision medicine with minimal operational overhead by allowing for the seamless integration of pre-trained deep learning-based clinical tools across multiple sites.

Breast cancer survival prediction in computational pathology presents a remarkable challenge due to tumor heterogeneity. For instance, different regions of the same tumor in the pathology image can show distinct morphological and molecular characteristics. This makes it difficult to extract representative features from whole slide images (WSIs) that truly reflect the tumor's aggressive potential and likely survival outcomes. In this paper, we present PathoHR, a novel pipeline for accurate breast cancer survival prediction that enhances any size of pathological images to enable more effective feature learning. Our approach entails (1) the incorporation of a plug-and-play high-resolution Vision Transformer (ViT) to enhance patch-wise WSI representation, enabling more detailed and comprehensive feature extraction, (2) the systematic evaluation of multiple advanced similarity metrics for comparing WSI-extracted features, optimizing the representation learning process to better capture tumor characteristics, (3) the demonstration that smaller image patches enhanced follow the proposed pipeline can achieve equivalent or superior prediction accuracy compared to raw larger patches, while significantly reducing computational overhead. Experimental findings valid that PathoHR provides the potential way of integrating enhanced image resolution with optimized feature learning to advance computational pathology, offering a promising direction for more accurate and efficient breast cancer survival prediction. Code will be available at https://github.com/AIGeeksGroup/PathoHR.