Agent-Driven Generative Priors for Pathology Image Synthesis and Segmentation

Computational pathology has made significant progress in recent years, fueling advances in both fundamental disease understanding and clinically ready tools. This evolution is driven by the availability of large amounts of digitized slides and specialized deep learning methods and models. Multiple self-supervised foundation feature extractors have been developed, enabling downstream predictive applications from cell segmentation to tumor sub-typing and survival analysis. In contrast, generative foundation models designed specifically for histopathology remain scarce. Such models could address tasks that are beyond the capabilities of feature extractors, such as virtual staining. In this paper, we introduce CytoSyn, a state-of-the-art foundation latent diffusion model that enables the guided generation of highly realistic and diverse histopathology H&E-stained images, as shown in an extensive benchmark. We explored methodological improvements, training set scaling, sampling strategies and slide-level overfitting, culminating in the improved CytoSyn-v2, and compared our work to PixCell, a state-of-the-art model, in an in-depth manner. This comparison highlighted the strong sensitivity of both diffusion models and performance metrics to preprocessing-specific details such as JPEG compression. Our model has been trained on a dataset obtained from more than 10,000 TCGA diagnostic whole-slide images of 32 different cancer types. Despite being trained only on oncology slides, it maintains state-of-the-art performance generating inflammatory bowel disease images. To support the research community, we publicly release CytoSyn's weights, its training and validation datasets, and a sample of synthetic images in this repository: https://huggingface.co/Owkin-Bioptimus/CytoSyn.

Synthetic histopathology image generation has emerged as an approach that may address data scarcity in computational pathology, yet current evaluation methodologies may not fully assess synthetic data quality for medical applications. This work investigates and addresses limitations in existing evaluation metrics, investigating an approach for assessing synthetic histopathology image quality through domain-specific metrics and downstream task validation. We show that conventional synthetic data evaluation metrics such as Frechet Inception Distance (FID) and Inception Score (IS) may have limitations when applied to histopathology images due to their reliance on ImageNet-pretrained feature extractors. To address these limitations, we propose for consideration modified FID and IS approaches utilizing foundation models pretrained on digital pathology datasets, supplemented by precision-recall based metrics as part of an additional quality assessment. Using conditional denoising diffusion models trained on four benchmark datasets, with a two-step training approach, we generated synthetic datasets with systematically varied quality characteristics. We also measured the correlation between the synthetic data quality metrics with downstream nuclei segmentation performance using common metrics including the aggregated Jaccard index (AJI+) and the Dice coefficient. The study results suggest that pathology-specific metrics may provide improved discriminative power. Specifically, the modified Inception Score indicates higher correlation with downstream task performance (r=0.6096 with AJI+, p=0.0122), compared to the original IS (r=0.0708, p=0.7944). Our observations indicate that increasing the variety of generated training data has a higher positive correlation with segmentation model performance than improving the visual fidelity of individual generated images.

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.