Histopathology Image Synthesis

Deep learning methods for pathology are constrained by the limited availability and high cost of large-scale pixel-level annotations. Synthetic data can alleviate this limitation, but existing pipelines often lack reliable quality control and remain weakly connected to downstream analysis. To address these issues, we propose a three-stage framework that integrates automated data screening, generative representation learning, and efficient adaptation to downstream tasks. First, we develop a pathology agent system to assess image quality and filter samples, resulting in TCGA-200K, a dataset containing 217,030 pathology patches selected from the public TCGA repository. Second, we train a generative model on the screened data. In addition to image synthesis, its backbone learns structural and semantic representations that can be transferred to downstream tasks. Third, we adapt the pretrained generative backbone to semantic segmentation using a lightweight task-specific head. We further introduce PathSeg-380K, a semantic segmentation dataset with expert annotations for approximately 380,000 cells across 12 cell types. Experiments on multiple pathology datasets show that the proposed framework achieves state-of-the-art segmentation performance. Our code is publicly available at https://github.com/script-Yang/Agent-GenPath.

Whole-slide images (WSIs) are gigapixel-scale digital scans of histopathology tissue and serve as the primary basis for cancer diagnosis. Existing histopathology generative models operate at the patch scale, producing fixed-size tiles of at most 1024$\times$1024 pixels which encompass only a small fraction of the WSI. In contrast, text reports for clinical diagnoses and slide-level diagnostic labels -- the supervision that exists at scale -- operate at the whole-slide level. We present BigCell, the first approach to generate coherent whole-slide histopathology images at native gigapixel resolution. BigCell trains a flow-matching transformer at 2048$\times$2048 pixels on over 120,000 publicly available WSIs spanning multiple organ types. Conditioning on embeddings from pathology foundation models and using an inference-time sliding-window pipeline, BigCell generates coherent images of up to 32,768$\times$32,768 pixels, outperforming prior tile generators on both tile-level and slide-level fidelity metrics. To make gigapixel synthesis practical, we introduce an adaptive scheduling strategy that prioritizes important slide regions, speeding up image generation by over 3\ttimes with minimal quality degradation. Furthermore, we propose the first text-to-image synthesis at 8k resolution by training a separate model that produces dense conditioning grids directly from pathology text reports. We demonstrate that augmenting with synthetic samples improves slide-level few-shot classification performance by up to $18 \%$ over baselines trained on real data.

Deep learning has demonstrated remarkable success in high-throughput histopathology image analysis. However, the performance of learning-based models critically depends on the quality and size of annotations by expert pathologists, which is a resource-intensive and time-consuming process. To address the limitations of data scarcity and annotation burden, several methods have been proposed to synthesize paired histopathology data. Nevertheless, these frameworks typically still require annotation data, albeit in reduced quantities, to impose structural constraints during training. In this work, we present CHIS, a plug-in framework that guides the sampling trajectory of a pretrained diffusion model through two key stages: structural initialization at the start and textural modulation during generation. The initial noise state is refined by fusing the phase information from a prior mask with the amplitude of Gaussian noise in the frequency domain, yielding a structurally informed starting point. During the reverse diffusion process, we adaptively modulate both coarse-grained and fine-grained textures at different wavelet decomposition levels. This enables a diffusion model pretrained solely on unlabeled images to generate outputs that align with prior structural masks while preserving the reference tissue style. We conducted extensive experiments demonstrating the superiority of CHIS in generation fidelity and its substantial benefits for downstream segmentation tasks. Code is available at https://github.com/IBIL-Code/CHIS.

Synthetic histopathology image generation addresses patient-privacy concerns and the growing data demands of foundation models. Existing state-of-the-art histopathology generative models use pretrained Vision Foundation Models (VFMs) as conditioning signals. We show this yields conditioning-dominated diversity: on TCGA-BRCA, 62-75% of their output diversity is attributable to the conditioning signal rather than the learned latent space, while de novo synthesis still requires a VFM at inference. We instead use histopathology VFMs as the latent space itself: their patch tokens are $\ell_2$-normalized on the unit hypersphere $\mathcal{S}^{d-1}$ with strong angular dominance and intrinsic curvature, motivating a Riemannian formulation. We present STREAM, the first framework to apply Riemannian flow matching in the histopathology domain, in two stages: 1) a bridge-type stochastic perturbation that establishes per-token rectifiability on $\mathcal{S}^{d-1}$ for training a Diffusion Transformer, and 2) a novel decoder training design whose noise covariance is anisotropic in the left-singular basis of the per-token tangent-projected velocity-field Jacobian, spending a large robustness budget on its low-response directions and a small one on its high-response directions. Across TCGA-BRCA and TCGA-COADREAD, STREAM achieves state-of-the-art gFID and ranks first on nearly all histopathology-specific metrics as well. Code and a public gallery of generated images are available at https://chokevin8.github.io/STREAM-Patho/.

Data scarcity in multimodal pathology motivates unified generative models that synthesize modality-specific appearance while preserving anatomically coherent structure. Although modalities differ in appearance statistics, morphological structures such as cellular topology and tissue boundaries are largely preserved across acquisition protocols. However, existing methods often model these factors within a homogeneous token stream, implicitly coupling structure with appearance and weakening structural controllability under modality shifts. To address this, we propose pathology Autorgressive modeling (PathAR), a structure-first autoregressive synthesis framework that explicitly factorizes structure and appearance for modality-label-conditioned pathology generation.PathAR employs a dual vector quantization (Dual-VQ) tokenizer to decompose samples into mask-grounded structure and appearance tokens, and an interleaved autoregressive (IAR) transformer with asymmetric attention visibility to enforce structure-to-appearance dependence. PathAR stabilizes morphology under heterogeneous modality-specific appearances and enables spatially aligned image--mask pair generation. Extensive experiments show that PathAR improves structural consistency and modality fidelity over baselines, maintains sample diversity, supports downstream segmentation in data-scarce regimes, and demonstrates extensibility to finer-grained intra-modality organ-label variation.

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.

Histopathology image synthesis plays an important role in tissue restoration, data augmentation, and modeling of tumor microenvironments. However, existing generative methods typically address restoration and generation as separate tasks, although both share the same objective of structure-consistent tissue synthesis under varying degrees of missingness, and often rely on weak or inconsistent structural priors that limit realistic cellular organization. We propose Dual-LoRA Controllable Diffusion, a unified centroid-guided diffusion framework that jointly supports Local Structure Completion and Global Structure Synthesis within a single model. Multi-class nuclei centroids serve as lightweight and annotation-efficient spatial priors, providing biologically meaningful guidance under both partial and complete image absence. Two task-specific LoRA adapters specialize the shared backbone for local and global objectives without retraining separate diffusion models. Extensive experiments demonstrate consistent improvements over state-of-the-art GAN and diffusion baselines across restoration and synthesis tasks. For local completion, LPIPS computed within the masked region improves from 0.1797 (HARP) to 0.1524, and for global synthesis, FID improves from 225.15 (CoSys) to 76.04, indicating improved structural fidelity and realism. Our approach achieves more faithful structural recovery in masked regions and substantially improved realism and morphology consistency in full synthesis, supporting scalable pan-cancer histopathology modeling.

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.