Semantic and Visual Crop-Guided Diffusion Models for Heterogeneous Tissue Synthesis in Histopathology

Synthetic data generation in histopathology faces unique challenges: preserving tissue heterogeneity, capturing subtle morphological features, and scaling to unannotated datasets. We present a latent diffusion model that generates realistic heterogeneous histopathology images through a novel dual-conditioning approach combining semantic segmentation maps with tissue-specific visual crops. Unlike existing methods that rely on text prompts or abstract visual embeddings, our approach preserves critical morphological details by directly incorporating raw tissue crops from corresponding semantic regions. For annotated datasets (i.e., Camelyon16, Panda), we extract patches ensuring 20-80% tissue heterogeneity. For unannotated data (i.e., TCGA), we introduce a self-supervised extension that clusters whole-slide images into 100 tissue types using foundation model embeddings, automatically generating pseudo-semantic maps for training. Our method synthesizes high-fidelity images with precise region-wise annotations, achieving superior performance on downstream segmentation tasks. When evaluated on annotated datasets, models trained on our synthetic data show competitive performance to those trained on real data, demonstrating the utility of controlled heterogeneous tissue generation. In quantitative evaluation, prompt‐guided synthesis reduces Fréchet Distance by up to 6× on Camelyon16 (from 430.1 to 72.0) and yields 2–3× lower FD across Panda and TCGA. Downstream DeepLabv3+ models trained solely on synthetic data attain test IoU of 0.71 and 0.95 on Camelyon16 and Panda, within 1–2% of real‐data baselines (0.72 and 0.96). By scaling to 11,765 TCGA whole‐slide images without manual annotations, our framework offers a practical solution for an urgent need for generating diverse, annotated histopathology data, addressing a critical bottleneck in computational pathology.