PCaPaint: Prostate Cancer Inpainting by Mitigating Shortcut Learning

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.

Deep learning models that synthesize PET from CT or MRI can reduce patient dose and scanner demand, but are typically optimized with global losses such as L1 or mean squared error (MSE) that treat all voxels similarly. In whole-body PSMA-PET, tumor voxels occupy only a small fraction of the volume, yet carry the clinically relevant activity signal; as a result, models can achieve high structural similarity index measure (SSIM) and peak signal-to-noise ratio (PSNR) while still underestimating lesion activity or failing to preserve tumor-specific structure. Radiomics provides biologically meaningful descriptors of tumor intensity and texture, but direct radiomics conditioning is time-consuming because it requires feature extraction from delineated lesion regions. We propose LAFNO, a Lesion-Aware Adaptive Fourier Neural Operator for CT-to-PSMA-PET synthesis that replaces high-dimensional radiomics conditioning with two efficient CT-derived proxy channels. Motivated by radiomics analysis of PSMA-avid tumor core and peritumoral regions, LAFNO uses a contrast proxy for local density variation and a disorder proxy for local texture heterogeneity, both injected into the model bottleneck. LAFNO combines whole-volume reconstruction with lesion-level total lesion activity (TLA), tumor-core contrast, and peritumoral supervision. We evaluated LAFNO against four baseline architectures on the TCIA PSMA-PET-CT-Lesions dataset. LAFNO remained competitive on whole-volume image quality, achieving SSIM of 0.960 and 0.938 for 18F- and 68Ga-PSMA, respectively, while reducing per-patient TLA error to 48.3% and 64.0% for 18F- and 68Ga-PSMA, respectively, and achieving the highest tumor-core radiomics reproducibility across all feature classes for both tracers. Peritumoral reproducibility remained tracer-dependent, indicating that biological fidelity in synthetic PSMA-PET remains challenging.

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.