Stain-Aware Wavelet Regularization for Instant Adversarial Purification in Histopathology

Stain variation across hospitals degrades histopathology models at deployment. Existing augmentation methods perturb color spaces with arbitrary hyperparameters, lacking both a principled budget and coverage guarantees for unseen centers. We propose \textbf{C}alibrated \textbf{A}dversarial \textbf{S}tain \textbf{A}ugmentation (\textbf{CASA}), which performs adversarial augmentation in the Macenko stain parameter space with a budget calibrated from multi-center statistics via the DKW inequality. On Camelyon17-WILDS (5 seeds), CASA achieves $93.9\% \pm 1.6\%$ slide-level accuracy -- outperforming HED-strong ($88.4\% \pm 7.3\%$), RandStainNA ($85.2\% \pm 6.7\%$), and ERM ($63.9\% \pm 11.3\%$) -- with the highest worst-group accuracy ($84.9\% \pm 0.9\%$) among all 10 compared methods.

Existing weakly supervised semantic segmentation (WSSS) methods in computational pathology rely on a multi-stage paradigm: class activation map (CAM) generation, offline pseudo-mask refinement, and fully supervised retraining. While established, this decoupled approach presents fundamental limitations. The multi-stage process not only incurs high computational training costs but also suffers from error propagation: local texture biases in shallow CNN layers generate false-positive artifacts that subsequent refinement steps often fail to correct. To address these persistent challenges through a simple yet highly effective approach, we propose the Single-Stage Hierarchical Rectification (SSHR) framework. Rather than passively refining CAMs post-hoc, our method proactively purifies intermediate feature representations during the forward pass. We introduce a Hierarchical Feature Rectification Module (HFRM) that utilizes deep global semantic context to filter out local anomalies in shallow layers. This mechanism generates high-fidelity activation maps directly within a single training loop. Experiments on the LUAD-HistoSeg and BCSS datasets demonstrate that SSHR outperforms state-of-the-art multi-stage methods. Furthermore, SSHR reduces training duration by 2 to 5 times. This efficiency minimizes computational overhead and accelerates clinical translation for large-scale histopathology workflows. The code is available at: https://github.com/trongduc-nguyen/SSHR

Conditional generative adversarial networks (cGANs) have enabled high-fidelity computational staining and destaining of hematoxylin and eosin (H&E) in digital pathology whole-slide images (WSI). However, their ability to generalize to out-of-distribution WSI across institutions without retraining remains insufficiently characterized. Previously developed cGAN models trained on 102 registered prostate core biopsy WSIs from Brigham and Women's Hospital were evaluated on 82 spatially unregistered WSIs acquired at Stanford University. To mitigate domain shift without retraining, a preprocessing pipeline consisting of histogram-based stain normalization for H&E-stained WSIs and channel-wise intensity calibration for unstained WSIs was developed. Because image registration was intentionally omitted for real-world deployment conditions, the reported quantitative results are conservative lower bounds reflecting both model performance and limited spatial alignment. Under these conditions, virtual destaining achieved a Pearson correlation coefficient (PCC) of 0.854, structural similarity index measure (SSIM) of 0.699, and peak signal-to-noise ratio (PSNR) of 18.41 dB. H&E restaining from computationally destained outputs outperformed direct staining from ground-truth unstained inputs across all metrics (PCC: 0.798 vs. 0.715; SSIM: 0.756 vs. 0.718; PSNR: 20.08 vs. 18.51 dB), suggesting that preprocessing quality may be more limiting than model capacity. Qualitative pathological review indicated preservation of benign glandular structures while showing that malignant glands were often rendered with vessel-like morphologies. These findings support the feasibility of applying cGAN-based computational H&E staining and destaining generative models to external WSI datasets using preprocessing-based adaptation alone while defining specific morphological targets for future domain adaptation.