DSA-CycleGAN: A Domain Shift Aware CycleGAN for Robust Multi-Stain Glomeruli Segmentation
Authors: Zeeshan Nisar, Friedrich Feuerhake, Thomas Lampert
Organizations: ⋆ICube, University of Strasbourg, France · †Institute of Pathology, Hannover Medical School, Germany
Abstract
A key challenge in segmentation in digital histopathology is inter- and intra-stain variations as it reduces model performance. Labelling each stain is expensive and time-consuming so methods using stain transfer via CycleGAN, have been developed for training multi-stain segmentation models using labels from a single stain. Nevertheless, CycleGAN tends to introduce noise during translation because of the one-to-many nature of some stain pairs, which conflicts with its cycle consistency loss. To address this, we propose the Domain Shift Aware CycleGAN, which reduces the presence of such noise. Furthermore, we evaluate several advances from the field of machine learning aimed at resolving similar problems and compare their effectiveness against DSA-CycleGAN in the context of multi-stain glomeruli segmentation. Experiments demonstrate that DSA-CycleGAN not only improves segmentation performance in glomeruli segmentation but also outperforms other methods in reducing noise. This is particularly evident when translating between biologically distinct stains. The code is publicly available at https://github.com/zeeshannisar/DSA-CycleGAN.
Histopathological examination primarily relies on hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining. Although IHC provides critical molecular information, it is costly and requires specialized expertise. Stain transfer provides an efficient alternative by computationally generating IHC from H&E images, but remains challenged by unified and interpretable modeling for heterogeneous biomarkers under pixel-unaligned supervision. We propose DMCoStain, a novel Data-Model Co-optimization framework for Stain transfer. It iteratively co-refines training data and model capability, improving staining accuracy and interpretability in both pathological and structural consistency. To refine training data in a clinically meaningful manner, it incorporates the Multimodal Expert-Guided Finer Selection (MEGFS) strategy, built upon a pioneering IHC-positive-expression (IPE) vision-language model (VLM) that emulates pathologist reasoning. To support MEGFS, we construct ImmunoInstruction, the first large-scale IPE instruction-following dataset with 150K VQA samples. Extensive experiments on multiple tissues and biomarkers demonstrate that DMCoStain achieves state-of-the-art (SOTA) accuracy. This paradigm offers strong practical value, and MEGFS also functions as a specialized evaluation tool for future model development. Dataset, code, and more details are in https://github.com/SikangSHU/DMCoStain.
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.
Semi-supervised histopathology segmentation is challenging due to scarce annotations and unreliable pseudo-labels in ambiguous gland regions. To address this problem, we propose Confidence-Guided Diffusion Refinement (CoDiR), a semi-supervised framework that combines a Mean Teacher segmentation model with diffusion-based pseudo-label refinement. Given an unlabeled image, the teacher first produces a soft prediction, and only low-confidence regions are refined by a conditional diffusion model trained to capture plausible mask structures from labeled data. The refined mask is then fused with reliable teacher predictions and used to train the student with confidence weighting and consistency regularization. On the GlaS and CRAG datasets CoDiR reaches 88.09% and 89.83% mDice with 10% labeled data, and 89.19% and 90.29% mDice with 20%, matching or exceeding the strongest published method on seven of the eight benchmark metrics. Ablations attribute the largest single contribution to the refinement module, which adds +6.36% mDice over the Mean Teacher baseline. The implementation code is publicly available at: https://github.com/vongla345/codir