Structure-Preserving Histopathological Stain Normalization via Attention-Guided Residual Learning

Staining variability in histopathological images compromises automated diagnostic systems by affecting the reliability of computational pathology algorithms. Existing normalization methods prioritize color consistency but often sacrifice critical morphological details essential for accurate diagnosis. This work proposes a novel deep learning framework, integrating enhanced residual learning with multi-scale attention mechanisms for structure-preserving stain normalization. The approach decomposes the transformation process into base reconstruction and residual refinement components, incorporating attention-guided skip connections and progressive curriculum learning. The method was evaluated on the MITOS-ATYPIA-14 dataset containing 1420 paired H&E-stained breast cancer images from two scanners. The framework achieved exceptional performance with a structural similarity index (SSIM) of 0.9663 ± 0.0076, representing 4.6% improvement over the best baseline (StainGAN). Peak signal-to-noise ratio (PSNR) reached 24.50 ± 1.57 dB, surpassing all comparison methods. An edge preservation loss of 0.0465 ± 0.0088 demonstrated a 35.6% error reduction compared to the next best method. Color transfer fidelity reached 0.8680 ± 0.0542 while maintaining superior perceptual quality (FID: 32.12, IS: 2.72 ± 0.18). The attention-guided residual learning framework successfully maintains structural integrity during stain normalization, with superior performance across diverse tissue types, making it suitable for clinical deployment in multi-institutional digital pathology workflows.