D-VST: Diffusion Transformer for Pathology-Correct Tone-Controllable Cross-Dye Virtual Staining of Whole Slide Images

Diffusion-based virtual staining methods of histopathology images have demonstrated outstanding potential for stain normalization and cross-dye staining (e.g., hematoxylin-eosin to immunohistochemistry). However, achieving pathologycorrect cross-dye virtual staining with versatile tone controls poses significant challenges due to the difficulty of decoupling the given pathology and tone conditions. This issue would cause non-pathologic regions to be mistakenly stained like pathologic ones, and vice versa, which we term "pathology leakage." To address this issue, we propose diffusion virtual staining Transformer (D-VST), a new framework with versatile tone control for cross-dye virtual staining. Specifically, we introduce a pathology encoder in conjunction with a tone encoder, combined with a two-stage curriculum learning scheme that decouples pathology and tone conditions, to enable tone control while eliminating pathology leakage. Further, to extend our method for billion-pixel whole slide image (WSI) staining, we introduce a novel frequency-aware adaptive patch sampling strategy for high-quality yet efficient inference of ultra-high resolution images in a zero-shot manner. Integrating these two innovative components facilitates a pathology-correct, tone-controllable, cross-dye WSI virtual staining process. Extensive experiments on three virtual staining tasks that involve translating between four different dyes demonstrate the superiority of our approach in generating high-quality and pathologically accurate images compared to existing methods based on generative adversarial networks and diffusion models. Our code and trained models are available at https://github.com/yangshurong/D-VST.