Maximilian Fischer, Alexander Muckenhuber, Robin Peretzke, Luay Farah, Constantin Ulrich, Sebastian Ziegler, Philipp Schader, Lorenz Feineis, Hanno Gao, Shuhan Xiao, Michael Goetz, Marco Nolden, Katja Steiger, Jens T. Siveke, Lukas Endrös, Rickmer Braren, Jens Kleesiek, Peter J. Schüffler, Peter Neher, Klaus Maier‐Hein
Pancreatic ductal adenocarcinoma (PDAC) subtyping typically relies on immunohistochemistry (IHC) staining for critical markers like HNF1A and KRT81, a labor-intensive manual staining process that introduces variability. Virtual staining methods offer promising alternatives by generating synthetic IHC images from routine hematoxylin and eosin (H&E) slides. However, most current approaches evaluate success by image quality measures rather than assessing diagnostically relevant features. Here, we introduce a novel cycleGAN framework utilizing a contrastive-inspired approach trained on semipaired datasets derived from consecutive tissue sections. Our method significantly enhances PDAC subtyping accuracy based on synthetic IHC images generated from standard H&E inputs, improving the classification F1-score from 0.66 to 0.77 for KRT81 and from 0.61 to 0.73 for HNF1A, compared with classification directly on H&E images. This approach also substantially outperforms baseline CycleGAN models. These results underscore the clinical potential of contrastive virtual staining to streamline PDAC diagnostics and improve their robustness. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.