A whole-slide image (WSI)-based immunohistochemical feature prediction system improves the subtyping of lung cancer.

Clinically, accurate pathological diagnosis is often challenged by insufficient tissue amounts and the unaffordability of additional immunohistochemical or genetic tests; thus, there is an urgent need for a universal approach to improve the subtyping of lung cancer without the above limitations. Here we aimed to develop a deep learning system to predict the immunohistochemistry (IHC) phenotype directly from whole-slide images (WSIs) to improve the subtyping of lung cancer from surgical resection and biopsy specimens.A total of 1914 patients with lung cancer from three independent hospitals in China were enrolled for WSI-based immunohistochemical feature prediction system (WIFPS) development and validation.The WIFPS could directly predict the IHC status of nine subtype-specific biomarkers, including CK7, TTF-1, Napsin A, CK5/6, P63, P40, CD56, Synaptophysin, and Chromogranin A, achieving average areas under the curve (AUCs) of 0.912, 0.906, and 0.888 and overall diagnostic accuracies of 0.925, 0.941, and 0.887 in the validation datasets of total, external surgical resection specimens and biopsy specimens, respectively. The histological subtyping performance of the WIFPS remained comparable with that of general pathologists (GPs), with Cohen's kappa values ranging from 0.7646 to 0.8282. Furthermore, the WIFPS could be trained to not only predict the IHC status of anaplastic lymphoma kinase (ALK), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1), but also predict EGFR and KRAS mutation status, with AUCs from 0.525 to 0.917, as detected in separate populations.In this study, the WIFPS showed its proficiency as a useful complement to traditional histologic subtyping for integrated immunohistochemical spectrum prediction as well as potential in the detection of gene mutations.