Abstract
Cervical cancer remains the fourth most common cancer among women worldwide. This study proposes an end-to-end deep learning framework to predict consensus molecular subtypes (CMS) in HPV-positive cervical squamous cell carcinoma (CSCC) from H&E-stained histology slides. Analysing three CSCC cohorts (n = 545), we show our Digital-CMS scores significantly stratify patients by both disease-specific (TCGA p = 0.0022, Oslo p = 0.0495) and disease-free (TCGA p = 0.0495, Oslo p = 0.0282) survival. In addition, our extensive tumour microenvironment analysis reveals differences between the two CMS subtypes, with CMS-C1 tumours exhibit increased lymphocyte presence, while CMS-C2 tumours show high nuclear pleomorphism, elevated neutrophil-to-lymphocyte ratio, and higher malignancy, correlating with poor prognosis. This study introduces a potentially clinically advantageous Digital-CMS score derived from digitised WSIs of routine H&E-stained tissue sections, offers new insights into TME differences impacting patient prognosis and potential therapeutic targets, and identifies histological patterns serving as potential surrogate markers of the CMS subtypes for clinical application.