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Background  Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8 th  edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value.    Material and methods  The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7 th  edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16 INK4a  or HPV-mRNA), p16 INK4a  positivity alone or the combination of HPV-DNA/p16 INK4a  positivity as diagnostic tests.    Results  A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16 INK4a  or HPV-mRNA), 83 (10.5%) were p16 INK4a  positive and 58 (7.4%) were double positive for HPV-DNA/p16 INK4a . ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16 INK4a -positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria.    Conclusion  HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients’ survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials.

HPV-relatedness definitions for classifying HPV-related oropharyngeal cancer patient do impact on TNM classification and patients’ survival