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 8th 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: 7th 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 (p16INK4a or HPV-mRNA), p16INK4a positivity alone or the combination of HPV-DNA/p16INK4a 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 (p16INK4a or HPV-mRNA), 83 (10.5%) were p16INK4a positive and 58 (7.4%) were double positive for HPV-DNA/p16INK4a. 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 p16INK4a-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.

This work was partially supported by grants from the Instituto de Salud Carlos III-ISCIII (Spanish Government) cofunded by FEDER funds/European Regional Development Fund (ERDF) - a way to build Europe (PI14/01819, PI15/00500 and PI11/02096); Ayudas Merck Serono-Fundación Salud 2000 de investigación 2015; Agéncia de Gestió d’Ajuts Universitaris i de Recerca, AGAUR (2017SGR1085 and 2017SGR1718), European Commission 7th Framework Programme COHEAHR (Health-F3-2013-603019) and Rio Hortega-SEOM (ISCIII-Spanish Society of Medical Oncology) (personal grant to MT). The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.