A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

1st Faculty of Medicine Institute of Hygiene and Epidemiology Charles University Prague Czech Republic

Bristol Dental School University of Bristol Bristol UK

Centre for Infectious Diseases Control National Institute for Public Health and the Environment Bilthoven The Netherlands

Centro de Investigación Biomédica en Red Epidemiología y Salud Pública Instituto de Salud Carlos 3 Madrid Spain

Centro di Riferimento Oncologico di Aviano IRCCS Aviano Italy

Dalla Lana School of Public Health University of Toronto Toronto Canada

Department of Cellular Pathology Royal Victoria Infirmary Newcastle upon Tyne UK

Department of Infectious Diseases Public Health Service of Amsterdam Amsterdam The Netherlands

Department of Social Medicine Care and Public Health Research Institute Maastricht University Maastricht The Netherlands

Division of Medical Oncology and Center for Cancer Research University of Tennessee Health Science Center Memphis Tennessee USA

Epidemiology Group School of Medicine Medical Sciences and Nutrition University of Aberdeen Aberdeen UK

Genomic Epidemiology Group International Agency for Research on Cancer Lyon France

Infections and Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Institute for Infection and Immunity Amsterdam UMC Amsterdam The Netherlands

NIHR Bristol Biomedical Research Centre Weston NHS Foundation Trust University of Bristol Bristol UK

Nutrition and Cancer Group Epidemiology Public Health Cancer Prevention and Palliative Care Program Bellvitge Biomedical Research Institute IDIBELL L'Hospitalet de Llobregat Spain

Princess Margaret Cancer Centre Temerty School of Medicine University of Toronto Toronto Ontario Canada

Prosserman Centre for Population Health Research Lunenfeld Tanenbaum Research Institute Sinai Health Toronto Ontario Canada

Reference Center for Epidemiology and Cancer Prevention Piemonte Italy

School of Medicine Dentistry and Nursing University of Glasgow Dublin UK

School of Medicine National and Kapodistrian University of Athens Athens Greece

School of Public Health University of Pittsburgh and UPMC Hillman Cancer Centre Pittsburgh Pennsylvania USA

School of Public Health University of West Attica Athens Greece

Trinity College School of Dental Science Dublin Ireland

Unit of Nutrition and Cancer Catalan Institute of Oncology ICO L'Hospitalet de Llobregat Spain

University of Bremen Bremen Germany

University of North Carolina Lineberger Comprehensive Cancer Center Chapel Hill North Carolina USA

University of Padova Padova Italy

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VOYAGER: an international consortium investigating the role of human papilloma virus and genetics in oral and oropharyngeal cancer risk and survival