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Tumors positive for both hrHPV and p16 (double positive) are assumed to be HPV\u2010driven, but only few large studies have investigated the combined prevalence of hrHPV and p16 positivity in vulvar cancer over time. In this Danish cross\u2010sectional study, we assessed the prevalence of p16 positivity and double positivity for hrHPV and p16 in a large sample of vulvar squamous cell carcinomas (VSCCs) diagnosed during 1990 to 2017. In a nationwide register, we identified VSCCs from 13 hospitals across Denmark, and collected archival tumor tissue for hrHPV testing with INNO\u2010LiPA and immunohistochemical p16 staining. We calculated the prevalence of hrHPV, p16 positivity and double positivity according to time, age and histological subtype and evaluated time trends through estimated annual percentage changes. We included 1278 VSCCs. Overall, 35.0% (95% confidence interval [CI]: 32.4\u201037.6) were positive for p16 and 31.0% (95% CI: 28.4\u201033.5) were positive for both hrHPV and p16. The prevalence of p16 positivity and double positivity increased over time, both in women aged \u226459 and \u226560\u2009years. The double positive prevalence was higher in nonkeratinizing (60.7%) and warty\/basaloid VSCCs (67.5%) than in keratinizing (16.1%) and verrucous VSCCs (5.0%). These results indicate that approximately one\u2010third of vulvar cancers were caused by hrHPV infection, supporting a substantial preventive potential of the HPV vaccine.<\/jats:p>","DOI":"10.1002\/ijc.34446","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T07:59:58Z","timestamp":1674633598000},"page":"2424-2432","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Time trends in prevalence of p16 positivity and combined <scp>HPV<\/scp>\/p16 positivity in a large cohort of Danish vulvar cancer patients"],"prefix":"10.1002","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3920-373X","authenticated-orcid":false,"given":"Christina Louise","family":"Rasmussen","sequence":"first","affiliation":[{"name":"Unit of Virus, Lifestyle and Genes Danish Cancer Society Research Center  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0738-8410","authenticated-orcid":false,"given":"Louise T.","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Unit of Virus, Lifestyle and Genes Danish Cancer Society Research Center  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5773-5169","authenticated-orcid":false,"given":"Louise","family":"Baandrup","sequence":"additional","affiliation":[{"name":"Unit of Virus, Lifestyle and Genes Danish Cancer Society Research Center  Copenhagen Denmark"},{"name":"Department of Pathology, Herlev Hospital University of Copenhagen  Herlev Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Benedicte","family":"Franzmann","sequence":"additional","affiliation":[{"name":"Department of Pathology Hvidovre University Hospital  Hvidovre Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander K.","family":"Kj\u00e6r","sequence":"additional","affiliation":[{"name":"Unit of Virus, Lifestyle and Genes Danish Cancer Society Research Center  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise Grupe","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Pathology University Hospital of Zealand  Naestved Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Else Mejlgaard","family":"Madsen","sequence":"additional","affiliation":[{"name":"Department of Pathology Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia Margeth Villena","family":"Salinas","sequence":"additional","affiliation":[{"name":"Department of Pathology Aalborg University Hospital  Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Schledermann","sequence":"additional","affiliation":[{"name":"Department of Pathology Odense University Hospital, University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitte Hjelm","family":"Winberg","sequence":"additional","affiliation":[{"name":"Department of Pathology, Herlev Hospital University of Copenhagen  Herlev Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorthe","family":"\u00d8rnskov","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology Vejle Hospital, Lillebaelt Hospital  Vejle Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Waldstr\u00f8m","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology Vejle Hospital, Lillebaelt Hospital  Vejle Denmark"},{"name":"Institute of Regional Health Research University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne K.","family":"Kj\u00e6r","sequence":"additional","affiliation":[{"name":"Unit of Virus, Lifestyle and Genes Danish Cancer Society Research Center  Copenhagen Denmark"},{"name":"Department of Gynecology, Rigshospitalet University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2]]},"reference":[{"key":"e_1_2_12_2_1","volume-title":"Cancer Incidence in Five Continents, Vol. XI. 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