title: Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma has a worse prognosis than HPV-associated disease: a retrospective cohort study.
abstract: OBJECTIVE
  Vulvar squamous cell carcinoma (VSCC) can be subdivided by human papillomavirus (HPV) status into two clinicopathological entities. Studies on the prognostic significance of HPV in VSCC are discordant.
  
  
  RESULTS
  We performed a retrospective analysis of overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS) in 217 patients with VSCC. Cases were extracted from an era of more aggressive en-bloc radical dissections (1985-95) and more localized radical surgery through separate vulvar and groin excisions (1996-2005). p16 immunohistochemistry was used as a surrogate for HPV status. HPV status could be determined in 197 tumours, 118 HPV-independent and 79 HPV-associated tumours. Patients with HPV-associated tumours were younger (mean 58.8 versus 71.6 years for HPV-independent tumours, P < 0.0001) and more likely to have prior abnormal cervical cytology (41.1 versus 5.6% for HPV-independent tumours, P < 0.0001). In univariable analysis, patients with HPV-associated tumours had superior PFS [hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.18-0.70], DSS (HR: 0.19, 95% CI: 0.08-0.41) and OS (HR: 0.35, 95% CI: 0.21-0.59). This was driven by worse outcomes (PFS, DSS and OS) for patients with HPV-independent tumours compared with HPV-associated tumours who underwent surgery after 1995. After adjusting for age and stage in multivariable analysis, patients with HPV-associated tumours showed superior PFS (HR: 0.25, 95% CI: 0.07-0.77) and DSS (HR: 0.21, 95% CI: 0.04-0.78).
  
  
  CONCLUSIONS
  VSCC can be stratified into two prognostically different diseases based on p16 immunostaining. HPV status was associated only with prognosis in the cohort that underwent surgery after 1995, suggesting that more conservative surgery may have led to worse outcomes for patients with HPV-independent tumours.
authors.affiliation: Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Samuel C Y
authors.initials: SCY
authors.lastname: Leung
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dianne
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Aline
authors.initials: A
authors.lastname: Talhouk
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Anthony N
authors.identifier: http://orcid.org/0000-0003-2924-1126
authors.initials: AN
authors.lastname: Karnezis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology* / Q000821:virology*; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D014846:Vulvar Neoplasms / Q000401:mortality / Q000473:pathology* / Q000821:virology*
keywords: carcinoma; cyclin-dependent kinase inhibitor p16 (D019941); immunohistochemistry (D007150); papillomaviridae (D027383); prognosis (D011379); squamous cell (D002294); vulvar neoplasms (D014846)