Time trends in the incidence and survival of vaginal squamous cell carcinoma and high-grade vaginal intraepithelial neoplasia in Denmark - A nationwide population-based study.

OBJECTIVE: To describe trends in incidence of high-grade vaginal intraepithelial neoplasia (VaIN) and vaginal squamous cell carcinoma (SCC) in Denmark. For vaginal SCC, we also examine 5-year relative survival and mortality. METHODS: All high-grade VaIN cases diagnosed 1997-2017 and vaginal SCCs during 1978-2017 were identified in two high-quality nationwide registers. Age-standardized incidence rates and average annual percentage change (AAPC) were assessed. For vaginal SCC, 5-year relative survival was calculated, and Cox regression was applied to study the effect of selected characteristics on mortality. RESULTS: Altogether, 831 cases of high-grade VaIN and 721 vaginal SCCs were identified. The age-standardized incidence rate of high-grade VaIN showed no clear trend over time. However, when we stratified by age and divided the study period according to HPV vaccine licensure in Denmark (2006), the incidence of high-grade VaIN decreased significantly by 15.6% per year (95% CI: -23.2, -7.3%) after 2007 onwards among the youngest women (<30 years). For vaginal SCC, the incidence decreased from 0.5 (1978-1982) to 0.3 (2013-2017) per 100,000 woman-years. The 5-year relative survival improved over time and was 67.9% (95% CI: 54.9, 84.1%) in the most recent time period. Mortality was significantly associated with calendar year, age, and stage at diagnosis. CONCLUSIONS: The overall incidence of high-grade VaIN showed no clear trend over time, but a significant decline was observed in women younger than 30 years after HPV vaccine licensure. The incidence of vaginal SCC was reduced by approximately 50% and survival after vaginal SCC improved over time.

Risk of vulvar, vaginal and anal high-grade intraepithelial neoplasia and cancer according to cervical human papillomavirus (HPV) status: A population-based prospective cohort study.

OBJECTIVES: All cervical cancers and some vulvar, vaginal and anal cancers are caused by high-risk human papillomavirus (hrHPV). However, little is known about the association between cervical HPV infection and subsequent intraepithelial neoplasia and cancer at other anogenital sites. In this prospective cohort study, we estimated the risk of vulvar, vaginal and anal intraepithelial neoplasia grade 2/3 or cancer (VIN2+, VaIN2+, AIN2+) according to cervical hrHPV status. METHODS: Liquid-based cervical cytology samples were collected from 40,399 women screened against cervical cancer in Copenhagen, Denmark, during 2002-2005. Samples were tested for hrHPV using Hybrid Capture 2 (HC2) and genotyped using INNO-LiPA. We linked the cohort with Danish nationwide registries to identify cases of VIN2+, VaIN2+ and AIN2+ during up to 15 years of follow-up. We estimated age-adjusted hazard ratios (HRs) using Cox regression and cumulative incidences using Aalen-Johansen's estimator. RESULTS: Women with cervical HPV16 infection had increased hazard of VIN2+ (HR = 2.6; 95% confidence interval [CI], 1.2-5.5), VaIN2+ (HR = 23.5; 95% CI, 6.8-81.6) and AIN2+ (HR = 3.7; 95% CI, 1.1-12.2) compared with HC2 negative women. Women with other hrHPV types than HPV16 also had increased hazard of VaIN2+ (HR = 7.1; 95% CI, 2.3-22.3) and a borderline statistically significantly increased risk of AIN2+ (HR = 2.2; 95% CI, 0.9-4.9) compared with HC2 negative women. The 10-year cumulative incidences of VIN2+, VaIN2+ and AIN2+ in women with cervical HPV16 were 0.3% (95% CI, 0.2%-0.7%), 0.2% (95% CI, 0.1%-0.5%) and 0.1% (95 CI, 0.0%-0.4%). CONCLUSIONS: Cervical HPV16 infection is associated with increased risk of VIN2+, VaIN2+ and AIN2+.

Human papillomavirus and p16 in squamous cell carcinoma and intraepithelial neoplasia of the vagina.

We estimated the overall and type-specific prevalence of human papillomavirus (HPV) and p16 overexpression in vaginal cancer and vaginal intraepithelial neoplasia (VaIN). We conducted a systematic search of PubMed, Embase and Cochrane Library to identify studies published between 1986 and 2017 using PCR-based or Hybrid Capture 2 tests to evaluate the presence of HPV DNA and/or using any method to detect p16 overexpression in VaIN, vaginal squamous cell carcinoma (VaSCC), or other types of vaginal cancer. Applying a random effects model, we estimated the pooled prevalence of HPV and p16 overexpression along with 95% confidence intervals (CIs). The I2 statistic was used to assess heterogeneity. We included 26 studies, reporting HPV prevalence and six studies evaluating p16 overexpression. The pooled HPV prevalences in VaSCC (n = 593) and VaIN (n = 1,374) were 66.7% (95% CI = 54.7-77.8) and 85.2% (95% CI = 78.2-91.0), respectively. Substantial inter-study heterogeneity was observed, and analyses stratified on geographic region, type of tissue, HPV detection method or PCR primer type did not fully explain the observed heterogeneity. The most predominant HPV type among the HPV positive VaSCC and VaIN cases was HPV16, followed by HPV33, and HPV45 (in VaIN) and HPV18, and HPV33 (in VaSCC). In pooled analyses, 89.9% (95% CI = 81.7-94.6) of HPV positive and 38.9% (95% CI = 0.9-90.0) of HPV negative vaginal cancers were positive for p16 overexpression. Our findings suggest that vaccination against HPV might prevent a substantial proportion of vaginal neoplasia and highlight the need for further studies of the possible clinical value of p16 testing in these patients.