High-risk human papillomavirus status and prognosis in invasive cervical cancer: A nationwide cohort study

Abstract

BackgroundHigh-risk human papillomavirus (hrHPV) infection is established as the major cause of invasive cervical cancer (ICC). However, whether hrHPV status in the tumor is associated with subsequent prognosis of ICC is controversial. We aim to evaluate the association between tumor hrHPV status and ICC prognosis using national registers and comprehensive human papillomavirus (HPV) genotyping.Methods and findingsIn this nationwide population-based cohort study, we identified all ICC diagnosed in Sweden during the years 2002–2011 (4,254 confirmed cases), requested all archival formalin-fixed paraffin-embedded blocks, and performed HPV genotyping. Twenty out of 25 pathology biobanks agreed to the study, yielding a total of 2,845 confirmed cases with valid HPV results. Cases were prospectively followed up from date of cancer diagnosis to 31 December 2015, migration from Sweden, or death, whichever occurred first. The main exposure was tumor hrHPV status classified as hrHPV-positive and hrHPV-negative. The primary outcome was all-cause mortality by 31 December 2015. Five-year relative survival ratios (RSRs) were calculated, and excess hazard ratios (EHRs) with 95% confidence intervals (CIs) were estimated using Poisson regression, adjusting for education, time since cancer diagnosis, and clinical factors including age at cancer diagnosis and International Federation of Gynecology and Obstetrics (FIGO) stage. Of the 2,845 included cases, hrHPV was detected in 2,293 (80.6%), and we observed 1,131 (39.8%) deaths during an average of 6.2 years follow-up. The majority of ICC cases were diagnosed at age 30–59 years (57.5%) and classified as stage IB (40.7%). hrHPV positivity was significantly associated with screen-detected tumors, young age, high education level, and early stage at diagnosis (p < 0.001). The 5-year RSR compared to the general female population was 0.74 (95% CI 0.72–0.76) for hrHPV-positive cases and 0.54 (95% CI 0.50–0.59) for hrHPV-negative cases, yielding a crude EHR of 0.45 (95% CI 0.38–0.52) and an adjusted EHR of 0.61 (95% CI 0.52–0.71). Risk of all-cause mortality as measured by EHR was consistently and statistically significantly lower for cases with hrHPV-positive tumors for each age group above 29 years and each FIGO stage above IA. The difference in prognosis by hrHPV status was highly robust, regardless of the clinical, histological, and educational characteristics of the cases. The main limitation was that, except for education, we were not able to adjust for lifestyle factors or other unmeasured confounders.ConclusionsIn this study, women with hrHPV-positive cervical tumors had a substantially better prognosis than women with hrHPV-negative tumors. hrHPV appears to be a biomarker for better prognosis in cervical cancer independent of age, FIGO stage, and histological type, extending information from already established prognostic factors. The underlying biological mechanisms relating lack of detectable tumor hrHPV to considerably worse prognosis are not known and should be further investigated.

HPV-prevalence in elderly women in Denmark

“…It is an attractive idea that another screen at 75 or 80 years in those who have not had 3 normal prior to 65 years might detect the interval cancers from persistent HPV. It should be noted, however, that an HPV infection may become undetectable at a late stage of the oncogenic process [22]; an observation supported by our data where the old age peak in cervical cancer incidence was not reflected in the HPV-prevalence pattern. At present, Danish women exit the regular screening program at age 60-64 with an HPV-test.…”

Understanding the proportion of cervical cancers attributable to HPV

“…This correlation between age and the likelihood of detecting HPV in cervical cancer is consistent with other international studies . In a 2018 analysis of 693 cervical cancers in the United States, HPV‐negative cancers were more likely to be poorly differentiated and to be metastatic at presentation, and were associated with poorer survival .…”

“…In a 2018 analysis of 693 cervical cancers in the United States, HPV‐negative cancers were more likely to be poorly differentiated and to be metastatic at presentation, and were associated with poorer survival . Similarly, a nationwide population‐based study in Sweden found poorer survival rates in HPV‐negative cancers in 2845 cervical cancers diagnosed at older ages, of a later stage at diagnosis and associated with poorer educational status, and were less likely to be detected through cervical cytology screening …”

Age-specific HPV type distribution in high-grade cervical disease in screened and unvaccinated women

“…Our findings should be carefully considered when applying HPV16/18 genotyping as a triage testonly approximately a third of HSIL+ in the older women was attributed to these types. Furthermore, in a large retrospective study approximately 20% of invasive cervical cancers were HPV negative [41], while 10% HSIL+ lesions in the oldest age group were also hrHPV negative here. These findings should be taken into consideration when shifting to HPVbased screening with the majority of screening-age population still being unvaccinated.…”