Date Published: October 1, 2018
Publisher: Public Library of Science
Author(s): Jiayao Lei, Alexander Ploner, Camilla Lagheden, Carina Eklund, Sara Nordqvist Kleppe, Bengt Andrae, K. Miriam Elfström, Joakim Dillner, Pär Sparén, Karin Sundström, Wei Zheng
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.
Partial Text: Cervical cancer is a major cause of morbidity and mortality in women worldwide. The role of high-risk human papillomavirus (hrHPV) in the development of invasive cervical cancer (ICC) is well established . Persistent infection with hrHPV in the cervical epithelium, especially types HPV16 and HPV18, is known to be associated with higher probability of progression to cervical intraepithelial lesion grade 3 (CIN3) and ICC compared to being negative for such infection . However, once a cancer has occurred, the extent to which hrHPV status in the actual invasive tumor tissue may be related to prognosis of ICC has been found to be variable between studies [3–9]. This is despite the fact that for oropharyngeal cancer, another tumor etiologically linked to hrHPV, there is consensus that presence of hrHPV in the tumor marks better prognosis [10,11].
In this large, nationwide study including 2,845 HPV-genotyped cervical cancer cases occurring over 10 years, we found that women with hrHPV-positive ICC had a statistically significant 39% lower excess mortality compared to women with hrHPV-negative tumors. The substantial survival difference by hrHPV status observed already within 2–3 years after ICC diagnosis illustrates this biomarker’s potential for distinguishing ICC associated with higher mortality. The difference in prognosis was highly robust regardless of the clinical, histological, and educational characteristics of the cases.
Since methods of HPV analysis have been substantially improved in recent years, and have also been implemented in cervical screening, hrHPV status in tumors may represent a routinely available biomarker for cervical cancer prognosis of potentially substantial value. We observed that women with hrHPV-positive cervical tumors had a substantially better prognosis than women with hrHPV-negative tumors. We thus posit that hrHPV appears to be a biomarker for ICC prognosis, extending information from the already established prognostic factors age, clinical stage, and histological type. The underlying biological mechanisms relating lack of detectable tumor hrHPV to considerably worse prognosis are not known and should be further investigated.