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

Background
High-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 findings
In 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.
Conclusions
In 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.

背景
高危型人乳头瘤病毒（high-risk human papillomavirus, hrHPV）感染已被确立为浸润性宫颈癌（invasive cervical cancer, ICC）的主要病因。然而，肿瘤组织中的hrHPV状态是否与浸润性宫颈癌的后续预后相关，目前仍存在争议。本研究旨在利用全国登记数据与全面的人乳头瘤病毒（human papillomavirus, HPV）基因分型结果，评估肿瘤hrHPV状态与浸润性宫颈癌预后之间的关联。

方法与研究结果
本项全国性基于人群的队列研究纳入了2002年至2011年期间瑞典境内确诊的所有浸润性宫颈癌病例（共4254例经确认的病例），我们调取了所有存档的福尔马林固定石蜡包埋组织块并开展HPV基因分型检测。25家病理生物样本库中有20家同意参与本研究，最终获得2845例具备有效HPV检测结果的确诊病例。研究对象自癌症确诊之日起被前瞻性随访至2015年12月31日、迁出瑞典或死亡，以最先发生的事件为准。本研究的主要暴露因素为肿瘤hrHPV状态，分为hrHPV阳性与hrHPV阴性两类；主要结局为截至2015年12月31日的全因死亡率。我们计算了五年相对生存率（relative survival ratios, RSRs），并采用泊松回归（Poisson regression）估计了带有95%置信区间（confidence intervals, CIs）的超额风险比（excess hazard ratios, EHRs），校正因素包括教育程度、确诊后时长、确诊年龄及国际妇产科联盟（International Federation of Gynecology and Obstetrics, FIGO）分期等临床特征。
在纳入的2845例病例中，2293例（80.6%）检测到hrHPV；平均6.2年的随访期间，共发生1131例（39.8%）死亡。大部分浸润性宫颈癌病例的确诊年龄为30~59岁（57.5%），分期为IB期（40.7%）。hrHPV阳性与筛查检出肿瘤、年轻年龄、高学历水平及确诊时处于早期分期显著相关（p<0.001）。与普通女性人群相比，hrHPV阳性病例的五年相对生存率为0.74（95%CI 0.72~0.76），hrHPV阴性病例为0.54（95%CI 0.50~0.59）；粗超额风险比为0.45（95%CI 0.38~0.52），校正后超额风险比为0.61（95%CI 0.52~0.71）。在29岁以上的各年龄组及IA期以上的各FIGO分期中，hrHPV阳性肿瘤患者的全因死亡风险（以EHR衡量）持续且具有统计学显著性的降低。无论病例的临床、组织学及教育特征如何，hrHPV状态对预后的差异均具有高度稳健性。本研究的主要局限性在于，除教育程度外，无法对生活方式因素或其他未测量的混杂因素进行校正。

结论
本研究显示，携带hrHPV阳性宫颈肿瘤的女性，其预后显著优于hrHPV阴性的女性。hrHPV似乎可作为宫颈癌预后良好的生物标志物，其关联独立于年龄、FIGO分期及组织学类型，补充了已有既定预后因素的信息。目前尚不清楚无法检测到肿瘤hrHPV与预后显著更差之间的潜在生物学机制，需开展进一步研究。