Clinical Utility of Human Papillomavirus Genotyping in Cervical Cancer Screening: A Systematic Review

Abstract

Objective: Thirteen human papillomavirus (HPV) genotypes are associated with the highest risk of cervical disease/cancer; however, the risk of disease progression and cancer is genotype dependent. The objective of this systematic review was to examine evidence for high-grade cervical intraepithelial neoplasia (≥CIN 3) risk discrimination using HPV genotyping.

Materials and methods: A systematic review of English and non-English articles through MEDLINE, Cochrane, clinicaltrials.gov, and abstracts presented at relevant professional society conferences were searched from 2000 to 2019. Search terms included: cervical cancer screening, HPV genotyping, CIN, HPV persistence, humans, and colposcopy; prospective, controlled trials, observational studies, and retrospective studies of residual specimens; evidence included HPV genotyping (beyond genotypes 16/18/45) results. Data were obtained independently by authors using predefined fields. Risk of bias was evaluated with a modified Newcastle-Ottawa Scale. The Grading of Recommendations, Assessment, Development and Evaluation methodology facilitated overall quality of evidence evaluation for risk estimation. The study protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42018091093). The primary outcome was CIN 3 or worse risk both at baseline and at different follow-up periods.

Results: Of 236 identified sources, 60 full texts were retrieved and 16 articles/sources were included. Risk of bias was deemed low; the overall quality of evidence for CIN 3 or worse risk with negative for intraepithelial lesions or malignancies or low-grade squamous intraepithelial cytology was assessed as moderate; that with atypical squamous cells-undetermined significance and "all cytology" was assessed as high. Clinical and methodological heterogeneity precluded meta-analysis. Human papillomavirus genotyping discriminated risk of CIN 3 or worse to a clinically significant degree, regardless of cytology result.

Conclusions: The evidence supports a clinical utility for HPV genotyping in risk discrimination during cervical cancer screening.

FIGURE 1

Cervical intraepithelial neoplasia 3 or worse risk values associated with individual HPV genotypes from previously described screening populations—regardless of cytology result. The x-axis represents time to follow-up in months or years (where indicated) and the y-axis represents increasing risk for CIN 3 or worse. Data were extracted from 7 articles that represent baseline results (Monsonego et al, 2015; Vaughan et al, 2018) and results at 36 months (Wheeler et al, 2014; Schiffman et al, 2016) 48 months (Naucler et al, 2007), 72 months (Kitchener et al, 2014), and 14 years (Smelov et al, 2015) following baseline in each of the respective studies. Trend lines are superimposed across time points from baseline to 14 years to help visualize the increasing risk associated with long-term HPV infection. Abbreviation: BL, baseline.

FIGURE 2

Individual genotype risk values in women with abnormal cytology. A–D, Cervical intraepithelial neoplasia 3 or worse risk values associated with individual HPV genotypes from previously described ASC-US/LSIL screening populations. In all panels, the x-axis represents time to follow-up in months and the y-axis represents CIN 3 or worse risk associated with individual HPV genotypes. A–C, The baseline values were obtained from Wright et al (2019); the 18-month values were obtained from Berkhof et al (2006); the 24-month values were obtained from Wheeler et al (2006). D, The 36-month values were obtained from Schiffman et al (2015). ^aPooled HPV 33/58 result. ^bPooled HPV 35/39/68 result. ^cPooled HPV 56/59/66 result.

FIGURE 3

Individual genotype risk values in women with abnormal cytology or from a colposcopy referral population. A–D, Relative risk ratios of individual genotypes to overall (any) HPV in women with abnormal baseline cytology or women referred to colposcopy after baseline screening. Baseline CIN 3 or worse risk values are shown from 3 prospective cervical cancer screening trials.^,, The populations shown here include any abnormal cytology in (E) and (F) (Monsonego et al, 2015), ASC-US or LSIL cytology in (G) (Wright et al, 2019); in (H), data were obtained from a colposcopy referral population (based on abnormal cytology or positive HPV status; Bonde et al, 2019). The risk ratios for each, individual genotypes, relative to the risk value for any HPV result, are plotted along the x-axis. The vertical, hashed line at x = 1 represents: individual genotypes risk value = risk value for any HPV result.

FIGURE 4

Cervical intraepithelial neoplasia 3 or worse risk values associated with individual HPV genotypes in women with NILM cytology from previously described screening populations. The x-axis represents time to follow-up in months or years (where indicated) and the y-axis represents increasing risk for CIN 3 or worse. Data were extracted from 8 articles that represent baseline results (Monsonego et al, 2015; Stoler et al, 2019) and results at 16 months (Schiffman et al, [JCM], 2015) 18 months (Berkhof et al, 2006), 36 months (Schiffman et al, 2016; Wheeler et al, 2014), 48 and 96 months (Thomsen et al, 2015), and 136 months (Kjaer et al, 2010) following baseline in each of the respective studies. Trend lines are superimposed across time points from baseline to 136 months to help visualize the increasing risk associated with long-term HPV infection. Abbreviation: BL, baseline.