Cumulative risk of cervical intraepithelial neoplasia for women with normal cytology but positive for human papillomavirus: Systematic review and meta-analysis

Talía Malagón, Karena D Volesky, Sheila Bouten, Claudie Laprise, Mariam El-Zein, Eduardo L Franco, Talía Malagón, Karena D Volesky, Sheila Bouten, Claudie Laprise, Mariam El-Zein, Eduardo L Franco

Abstract

Most women positive for human papillomavirus (HPV) are cytology normal. The optimal screen-management of these women is unclear given their risk of developing precancer. We performed a systematic review and meta-analysis of progression rates to precancer and cancer for HPV-positive, cytology normal women. We searched MEDLINE, EMBASE and Scopus for prospective studies measuring the cumulative incidence of precancer and cervical cancer in HPV-positive, cytology/histology normal women. Record screening was performed independently by two reviewers. We modeled the cumulative incidence over time using a multilevel random-effects meta-regression model. We used the model to predict HPV type-specific risks of precancer and cancer over follow-up. Data from 162 unique records were used in our analysis. The average incidence rate of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in high-risk HPV positive but cytology/histology normal women was 1.0 per 100 women-years (95% CI: 1.0-1.1). This corresponds to an average cumulative risk at 1, 3 and 5 years of 2.1% (95% prediction interval 0.0-9.5), 4.3% (95% prediction interval 0.0-11.5) and 6.4% (95% prediction interval 0.0-13.5). HPV type was a strong predictor of the risk of oncogenic progression. There was substantial heterogeneity in the background precancer risk across studies (P-value < .0001). Our HPV type-specific progression risk estimates can help inform risk-based cervical cancer screening guidelines for HPV-positive women. However, precancer and cervical cancer risks are highly variable and may not be generalizable between populations.

Keywords: cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; prospective; risk.

© 2020 UICC.

References

REFERENCES

    1. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121:829-846.
    1. Cancer Council Australia Cervical Cancer Screening Guidelines Working Party. National Cervical Screening Program: Guidelines for the management of screen-detected abnormalities, screening in specific populations and investigation of abnormal vaginal bleeding. Sydney: Cancer Council Australia; 2017.
    1. Public Health England. Cervical screening: implementation guide for primary HPV screening. London: Public Health England; 2019.
    1. Koliopoulos G, Nyaga VN, Santesso N, et al. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst Rev. 2017;8:CD008587.
    1. Ronco G, Dillner J, Elfström KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. The Lancet. 2014;383:524-532.
    1. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136:189-197.
    1. Ogilvie GS, van Niekerk D, Krajden M, et al. Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial. JAMA. 2018;320:43-52.
    1. Dijkstra MG, van Niekerk D, Rijkaart DC, et al. Primary hrHPV DNA testing in cervical cancer screening: how to manage screen-positive women? A POBASCAM trial substudy. Cancer Epidemiol Biomarkers Prev. 2014;23:55-63.
    1. Isidean SD, Mayrand MH, Ramanakumar AV, et al. Comparison of triage strategies for HPV-positive women: Canadian cervical cancer screening trial results. Cancer Epidemiol Biomarkers Prev. 2017;26:923-929.
    1. Machalek DA, Roberts JM, Garland SM, et al. Routine cervical screening by primary HPV testing: early findings in the renewed National Cervical Screening Program. Med J Aust. 2019;211:113-119.
    1. Katki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 3+ and cervical cancer among women who test pap-negative but are HPV-positive. J Low Genit Tract Dis. 2013;17:S56-S63.
    1. Polman NJ, Snijders PJF, Kenter GG, Berkhof J, Meijer C. HPV-based cervical screening: rationale, expectations and future perspectives of the new Dutch screening programme. Prev Med. 2019;119:108-117.
    1. Demarco M, Lorey TS, Fetterman B, et al. Risks of CIN 2+, CIN 3+, and cancer by cytology and human papillomavirus status: the Foundation of Risk-Based Cervical Screening Guidelines. J Low Genit Tract Dis. 2017;21:261-267.
    1. American Society for Colposcopy and Cervical Pathology. ASCCP Risk-Based Management Consensus Guidelines: New Recommendations for Public Comment. Rockville, MD: ASCCP; 2019.
    1. Cantor SB, Atkinson EN, Cardenas-Turanzas M, Benedet JL, Follen M, MacAulay C. Natural history of cervical intraepithelial neoplasia: a meta-analysis. Acta Cytol. 2005;49:405-415.
    1. Insinga RP, Dasbach EJ, Elbasha EH. Epidemiologic natural history and clinical management of human papillomavirus (HPV) disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model. BMC Infect Dis. 2009;9:119.
    1. Ting J, Rositch AF, Taylor SM, et al. Worldwide incidence of cervical lesions: a systematic review. Epidemiol Infect. 2015;143:225-241.
    1. Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102:1478-1488.
    1. Schiffman M, Glass AG, Wentzensen N, et al. A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser cohort study. Cancer Epidemiol Biomarkers Prev. 2011;20:1398-1409.
    1. Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012;13:78-88.
    1. Ronco G, Giorgi-Rossi P, Carozzi F, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 2010;11:249-257.
    1. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016;5:210.
    1. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1-48.
    1. Kirkwood B, Sterne J. Essential Medical Statistics. Hoboken, NJ: Wiley; 2003.
    1. Young DA, Zerbe GO, Hay WW Jr. Fieller's theorem, Scheffe simultaneous confidence intervals, and ratios of parameters of linear and nonlinear mixed-effects models. Biometrics. 1997;53:838-847.
    1. Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:d549.
    1. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101-129.
    1. Cook RD. Detection of influential observation in linear regression. Dent Tech. 1977;19:15-18.
    1. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12:663-672.
    1. Schiffman M, Hyun N, Raine-Bennett TR, et al. A cohort study of cervical screening using partial HPV typing and cytology triage. Int J Cancer. 2016;139:2606-2615.
    1. Wheeler CM, Hunt WC, Cuzick J, Langsfeld E, Robertson M, Castle PE. The influence of type-specific human papillomavirus infections on the detection of cervical precancer and cancer: a population-based study of opportunistic cervical screening in the United States. Int J Cancer. 2014;135:624-634.
    1. Chen H-C, Schiffman M, Lin C-Y, et al. Persistence of type-specific human papillomavirus infection and increased long-term risk of cervical cancer. J Natl Cancer Inst. 2011;103:1387-1396.
    1. Bae J, Seo S-S, Park Y-S, et al. Natural history of persistent high-risk human papillomavirus infections in Korean women. Gynecol Oncol. 2009;115:75-80.
    1. Thomsen LT, Frederiksen K, Munk C, Junge J, Iftner T, Kjaer SK. Long-term risk of cervical intraepithelial neoplasia grade 3 or worse according to high-risk human papillomavirus genotype and semi-quantitative viral load among 33,288 women with normal cervical cytology. Int J Cancer. 2015;137:193-203.
    1. Dijkstra MG, van Zummeren M, Rozendaal L, et al. Safety of extending screening intervals beyond five years in cervical screening programmes with testing for high risk human papillomavirus: 14 year follow-up of population based randomised cohort in The Netherlands. BMJ (Clin Res Ed). 2016;355:i4924.
    1. Hildesheim A, Gonzalez P, Kreimer AR, et al. Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment. Am J Obstet Gynecol. 2016;215:212.e1-e15.
    1. Guan P, Howell-Jones R, Li N, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer. 2012;131:2349-2359.
    1. van de Velde N, Brisson M, Boily MC. Modeling human papillomavirus vaccine effectiveness: quantifying the impact of parameter uncertainty. Am J Epidemiol. 2007;165:762-775.
    1. Kim JJ, Burger EA, Regan C, Sy S. Screening for cervical cancer in primary care: a decision analysis for the US preventive services task ForceUSPSTF modeling study: screening for cervical cancer in primary CareUSPSTF modeling study: screening for cervical cancer in primary care. JAMA. 2018;320:706-714.
    1. Lew JB, Simms KT, Smith MA, et al. Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program. Lancet Public Health. 2017;2:e96-e107.
    1. Landy R, Cheung LC, Schiffman M, et al. Challenges in risk estimation using routinely collected clinical data: the example of estimating cervical cancer risks from electronic health-records. Prev Med. 2018;111:429-435.
    1. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072-1079.
    1. Gage JC, Hunt WC, Schiffman M, et al. Similar risk patterns after cervical screening in two large U.S. populations: Implications for Clinical Guidelines. Obstet Gynecol. 2016;128:1248-1257.
    1. Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754.
    1. Cuzick J, Clavel C, Petry KU, et al. Overview of the European and north American studies on HPV testing in primary cervical cancer screening. Int J Cancer. 2006;119:1095-1101.
    1. Mustafa RA, Santesso N, Khatib R, et al. Systematic reviews and meta-analyses of the accuracy of HPV tests, visual inspection with acetic acid, cytology, and colposcopy. Int J Gynaecol Obstet. 2016;132:259-265.

Source: PubMed

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