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

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 typespecific 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. K E Y W O R D S cervical cancer, cervical intraepithelial neoplasia, human papillomavirus, prospective, risk 1 | INTRODUCTION Tests for the human papillomavirus (HPV) are increasingly replacing cytology as the primary screening test for cervical cancer in many countries, such as the United States (US), Australia and England. 1-3 Clinical trials have demonstrated that HPV tests are more sensitive and have a higher long-term negative predictive value than cytology. 4,5 However, these trials have also shown that more screenpositive women will require follow-up and management with HPV testing than with cytology. 6,7 The majority of HPV-positive women are cytology negative. 8,9 For example, 65% of women in the Australian screening program who are positive for any oncogenic HPV do not have any cervical abnormality. 10 While these women are at a lower risk of progressing to precancerous lesions than women with Abbreviations: CIN, cervical intraepithelial neoplasia; HR-HPV, high-risk human papillomavirus; HPV, human papillomavirus; HC2, hybrid capture 2; SE, Standard error; US, United States.

Type-specific Distribution of Cervical hrHPV Infection and the Association with Cytological and Histological Results in a Large Population-based Cervical Cancer Screening Program: Baseline and 3-year Longitudinal Data

“…The prevalence of HPV-positive/normal cytology result was reported ranged from 1.9% to 9.8% (Here was 7.5%) 10 , 18 , 27 . This is one of the most common positive screening results encountered in daily practice 28 and more than twice that of HPV-positive/abnormal cytology results (Here was 3.6%) 7 . The HPV-positive women with normal cytology should be followed by either repeated co-testing within 12 months or immediate colposcopy for positive genotyping of HPV16 alone (11.5%, 81/707) or HPV16/18 (17.5%, 124/707) according to the guidelines 7 , which reduces the burden of follow-up and mental stress of women involved.…”

Comments on “Cumulative risk of cervical intraepithelial neoplasia for women with normal cytology but positive for human papillomavirus: Systematic review and meta‐analysis”

“…The authors declare no conflict of interest. Rama Jayaraj 1,2 Peter Shaw 1,3 Chellan Kumarasamy 4 Sameep S. Shetty 5,6 1 Department of Artificial Intelligence, Nanjing University of Information…”

Cervical Neoplasia: Papillomavirus Infection and Resistance to Anti Tumor Immunity

“…Intraepithelial neoplasia of the cervix is associated with the persistence of Papillomavirus infection within epithelial cells of the cervix [1][2][3]. This persistence of Papillomavirus infection is due to several mechanisms [4][5][6][7] and causes morphological changes in the cells of the cervix [8].…”