Clinical human papillomavirus detection forecasts cervical cancer risk in women over 18 years of follow-up

Abstract

Purpose: To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus (HPV) DNA testing for cervical precancer and cancer risk prediction.

Methods: Cervicovaginal lavages collected from 19,512 women attending a health maintenance program were retrospectively tested for HPV using a clinical test. HPV positives were tested for HPV16 and HPV18 individually using a research test. A Papanicolaou (Pap) result classified as atypical squamous cells of undetermined significance (ASC-US) or more severe was considered abnormal. Women underwent follow-up prospectively with routine annual Pap testing up to 18 years. Cumulative incidence rates (CIRs) of ≥ grade 3 cervical intraepithelial neoplasia (CIN3+) or cancer for enrollment test results were calculated.

Results: A baseline negative HPV test provided greater reassurance against CIN3+ over the 18-year follow-up than a normal Pap (CIR, 0.90% v 1.27%). Although both baseline Pap and HPV tests predicted who would develop CIN3+ within the first 2 years of follow-up, only HPV testing predicted who would develop CIN3+ 10 to 18 years later (P = .004). HPV16- and HPV18-positive women with normal Pap were at elevated risk of CIN3+ compared with other HPV-positive women with normal Pap and were at similar risk of CIN3+ compared with women with a low-grade squamous intraepithelial Pap.

Conclusion: HPV testing to rule out cervical disease followed by Pap testing and possibly combined with the detection of HPV16 and HPV18 among HPV positives to identify those at immediate risk of CIN3+ would be an efficient algorithm for cervical cancer screening, especially in women age 30 years or older.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram for women enrolled onto the Portland Kaiser cohort in from 1989 to 1990. BL, baseline; CIN2+, cervical intraepithelial neoplasia grade 2 or more severe; CVL, cervicovaginal lavage; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; Pap, Papanicolaou.

Fig 2.

The risk of a diagnosis of (A) cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN2+) and (B) CIN grade 3 or more severe (CIN3+) after a baseline test for human papillomavirus (HPV) and by the clinical center Papanicolaou (Pap) test. High-risk HPV (HR-HPV) testing was categorized as positive or negative; Pap smears were categorized as atypical squamous cells of undetermined significance or more severe (ASC-US+) or as normal. Open symbols indicate statistically significant patient cases of CIN2+ or CIN3+ in the test positive (HR-HPV positive or ASC-US+) versus the corresponding test negative (HR-HPV negative or normal) in that year time interval. Years 16 to 18 of follow-up were collapsed into a single time bin labeled as year 16. The 18-year cumulative incidence ratios (CIRs) of CIN2+ for women with a baseline ASC-US+ Pap, normal Pap, HPV-positive test, and HPV-negative test were 13.92% (95% CI, 11.79% to 16.39%), 2.47% (95% CI, 2.17% to 2.82%), 11.46 (95% CI, 9.88% to 13.29%), and 1.85% (95% CI, 1.58% to 2.16%), respectively. The 18-year CIRs of CIN3+ for women with a baseline ASC-US+ Pap, normal Pap, HPV-positive test, and HPV-negative test were 6.41% (95% CI, 5.00% to 8.21%), 1.27% (95% CI, 1.05% to 1.53%), 5.98% (95% CI, 4.80% to 7.43%), and 0.90% (95% CI, 0.71% to 1.14%), respectively. HC2, Hybrid Capture 2.

Fig A1.

The percent positive (prevalence) by Hybrid Capture 2 (HC2) and Papanicolaou (Pap; atypical squamous cells of undetermined significance or more severe) with 95% CIs (indicated by vertical bars) by age group.