Role of Screening History in Clinical Meaning and Optimal Management of Positive Cervical Screening Results

Abstract

Background: Cervical cancer is caused by persistent human papillomavirus (HPV) infection. US consensus management guidelines for a positive cervical screening result typically focus on the current screening result only. A negative testing history may alter risk of the following positive screening results, caused by a new HPV infection, and therefore its optimal management.

Methods: Women ages 30 years and older were screened with triennial HPV and cytology co-testing at Kaiser Permanente Northern California from 2003 to 2014. We estimated the subsequent 5-year risks of cervical intraepithelial neoplasia grade 3 or more severe diagnoses (CIN3+) in a cohort of 1 156 387 women following abnormal (atypical squamous cells of undetermined significance [ASC-US] or worse) cytology and/or positive HPV testing, when the test result followed 0 (n = 990 013), 1 (n = 543 986), 2 (n = 245 974), or 3 (n = 79 946) consecutive negative co-test(s). All statistical tests were two-sided.

Results: Following 0-3 successive negative co-tests, 5-year CIN3+ risks following a positive HPV test decreased progressively from 7.2% (95% CI = 7.0% to 7.4%) to 1.5% (95% CI = 0.7% to 3.4%) (Ptrend < .001). Similarly, risks following an abnormal (ASC-US or worse) cytology result decreased from 6.6% (95% CI = 6.4% to 6.9%) to 1.1% (95% CI = 0.5% to 2.3%) (Ptrend < .001). Risks following low-grade squamous intraepithelial lesion, the risk threshold for referral to colposcopy in the United States, decreased from 5.2% (95% CI = 4.7% to 5.7%) to 0.9% (95% CI = 0.2% to 4.3%). Risks following high-grade squamous intraepithelial lesion or more severe, a specific marker for the presence of precancerous lesions, decreased from 50.0% (95% CI = 47.5% to 52.5%) to 10.0% (95% CI = 2.6% to 34.4%).

Conclusions: Following one or more sequential antecedent, documented negative co-tests or HPV tests, women with HPV-positive ASC-US or low-grade squamous intraepithelial lesion might have sufficiently low CIN3+ risk that they do not need colposcopy referral and might instead undergo 6-12-month surveillance for evidence of higher risk before being referred to colposcopy.

Figure 1.

A diagram of the inclusions/exclusions by round of screening. A positive co-test was a positive HPV test and/or a positive cytology (ASC-US or more severe cytology) and a negative co-test was a negative HPV test and negative cytology. The gray-shaded boxes indicate the study groups of the first, second, third, and fourth positive co-tests following 0–3 consecutive negative co-tests, respectively. AGC = atypical glandular cells; ASC-H = atypical squamous cells, cannot rule out HSIL; ASC-US = atypical squamous cells of undetermined significance; CIN2 = cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+); HPV = human papillomavirus; HSIL+ = high-grade squamous intraepithelial lesion (HSIL) or more severe; LSIL = low-grade squamous intraepithelial lesion.

Figure 2.

Diagnostic yield of CIN3+ by round of screening. Five-year cumulative detection (risk) of cervical intraepithelial neoplasia grade 3 (CIN3) or more severe diagnoses CIN3+, irrespective of screening result, for the first, second, third, and fourth co-test, following 0–3 negative co-tests. Bars show 95% CIs.