Evaluation of Human Papillomavirus Testing in Primary Screening for Cervical Abnormalities

Human Papillomavirus (HPV) DNA testing of women having Papanicolaou (Pap) smears showing atypical squamous cells of undetermined significance (ASCUS) has clinical usefulness. Whether HPV DNA testing alone is useful in primary screening remains to be determined.

In the current study, researchers evaluated the potential of HPV DNA testing for improving screening accuracy for detection of high-grade lesions (cervical intraepithelial neoplasia [CIN] grade 3) or cancer among a population of women of reproductive age and to see whether the level of accuracy varied by age. Two different assays for HPV DNA testing were compared: a polymerase chain reaction (PCR)-based assay and a liquid-based DNA-RNA hybridization capture with signal amplification assay.

Between December 1997 and October 2000, 4,075 women who attended Planned Parenthood clinics in Washington state were screened simultaneously using thin-layer Pap and HPV DNA testing by the PCR-based method and by the liquid-based (signal amplification) assay. Women were referred for colposcopy and biopsy if they had ASCUS, atypical glandular cells of undetermined significance (AGUS), low-grade squamous intraepithelial lesion (LSIL), or high-grade squamous intraepithelial lesion (HSIL) or higher on thin-layer Pap; or a positive PCR test result for high-risk HPV types. Additionally, a random sample of women with negative screening test results was referred for colposcopy. Based on individual and combined thin-layer Pap, HPV PCR, and HPV signal amplification test results from the screening and the colposcopy visits, seven colposcopy triage strategies were defined and evaluated.

The estimated prevalence of CIN 3 or higher was 3.2 percent. The sensitivity (95 CI) of thin-layer Pap with a result greater than or equal to ASCUS for identifying women with CIN three or higher was only 61.3 percent (48.5-70.9 percent), compared with 88.2 percent (78.9-93.8 percent) for HPV testing by PCR and 90.8 percent (83.1-95.8 percent) by signal amplification. Differences in specificities were also observed: 82.4 percent (81.8-83.1 percent) for thin-layer Pap with a result greater than or equal to ASCUS, 78.8 percent (77.9-79.7 percent) for PCR, and 72.6 percent (69.4-75 percent) for signal amplification.

Compared with referral for colposcopy of all women with ASCUS or higher, signal amplification testing of women with ASCUS and referral of those with a positive result was about as sensitive (61.3 percent versus 60.3 percent, respectively) and significantly more specific (82.4 percent versus 88.9 percent, respectively). The strategy requiring repeat positive PCR tests on two visits had a sensitivity of 84.2 percent (75.3-91 percent) and a specificity of 86.2 percent (85.1-87.3 percent). All tests were more specific and less sensitive in older (greater than or equal to 30 years) women compared to younger women, perhaps due to the age-related shifting of the squamocolumnar junction from the ectocervix to the endocervix.

Overall, more women were positive for high-risk HPV DNA by signal amplification (27.4 percent) than by PCR (18.3 percent). Although a similar proportion of women with HSIL were positive by signal amplification and PCR, more women with LSIL, ASCUS, or normal cytology results were positive by signal amplification than by PCR. One explanation for this difference is that the signal amplification test for high-risk HPV types will detect the low- and indeterminate-risk types that are frequently found in samples from women with normal, ASCUS, or LSIL Pap results, but not in samples from women with HSIL. Limiting HPV testing to women ages 30 to 50 resulted in improved specificity.

Comparing screening by thin-layer Pap smear to screening by HPV DNA tests for detection of CIN 3 or higher, HPV DNA testing was significantly more sensitive, but significantly less specific, than thin-layer Pap testing. Compared with referring all women with abnormal smear results for colposcopy, strategies that incorporated HPV DNA testing of ASCUS resulted in significant improvements in specificity, with only slight decreases in sensitivity. Requiring two positive PCR tests for HPV DNA was both more sensitive and specific than referral of women with abnormal smear results for colposcopy. In some settings, particularly where screening intervals are long or haphazard, screening for HPV DNA may be a reasonable alternative to cytology-based screening of reproductive-age women, the authors concluded.

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