Triage of women with ASCUS and LSIL on Pap smear reports: management by repeat Pap smear, HPV DNA testing, or colposcopy? - atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion, human papillomavirus

Journal of Family Practice, Feb, 1998 by Daron G. Ferris, Thomas C. Wright, Jr., Mark S. Litaker, Ralph M. Richart, Attila T. Lorincz, Xiao-Wei Sun, Lynn Borgatta, Henry Buck, Larry Kramer, Richard Rubin

BACKGROUND. The purpose of this study was to determine the efficacy of a repeat Papanicolaou (Pap) smear and the Hybrid Capture tube-based (HCT) HPV DNA test for detecting cervical intraepithelial neoplasia (CIN) grade 2 or 3 in women with recent atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Pap smear reports.

METHODS. Women with a recent Pap smear report of ASCUS (n=169) or LSIL (n=110) had a repeat Pap smear, sampling of the cervix for HCT HPV DNA assay and a colposcopy examination. Data were evaluated using three different triage thresholds for colposcopy examination: a repeat Pap smear of persistent ASCUS or more severe dysplasia, a finding of persistent LSIL or more severe dysplasia, and a carcinogenic HPV test result.

RESULTS. The sensitivity, specificity, and positive and negative predictive values for detecting CIN 2/3 were 70%, 45%, 7%, and 96% for a repeat Pap smear using an ASCUS-positive threshold and 20%, 86%, 8%, and 94% for a repeat Pap smear using an LSIL-positive threshold, respectively, when women with an initial ASCUS Pap smear were considered. HPV testing for carcinogenic viruses alone or in combination with a repeat Pap smear (using ASCUS as a positive threshold) yielded results of 50%, 67%, 9%, and 96%, respectively, and 70%, 37%, 7%, and 95%, respectively, for detecting CIN 2/3. In women with an initial LSIL Pap smear, respective values for detecting CIN 2/3 by a repeat Pap smear with an ASCUS threshold were 92%, 26%, 14%, and 96%, and for an LSIL threshold 23%, 64%, 8%, and 86%, respectively. Hybrid Capture HPV testing alone or in combination with a repeat Pap smear yielded 69%, 43%, 14%, and 91%, respectively, and 100%, 21%, 14%, and 100%, respectively.

CONCLUSIONS. A Pap smear triage threshold restricted to LSIL or more severe dysplasia for women with prior ASCUS or LSIL Pap smear results was clearly ineffective for detecting high-grade cervical precancerous lesions. In contrast, when the repeat Pap smear triage threshold was expanded to include persistent ASCUS as abnormal, 83% of the women with CIN 2/3 were detected. Detection of carcinogenic HPV DNA using the HCT test was almost as sensitive for detecting CIN 2/3 as a solitary repeat Pap smear using an ASCUS or more severe positive threshold. Combining the HPV test with a repeat Pap smear did not significantly improve the sensitivity of cytology for detecting high-grade CIN. This study suggests that women with ASCUS and particularly LSIL Pap smears should be referred for a colposcopy examination until better triage methods become available.

KEY WORDS. Papanicolaou; DNA probes, HPV; colposcopy; cervical dysplasia; cervical intraepithelial neoplasia; sensitivity and specificity. (J Fam Pract 1998; 46:125-34)

Among the approximately 50 million Papanicolaou (Pap) smears obtained annually in the United States, 5% to 10% are reported as either atypical squamous cells of undetermined significance (ASCUS) or as low-grade squamous intraepithelial lesion (LSIL). Diagnoses made on the basis of Pap smears are known to frequently underestimate cervical disease severity, as confirmed by colposcopically directed biopsies of the cervix. However, very few women with mildly abnormal Pap smears actually have invasive cervical cancer, and less than 25% have high-grade squamous intraepithelial lesions (HSIL). Regardless of this low but clinically significant risk, many experts advocate performing colposcopy examinations on all women with mildly abnormal Pap smears to avoid the risk of failing to diagnose a cervical intraepithelial neoplasia (CIN) grade 2 or 3 or an early invasive cancer. Other experts advocate simply monitoring these patients with serial Pap smears and performing colposcopy only if subsequent Pap smears demonstrate persistent mild abnormalities or neoplasia. These divergent management approaches have created considerable controversy as to the safest and most effective way to further evaluate women with Pap smear reports of ASCUS and LSIL.[1]

The essential role of human papillomavirus (HPV) in the pathogenesis of cervical neoplasia is now well substantiated.[2-4] In particular, specific HPV types have been shown to convey a significant risk for the development of CIN 2/3 and cervical cancer.[5] Commercial methods are available to detect the presence of carcinogenic human papillomaviruses that infect the lower genital tract.[6] One of these tests, the Hybrid Capture tube-based (HCT) HPV DNA assay, permits quantification of the amount of virus present at the sampled site.[7]

Recently, it has been suggested that evaluating women with mildly abnormal Pap smears using an "intermediate triage" approach of HPV testing alone or in combination with a repeat Pap smear might provide the sensitivity of colposcopy and the convenience and lower cost of viral and cytologic monitoring.[8] However, the studies that have critically evaluated this intermediate triage approach have produced somewhat conflicting results.[8-10] Although all studies to date have found that, combining HCT HPV testing with a repeat Pap smear increases the sensitivity of intermediate triage, the efficacy and estimated cost savings of this approach have varied greatly.[8,10] Differing patient characteristics, specimen collection modalities, HPV spectrum of disease, and HPV test sensitivity issues may explain, in part, the conflicting results with respect to efficacy and cost savings of using HPV testing for intermediate triage.