Managing atypical squamous cells of undetermined significance (ASCUS): Human papillomavirus testing, ASCUS subtyping, or follow-up cytology?

OBJECTIVE: This study related morphologic subtype, human papillomavirus status, and a second cytologic examination to the follow-up biopsy-proven high-grade squamous intraepithelial lesion (HSIL; grade II or III cervical intraepithelial neoplasia) after a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). STUDY DESIGN: Seven hundred four liquid-based cervical cytology specimens were classified as normal, "ASCUS, favor reactive" (AFR), "ASCUS, not otherwise specified," "ASCUS, favor low-grade squamous intraepithelial lesion," "ASCUS, favor HSIL" (AFHS), low-grade squamous intraepithelial lesion, and HSIL. Human papillomavirus typing used polymerase chain reaction-restriction fragment length polymorphism analysis. A longitudinal review of the cytologic and histologic records of ASCUS cases with ≥1 follow-up test or biopsy ascertained the frequency of a follow-up diagnosis of biopsy-proven HSIL (grade II or III cervical intraepithelial neoplasia). RESULTS: Three hundred eighty-six cases (208 ASCUS, 68 normal, 86 with low-grade squamous intraepithelial lesions, and 24 with HSIL) were evaluated. High-risk human papillomavirus (HRHPV positive) was lowest with normal cytology (13%), highest with HSIL (71%), and was present in 29.8% of ASCUS cases, ranging from 22.2% (AFR) to 75% (AFHS). Most ASCUS tests (64%) were followed by a negative cytologic or histologic examination. Overall, 3.8% and 11% of ASCUS and HRHPV-positive ASCUS had histologic outcomes of HSIU AFHS had the highest (25%) and AFR had the lowest (1.1%) proportion of HSIL outcomes. Sensitivity, specificity, and positive predictive values of human papillomavirus testing for biopsy-proven HSIL were 87.5%, 72.5%, and 11.3%, respectively. CONCLUSION: HSIL and AFHS are distinguished by the highest frequency of HRHPV types and higher rates of HSIL outcome. The remaining categories of ASCUS are heterogeneous with respect to human papillomavirus type and HSIL risk, and the value of subclassification of these entities is dependent on the practice. A human papillomavirus detection system based on polymerase chain reaction-restriction fragment length polymorphism identifies a smaller percentage of high-risk human papillomaviruses than mixed probe-based methods, probably because of the more precise exclusion of cross-reacting low-risk human papillomavirus. Negative HRHPV findings by either system show a markedly reduced risk of an HSIL outcome. However, the relative advantage of human papillomavirus testing over follow-up cytology will be influenced by the frequency of negative follow-up cytologic examination and sensitivity of liquid-based preparations in a given practice.