The Bethesda System 2001 defined a new subset of atypical squamous cells to include those cases in which a high-grade squamous intraepithelial lesion, or HSIL, could not be excluded (ASC-H). Though morphologic criteria for the ASC-H category have been proposed, poor interobserver agreement for the diagnosis has been demonstrated. However, the spectrum of diagnoses associated with ASC-H (negative, ASC-H, and HSIL) is different from that associated with ASC-US (negative, ASC-US, and low-grade SIL). The ASC-H category was developed to identify a small portion of equivocal cytology that carry a greater risk of high-grade dysplasia, the identification of which might be bolstered by more rigorous followup, including immediate colposcopy and biopsy.
Sherman, et al used two years of followup data from the Atypical Squamous Cells of Undetermined Significance Low-Grade SIL Triage Study (ALTS) to address several questions about the ASC-H category [Sherman ME, Castle PE, Solomon D. Cervical cytology of atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion (ASC-H): characteristics and histologic outcomes. Cancer. 2006;108(5):298–305]. First, what is the cumulative detection rate of cervical intraepithelial neoplasia (CIN), grades 2–3, during followup of ASC-H diagnoses? Second, what is the risk of CIN 2–3 after an initial colposcopy that does not prompt treatment? Third, what are the associations of ASC-H and high-risk HPV types?
The ALTS study included women who had received a cytologic report of ASC-US or LSIL on conventional Pap tests from their community hospitals. Upon enrollment, a pathology quality control panel was assembled to review all enrollment cytology and thin-layer followup cytology. The current analysis was based on the QC panel cytology interpretations, which included the ASC-H category. In ALTS, women with ASC-H were managed the same as were women with ASC-US. The trial protocol included repeat cytology every six months for two years with colposcopy referral for HSIL. Women with a histologic diagnosis of CIN 2 or greater were referred for loop electrosurgical excision procedure, or LEEP, and at study exit, all women underwent colposcopy and those with persistent ASC with positive HPV test, LSIL, or more severe abnormality received a LEEP. Thus, extensive histologic outcomes data were available.
Comparison was made between the QC cytology results at the time of enrollment (ASC-US, LSIL, ASC-H, and HSIL) and the most severe histologic diagnosis reported per woman over the two-year trial period. These results were stratified by Hybrid Capture 2 HPV results. ASC-H cytology was found to be associated with a substantially higher rate of HPV detection and histologic outcome of CIN 2 or greater than ASC-US, but less than that of HSIL. This confirms previous findings that showed ASC-H diagnoses were intermediate between ASC-US and HSIL in their predictive value of high-grade dysplasia.
Evaluation of women who were enrolled in ALTS and had colposcopy findings that did not prompt further treatment (CIN 1 or normal findings) revealed a significantly higher risk of CIN 2 or greater outcome in women with ASC-H and HSIL diagnoses compared with women with ASC-US. Twenty-eight percent of women with ASC-H diagnoses and 26 percent with HSIL diagnoses were subsequently found to have histologic confirmation of CIN 2 or greater, compared with seven percent of women with ASC-US diagnoses. Though the numbers were small in this subset, the findings underscore the need for post-colposcopy monitoring of women with ASC-H and HSIL cytology.
The HPV positivity rate for ASC-H diagnoses overall was 84 percent. However, significant differences appeared when patients were stratified by age. In women under age 35 with ASC-H cytology, HPV detection was 85 percent to 91 percent. However, in women older than 35 years, positive HPV tests were found in only 40 percent of ASC-H diagnoses. These data affirm the utility of immediate colposcopy in younger women with ASC-H cytology, but HPV testing may be more useful in older women, either as a triage tool for the cytologic diagnosis of ASC-H or for reassurance after a negative colposcopy. Additional studies in clinical practice are needed to confirm the findings of the ALTS data.
Dr. Clary, a member of the CAP Cytopathology Committee, is in the Department of Pathology, Rochester (NY) General Hospital.