Human papillomavirus testing for triage of women with low-grade squamous intraepithelial lesions

Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. .
International Journal of Cancer (Impact Factor: 5.01). 02/2013; 132(4). DOI: 10.1002/ijc.27723
Source: PubMed

ABSTRACT Low-grade squamous intraepithelial lesion (LSIL) is a common cytologic finding in cervical screening, yet only about 10-20% have significant histologic abnormalities and these are almost always positive for high-risk human papillomavirus (hrHPV). This analysis aims to clarify the role of hrHPV DNA testing in the triage of women with LSIL cytology. In the ATHENA screening trial, we examined 1,084 cases of LSIL, of which 925 had an evaluable biopsy, to determine the extent to which hrHPV testing can identify those patients who have precursor lesions in need of immediate clinical referral and those who have changes more likely to regress spontaneously. Overall, 71.2% of LSIL cases were hrHPV positive, but the prevalence was age dependent, with only 56.1% in women ≥40 years. Among women with LSIL, 11.6% (107/925) had a cervical intraepithelial neoplasia grade 2 or worse (CIN2+) histologic diagnosis and, of these, only nine were hrHPV negative. For CIN3+, 91.7% (44/48) of women with LSIL were hrHPV positive. The negative predictive value of hrHPV testing for CIN3+ in LSIL was 100% for women aged ≥40 years. Women who were HPV16 positive had a higher positive predictive value for CIN2+ (25.4%) than those who were positive for 12 other pooled hrHPV types (11.5%). Testing for hrHPV in women with LSIL is effective in identifying high-grade cervical lesions, thereby avoiding unnecessary referrals to colposcopy and potential over-treatment of non-progressive lesions, especially for women aged ≥40 years.

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    ABSTRACT: Objective Our previous work revealed that host genes ZNF582, PTPRR, PAX1, and SOX1 are highly methylated in cervical intraepithelial neoplasias grade 3 or worse (CIN3+). In this study, we used a standardized testing assay to evaluate the clinical efficacy of these biomarkers in the triage of cytological diagnoses of low-grade squamous intraepithelial lesions (LSILs), and compared the performance with human papillomavirus (HPV) testing. Methods This 2-year multicenter prospective study examined a population of 230 women from 12 medical centers who were diagnosed with LSILs on cervical cytology. Cervical scrapings were obtained prior to a colposcopy-directed biopsy for quantitative methylation analysis of ZNF582, PTPRR, PAX1, and SOX1, and HPV testing. Using logistic regression and receiver operating characteristic curve analyses, the abilities of methylated genes and HPV to predict CIN3+ were assessed. Results Fifteen (6.5%) of the 230 women with a cytological diagnosis of LSIL were confirmed to have CIN3+ after a colposcopy-directed biopsy. Among the 4 methylated genes, ZNF582 was found to be the best biomarker for detecting CIN3+. The sensitivities for methylated ZNF582 and HPV testing were 73% and 80%, and the specificities were 71% and 28%, respectively. The odds ratio for predicting CIN3+ using methylated ZNF582 was 6.8 (95% confidence interval (CI) 2.1–22.1), which was much better than HPV testing (OR = 1.6, 95% CI 0.4–5.8). Conclusion This is the first study to show that ZNF582 methylation analysis of cervical swabs may be a promising choice in the positive triage of cytological diagnoses of LSILs.
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