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: 5.09). 02/2013; 132(4). DOI: 10.1002/ijc.27723
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: Atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman.Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management.This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) - the main causal factor of cervical cancer. Main objectiveTo compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+).Secondary objectiveTo assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done. We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer.More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review. Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification. The review authors independently extracted data from the selected studies, and obtained additional data from report authors.Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL. The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests. The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001). HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology. When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account.Cochrane database of systematic reviews (Online) 04/2013; 3(3):CD008054. DOI:10.1002/14651858.CD008054.pub2 · 6.03 Impact Factor
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ABSTRACT: Cervical cancer screening incorporating high-risk human papillomavirus (HPV) detection has become the preferred screening strategy in some countries and is increasingly more widespread in other countries with organized or opportunistic screening programs. Given knowledge that high-risk HPV genotypes differ in their oncogenic potential, commercial HPV assays with genotyping capabilities have been developed and have garnered attention in the recent literature. The cobas(®) 4800 HPV Test is a qualitative multiplex assay that provides specific genotyping information for HPV types 16 and 18, while concurrently detecting 12 other high-risk HPV genotypes as a pooled result. It is currently the only clinically validated, US FDA-approved assay with this capability. Since HPV types 16 and 18 have been designated as conferring the greatest risk for cervical disease, their detection may prove useful in guiding patient management.Expert Review of Molecular Diagnostics 12/2013; 14(1). DOI:10.1586/14737159.2014.865521 · 3.52 Impact Factor
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ABSTRACT: Background: High-risk human papilloma virus (hrHPV) testing was added to the cytology triage of women with equivocal screening smears in the Norwegian programme for cervical cancer screening in 2005. In this population-based observational before and after study we assessed the effect of changing the screening algorithm. Material and methods: In periods before and after the change 75 852 and 66 616 women, respectively, were eligible for triage, i.e. they had smear results of unsatisfactory, atypical squamous cells of undetermined significance (ASC-US), or low-grade squamous intraepithelial lesion (LSIL) at routine screening. The triage was delayed as supplementary testing started six months after the initial screening. The groups were compared with respect to results of triage and later three-year cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Results: Before and after the change in the screening algorithm 5.2% (3964/75 852) and 8.1% (5417/66 616) of women, respectively, were referred to colposcopy. Among women referred to colposcopy cumulative incidence of CIN2+ (positive predictive value of referral) increased from 42.0% [95% confidence interval (CI): 40.3 - 43.7%] in the period with cytology only to 48.0% (95% CI 46.6 - 49.4%) after the start of HPV testing. For women recalled to ordinary screening the three-year cumulative incidence decreased from 2.7% (95% CI 2.5 - 2.9%) to 1.0% (95% CI 0.9 - 1.2%) during the same period. Among women with LSIL at routine screening and HPV testing in triage, 52.5% (1976/3766) were HPV positive. Conclusion: The new algorithm with HPV testing implemented in 2005 resulted in an increased rate of referral to colposcopy, but in a better risk stratification with respect to precancerous disease.Acta oncologica (Stockholm, Sweden) 06/2014; 54(2):1-10. DOI:10.3109/0284186X.2014.932433 · 3.00 Impact Factor
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