Abstract
Infections with high-risk human papillomaviruses (Hr-HPV) can cause malignant transformation of the human cervical epithelium. HPV DNA tests generally are very sensitive to detect cervical neoplastic lesions but also identify transient HPV infections. As a consequence, the specificity and positive predictive value are low. We analyzed viral load of Hr- and possibly Hr-HPV types more than seven orders of magnitude (on a log10 scale) in 999 consecutive BD-SurePath liquid-based cervical cytology samples from routine cervical screening enriched with atypical squamous cells of undetermined significance (n = 100), low-grade squamous intraepithelial lesions (LSIL; n = 100), and high-grade squamous intraepithelial lesions (HSIL; n = 97) using type-specific multiplex quantitative real-time PCR and the BSGP5+/6+-PCR/MPG assay. In the 36-month follow-up, 79 histologically verified CIN2+ and 797 double-negative cytology cases were identified. Viral loads in LSIL and HSIL were significantly increased compared with no intraepithelial lesion or malignancy in both the quantitative PCR (qPCR) and BSGP5+/6+-PCR/MPG assay (P < 0.0001). The mean viral loads in LSIL and HSIL were not significantly different. Using a newly determined high viral load cut off for 14 Hr-HPV types, the sensitivity for prevalent CIN3+ remained at 100% for both assays compared with the minimal detection threshold. The specificity (corresponding to double-negative cytology at subsequent screening episodes) increased substantially (qPCR, from 91.1% to 95.7%; BSGP5+/6+-PCR/MPG, from 79.8% to 96.2%). Compared with DNA positivity alone, high Hr-HPV viral loads could reduce the amount of false positive results detected by the BSGP5+/6+-PCR/MPG and qPCR by 81.4% and 52.1%, respectively. Quantitative type-specific HPV DNA assays show high flexibility in defining thresholds that allow optimizing clinical accuracy for cervical cancer precursors.
Highlights
Human papillomaviruses (HPV) are DNA viruses that infect cutaneous and mucosal epithelia
Two groups of patient material are considered: (i) 1,000 consecutive samples from women participating in cervical cancer screening and in addition (ii) 100 women with a cytology result of atypical squamous cells of undetermined significance" (ASC-US), 100 with low-grade squamous intraepithelial lesions" (LSIL), and 100 with high-grade squamous intraepithelial lesions" (HSIL), which are all derived from the screening population as well
We analyzed the viral load data of (p)high-risk human papillomaviruses (Hr-HPV) types in CIN2þ (n 1⁄4 76), CIN3þ (n 1⁄4 49), and absent disease (n 1⁄4 797; corresponding to double-negative cytology at subsequent screening episodes) by Receiver Operating Characteristic (ROC) curve analysis to determine assay-specific general high viral load cut off that could be applied to all Hr- and possibly high-risk HPV (pHr-HPV) types
Summary
Human papillomaviruses (HPV) are DNA viruses that infect cutaneous and mucosal epithelia. There are 51 known mucosal HPV types, which are further divided into three groups based on their epidemiologic association with cervical cancer: high-risk. Cervical cancer (CxCa) develops from persistent Hr-HPV infections through precursor lesions, defined histologically as high-grade cervical intraepithelial neoplasia. Still the standard cervical cancer screening method, distinguishes between the classes "no intraepithelial lesion or malignancy" (NIL/ M), "atypical squamous cells of undetermined significance" (ASC-US), "atypical glandular cells" (AGC), "atypical squamous cells of undetermined significance cannot exclude high-grade squamous intraepithelial lesions" (ASC-H), "low-grade squamous intraepithelial lesions" (LSIL), and "high-grade squamous intraepithelial lesions" (HSIL), based on microscopic morphologic criteria and the probability of underlying CIN3 lesion [4]. Infections with high-risk human papillomaviruses (Hr-HPV) can cause malignant transformation of the human cervical epithelium. The specificity and positive predictive value are low
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