HPV tests with P16INK4A expression increase sensitivity for detecting precancerous cervical lesions

September 08, 2008

Human papillomavirus (HPV) testing with P16INK4A expression increases the sensitivity for detection of high-grade, precancerous cervical lesions compared with conventional cytology, without increasing referral to colposcopy, according to findings from a substudy of the New Technologies for Cervical Cancer Screening (NTCC) study, published early Online and in the October edition of The Lancet Oncology.

HPV testing is more sensitive (ie, detects more true positives), but less specific (ie, has more false-positive results) than conventional cytology for detection of high-grade cervical intraepithelial neoplasia (CIN), resulting in increased referral for colposcopy. HPV testing has high sensitivity through the ability to detect the presence of HPV DNA in cervical cells, but has less specificity than cytology because many HPV infections regress without causing high-grade lesions.

Dr Guglielmo Ronco (Centre for Cancer Prevention, Turin, Italy) and Dr Francesca Carozzi (Centre for Cancer Study and Prevention, Florence, Italy) with colleagues from Italy and London, UK, did a substudy of women who were enrolled on the NTCC trial that compared HPV testing with that of conventional cytology. In the substudy, the researchers assessed whether HPV testing with triage according to overexpression of the cellular protein P16INK4A maintains the increased sensitivity of HPV testing compared with cytology, but increases its specificity. P16INK4A is usually expressed in low concentrations in healthy cells, whereas it is overexpressed in cervical-cancer cell lines as a result of HPV oncoprotein activity.

Ronco and colleagues obtained cervical cell samples from women who had tested positive for presence of this virus. Most of the women (94%) had undergone colposcopy. Samples from 1170 women were tested for P16INK4A overexpression by use of immunostaining and histological analyses. Results were available for 1137 of these women, 50 of whom had CIN grade 2 and 42 CIN grade 3 or cancer.

Sensitivity of P16INK4A triage for women who tested HPV positive was 88% (ie, triage detected high-grade CIN in 81 of 92 HPV-positive women). Specificity of triage was 61% (ie, triage correctly classified 633 of 1045 HPV-positive women as not having high-grade CIN). For women aged 35�� years, sensitivity of HPV testing and P16INK4A triage to detect ≥CIN grade 2 was significantly higher than for cytology (1•53 [95% CI 1•15��•02]), but importantly frequency of referral to colposcopy did not differ between triage and conventional cytology (relative referral rate 1•08 [0•96��•21]). In the 25�� age-group, sensitivity was also significantly higher for triage than for cytology (3•01 [1•82��•17]) and referral to colposcopy was much the same between groups (1•15 [0•96��•37]).

Dr Ronco says: "Our data show that in HPV-positive women, P16INK4A overexpression is strongly associated with the presence of histologically confirmed CIN2+, suggesting that it actually is a marker of progression. This study supports the application of triage by P16INK4A immunostaining in HPV-positive women".
Dr Guglielmo Ronco, Centre for Cancer Prevention, Turin, Italy, T) +39 335 755 3701 guglielmo.ronco@cpo.it

Full paper: http://press.thelancet.com/TLOpapillomavirus.pdf


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