New paradigms in cervical cancer prevention: opportunities and risks

Both studies based on double-testing of the same women [1,2] and large population trials [3-8] showed that testing for the DNA of high-risk HPV types is more sensitive but less specific than conventional cytology in identifying high-grade cervical intraepithelial neoplasia (CIN).HPV testing detects almost all high-grade CINs identified by cytology [1,2]. As a result, almost the same sensitivity is obtained with HPV alone as with both cytology and HPV together as primary screening tests (i.e. if only HPV-positive or also HPV-negative women with abnormal cytology are referred to colposcopy). However, with the combined strategy, referrals to colposcopy are much more frequent and the probability that test-positive women actually have a high-grade CIN (the Positive Predictive Value, PPV) is substantially lower [3,4].In women at least 35 years of age, in the "New Technology in Cervical Cancer" (NTCC) trial, HPV testing was found to be 63% more sensitive than cytology when all HPV-positive women are referred to colposcopy [8]. At this age loss in specificity is small: in a pooled analysis of European and North American studies based on double-testing [1], specificity was 93.3% with HPV DNA testing vs. 97.1% with cytology. However, even with HPV alone there is a remarkable loss in PPV. In the NTCC trial the relative ratio in PPV between HPV and cytology (relative PPV) was 0.67 [8].Thus, a number of strategies to increase specificity have been or are being evaluated. The most studied strategy – that we will refer to as "cytological triage" – involves directly referring to colposcopy only HPV-positive women who also show cytological abnormalities, while the remaining HPV-positives are retested at shorter interval and referred to colposcopy only if they retest as HPV positive [9]. This approach is based on knowledge that only persistent HPV infections are relevant to carcinogenesis. Trials based on combined HPV and cytology screening but with cytological triage of HPV-positive