Despite widespread cervical cancer-screening programmes, 30000 of the 190 million women living in Europe still die every year from this disease (Ferlay et al, 1988). The overall decline in cervical cancer incidence observed since the introduction of the Papanicolaou (PAP) smear has levelled off and even started to increase in countries such as England, Wales and Finland (Vizcaino et al, 2000), where organised screening programmes with extensive quality control have been in place for many years.
In Germany, an opportunistic cervical cancer-screening programme was established in 1971, which made free annual cervical cancer screening available to all women 20 years of age or older. The average annual participation rate in 1997 was roughly 50% (Kahl et al, 1999; Klug et al, 2000; Klug and Blettner, 2003). When looked at over a 3-year period, which is the screening interval used in many European countries, the population coverage reaches 80% (Schenck and von Karsa, 2000) or higher in the 25–50-year-old age group. Despite this considerable effort, Germany has one of the highest cervical cancer incidence rates (13.28 per 100.000) and standardised mortality rates (4.4 per 100.000 for 1993) in Western Europe, which is higher than in neighbouring countries with similar socio-economic structures such as France, Italy and the Netherlands.
Infection with high-risk human papillomavirus (HR-HPV) is the major risk factor for the development of cervical cancer (Bosch et al, 1995; Walboomers et al, 1999) and it has been suggested that testing for HR-HPV should be included in existing cervical cancer-screening programmes (Vizcaino et al, 2000). Large-scale screening studies by Schiffman et al (2000), Clavel et al (2001) and Schneider et al (1996),(2000) demonstrated that HPV testing is more sensitive for the detection of high-grade cervical lesions than cytology although the lower specificity of HPV testing made its use in primary cervical cancer screening questionable. However, the majority of these studies did not compare HPV testing to routine cytology, but rather used a team of expert cytologists thereby not allowing to draw conclusions about the performance of HPV testing under routine screening conditions. In addition, these studies included a high proportion of younger women aged 18 years and above, although it is known that young, sexually active women have a high prevalence of both HR-HPV and high-grade cervical intraepithelial neoplasia (CIN), the overwhelming majority of which resolves spontaneously (Evander et al, 1995; Ho et al, 1995). It is possible that the higher sensitivity of HR-HPV testing in these young populations in comparison with cytology may partially be because of the identification of transient disease with a high tendency for regression. To address this particular issue, Cuzick et al (1999) examined the performance of HPV testing in women 35 years of age or older and again found that HR-HPV testing had a higher sensitivity than cytology, but a lower specificity and positive predictive value (PPV) leading to a higher referral rate than cytology alone. Importantly, all of the former studies are characterised by the lack of an HPV−/Pap− control group examined by colposcopy, thereby not allowing an accurate estimate of the false-negative rate of the screening regimen (Ratnam et al, 2000).
Our aim was to determine the value of HPV testing in the routine primary cervical cancer-screening programme in Germany for the detection of high-grade cervical cancer precursors (CIN2). To avoid confounding factors, we implemented different levels of quality controls (see study protocol in Figure 1) to evaluate the use of HPV testing. All the 8083 study participants finally included were aged 30 years or older attending for routine cancer screening and represented a random unselected population that was highly representative of Western Germany as a whole.
All positive and 5% of the negative HC2 samples were retested by a highly sensitive, broad-range, consensus-primer PCR with direct sequencing to evaluate HC2 performance. Digital images of the cervix were taken at the colposcopic examination and reviewed by independent experts blinded to previous findings. Additional expert reviews were performed on all histology samples and all cytology samples with any degree of dyskaryosis, all cytology samples from HR-HPV+ women and 5% of randomly selected cyto-/HPV-cytology samples. Most importantly, a colposcopic examination of a random sample of 250 women who were cytology and HPV− was performed in order to estimate the bias that would be introduced by disease missed in women who were falsely negative on both tests (Ratnam et al, 2000). Cytology labs undertaking the primary cytology were not informed about which Pap smears were included in the trial and the samples were therefore screened under routine conditions. The statistical analysis of the raw data was performed by an independent group (Erasmus University, Rotterdam) that was not involved in the screening trial nor in the collection of the data.