http://repub.eur.nl/res/aut/28100/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/32165/ 2012-05-02T00:00:00Z As cervical cancer is an important health problem worldwide with over a half million patients a year and as it is the fourth most common cause of cancer-related death in women, improving the prevention of this disease is a continuing and important process. A major reduction of cancer incidence and mortality has occurred in countries with cervical cancer screening. Because cervical cancer develops through different premalignant stages it can be detected in a premalignant stage, allowing treatment before these stages would be able to develop into cervical cancer. Chapter 1 gives a general introduction about the cervix, human papillomavirus (HPV), the model(s) of cervical carcinogenesis and different measures that are taken to prevent cervical cancer. These measures include screening, triaging of abnormal test results, colposcopic examination, treatment and post-treatment surveillance. In the vast majority of cervical cancers a persistent infection with high-risk HPV types (hrHPV) has been proven to be the causative agent in their carcinogenesis. Besides almost all cervical squamous cell carcinomas, approximately 95% of all cervical adenocarcinomas (ACs) are caused by a transforming infection with a hrHPV type. The remaining ACs are rare and sometimes seem hrHPV-unrelated, which could be caused by detection error or because these tumours are indeed caused by another, not HPV-related carcinogenic mechanism. Chapter 2 describes the attribution of hrHPV in cervical clear-cell adenocarcinoma (CCAC), relatively rare tumours (<<1% of all cervical carcinoma). These tumours have a bimodal age distribution with one peak in the early twenties and another after menopause and are characterised by clear cytoplasm and Hobnail cells. In approximately 60% of the cases this tumour has been associated with intrauterine exposure to diethylstilbestrol (DES), a synthetic oestrogen in the past (falsely) used to prevent miscarriages. In this study of 28 women with CCAC, of whom 15 were DES-exposed in utero, hrHPV was found in 13 (46.4%) tumours. However, after performing immuno-histochemistry with p16INK4a and p53 to distinguish transient hrHPV infections from transforming, carcinogenic infections, only three carcinomas remained in which a causal relation of hrHPV and CCAC was plausible. This demonstrated a very limited role of hrHPV in the carcinogenesis of CCAC. None of the hrHPV-associated tumours were found in women prenatally exposed to DES. In DES-unrelated tumours only a minority (20-25%) seemed hrHPV mediated. In the Dutch population-based screening programme approximately 2.5% of screened women have borderline or mild dysplasia (BMD, PAP2/3a1). These women are retested after 6 months with either cytology of a combination of both cytology and HPV (co-testing), and after 18 months with cytology. If the tests remain abnormal, women are referred for colposcopy. However, not all women with BMD comply with this protocol. Many studies have examined the short-term value of hrHPV-testing in predicting the cumulative risk of CIN3+. In Chapter 3 we have evaluated the long-term cumulative CIN3+ risk in a group of 342 women with an abnormal cytological test result (≥ BMD). These women were followed for a time period of 17 to 19.5 years after detection. Immediate hrHPV-testing clearly stratified the CIN3+ risk; almost all CIN3+ lesions (97.1%) were found in women who tested hrHPV positive. Almost half of all hrHPV-positive women were infected with HPV16; these women had a significantly higher CIN3+ risk than women infected with other hrHPV types. This risk difference between HPV16-positive women and women positive for other hrHPV types, was only found in younger women (<30 years). In older women (≥30 years) the risks in both age groups were similar. The 5-year CIN3+ risk was lower in women who had cleared the virus within 6 months than in women with persistent hrHPV infections (2.2% versus 56.0%), with the highest risks for women with a persistent HPV16 infection (67%). We stratified the CIN3+ risks according to referral cytology and found that both women with BMD and women with >BMD referral cytology had an increased risk of developing CIN3+ within the first 5 years after detection. This risk was twice as high in women with >BMD compared to women with BMD (45% versus 22%). In the subsequent 5 years an increased risk (3.5%) remained for women with >BMD, while for women referred with BMD this risk was with 0.7% similar to that of the general population. Immediate (or delayed, i.e. after 6 months) hrHPV testing clearly stratified the risk in women with BMD; the 5-year risk in hrHPV-negative women was 0.01%, and in hrHPV-positive women 37.5%. Therefore we support the strategy to refer hrHPV-negative women with BMD to routine screening and to refer those who are hrHPV positive for additional testing or colposcopy. When these women do not develop CIN3+ within 5 years, they also may be referred to population-based screening. Additional (baseline) hrHPV-testing in women with >BMD did not result in a group with a risk low enough to refrain from colposcopy, therefore we do not advocate hrHPV testing in this group and advise to refer all these women for colposcopy. As their CIN3+ risk is elevated for at least 10 years, long-term monitoring is required. Chapter 4 focuses on women treated for high-grade cervical disease (CIN2/3). As over 10% of treated women will develop residual/recurrent (post-treatment) high-grade cervical disease, they are closely monitored by cytological testing after treatment. Most published studies concern the risk-assessment of developing post-treatment disease up to a maximum of two years. Currently, treated women in the Netherlands are referred to population-based screening when they have three consecutive negative cytological test results after treatment. This means that it would take at least another three years before women are invited for population-based screening again. In order to evaluate the safety of the current regimen, long-term follow up data is essential. Also because in several other countries yearly follow-up for up to 10 years after treatment. As successful treatment is associated with the elimination of hrHPV, hrHPV testing has been suggested as an improvement in post-treatment surveillance. In Chapter 4.1 a multi-cohort study is described that includes 435 women followed between 5 and 21.5 years after treatment. Different post-treatment test algorithms were analysed; sole cytological testing, sole hrHPV-testing and combined testing with both cytology and hrHPV (co-testing). The overall 5-year CIN2+-risk in this cohort was 16.5%. However, in women who tested consecutively negative for cytology (at 6,12 and 24 months after treatment) this risk was lowered to 2.9% and even to 1.0% in women who tested negative for co-testing at both 6 and 24 months after treatment. The risk of developing CIN3+ in treated women with three consecutive negative cytological test results is similar to the risk of developing high-grade cervical disease in women who test negative for cytology (PAP1) in population-based screening. However, by adding hrHPV-testing to post-treatment surveillance, a better risk-assessment could be reached with even fewer visits. In order to judge the results found in this multi-cohort study, studies which compared different surveillance methods (cytology, hrHPV or co-testing), tested six months after treatment, were systematically reviewed in Chapter 4.2. After a bibliographic database search, relevant studies published between January 2003 and May 2011 were identified by two reviewers with a multi-step process. Then the selected studies were methodological assessed with a modified version of the QUADAS tool (QUality Assessment of Diagnostic Accuracy Studies). Eventually, only eight out of 2410 identified studies remained, incorporating 1513 treated women. The sensitivity of hrHPV testing to predict post-treatment CIN2+ was significantly higher than of cytology (relative sensitivity 1.15; 95%CI 1.06-1.25), while the specificity of these tests was similar (relative specificity 0.95, 95%CI 0.88-1.02). The sensitivity of co-testing was the highest (95%), however this combined test had the lowest specificity (67%). In summary, this review supports the inclusion of hrHPV testing in post-treatment monitoring protocols. The general discussion in Chapter 5 summarizes the findings of this thesis and discusses possible future prospects and clinical consequences. http://repub.eur.nl/res/pub/37890/ 2012-03-01T00:00:00Z Objective: To study the effect of hrHPV-testing on the detection of CIN2/3+ in women referred to a gynecology outpatient clinic, and to assess a useful risk profile in relation to the referral reason to identify who should be tested for cervical pathology. Methods: This study was designed as an observational cohort study. In the first six months of 2007, we categorized the referral reason of 1149 consecutive women who visited our gynecology outpatient clinic and assessed the risk for CIN2/3+ as found by cytology or co-testing with a hrHPV-test and cytology. Results: Three different categories of referral reasons were identified; women with presumed cervix pathology, women with presumed endometrial pathology and women with other referral indications. The cumulative 18-month CIN2+ and CIN3+ risks were highest in the group with presumed cervical disease (adjusted risks 11.1% and 5.4% respectively) and lowest in the miscellaneous group with no suspicion of cervical and/or endometrial pathology (adjusted risks 4.1% and 1.8% respectively). HrHPV-testing detected significantly more CIN2/3+ lesions than cytology (relative detection rate: 1.42 (95%CI 1.05-1.92) and 1.38 (95%CI 0.95-2.05) respectively). Conclusions: The high (> 2%) cumulative 18-month CIN2/3+ risk in patients with presumed cervical and/or endometrial pathology warrants routine cervical testing. In these women a hrHPV-test should be added to cytology because this identifies a significant number of additional women with a substantial risk of CIN2/3+ lesions who would not be identified with cytology alone. Women referred for other reasons should not have cervical testing beforehand, because of their low risk of CIN2/3+. http://repub.eur.nl/res/pub/30729/ 2011-10-01T00:00:00Z We have developed a Europe-wide consensus statement on "HPV Vaccination and Colposcopy" under the aegis of the European Federation for Colposcopy. We look at the historical perspective, the currently available vaccines, cervical vaccination programs, future perspectives, and the impact all this will have on cervical cancer screening and colposcopy services. http://repub.eur.nl/res/pub/31460/ 2011-08-01T00:00:00Z Objective: Over 90% of all cervical adenocarcinoma are caused by a transforming infection with a high-risk type human papillomavirus (hrHPV). Previous studies demonstrated that the association between hrHPV positivity and cervical clear-cell adenocarcinoma (CCAC) varies between 0% and 100%. As approximately 60% of all CCAC are associated with intra-uterine diethylstilbestrol (DES) exposure, we determined in a cohort of both DES-exposed and DES-unexposed women the prevalence of hrHPV infections, and the potential etiological role of hrHPV by additional analysis of p16INK4a and p53 expression. Methods: Representative slides of 28 women diagnosed with CCAC were tested for hrHPV by two PCR methods (the clinically validated GP5+/6+ PCR and the very sensitive SPF10PCR/LiPA25). Fifteen women were DES-exposed, 10 unexposed and of 3 women DES-exposure was unknown. Twenty-one cases with sufficient material were immuno-histochemically stained for p16INK4a and p53. Results: Seven tumors, of which four DES-exposed and two unexposed tested positive for hrHPV with GP5+/6+ PCR. Thirteen tumors, of which five DES-exposed and seven unexposed, tested positive with SPF10PCR/ LiPA25. In one women with unknown exposure, a CCAC tested positive in both assays. Only three cases, none in DES-exposed women, and all positive with both hrHPV assays, revealed diffuse p16INK4a immuno-staining and weak p53 staining as well, supporting indisputable hrHPV involvement. Conclusions: Although the prevalence of hrHPV was high, only two DES-unrelated CCAC (25%) and one tumor in a woman with unknown exposure could be attributed to hrHPV. http://repub.eur.nl/res/pub/25854/ 2011-05-01T00:00:00Z Background: 15% of women treated for high-grade cervical intraepithelial neoplasia (CIN grade 2 or 3) develop residual or recurrent CIN grade 2 or 3 or cervical cancer, most of which are diagnosed within 2 years of treatment. To gain more insight into the long-term predictive value of different post-treatment strategies, we assessed the long-term cumulative risk of post-treatment CIN grade 2 or 3 or cancer and different follow-up algorithms to identify women at risk of residual or recurrent disease. Methods: Women who were included in three studies in the Netherlands and who were treated for CIN grade 2 or 3 between July, 1988, and November, 2004, were followed up by cytology and testing for high-risk human papillomavirus (hrHPV) at 6, 12, and 24 months after treatment, and subsequently received cytological screening every 5 years. The primary endpoint was the cumulative risk of post-treatment CIN grade 2 or higher by December, 2009. We also assessed the cumulative risk of CIN grade 2 or higher in women with three consecutive negative cytological smears and women with negative co-testing with cytology and hrHPV at months 6 and 24. This study is registered in the Dutch trial register, NTR1468. Findings: 435 women were included, 76 (17%) of whom developed post-treatment CIN grade 2 or higher, of which 39 were CIN grade 3 or higher. The 5-year risk of developing post-treatment CIN grade 2 or higher was 16·5% (95% CI 13·0-20·7) and the 10-year risk was 18·3% (13·8-24·0). The 5-year risk of developing post-treatment CIN grade 3 or higher was 8·6% (95% CI 6·0-12·1) and the 10-year risk was 9·2% (5·8-14·2). Women with three consecutive negative cytological smears had a CIN grade 2 or higher risk of 2·9% (95% CI 1·2-7·1) in the next 5 years and of 5·2% (2·1-12·4) in the next 10 years. The 5-year risk of CIN grade 3 or higher was 0·7% (95% CI 0·0-3·9) and the 10-year risk was 0·7% (0·0-6·3). Women with negative results for co-testing had a 5-year risk of CIN grade 2 or higher of 1·0% (95% CI 0·2-4·6) and a 10-year risk of 3·6% (1·1-10·7). The 5-year risk of CIN grade 3 or higher was 0·0% (95% CI 0·0-3·0) and the 10-year risk was 0·0% (0·0-5·3). Interpretation: The 5-year risk of post-treatment CIN grade 2 or higher in women with three consecutive negative cytological smears or negative co-testing for cytology and hrHPV at 6 and 24 months was similar to that of women with normal cytology in population-based screening and therefore justifies their return to regular screening. Funding: VU University Medical Center, Erasmus University Medical Center, Netherlands. http://repub.eur.nl/res/pub/22913/ 2011-02-01T00:00:00Z Objective To validate the dynamic spectral imaging (DSI) colposcope's colour-coded map in discriminating high- from low-grade cervical lesions and non-neoplastic tissue. Design Prospective, comparative, multicentre clinical trial. Setting The colposcopy clinics of three Dutch hospitals. Population Women of 18 years or over with an intact cervix, referred for colposcopy. Methods During a 3-minute image acquisition phase, the DSI colposcope was used as a regular video colposcope: the colposcopist located and graded potential lesions based on conventional colposcopic criteria. Subsequently, a colour-coded map was calculated and displayed, representing localisation and severity of the cervical lesion. Biopsies were collected from all atypical sites, as identified by digital mapping and/or conventional colposcopy. Furthermore, one additional biopsy was taken. Main outcome measures Histologically confirmed high-grade cervical disease (CIN2+). Results In total 275 women were included in the study: 183 women were analysed in the 'according-to-protocol' (ATP) cohort and 239 women in the 'intention-to-treat' (ITT) cohort. In the ATP cohort, the sensitivity of DSI colposcopy to identify women with high-grade (CIN2+) lesions was 79% (95% CI 70-88) and the sensitivity of conventional colposcopy was 55% (95% CI 44-65) (P = 0.0006, asymptotic McNemar test). When the DSI colour-coded map was combined with conventional colposcopy, the sensitivity was 88% (95% CI 82-95). Conclusions DSI colposcopy has a significantly higher sensitivity to detect cervical lesions than conventional colposcopy. If the colour-coded map is combined with conventional colposcopic examination, the sensitivity increases further. http://repub.eur.nl/res/pub/28337/ 2010-01-01T00:00:00Z OBJECTIVE. Because high-risk human papillomavirus (hrHPV) is the necessary factor in the development of high-grade cervical lesions, knowing the colposcopic differences between hrHPV-positive and hrHPV-negative lesions could be of value. We have evaluated whether there are colposcopic differences between lesions testing hrHPV-positive or hrHPV-negative. MATERIALS AND METHODS. This study was conducted as a retrospective case-control study. We designed a scoring system for colposcopic criteria that might be of relevance to distinguish hrHPV-positive from hrHPV-negative lesions. Colposcopic images were analyzed from patients at the VU University Medical Center Amsterdam, the Netherlands, in whom a GP5+/6+ polymerase chain reaction hrHPV test had been performed within a month of the colposcopic examination (n = 507). RESULTS. Visibility of the transformation zone (corrected for age), a (very) coarse and irregular punctation pattern, and a large lesion (>25% of the visible cervix) were more often associated with a positive hrHPV test status (p =.001, odds ratio [OR] = 2.29, 95% CI = 1.41-3.73; p =.036, OR 2.37, 95% CI = 1.08-5.19; and p =.044, OR = 1.78, 95% CI = 1.08-2.94, respectively). After correction for histologic diagnosis, the difference between hrHPV-positive and hrHPV-negative lesions for visibility of the transformation zone and lesion size remained statistically significant (OR = 2.44, 95% CI = 1.35-4.41 and OR = 1.92, 95% CI = 1.04-3.54, respectively). CONCLUSIONS.: This study indicates that visibility of the transformation zone, (very) coarse punctation pattern, and larger lesion size were the main colposcopic features associated with a hrHPV-positive test status.