Berkhof, J.

HrHPV-testing in a university hospital gynecology outpatient clinic: Recommendations for clinical practice (Article)

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+.

Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: A long-term multi-cohort study (Article)

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.

Dynamic spectral imaging colposcopy: Higher sensitivity for detection of premalignant cervical lesions (Article)

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.

The health and economic effects of HPV DNA screening in the Netherlands (Article)

2010-11-01T00:00:00Z

We studied the health and economic effects of human papillomavirus (HPV) DNA testing in cervical screening using a simulation model. The key data source was a Dutch longitudinal screening trial. We compared cytological testing with repeat cytology (for borderline/mildly abnormal smears) to HPV testing with cytology triage (for HPV-positive smears), combination testing (combined HPV and cytology) and cytological testing with HPV triage (for borderline/mildly abnormal smears). We varied the screening interval from 5 to 10 years. The main outcome measures were the number of cervical cancer cases, the number of quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). The base-case estimates were accompanied with ranges across 118 calibrated parameter settings (calibration criteria: cervical intraepithelial neoplasia 2/3, cancer and mortality rates). In comparison to 5-yearly cytology, 5-yearly HPV testing with cytology triage gave a reduction in the number of cancer cases of 23% (range, 9-27%). The reduction was 26% (range, 10-29%) for combination testing and 3% (range, -1 to 8%) for cytology with HPV triage. For strategies with primary HPV testing, the model also estimated a reduction in cancer cases when the screening interval was extended to 7.5 years. Five-yearly cytology with HPV triage and 5 to 7.5-yearly HPV testing with cytology triage were cost effective for the base-case settings and the majority of calibrated parameter settings (ICER below Dutch willingness-to-pay threshold of -20,000/QALY). Our model indicates that HPV testing with cytology triage is likely to be cost effective. An extension of the screening interval may be considered to control costs.

Colposcopic characteristics of high-risk human papillomavirus-related cervical lesions (Article)

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.

Association between dense CADM1 promoter methylation and reduced protein expression in high-grade CIN and cervical SCC (Article)

2008-08-01T00:00:00Z

We previously showed that silencing of TSLC1, recently renamed CADM1, is functionally involved in high-risk HPV-mediated cervical carcinogenesis. CADM1 silencing often results from promoter methylation. Here, we determined the extent of CADM1 promoter methylation in cervical (pre)malignant lesions and its relation to anchorage-independent growth and gene silencing to select a CADM1-based methylation marker for identification of women at risk of cervical cancer. Methylation-specific PCRs targeting three regions within the CADM1 promoter were performed on high-risk HPV-containing cell lines, PBMCs, normal cervical smears, and (pre)malignant lesions. CADM1 protein expression in cervical tissues was analysed by immunohistochemistry. All statistical tests were two-sided. Density of methylation was associated with the degree of anchorage-independent growth and CADM1 gene silencing in vitro. In cervical squamous lesions, methylation frequency and density increased with severity of disease. Dense methylation (defined as ≥2 methylated regions) increased from 5% in normal cervical samples to 30% in CIN3 lesions and 83% in squamous cell carcinomas (SCCs) and was significantly associated with decreased CADM1 protein expression (p < 0.00005). The frequency of dense methylation was significantly higher in ≥ CIN3 compared with ≤ CIN1 (p = 0.005), as well as in SCCs compared with adenocarcinomas (83% versus 23%; p = 0.002). Detection of dense CADM1 promoter methylation will contribute to the assembly of a valuable marker panel for the triage of high-risk HPV-positive women at risk of ≥ CIN3. Copyright

Vaccination against HPV: Indications for women and the impact on the cervical screening programme (Article)

2008-07-01T00:00:00Z

A novel approach for primary prevention of cervical cancer has become available by the discovery of efficient prophylactic human papillomavirus (HPV) vaccines based on virus-like particles. This review elaborates on the progress in the field of prophylactic HPV vaccination achieved in the past decade, provides indications for prophylactic HPV vaccination, and discusses the impact on public health and the current secondary prevention system. In summary, with current vaccines, effective prevention and control of cervical cancer within the next decades requires an integrated vaccination-screening approach, including routine prophylactic vaccination to young women and adapted cervical screening for older women (≥30 years).

Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial (Article)

2007-11-24T00:00:00Z

Background: Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. Methods: Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. Findings: 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (≥6·5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0·007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0·001). The number of CIN3+ lesions over the two rounds did not differ between groups. Interpretation: The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

Human papillomavirus testing on self-sampled cervicovaginal brushes: An effective alternative to protect nonresponders in cervical screening programs (Article)

2007-04-01T00:00:00Z

Women not attending cervical screening programs are at increased risk of cervical cancer. We investigated in these nonresponders to what extent offering self-sampling devices for cervicovaginal brushes for high-risk human papillomavirus (hrHPV) testing would induce participation and, if so, what the yield of precursor (i.e. CIN2 or worse) lesions following self-sampling would be. In addition, we assessed screening history of participants and costs per detected high-grade CIN2 or worse ("CIN2+") lesion in comparison to the regular program in the Netherlands. Nonresponders received a device for hrHPV testing (self-sampling group, n = 2,546) or an extra recall for conventional cytology (control group, n = 284). The percentage of self-sampling responders were compared with responders in the recall group. hrHPV positive self-sampling responders were invited for cytology and colposcopy. CIN2+ yield and costs per detected C1N2+ were evaluated. Active response was higher in the self-sampling than in the control group (34.2 vs. 17.6%; p < 0.001). hrHPV positive self-sampling responders were less likely to have a prior screening history than screening participants (p < 0.001), indicating that they are regular nonresponders. hrHPV prevalence was similar (8.0 vs. 6.8%; p = 0.11), but CIN2+ yield was higher in self-sampling responders compared to screening participants (1.67 vs. 0.97%; OR = 2.93, 95% CI 1.48-5.80; p = 0.0013). Costs per CIN2+ lesion detected via self-sampling were in the same range as those calculated for conventional cytological screening (€8,836 vs. €7,599). Offering self-sampling for hrHPV testing in nonresponders is an attractive adjunct to effectively increase population coverage of screening without the adverse effect of markedly increased costs per detected CIN2+ lesion.

HPV16 and increased risk of recurrence after treatment for CIN (Article)

2007-02-01T00:00:00Z

Objective.: Addition of high-risk human papillomavirus (hrHPV) testing to post-treatment monitoring policies of women treated for high-grade cervical intraepithelial neoplasia (CIN) may improve the effectiveness of detecting recurrent/residual disease. Recent studies have shown that HPV type 16 confers an increased risk of high-grade CIN and cervical cancer. This study aimed to find out whether the post-treatment CIN3 rate is increased in HPV16-positive women treated for CIN3. Methods.: We included 229 hrHPV-positive women treated for CIN3. HPV typing was performed by GP5+/6+-PCR followed by reverse line blotting on a cervical scrape taken before treatment. HPV typing data were related to the occurrence of post-treatment CIN3 within a median follow-up time of 20.1 months (range 3-85.4 months) following treatment. Results.: Twenty nine of the 151 (19%) HPV16-positive women versus 6 of the 78 (8%) women with other hrHPV types had recurrent/residual CIN3. Post-treatment CIN3 rate was significantly increased in women with HPV16 compared to those harboring other hrHPV types (p = 0.03). None of the other hrHPV types were associated with higher post-treatment CIN3 rates. Conclusion.: Women treated for HPV16 containing CIN3 should be monitored more intensively because of their increased risk of post-treatment CIN3. Thus, the HPV genotype should be considered in post-treatment monitoring policies.