Publications by authors named "Alexander Luyten"

24 Publications

  • Page 1 of 1

Significant decline of HPV 6 infection and genital warts despite low HPV vaccination coverage in young women in Germany: a long-term prospective, cohort data analysis.

BMC Infect Dis 2021 Jul 2;21(1):634. Epub 2021 Jul 2.

Department of Obstetrics and Gynecology, Klinikum Wolfsburg, Wolfsburg, Germany.

Background: The introduction of human papillomavirus (HPV) vaccination has resulted in a remarkable decline of genital warts in women and men, but in Germany historical rates of vaccination are relatively low. We report long-term surveillance data on changes in HPV 6 and HPV 11 infection and the prevalence of genital warts in young women in the Wolfsburg HPV epidemiological study (WOLVES).

Methods: Women born in 1983/84, 1988/89, and 1993/94 participated in four cohorts between 2009/10 and 2014/15. Quadrivalent vaccination coverage and prevalence of HPV 6/11 infection and genital warts are reported for participants aged 19-22 years and 24-27 years at the time of sample collection. Statistical analyses were done to compare similarly aged participants using 2 × 2 contingency tables (Röhmel-Mansmann unconditional exact test; two-side alpha of 0.05).

Results: A total of 2456 women were recruited. Between 2010 and 2015, there was a statistically significant decrease in the prevalence of HPV 6 infection among women aged 24-27 years (2.1% versus 0.0%; P < 0.0001) and women aged 19-22 years (2.0% versus 0.0%; P = 0.0056). There was no significant decline in HPV 11 infection. In total, 52 of 2341 participants were diagnosed with genital warts. There was a statistically significant drop in the risk of developing genital warts in women aged 24-27 years between 2010 and 2015 (4.7% versus 1.7%, respectively; P = 0.0018). The overall risk of developing genital warts in women aged 19-27 years decreased from 3.1% in 2010 to 1.2% in 2015 (P = 0.0022).

Conclusions: An increase in vaccination coverage was associated with a decreased prevalence of genital warts in young women. A protective effect greater than herd immunity alone was seen despite low vaccination rates. Quadrivalent vaccine had a protective effect on genital HPV 6 infection and an almost fully protective effect on the development of genital warts in the youngest population.
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http://dx.doi.org/10.1186/s12879-021-06139-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252220PMC
July 2021

Association of genomic variants at PAX8 and PBX2 with cervical cancer risk.

Int J Cancer 2021 Apr 27. Epub 2021 Apr 27.

Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany.

Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta-analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case-control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.91, P = 2.4 × 10 ; rs2856437: OR 1.52, 95% CI 1.14-2.02, P = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68-0.94, P = .006; rs2856437: OR 1.56, 95% CI 1.03-2.36, P = .036) and with high-grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70-0.90, P = 1.9 × 10 ; rs2856437: OR 1.58, 95% CI 1.15-2.17, P = .005). A combined analysis of high-grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73-0.91, P = 2.4 × 10 ; rs2856437: OR 1.57, 95% CI 1.18-2.10, P = .002). No association was detected for rs2856437 with low-grade dysplasia, while rs10175462 showed weak evidence of association (P = .05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV-positive lesions (P = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8-AS1 (P < .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (PBX2) with cervical disease and support PAX8 as the first consistent non-HLA cervical cancer susceptibility locus.
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http://dx.doi.org/10.1002/ijc.33614DOI Listing
April 2021

Pelvic Lymphadenectomy in Vulvar Cancer - Does it make sense?

Geburtshilfe Frauenheilkd 2020 Dec 3;80(12):1221-1228. Epub 2020 Dec 3.

Department of Gynecology and Gynecologic Oncology, University Medical Center Köln, Köln, Germany.

Since the publication of the updated German guideline in 2015, the recommendations for performing pelvic lymphadenectomy (LAE) in patients with vulvar cancer (VSCC) have changed considerably. The guideline recommends surgical lymph node staging in all patients with a higher risk of pelvic lymph node involvement. However, the current data do not allow the population at risk to be clearly defined, therefore, the indication for pelvic lymphadenectomy is still not clear. There are currently two published German patient populations who had pelvic LAE which can be used to investigate both the prognostic effect of histologically verified pelvic lymph node metastasis and the relation between inguinal and pelvic lymph node involvement. A total of 1618 patients with primary FIGO stage ≥ IB VSCC were included in the multicenter AGO CaRE-1 study (1998 - 2008), 70 of whom underwent pelvic LAE. During a retrospective single-center evaluation carried out at the University Medical Center Hamburg-Eppendorf (UKE), a total of 514 patients with primary VSCC treated between 1996 - 2018 were evaluated, 21 of whom underwent pelvic LAE. In both cohorts, around 80% of the patients who underwent pelvic LAE were inguinally node-positive, with a median number of three affected groin lymph nodes. There were no cases of pelvic lymph node metastasis without inguinal lymph node metastasis in either of the two cohorts. Between 33 - 35% of the inguinal node-positive patients also had pelvic lymph node metastasis; the median number of affected groin lymph nodes in these patients was high (> 4), and the maximum median diameter of the largest inguinal metastasis was > 40 mm in both cohorts. Pelvic lymph node staging and pelvic radiotherapy is therefore probably not necessary for the majority of node-positive patients with VSCC, as the relevant risk of pelvic lymph node involvement was primarily found in node-positive patients with high-grade disease. More, ideally prospective data collections are necessary to validate the relation between inguinal and pelvic lymph node involvement.
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http://dx.doi.org/10.1055/a-1120-0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714620PMC
December 2020

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels.

Int J Cancer 2020 11 10;147(9):2458-2468. Epub 2020 Jul 10.

Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, Hannover, Germany.

The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single-nucleotide polymorphisms in a large case-control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA-DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79-0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04-1.31, P = .008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87, P = 7.1 × 10 ; rs2844511: OR 1.13, 95% CI 1.01-1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91, P = 6.9 × 10 ; rs2844511: OR 1.14, 95% CI 1.04-1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low-grade dysplasia (OR 1.26, 95% CI 1.04-1.54, P = .019). In case-only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated with HLA-DQA1 levels, specifically in HPV-positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA-DQA1. Altogether, our results support 6p21.32-33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA-DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.
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http://dx.doi.org/10.1002/ijc.33171DOI Listing
November 2020

Predictive factors for lymph node metastases in vulvar cancer. An analysis of the AGO-CaRE-1 multicenter study.

Gynecol Oncol 2019 09 18;154(3):565-570. Epub 2019 Jun 18.

Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Background: Lymph node (LN) metastasis is the most important prognostic factor in primary vulvar cancer. Assessing risk factors for the incidence and extent of LN metastases may help to select the optimal treatment strategy for each individual patient.

Methods: In a subgroup analysis of the large multicenter AGO-CaRE-1 study we included all patients treated with radical groin dissection. Univariate and multivariate regression analyses were performed in order to detect factors associated with the prevalence and extent of nodal involvement.

Results: In total, 1162 patients were analyzed. Univariate analyses detected age, ECOG as well as multiple tumor characteristics such as FIGO stage, grading, depth of invasion, tumor diameter, and (lymph)vascular space invasion to be related with the prevalence of LN metastases. Interestingly, only tumor stage, tumor diameter and depth of infiltration were found to be significantly associated with the number of LN metastases. In multivariate analysis, age (OR 1.03), lymphvascular space invasion (OR 4.97), tumor stage (OR 2.22) and depth of infiltration (OR 1.08) showed an association with the prevalence of LN metastases. Regarding the number of metastatic LNs, only tumor stage (OR 2.21) or, if excluded, tumor diameter (OR 1.02) were tested significant.

Conclusion: This large analysis of the multicenter AGO-CaRE-1-study identified lymphvascular space invasion, tumor stage, and depth of infiltration as factors with the strongest association regarding the prevalence of LN metastasis. Interestingly, tumor stage or, if excluded, tumor diameter were the only factors associated with the prevalence as well as the extent of LN metastases.
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http://dx.doi.org/10.1016/j.ygyno.2019.06.013DOI Listing
September 2019

Reduction of cervical cancer incidence within a primary HPV screening pilot project (WOLPHSCREEN) in Wolfsburg, Germany.

Br J Cancer 2019 05 16;120(10):1015-1022. Epub 2019 Apr 16.

Department of Obstetrics and Gynecology, Klinikum Wolfsburg, Wolfsburg, Germany.

Background: Randomised controlled trials showed human papillomavirus (HPV)-based screening leads to a significant reduction in cervical cancer incidence compared with cytology-based screening only.

Methods: Non-hysterectomised participants ≥30 years underwent co-testing with Papanicolaou (Pap) smear and HR-HPV testing (Hybrid Capture 2; HC2). Women with normal findings had their next screening round after 5 years, and HC2+ and Pap abnormal cases were immediately referred for colposcopy, while cases with discordant findings had repeat testing after 12 months with referral to colposcopy in cases with persistent positive findings.

Results: Twenty-six thousand six hundred and twenty-four women were recruited between February 2006 and December 2016. Two hundred and seventy-four CIN3+ cases were diagnosed (270 HPV+, 4 HPV-), including 31 invasive cervical cancers (29 HPV+, 2 HPV-). No CIN3+ was detected in HPV- women with abnormal cytology. We observed a significant decline in the 5-year incidence of CIN3+ (from 0.96% [95% CI 0.85-1.09%] to 0.16% [95% CI 0.10-0.25%]; p < 0.0001) and cervical cancer (from 0.10% [95% CI 0.07%-0.15%] to 0.025% [95% CI 0.01-0.08%]; p = 0.01) between the first and subsequent rounds. Approximately 90% (246/274) of CIN3+ cases were diagnosed at first colposcopy.

Conclusions: The decline in disease rates with 5-yearly co-testing seems mainly attributable to HPV testing since no CIN3+ occurred in HPV-/Pap+ women.
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http://dx.doi.org/10.1038/s41416-019-0453-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734660PMC
May 2019

Surgical staging identified false HPV-negative cases in a large series of invasive cervical cancers.

Papillomavirus Res 2017 12 19;4:85-89. Epub 2017 Oct 19.

Institute of Experimental Virology, University of Tübingen, Germany.

Objective: We examined a large series of biopsy-proven invasive cervical cancers with surgical staging and HPV re-testing to estimate the relevance of HPV-negative cervical cancers in a Caucasian population.

Methods: We prospectively collected smears from 371 patients with a biopsy-proven diagnosis of cervical cancer for HC2 testing of high-risk HPV (HR-HPV). In HC2-negative cases, smears and paraffin embedded tissue blocks underwent additional HPV genotyping.

Results: HC2 tests showed 31/371 cases (8.8%) had negative findings. Surgical staging showed that 21/31 HC2-negative cases (68%) were not cervical cancer. Overall, 340/350 cases of primary cervical cancer confirmed by surgical staging tested HC2 positive (97.2%). Non-high-risk HPV subtypes were detected in five cases (one HPV-53, one HPV-70, and three HPV-73) and high-risk subtypes in four patients with HC2-negative cervical cancer (two HPV 16 and two HPV-18). The remaining case, a primary undifferentiated carcinoma of the uterine cervix, tested negative for HPV-DNA with all tests.

Conclusions: The main explanation for HPV-negative cervical cancer was a false diagnosis, followed by cancers associated with non-HR-HPV types, and false-negative HR-HPV results. Truly HPV negative seem to be very rare in Caucasian populations. Retrospective analyses without surgical staging may overestimate the proportion of HPV negative cervical cancers.
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http://dx.doi.org/10.1016/j.pvr.2017.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883200PMC
December 2017

Outcome After Sentinel Lymph Node Dissection in Vulvar Cancer: A Subgroup Analysis of the AGO-CaRE-1 Study.

Ann Surg Oncol 2017 May 28;24(5):1314-1321. Epub 2016 Nov 28.

Elbland Hospital Meißen-Radebeul, Radebeul, Germany.

Purpose: Analyzing the large patient cohort of the multicenter AGO-CaRE-1 study, we compared isolated sentinel lymph node dissection (SLND) with radical lymph node dissection (LND) of the groin in relation to recurrence rates and survival.

Methods: The AGO-CaRE-1 study retrospectively collected data on treatment patterns and follow-up of vulvar cancer patients [International Federation of Gynecology and Obstetrics (FIGO) stage ≥1B] treated at 29 gynecologic cancer centers between 1998 and 2008. This subgroup analysis evaluated the influence of SLND alone on progression-free survival (PFS) and overall survival (OS).

Results: In 487 (63.1%) of 772 included patients with tumors smaller than 4 cm, an LND was performed and no metastatic lymph nodes were detected (LN0). Another 69/772 (8.9%) women underwent SLND alone, showing a negative SLN (SLN0). Tumors in the LN0 group were larger and showed a deeper invasion (LN0 vs. SLN0 tumor diameter: 20.0 vs. 13.0 mm, p < 0.001; depth of invasion: 4.0 vs. 3.0 mm, p = 0.002). After a median follow-up of 33 months (0-156), no significant differences in relation to isolated groin recurrence rates (SLN0 3.0% vs. LN0 3.4%, p = 0.845) were detected. Similarly, univariate 3-year PFS analysis showed no significant differences between both groups (SLN0 82.7% vs. LN0 77.6%, p = 0.230). A multivariate Cox regression analysis, including tumor diameter, depth of invasion, age, grading, and lymphovascular space invasion was performed: PFS [hazard ratio (HR) 0.970, 95% confidence interval (CI) 0.517-1.821] and OS (HR 0.695, 95% CI 0.261-1.849) did not differ significantly between both cohorts.

Conclusion: This subgroup analysis of the large AGO-CaRE-1 study showed similar results for groin LND and SLND alone with regard to recurrence rates and survival in node-negative patients with tumors <4 cm.
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http://dx.doi.org/10.1245/s10434-016-5687-0DOI Listing
May 2017

Role of tumour-free margin distance for loco-regional control in vulvar cancer-a subset analysis of the Arbeitsgemeinschaft Gynäkologische Onkologie CaRE-1 multicenter study.

Eur J Cancer 2016 12 10;69:180-188. Epub 2016 Nov 10.

Gynecologic Oncology Center, Kiel, Germany.

Aim Of The Study: A tumour-free pathological resection margin of ≥8 mm is considered state-of-the-art. Available evidence is based on heterogeneous cohorts. This study was designed to clarify the relevance of the resection margin for loco-regional control in vulvar cancer.

Methods: AGO-CaRE-1 is a large retrospective study. Patients (n = 1618) with vulvar cancer ≥ FIGO stage IB treated at 29 German gynecologic-cancer-centres 1998-2008 were included. This subgroup analysis focuses on solely surgically treated node-negative patients with complete tumour resection (n = 289).

Results: Of the 289 analysed patients, 141 (48.8%) had pT1b, 140 (48.4%) pT2 and 8 (2.8%) pT3 tumours. One hundred twenty-five (43.3%) underwent complete vulvectomy, 127 (43.9%) partial vulvectomy and 37 (12.8%) radical local excision. The median minimal resection margin was 5 mm (1 mm-33 mm); all patients received groin staging, in 86.5% with full dissection. Median follow-up was 35.1 months. 46 (15.9%) patients developed recurrence, thereof 34 (11.8%) at the vulva, after a median of 18.3 months. Vulvar recurrence rates were 12.6% in patients with a margin <8 mm and 10.2% in patients with a margin ≥8 mm. When analysed as a continuous variable, the margin distance had no statistically significant impact on local recurrence (HR per mm increase: 0.930, 95% CI: 0.849-1.020; p = 0.125). Multivariate analyses did also not reveal a significant association between the margin and local recurrence neither when analysed as continuous variable nor categorically based on the 8 mm cutoff. Results were consistent when looking at disease-free-survival and time-to-recurrence at any site (HR per mm increase: 0.949, 95% CI: 0.864-1.041; p = 0.267).

Conclusions: The need for a minimal margin of 8 mm could not be confirmed in the large and homogeneous node-negative cohort of the AGO-CaRE database.
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http://dx.doi.org/10.1016/j.ejca.2016.09.038DOI Listing
December 2016

Propensity Scoring after Multiple Imputation in a Retrospective Study on Adjuvant Radiation Therapy in Lymph-Node Positive Vulvar Cancer.

PLoS One 2016 1;11(11):e0165705. Epub 2016 Nov 1.

Department of Gynecology and Obstetrics, Ludwig-Maximilians-University, Munich, Germany.

Propensity scoring (PS) is an established tool to account for measured confounding in non-randomized studies. These methods are sensitive to missing values, which are a common problem in observational data. The combination of multiple imputation of missing values and different propensity scoring techniques is addressed in this work. For a sample of lymph node-positive vulvar cancer patients, we re-analyze associations between the application of radiotherapy and disease-related and non-related survival. Inverse-probability-of-treatment-weighting (IPTW) and PS stratification are applied after multiple imputation by chained equation (MICE). Methodological issues are described in detail. Interpretation of the results and methodological limitations are discussed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165705PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089685PMC
June 2017

Utility of EFC quality indicators for colposcopy in daily practice: results from an independent, prospective multicenter trial.

Eur J Obstet Gynecol Reprod Biol 2015 Aug 30;191:43-7. Epub 2015 May 30.

Klinikum Wolfsburg, Department of Obstetrics and Gynecology, Sauerbruchstr. 7, Wolfsburg, Germany. Electronic address:

Objectives: The accuracy of colposcopy as the gold standard to manage abnormal screening tests depends on qualification and well defined standards. A recent survey of the European Federation for Colposcopy (EFC) found strong heterogeneity in the practice of colposcopy across Europe. EFC defined four quality indicators (QIs) to enable quality assessment in colposcopy as one tool to harmonize colposcopy standards. We undertook a pilot project to estimate the utility of these QIs for an independent external quality assessment in daily routine colposcopy.

Study Design: Participating colposcopy clinics used newly developed software for data collection. Data were automatically anonymized, encrypted and stored in a secure relational database located within the clinics' network and allowed for an independent external benchmarking comparing the performance of participating clinics according to EFC QIs.

Results: 10,869 patients referred for routine colposcopy were included. On average none of the four EFC QIs was fulfilled. One target was almost met with 83.3% instead of 85% excisional treatments/conizations containing CIN2+ and for another QI the difference of 94.4% instead of 100% cases having a colposcopic examination prior to treatment for abnormal cervical cytology was mainly explained by wrong documentation. For a third QI, visibility of the squamocolumnar junction (SCJ) was only reported in 90.9% instead of 100% but reporting improved to 94.7% after a consensus meeting. The last QI, >80% clear margins in excised lesions/conizations were not considered as useful by some clinics and therefore not documented.

Discussion And Conclusions: At least 3 out of 4 QIs seemed to be useful for quality assessment in colposcopy but will need rewording and readjustment. All tools for an independent electronic quality assessment with the use of EFC-QI are available and could be used to achieve a high quality standard in colposcopy across Europe.
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http://dx.doi.org/10.1016/j.ejogrb.2015.05.020DOI Listing
August 2015

Incidence patterns and temporal trends of invasive nonmelanotic vulvar tumors in Germany 1999-2011. A population-based cancer registry analysis.

PLoS One 2015 28;10(5):e0128073. Epub 2015 May 28.

Robert Koch-Institute, Department of Epidemiology and Health Monitoring, German Centre for Cancer Registry Data, Berlin, Germany.

Objectives: Time trends on the incidence and characteristics of invasive vulvar cancer in Germany have so far been studied in few local population- and hospital based tumor registries. We aimed to provide an overview on recent developments of vulvar cancer in Germany, using population-based cancer registry data.

Methods: We analyzed the data on vulvar cancer of eight population-based German cancer registries for the period 1999-2011. ICD-10 codes and ICD-O-3 morphology codes were used to select site and histologic types. The annual percentage change was calculated on age-adjusted incidence rates with a joinpoint regression model.

Results: A total of 12,711 registered cases of invasive carcinoma of the vulva were included in the analyses, hereof were 12,205 of squamous cell origin. Age-standardized incidence rates of vulvar cancer annually increased by 6.7% (95% confidence limits: 5.6-7.9) from 1.7 per 100,000 women in 1999 to 3.6 per 100,000 women in 2011. An increase was observed among women of all ages, and especially between 30 and 69 years of age.

Conclusion: The annual incidence of invasive carcinoma of the vulva nearly doubled in the past decade in Germany, considerably exceeding the rates observed in other Western European countries. A combination of changes in risk factors, and documentation practice might have contributed to the observed substantial increase in vulvar cancer incidence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128073PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447423PMC
April 2016

Laser-skinning colpectomy for extended vaginal intraepithelial neoplasia and microinvasive cancer.

Gynecol Oncol 2014 Nov 23;135(2):217-22. Epub 2014 Aug 23.

Department of Gynecology, Obstetrics and Gynecologic Oncology, Klinikum Wolfsburg, Germany. Electronic address:

Objective: The aim of this study is to analyze the efficacy of colposcopic-guided laser-skinning colpectomy to treat extended high-grade vaginal intraepithelial neoplasia (VaIN).

Methods: Retrospective review of 33 heavily pretreated patients with high-grade VaIN extending over 20-100% of the vaginal surface treated between 2003 and 2013 with colposcopic-guided laser-skinning colpectomy. The vaginal epithelium including all VaIN lesions was excised in one piece with a depth of 2-3mm.

Results: Vaginal cancer was diagnosed in 10 patients (nine microinvasive squamous cell carcinoma and one vaginal carcinoma). No serious adverse events related to laser-skinning colpectomy were observed. Of 33 patients, 23 were followed up with cytology and colposcopy for at least 12months at our institution (median follow 26.5months; range 12-104months), while five had a shorter follow-up, four an external follow-up and one patient was lost. Of 23 patients with follow-up ≥12months, 20 were disease free after a single laser-skinning colpectomy (overall cure rate 87.0%). Moderate shortening of the vagina was observed in two patients and another two required reconstruction of vaginal strictures during long-term follow-up.

Conclusion: Laser-skinning colpectomy appears to be a feasible treatment for extended high-risk VaIN3. The procedure avoids the mutilation associated with colpectomy and allows early diagnosis and staging of invasive disease.
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http://dx.doi.org/10.1016/j.ygyno.2014.08.019DOI Listing
November 2014

Utility and Reproducibility of the International Federation for Cervical Pathology and Colposcopy Classification of Transformation Zones in Daily Practice: A Multicenter Study of the German Colposcopy Network.

J Low Genit Tract Dis 2015 Jul;19(3):185-8

1Klinikum Wolfsburg, Department of Obstetrics and Gynecology, Sauerbruchstr, Wolfsburg; 2German Centre for Cancer Registry Data, Department of Epidemiology and Health Monitoring, Robert Koch Institute, Berlin; 3Cancer Epidemiology, University Cancer Center Dresden, Technische Universität Dresden, Dresden; 4Partnerschaftsgesellschaft abts+partner Prüner Gang, Kiel, Germany Deutsche Klinik; 5Gynäkologische Gemeinschaftspraxis, Karrenführerstraße, Braunschweig; 6Institute for Cytology and Cytology, Theaterstr, Hannover, Germany, 7University Medical Center Hamburg-Eppendorf, Department of Gynecology, Martinistraße, Hamburg; 8Frauenarztpraxis, Am Herzogenkamp, Bremen; 9University Düsseldorf, Clinic for Gynecology and Obstetrics, Moorenstr, Düsseldorf; 10Frauenarztpraxis, Heussweg, Hamburg; and 11Asthenis GmbH, Aschheim, Germany.

Objective: To compare the distribution of International Federation for Cervical Pathology and Colposcopy (IFCPC) transformation zone (TZ) types among women in different age groups referred to 8 colposcopy clinics.

Materials And Methods: Between February 2012 and February 2013, we prospectively collected individual patient data from 8 clinics within the German Colposcopy Network (G-CONE). Data were analyzed using ODSdysplasie, software designed to allow continuous quality assessment in colposcopy clinics. The distribution of IFCPC-classified TZ was compared between different centers for the following age groups: younger than 30 years, between 30 and 50 years, and older than 50 years.

Results: Of 3,761 patients included in the analysis, 2,153 (57%) were classified as having type 2 TZ, 906 (24%) as type 1 TZ, and 702 (19%) as type 3 TZ. Type 3 TZ was the most commonly reported type in women older than 50 years (70%). We found that the relative distribution of type 3 TZ between age groups was similar in the participating colposcopy clinics. However, there was evidence of heterogeneous distribution of types 1 and 2 TZ between age groups in different clinics, ranging from 7.8% to 66.4% for type 1 TZ in women younger than 30 years and 28.9% to 78.1% for type 2 TZ in women 30 to 50 years old.

Conclusions: Although IFCPC type 3 TZ seems to be a reproducible finding, the distribution of types 1 and 2 TZ showed significant heterogeneity. A more precise anatomic distinction between types 1 and 2 TZ in the IFCPC terminology could improve reporting of colposcopy findings.
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http://dx.doi.org/10.1097/LGT.0000000000000069DOI Listing
July 2015

Efficacy and safety of hexaminolevulinate photodynamic therapy in patients with low-grade cervical intraepithelial neoplasia.

Lasers Surg Med 2014 Aug 6;46(6):456-61. Epub 2014 May 6.

Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.

Objective: Non-surgical therapies are needed to reduce the rate of progression of low-grade cervical intraepithelial neoplasia (CIN 1) to high grade CIN (CIN 2/3). The aim of this study was to assess the efficacy and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT) in the treatment of patients with CIN 1.

Study Design: This phase IIa prospective double-blind study randomized patients with CIN 1 into three groups: HAL vaginal suppository, placebo vaginal suppository or follow-up only. Patients in the first two groups received HAL or placebo suppositories 5 hours before illumination with 50 J/cm(2) red coherent light (633 nm) using a special light catheter. All patients had a follow up including colposcopy, cytology and human papilloma virus (HPV) testing 3 and 6 months and additional biopsy 6 months after PDT. The main outcome measure was efficacy, defined as complete histologic remission 6 months after PDT. Secondary outcomes were histologic remission 3 months and HPV eradication 6 months after first PDT.

Results: Seventy patients were randomized: 47 to HAL, 12 to placebo, 11 to follow up only. After 6 months CIN lesions had cleared in 57% of patients in the HAL-PDT group compared to 25% in the combined control group (per protocol population, P = 0.04). Twenty-six patients (37%) reported 44 adverse events (AEs), of which 40 were mild or moderate. Nineteen treatment-related AEs were reported by 15 patients (32%) in the HAL PDT group, one in the placebo PDT group (8%), and none in the follow-up group. The most common adverse events were local discomfort including mild pain/cramping (11) and leucorrhoea (2).

Conclusion: HAL PDT shows a favorable efficacy and safety profile and represents a promising alternative to observation and surgical procedures in patients with CIN 1.
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http://dx.doi.org/10.1002/lsm.22255DOI Listing
August 2014

Early detection of CIN3 and cervical cancer during long-term follow-up using HPV/Pap smear co-testing and risk-adapted follow-up in a locally organised screening programme.

Int J Cancer 2014 Sep 27;135(6):1408-16. Epub 2014 Feb 27.

Department of Gynaecology and Obstetrics, Klinikum Wolfsburg, Wolfsburg, Germany.

We evaluated compliance with human papillomavirus (HPV) testing and risk-adapted patient pathways and monitored changes in high-grade cervical disease during long-term follow-up. Women aged >30 years attending routine screening for cervical cancer were managed according to results from first-round screening tests (cytology and high-risk HPV; Hybrid Capture 2). Between February 2006 and January 2011, 19,795 of 19,947 women agreed to participate, of whom 4,067 proceeded to a second screening round 5 years after recruitment. Predefined endpoints were compliance, grade 3 cervical intraepithelial neoplasia or cancer (CIN3+), new HPV infection, HPV persistence and abnormal smears in round 2. A total of 765 of 19,795 women (3.9%) in round 1 and 41 of 4,067 (1.0%) in round 2 were referred for colposcopy. Compliance rates with colposcopy were 93.1 and 92.7%, respectively, while histological assessment was performed in 680 of 712 (95.5%) and 36 of 38 (94.7%), respectively. CIN3+ rates were 172 of 19,795 (0.87%; 95% confidence intervals: 0.7-1.0) in round 1 and 2 of 4,064 (0.05%; 95% confidence intervals: 0.006-0.2) in round 2; the difference was statistically significant (Fisher's exact test, p<0.001). After 5 years, the incidence of new HPV infection was 124 of 3,906 (3.2%) and HPV persistence was observed in 22 of 161 (13.7%). Locally organised HPV/cytology co-testing is feasible and acceptable to women. Risk-adapted management rapidly detected a high rate of prevalent CIN3+, while the subsequent long-term risk of new high-grade cervical disease was surprisingly low. It remains unclear if this phenomenon is explained by CIN3 mostly occurring early in life or by modifying the natural course of HPV infection with colposcopy and histological assessment.
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http://dx.doi.org/10.1002/ijc.28783DOI Listing
September 2014

Treatment of extramammary Paget disease of the vulva with imiquimod: a retrospective, multicenter study by the German Colposcopy Network.

J Am Acad Dermatol 2014 Apr 14;70(4):644-650. Epub 2014 Jan 14.

Klinikum Wolfsburg, Klinik für Frauenheilkunde, Geburtshilfe und Gynäkologische Onkologie, Wolfsburg, Germany.

Background: Extramammary Paget disease (EMPD) is a very rare genital neoplasia associated with a high frequency of local recurrences. Surgical excision is the standard treatment, but results in mutilating procedures in patients with advanced or recurrent disease. Case reports have shown clinical responses to imiquimod in patients with EMPD, but this therapy has not been evaluated systematically.

Objective: The aim of this study was to evaluate imiquimod as local treatment of first-time and recurrent EMPD.

Methods: All cases of biopsy-proven EMPD of the vulva treated within the German Colposcopy Network or other institutions specializing in vulvar diseases in Germany were included in this retrospective analysis.

Results: A total of 21 women with EMPD treated with imiquimod were identified: 11 (52.4%) achieved complete response, 6 (28.6%) achieved partial response, and there were no cases of progressive disease. The dose and duration of imiquimod differed between patients. The mean duration of treatment exceeded 16 weeks in women achieving complete response.

Limitations: EMPD is rare and this retrospective study is limited by the small number of patients identified.

Conclusion: When associated cancers and invasive growth are excluded, imiquimod appears to be a useful treatment option for recurrent EMPD and may avoid extensive mutilating surgical treatment.
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http://dx.doi.org/10.1016/j.jaad.2013.12.008DOI Listing
April 2014

Annual Papanicolaou screening for 5 years among human papillomavirus-negative women.

BMC Cancer 2013 Aug 9;13:379. Epub 2013 Aug 9.

Zentrum für Frauenheilkunde, Medizinische Hochschule Hannover (MHH), Carl-Neuberg-Street 1, 30625 Hannover, Germany.

Background: Primary human papilloma virus (HPV) screening is more effective than cytology in reducing the risk of cervical cancer, but screening intervals should be extended in HPV-negative women. However, some Markov models predicted that long intervals are associated with an excess risk of cervical cancer. The aim of this analysis was to estimate the real-life risks and benefits of annual Papanicolaou (Pap) screening in HPV-negative women with normal cytology.

Methods: Women with negative Hybrid Capture 2 (HC2) results and normal cytology at the time of inclusion in the Hannover HPV screening trial underwent annual Pap smears for 5 years. A subgroup was randomly selected for retesting with cytology, HC2, and colposcopy 60-68 months after recruitment.

Results: Of 4236 women included, 3406 had at least one Pap smear, but only 1185 attended all five annual screening visits. The proportion of women with at least one abnormal smear was 14.4% in 60 months. The probability of abnormal smears increased continuously over time. No case of ≥ CIN2+ was observed during 5 years. Of 605 women selected for subgroup analysis, 292 agreed to be retested (48.3%). The rate of high-risk HPV at 60-68 months was 3.0% (9/296).

Conclusions: The long-term risk of high-grade neoplasia after an initial negative HC2 test and normal cytology result was low, while the rate of false-positive abnormal Pap smears was significant and increased constantly over time. Pap smear screening of HPV-negative women more frequently than every 5 years could be potentially harmful and seems to be of little clinical value.
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http://dx.doi.org/10.1186/1471-2407-13-379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751119PMC
August 2013

Prevalence of high-risk HPV types and associated genital diseases in women born in 1988/89 or 1983/84--results of WOLVES, a population-based epidemiological study in Wolfsburg, Germany.

BMC Infect Dis 2013 Mar 13;13:135. Epub 2013 Mar 13.

Klinikum Wolfsburg, Frauenklinik, Schwerpunkt gynäkologische Onkologie, Sauerbruchstr.7, Wolfsburg 38440, Germany.

Background: High-risk human papilloma virus (HR-HPV) infection is associated with the development of cervical cancer. HPV vaccination reduces the risk of developing malignant lesions and is expected to change the dynamics of HPV transmission. Data from non-vaccinated women may provide an important benchmark to allow the impact of HPV vaccination programs to be assessed.This study was designed to prospectively determine the changing dynamics of HR-HPV infection and associated genital diseases in young women, most of whom were non-vaccinated.

Methods: Data from a population-based cohort study, comprising women of two predefined birth cohorts (women born in 1983/84 or 1988/89), were analyzed between 19 October 2009 and 31 December 2010 to determine risk factors for high-risk HPV infection and the association between specific HR-HPV types and atypical Pap smear test results. HPV status was determined by Hybrid Capture 2 (HC2) assay and genotyping.

Results: The prevalence of HR-HPV was 22.8% in the 1983/84 cohort (150/659) and 23.7% in the 1988/99 cohort (142/599). Only the number of sexual partners was a significant risk factor for HPV infection (odds ratios 22.687 and 6.124 for more than five versus one partner 84 cohort,/84 and 1988/89 cohorts, respectively) in multivariate analysis. HPV16 positive-women were significantly more likely to have abnormal Pap smears of any degree than HPV16-negative women (22.0% versus 3.61%, p < 0.0001 for the 1983/84 cohort and 9.09% versus 2.52%, p = 0.0482 for the 1988/89 cohort). CIN3 was diagnosed in six women 84 cohort,/84 cohort and two in the 1988/89 cohort. All women with CIN3 tested positive for HC2-HR and all six CIN3 cases 84 cohort,/84 cohort tested positive for HPV16. In the 1988/89 cohort, the rate of HPV16 infection was significantly lower in vaccinated than non-vaccinated women (1.59% versus 8.88%; p = 0.003).

Conclusions: HR-HPV infection was highly prevalent in both cohorts and associated with an increased risk of abnormal Pap smears and biopsy proven CIN2+. HPV16 infection was associated with a high risk of clinically relevant lesions. HPV vaccination significantly decreased the risk of HPV16 infection.
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http://dx.doi.org/10.1186/1471-2334-13-135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623770PMC
March 2013

Prevalence of low-risk HPV types and genital warts in women born 1988/89 or 1983/84 -results of WOLVES, a population-based epidemiological study in Wolfsburg, Germany.

BMC Infect Dis 2012 Dec 21;12:367. Epub 2012 Dec 21.

Klinikum Wolfsburg, Frauenklinik, Schwerpunkt gynäkologische Onkologie, Sauerbruchstr, 7, 38440, Wolfsburg, Germany.

Background: Wolfsburg HPV Epidemiological Study (WOLVES) is a population-based cohort study on HPV infections and associated diseases in the pre-vaccination era in young women in Wolfsburg, Germany.

Methods: Women born 1983/84 or 1988/89 were invited to participate. Participants were recruited in gynecology practices, and completed a questionnaire with socioeconomic, sexual and medical data including vaccination status. Pelvic examination with Pap smear and HPV testing (HC2 = Hybrid Capture 2) was obligatory. HC2-positive and 10% of HC2-negative samples were tested for specific HPV types with SPF-10-PCR, and in inconclusive cases with DNA sequencing. Women with genital warts (GW) and those with atypical Pap smears were transferred for colposcopy. GWs were classified as typical condylomata acuminata (TCA), flat condyloma (FC) and seborrheic wart-like (SWL).

Results: In total, 1258 subjects were recruited from the target population of 2850 (44.1%). Overall the prevalence of HC2 low-risk (LR) types was 8.5%. HPV6 was the most frequent LR type (2.1%), followed by HPV42 (1.1%), HPV11 and HPV44 (each 0.4%). LiPA showed a low sensitivity for HPV types 42, 90 and 91, which were detected only by HC2 and HPV sequencing. Nine women (0.7%) were transferred with incident GW: five TCA, two FC and two SWL. All TCA were associated with HPV6 in corresponding cervical swabs and warts. Tissues of SWL contained HPV6 (n = 1) and HPV16 (n = 1). The cumulative life-risk for GW was 1.4% in the 1988/89 and 4.8% in the 1983/84 cohort. Eight of 107 HC2-LR + and five of nine cases of GW had concomitant abnormal Pap smears. All CIN lesions could be linked to high-risk HPV types but borderline and low-grade abnormal smears were explained by vaginal and cervical TCA in four cases.

Conclusions: HC2 was a specific test for the detection of established and potential LR types. In this first WOLVES analysis, HPV6 was the most frequent HPV type and the single LR type linked to disease. The observed GW incidence of 715 per 100,000 fits well with estimates of healthcare providers. Although life risks for GW were lower than in Scandinavian analyses, the societal burden within the WOLVES populations was considerable.
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http://dx.doi.org/10.1186/1471-2334-12-367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536688PMC
December 2012

Accuracy of colposcopy management to detect CIN3 and invasive cancer in women with abnormal screening tests: results from a primary HPV screening project from 2006 to 2011 in Wolfsburg, Germany.

Gynecol Oncol 2013 Feb 23;128(2):282-7. Epub 2012 Oct 23.

Department of Obstetrics and Gynecology, Klinikum Wolfsburg, Wolfsburg, Germany.

Objective: Combining HPV and Pap screening achieves very good risk stratification and sensitive detection of CIN3 and cancer (CIN3 +), but poorer specificity, and may result in an increased risk of glandular and new lesions during follow-up. We examined if this phenomenon may compromise the accuracy of colposcopy.

Methods: As part of a primary HPV screening pilot project comprising 19,624 participants aged over 30 years, the failure rate to detect CIN3 at first visit was measured over a five-year period to assess the quality of colposcopy as an overall management concept. Management relied on excisional biopsies in all HSIL cytology or major findings on colposcopy, endocervical assessment in type 3 transformation zones (TZ) and guided biopsies in type 1 or 2 TZ.

Results: Of 667 women referred for colposcopy because of atypical Pap smears and/or HPV persistency, 171 were diagnosed with CIN3+. All 18 cancers and 140/153 CIN3 cases were diagnosed at the first visit. Of 13 CIN3 observed during follow-up, five were classified as new cases, five as definite and three as probably colposcopy failures, giving a failure rate of 4.7% (8/171). Only three failures were related to false-negative punch biopsies while five occurred because of false-negative endocervical assessment in type 3 TZ.

Conclusions: Colposcopy management following defined pathways was safe in this HPV screening program with an acceptable failure rate. Further improvements may depend on developing better methods for endocervical assessment rather than for ectocervical biopsies.
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http://dx.doi.org/10.1016/j.ygyno.2012.10.017DOI Listing
February 2013

Evaluation of a new multiplex real-time polymerase chain reaction assay for the detection of human papillomavirus infections in a referral population.

Int J Gynecol Cancer 2012 Jul;22(6):1050-6

Department of Gynaecology and Obstetrics, Hannover Medical School, Germany.

Objectives: Human papillomavirus (HPV) testing is an important part of cervical cancer screening and management of women with atypical screening results. This study was conducted to evaluate the analytical and clinical performance of the Abbott RealTime High-Risk HPV assay (RealTime) in a referral population, in comparison to the Qiagen Hybrid Capture 2 High-Risk HPV DNA Test (hc2).

Methods: RealTime is a new polymerase chain reaction assay that detects 14 high-risk HPV genotypes with simultaneous differentiation between HPV 16 and HPV 18. Five hundred forty-five routine cervical smear samples (ThinPrep) from women who were referred to 2 German colposcopy clinics were included in the study. All samples were tested with both assays for the detection of high-risk HPV DNA. Specimens with repeatedly discordant results were genotyped by Linear Array (Roche) and in-house polymerase chain reaction assays.

Results: Both assays showed excellent overall agreement (92.8%; κ = 0.86) on 545 samples. Analytical sensitivity of RealTime was comparable to that of hc2 (97.6% vs 95.1%, P = 0.189), whereas RealTime demonstrated significantly higher analytical specificity compared with hc2 (100% vs 93.1%, P < 0.0001). RealTime showed no cross-reactivity with untargeted HPV genotypes in this study. The clinical performance of the assays was evaluated based on histology results available from 319 women (90 nonpathological, 73 cervical intraepithelial neoplasia [CIN] 1, 75 CIN 2, 74 CIN 3, and 7 invasive cancers). High-risk HPV detection rates observed in women with CIN 1, CIN 2+, and CIN 3+ diagnosis, respectively, were comparable for both assays: 47.9%, 92.3%, and 97.5% (RealTime) and 47.9%, 92.3%, and 93.8% (hc2). Detection of HPV 16/18 with RealTime was highly correlated with severity of dysplasia: less than CIN 2, 30.5%; CIN 2+, 59.0%; CIN 3+, 71.6%.

Conclusions: These results support the use of RealTime for routine detection of HPV infections in a referral population.
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http://dx.doi.org/10.1097/IGC.0b013e31825529b7DOI Listing
July 2012

Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 Dual-stained cytology.

Gynecol Oncol 2011 Jun 21;121(3):505-9. Epub 2011 Mar 21.

Klinikum der Stadt Wolfsburg, Department of Obstetrics and Gynecology, Wolfsburg, Germany.

Objective: Testing for human papillomavirus (HPV) has been shown to increase the sensitivity and negative predictive value for detection of high-grade cervical intraepithelial neoplasia (CIN2+), either when used in conjunction with Pap cytology testing or alone. However, there is no satisfying clinical management algorithm for women testing Pap negative/HPV positive. We therefore evaluated the clinical utility of a novel dual biomarker-based approach (p16/Ki-67 Dual-stained cytology) for the identification of CIN2+ in women with Pap negative/HPV positive screening results, without the need to refer all women to immediate colposcopy.

Methods: All women aged ≥30 enrolled during 2007/2008 into a regional prospective Pap/HPV co-testing screening pilot project and tested Pap negative, but positive for HPV (n=425) were included in the analysis. p16/Ki-67 Dual-stained cytology was performed from residual cellular material available from the liquid-based cytology vial collected during the initial Pap/HPV co-testing screening visit. Results were correlated to the presence of CIN2+ confirmed during preliminary follow-up.

Results: p16/Ki-67 Dual-stained cytology tested positive at baseline in 108 out of 425 (25.4%) Pap negative/HPV positive cases. Sensitivity of Dual-stain testing for the detection of biopsy-confirmed CIN2+ during preliminary follow-up within the group of Pap negative/HPV positive women was 91.9% for CIN2+ (34/37 cases), and 96.4% for CIN3+ (27/28 cases). Specificity was 82.1% for CIN2+ on biopsy, and 76.9% for CIN3+, respectively.

Conclusions: Triaging Pap negative/HPV positive screening test results with p16/Ki-67 Dual-stained cytology may identify women with a high probability of underlying CIN2+ and may efficiently complement HPV-based screening programs to prevent cervical cancer.
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http://dx.doi.org/10.1016/j.ygyno.2011.02.033DOI Listing
June 2011

Risk-adapted primary HPV cervical cancer screening project in Wolfsburg, Germany--experience over 3 years.

J Clin Virol 2009 Nov;46 Suppl 3:S5-10

Klinikum der Stadt Wolfsburg, Germany.

Background: Currently, the German cervical cancer screening program encompasses an annual cytological Papanicolaou (Pap) smear. However, primary screening for cervical cancer using human papillomavirus (HPV) DNA testing detects cervical pre-cancerous lesions with a significantly higher sensitivity than the Pap smear-based cytology.

Objectives: In order to develop viable modalities for primary cervical screening incorporating DNA testing for high-risk (HR) types of HPV, we started a pilot project in the city of Wolfsburg, Germany, in February 2006. This program provided a risk-adapted HPV testing-based strategy with defined patient pathways and extended screening intervals for women of 30 years or older. We report here the data of a 3-year follow-up.

Study Design: In the context of the usual routine screening at their office-based gynecologists, women were offered conventional cytology plus the Hybrid Capture 2 (HC2) HPV DNA test. Women with inconspicuous cytological findings (Pap I/II) and negative HC2 test were re-tested after 5 years but continued their annual gynecological examinations. When cytology and HC2 were positive, women were immediately referred to colposcopy. In women with a negative cytology but positive HC2 test, Pap smear was repeated after 6 mo and HC2 testing after 12 mo, and women were called for colposcopy if the HC2 test was persistently positive.

Results: From February 2006 to December 2008, 16,724 women agreed to participate in the project. Overall, 906 (5.41%) had positive HC2 results and 338 (2.02%) showed atypical Pap smears at recruitment. There were 417 (2.48%) women referred for colposcopy, 104 of whom were diagnosed with cervical intraepithelial neoplasia (CIN) 3 or worse, including 8 invasive cancers and 8 adenocarcinoma in situ (ACIS). No case of CIN 3 or worse occurred in HC2 negative women.

Conclusions: The presented risk-adapted Wolfsburg Cervical Cancer Prevention Project ("Wolfsburg Model") has been shown to be effective and feasible in identifying women at risk and for avoiding unnecessary procedures for those who are double negative, thus allowing longer screening intervals and cost savings. Acceptance rates for the program were high for both participating women and gynecologists.
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http://dx.doi.org/10.1016/S1386-6532(09)70294-XDOI Listing
November 2009
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