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Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view.

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 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.

Introduction: Human papillomavirus–vaccinated cohorts, irrespective of age, will likely reduce their subsequent screening requirements, thus opening opportunities for global cost reduction and program sustainability. The determinants of uptake and completion of a 3-dose human papillomavirus vaccination program by adult women in a European context were estimated. Study design: This was an intervention study. Setting/participants: Study participants were women aged 25–45 years, attending opportunistic or population-based cervical cancer screening in Belgium, Denmark, Finland, France, Germany, Slovenia, Spain, Sweden, and the United Kingdom between April 2016 and May 2018. Intervention: Study participants completed a questionnaire on awareness and attitudes on adult female human papillomavirus vaccination and were invited to receive free human papillomavirus vaccination. Main outcome measures: Main outcome measures were acceptance, uptake, and completion of vaccination schedule. Determinants of vaccine uptake were explored using multilevel logistic models in 2019. Results: Among 3,646 participants, 2,748 (range by country=50%–96%) accepted vaccination, and 2,151 (range=30%–93%) received the full vaccination course. The factors associated with higher vaccine acceptance were previous awareness of adult female (OR=1.22, 95% CI=1.00, 1.48) and male (OR=1.59, 95% CI=1.28, 1.97) vaccination. Women in stable relationships (OR=0.56, 95% CI=0.45, 0.69) or with higher educational level (OR=0.76, 95% CI=0.63, 0.93) were more likely to refuse vaccination. Recruitment by postal invitation versus personal invitation from a healthcare professional resulted in lower vaccine acceptance (OR=0.13, 95% CI=0.02, 0.76). Vaccination coverage of >70% of adolescent girls in national public programs was of borderline significance in predicting human papillomavirus vaccine uptake (OR=3.23, 95% CI=0.95, 10.97). The main reasons for vaccine refusal were vaccine safety concerns (range=30%–59%) and the need for more information on human papillomavirus vaccines (range=1%–72%). No safety issues were experienced by vaccinated women. Conclusions: Acceptance and schedule completion were largely dependent on recruitment method, achieved coverage of national vaccination programs, and personal relationship status. Knowledge of benefits and safety reassurance may be critical to expanding vaccination target ages. Study results suggest that there are no major opinion barriers in adult women to human papillomavirus vaccination, especially when vaccination is offered face to face in healthcare settings. Trial Registration: EudraCT Number 2014-003177-42. publishedVersion

Widespread adoption of primary human papillomavirus (HPV)‐based screening has encouraged the search for a triage test which retains high sensitivity for the detection of cervical cancer and precancer, but increases specificity to avoid overtreatment. Methylation analysis of FAM19A4 and miR124‐2 genes has shown promise for the triage of high‐risk (hr) HPV‐positive women. In our study, we assessed the consistency of FAM19A4/miR124‐2 methylation analysis in the detection of cervical cancer in a series of 519 invasive cervical carcinomas (n = 314 cervical scrapes, n = 205 tissue specimens) from over 25 countries, using a quantitative methylation‐specific PCR (qMSP)‐based assay (QIAsure Methylation Test®). Positivity rates stratified per histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region were calculated. In total, 510 of the 519 cervical carcinomas (98.3%; 95% CI: 96.7–99.2) tested FAM19A4/miR124‐2 methylation‐positive. Test positivity was consistent across the different subgroups based on cervical cancer histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region. In conclusion, FAM19A4/miR124‐2 methylation analysis detects nearly all cervical carcinomas, including rare histotypes and hrHPV‐negative carcinomas. These results indicate that a negative FAM19A4/miR124‐2 methylation assay result is likely to rule out the presence of cervical cancer., What's new? Methylation analysis of host cell genes is a promising strategy for the triage of women who test positive for high‐risk human papillomavirus (hrHPV). Its ability to consistently detect cervical cancer, however, warrants further evaluation. In this retrospective cross‐sectional study of more than 500 cervical cancer cases worldwide, methylation analysis using FAM19A4 and miR124‐2 genes successfully detected the vast majority of cervical carcinomas. Detection by FAM19A4/miR124‐2 methylation analysis was consistent regardless of multiple factors, including hrHPV status and genotype, cancer histotype, sample type, and geographical region. The findings suggest that a negative FAM19A4/miR124‐2 methylation test result is likely to rule out cervical cancer.

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 × 10-6 ; 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 × 10-5 ; 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.

Summary Background Incomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure. Methods We did a systematic review and meta-analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta-analysis of binomial data and analysed using random-effects models. Findings 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23·1% (95% CI 20·4–25·9) overall and varied by treatment procedure (ranging from 17·8% [12·9–23·2] for laser conisation to 25·9% [22·3–29·6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6·6% (95% CI 4·9–8·4) and was increased with positive compared with negative resection margins (relative risk 4·8, 95% CI 3·2–7·2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55·8% (95% CI 45·8–65·5) and 84·4% (79·5–88·4), respectively, for the margin status, and 91·0% (82·3–95·5) and 83·8% (77·7–88·7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0·8%, whereas this risk was 3·7% when margins were free. Interpretation The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than margin status. Funding European Federation for Colposcopy and Institut national du Cancer (INCA).

BACKGROUND: HPV-based cervical screening detects women at an increased risk of cervical cancer and precancer. To differentiate among HPV-positive women those with (pre)cancer, triage testing is necessary. The detection of cancer-associated host-cell DNA methylation (FAM19A4 and hsa-mir124-2) in cervical samples has shown valuable as triage test. This multicenter study from 6 collaborating European laboratories and one reference laboratory was set out to determine the intra- and inter-laboratory agreement of FAM19A4/mir124-2 DNA methylation analysis utilizing the QIAsure Methylation Test.METHODS: Agreement analysis for the QIAsure Methylation Test was assessed on high-risk HPV-positive cervical specimens (n = 1680) both at the level of the assay and at the full workflow, including bisulfite conversion.RESULTS: Intra- and inter-laboratory assay agreement were 91.4% (534/584; 95% CI 88.9-93.5; κ = 0.82) and 92.5% (369/399; 95% CI 90.0-94.7; κ = 0.83), respectively. The inter-laboratory workflow (bisulfite conversion and assay combined) agreement was 90.0% (627/697; 95% CI 87.5%-92.0%; κ = 0.76).CONCLUSION: These data show that the QIAsure Methylation Test performs robust and reproducible in different laboratory contexts. These results support the use of the QIAsure Methylation Test for full molecular screening for cervical cancer, including primary HPV testing and triage testing by methylation analysis.

Background: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma—a human papillomavirus–dependent pathway characterized by p16 overexpression and a human papillomavirus–independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed.Objective: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance.Study Design: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction.Results: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53− (n=132), and p16−/p53− (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53− tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16−/p53− tumors; PConclusion: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53−/p16− phenotype showing an intermediate prognosis that needs to be further characterized.

Introduction: Since 2007, the German Standing Vaccination Committee recommends HPV vaccination for girls aged 12–17 with a 2- (Cervarix®) or 4-valent (Gardasil®) vaccine. A 9-valent vaccine (Gardasil 9®) recently received a European market authorization in 2015.Methods: A dynamic transmission model was calibrated to the German setting and used to estimate costs and QALYs associated with vaccination strategies.Results: Compared to the current vaccination program, the 9-valent vaccine extended to boys shows further reductions of 24% in the incidence of cervical cancer, 30% and 14% in anal cancer for males and females, as well as over a million cases of genital warts avoided after 100 years. The new strategy is associated with an ICER of 22,987€ per QALY gained, decreasing to 329€ when considering the vaccine switch for girls-only.Conclusion: Universal vaccination with the 9-valent vaccine can yield significant health benefits when compared to the current program.

A post hoc analysis of the ATHENA study was performed to determine whether true HPV‐negative cervical lesions occur and whether they have clinical relevance. The ATHENA database was searched for all CIN2 or worse (CIN2+) cases with cobas HPV‐negative results and comparison was made with Linear Array (LA) and Amplicor to detect true false‐negative HPV results. Immunostaining with p16 was performed on these cases to identify false‐positive histology results. H&E slides were re‐reviewed by the study pathologists with knowledge of patient age, HPV test results and p16 immunostaining. Those with positive p16 immunostaining and/or a positive histopathology review underwent whole tissue section HPV PCR by the SPF10/LiPA/RHA system. Among 46,887 eligible women, 497 cases of CIN2+ were detected, 55 of which tested negative by the cobas® HPV Test (32 CIN2, 23 CIN3/ACIS). By LA and/or Amplicor, 32 CIN2+ (20 CIN2, 12 CIN3/ACIS) were HPV positive and categorized as false‐negatives by cobas HPV; nine of 12 false‐negative CIN3/ACIS cases were p16+. There were 23 cases (12 CIN2, 11 CIN3/ACIS) negative by all HPV tests; seven of 11 CIN3/ACIS cases were p16+. H&E slides were available for six cases for re‐review and all were confirmed as CIN3/ACIS. Tissue PCR was performed on the six confirmed CIN3/ACIS cases (and one without confirmation): four were positive for HPV types not considered oncogenic, two were positive for oncogenic genotypes and one was indeterminate. In summary, subanalysis of a large cervical cancer screening study did not identify any true CIN3/ACIS not attributable to HPV., What's new? Human papillomavirus (HPV) testing has a high negative predictive value for detecting histological cervical intraepithelial neoplasia (CIN). False‐negative HPV results can occur, however, though their clinical relevance is little understood. Using data from the U.S.‐based ATHENA study, the authors of the present report show that only a very small percentage of CIN grade 3/adenocarcinoma in situ (ACIS) lesions were missed by the cobas HPV Test, which identifies 14 high‐risk HPV types. False‐negatives by cobas testing were compared with Linear Array and Amplicor testing. Most missed CIN3/ACIS cases were associated with HPV types not included in current tests.

Background: The nonavalent HPV (9vHPV) vaccine is indicated for active immunisation of individuals from the age of 9 years against cervical, vulvar, vaginal and anal premalignant lesions and cancers causally related to vaccine HPV high risk types 16, 18, 31, 33, 45, 52 and 58, and to the HPV low risk types 6 and 11, causing genital warts. Objective: To estimate the lifetime risk (up to the age of 75 years) for developing cervical cancer after vaccinating a HPV naive girl (e.g. 9 to 12 years old) with the 9vHPV vaccine in the hypothetical absence of cervical cancer screening. Methods: We built Monte Carlo simulation models using historical pre-screening age-specific cancer incidence data and current mortality data from Denmark, Finland, Norway, Sweden and the UK. Estimates of genotype contribution fractions and vaccine efficacy were used to estimate the residual lifetime risk after vaccination assuming lifelong protection. Results: We estimated that, in the hypothetical absence of cervical screening and assuming lifelong protection, 9vHPV vaccination reduced the lifetime cervical cancer and mortality risks 7-fold with a residual lifetime cancer risks ranging from 1/572 (UK) to 1/238 (Denmark) and mortality risks ranging from 1/1488 (UK) to 1/851 (Denmark). After decades of repetitive cervical screenings, the lifetime cervical cancer and mortality risks was reduced between 2- and 4-fold depending on the country. Conclusion: Our simulations demonstrate how evidence can be generated to support decision-making by individual healthcare seekers regarding cervical cancer prevention.

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.

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.

Summary Human papillomavirus vaccination began using a 3-dose schedule. Compared with the 3-dose schedule in women, the 2-dose schedules are effective options in young girls as of 36 months after first dose. Two-dose schedules could improve compliance and vaccination coverage., Background. We previously reported the noninferiority 1 month after the last dose of 2-dose human papillomavirus 16/18 AS04-adjuvanted (AS04-HPV-16/18) vaccine schedules at months 0 and 6 (2D_M0,6) and months 0 and 12 (2D_M0,12) in girls aged 9–14 years compared with a 3-dose schedule at months 0, 1, and 6 (3D_M0,1,6) in women aged 15–25 years. Here, we report the results at study end (month 36 [M36]). Methods. Girls were randomized 1:1 and received 2 vaccine doses either 6 months (2D_M0,6) or 12 months apart (2D_M0,12); women received 3 doses at months 0, 1, and 6 (3D_M0,1,6). Endpoints included noninferiority of HPV-16/18 antibodies for 2D_M0,6 versus 3D_M0,1,6; 2D_M0,12 versus 3D_M0,1,6; and 2D_M0,12 versus 2D_M0,6; and assessment of neutralizing antibodies, T cells, B cells, and safety. Results. At M36, the 2D_M0,6 and 2D_M0,12 schedules remained noninferior to the 3D_M0,1,6 schedule in terms of seroconversion rates and 3D/2D geometric mean titers for anti-HPV-16 and anti-HPV-18. All schedules elicited sustained immune responses up to M36. Conclusions. Both 2-dose schedules in young girls remained noninferior to the 3-dose schedule in women up to study conclusion at M36. The AS04-HPV-16/18 vaccine administered as a 2-dose schedule was immunogenic and well tolerated in young girls.

In recent analyses of the global burden of cancer among women, cervical cancer ranked second to breast cancer. Numbers of new cervical cancer cases are increasing constantly although this tumor is one of the best preventable malignancies of all relevant human cancers. The genesis of cervical cancer depends essentially on an infection of the uterine cervix with human papillomavirus (HPV) that needs to persist for many years and decades. Oncogenic cell transformation occurs almost exclusively in a discrete cell population at the squamous columnar junction (SCJ). These peculiarities enable primary prevention with HPV-vaccination as well as secondary prevention by detecting and treating true precursor lesions. The actual screening program with annual cytology smears is already effective but results in a high number of false positive results and unnecessary treatments. Based on a good understanding of the etiology and high evidence from large randomized controlled trials a significant improvement in the prevention of cervical cancer by shifting to HPV screening in women aged 30 years or older is feasible. This would result in a further reduction of new cancer cases by 70-80 % with less screening examinations and interventions when well-defined patient pathways are followed and colposcopy in accordance with international quality standards is used as the gold standard for the minimal invasive management of abnormal findings. HPV vaccination prevents the development of approximately 80 % of true precursors and should have a similar impact on the incidence of cervical cancer. A combination of HPV vaccination and screening could almost eradicate cervical cancer and reduce the burden of other tumors and diseases related to HPV.

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/cm2 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. Lasers Surg. Med. 46:456–461, 2014. © 2014 Wiley Periodicals, Inc.

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

BACKGROUND: Persistent HPV infection can lead to high-grade squamous intraepithelial lesions (HSIL) in cervical cells; current treatments are exclusively ablative which can lead to long-term reproductive morbidity. VB10.16, an investigational immunotherapy designed to treat precancers and cancers induced by HPV16, is a highly potent DNA plasmid vaccine with intrinsic adjuvant effect designed for efficient delivery of antigens E6 and E7 from HPV16 to elicit strong immune responses. Here we explored in a first in human clinical study the safety/tolerability, immunogenicity and efficacy of VB10.16 in patients with HPV16+ CIN 2/3. METHODS: Safety, efficacy and immunogenicity of VB10.16 were assessed in patients with HPV16+ associated CIN2/3 in an exploratory open-label phase I/2a study. 16 patients were enrolled and treated in the dosing phase to assess two different vaccination schedules (week 0, 3, 6 or week 0, 4, 12) and 17 patients completed four injections with VB10.16 in the subsequent expansion cohort (dosed week 0, 3, 6 and 16). VB10.16 is delivered i.m. using the needle-free PharmaJet™ Stratis injector device. The trial is registered at ClinicalTrials.gov (NCT02529930). RESULTS: Vaccinations were well tolerated. The AEs were mainly mild to moderate and related to the injection site. No SAEs or DLTs were reported. A strong HPV16-specific T cell response (IFN-γ ELISpot) was observed correlating with lesion size regression. Mean T cell response was stronger in patients dosed with shorter intervals. Mean peak response was observed at week 24 when a boost vaccination was administrated in week 16. Flow cytometric analysis revealed the induction of HPV16-specific CD8(+) T cells. Interim analysis of 17 patients in the Expansion cohort 8 weeks after last dose (week 24), demonstrated regression in lesion size in 14 patients and in lesion grade (CIN1/0) in 8 patients. 15 patients were assessed as responders (PR/CR) by investigator. Patients not achieving CIN1/0 at week 24 had persistent other high-risk HPV infections or locally upregulated PD-L1 which might be induced by the strong immune response elicited by the vaccine. CONCLUSION: We report strongly encouraging phase 1/2a safety, tolerability, and immunogenicity results for a therapeutic HPV16 DNA plasmid vaccine VB10.16. These data demonstrate that VB10.16 is capable of eliciting CD8+ T cells and driving robust immune responses to antigens from HPV16 contributing to elimination of HPV16-infected cells, subsequent regression in lesion size and grade in treated CIN2/3 patients. Up-regulation of PD-L1 argues for the rationale for investigating the combination of checkpoint inhibitors with VB10.16 in HPV16-associated cancers in future trials. Citation Format: Peter Hillemanns, Karl Ulrich Petry, Linn Woelber, Gerd Böhmer, Elisabeth Stubsrud, Irene Skjørestad, Karoline Schjetne, Agnete Fredriksen, Mads Axelsen. Safety, efficacy and immunogenicity of VB10.16, a therapeutic DNA vaccine targeting human papillomavirus (HPV) 16 E6 and E7 proteins for high grade cervical intraepithelial neoplasia (CIN 2/3): 6-month data from an exploratory open-label phase I/2a trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT209.

Objective Optimization of colposcopy practice requires a program of quality assurance including the monitoring of performance indicators. The European Federation of Colposcopy (EFC) aimed to identify a list of quality indicators for colposcopic practice, which are relevant, reproducible and practical across all of the member countries. Study design A five-round Delphi consultation was conducted in 30 full, 5 associate and 4 potential member countries in order to determine a core list of quality indicators including optimal target ranges. Results Six indicators were selected from a list of 37 proposed standards. Two further rounds of consultation were conducted to determine expert opinion on the target level for each of the standards. The six indicators identified and corresponding targets were: documentation of whether or not the squamocolumnar junction has been seen (100%); colposcopy prior to treatment for abnormal cervical cytology (100%); percentage of excisional treatments/conizations to contain cervical intra-epithelial neoplasia grade two or worse (≥85%); percentage of excised lesions/conizations with clear margins (≥80%); and two indicators concerned the number of cases to be colposcoped per year: ≥50 low-grade/minor and ≥50 high-grade/major cytological abnormalities. Conclusions A Delphi consultation identified six EFC quality indicators. These are a first step in an international attempt to optimize colposcopy practice throughout Europe. The current targets are based on expert opinion and may need adaptation in the future. Data are needed from European colposcopy settings to determine whether the indicators are achievable practice-based benchmarks and will help in improving and fine tuning the list of performance indicators and targets.

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 30years, 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.

Objectives We modelled human papilloma virus (HPV) primary screening scenarios compared with Pap cytology to evaluate clinical effectiveness and projected annual costs in Germany. Study design A Markov cohort model was built to compare the budget impact of annual Pap cytology with different 5-yearly HPV screening scenarios: (1) a positive HPV test followed by Pap cytology; (2) a positive HPV test followed by p16/Ki-67 dual-stained cytology; (3) a positive HPV test followed by colposcopy if HPV-16/18-positive or p16/Ki-67 dual-stained cytology if positive for other subtypes; (4) co-testing with HPV and Pap. Screening scenarios were based on a 10-year horizon. Results All HPV screening scenarios in the model were associated with fewer deaths from missed diagnosis of cervical cancer compared with Pap screening; 10-year totals n = 172–344 (1.5–3 per 100,000) versus n = 477 (4.1 per 100,000), respectively. Total annual costs were lower with HPV screening than Pap cytology. The projected average annual cost for HPV screening ranged from €117 million to €136 million compared with €177 million for Pap screening, representing annual savings of €41–60 million. The greatest clinical impact was achieved with primary HPV screening (with genotyping) followed by colposcopy for HPV 16/18-positive women or p16/Ki-67 dual-stained cytology for women positive for other HPV subtypes. Conclusion Screening strategies including primary HPV testing for high-risk subtypes (HPV-16/18) in conjunction with p16/Ki-67 dual-stained cytology can improve the detection of cervical cancer at a lower total annual cost than conventional Pap cytology screening.

Human papillomavirus (HPV)-related screening technologies and HPV vaccination offer enormous potential for cancer prevention, notably prevention of cervical cancer. The effectiveness of these approaches is, however, suboptimal owing to limited implementation of screening programmes and restricted indications for HPV vaccination. Trials of HPV vaccination in women aged up to 55 years have shown almost 90% protection from cervical precancer caused by HPV16/18 among HPV16/18-DNA-negative women. We propose extending routine vaccination programmes to women of up to 30 years of age (and to the 45-50-year age groups in some settings), paired with at least one HPV-screening test at age 30 years or older. Expanding the indications for HPV vaccination and much greater use of HPV testing in screening programmes has the potential to accelerate the decline in cervical cancer incidence. Such a combined protocol would represent an attractive approach for many health-care systems, in particular, countries in Central and Eastern Europe, Latin America, Asia, and some more-developed parts of Africa. The role of vaccination in women aged >30 years and the optimal number of HPV-screening tests required in vaccinated women remain important research issues. Cost-effectiveness models will help determine the optimal combination of HPV vaccination and screening in public health programmes, and to estimate the effects of such approaches in different populations.

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection. (C) 2016 The Authors. Published by Elsevier Ltd.

Objectives: To systematically evaluate the long-term effectiveness and cost-effectiveness of HPV-based primary cervical cancer screening in the German health care context using a decision-analysis approach. Methods: A Markov-model for HPV-infection and cervical cancer was developed for the German health care context, and applied to evaluate various screening strategies that differ by screening interval and test algorithms, including HPV-testing alone or in combination with cytology. German clinical, epidemiological, and economic data, and test accuracy data from international meta-analyses were used. Outcomes predicted included the reduction in cervical cancer cases and deaths, life expectancy and discounted incremental cost-effectiveness ratios (ICER). The analysis was performed from the perspective of the healthcare system adopting a 3% annual discount rate for costs and outcomes. Extensive sensitivity analyses were performed. Results: HPV-based screening is more effective than cytology alone. It results in a 71-97% reduction in cervical cancer cases as compared to 53-93% for cytology alone. The ICER range from 2600 Euro/LYG (cytology, 5-year-interval) to 155,500 Euro/LYG (annual HPV-testing starting at age 30 years, cytology age 20-29 years). Annual cytology alone, the current recommended screening strategy in Germany, is dominated by HPV-strategies. Increasing the age at screening initiation from 20 to 25 years does not result in a relevant loss in effectiveness but results in lower costs. Conclusions: Based on our analyses, HPV-based cervical cancer screening is more effective than cytology alone and could be cost-effective if performed at intervals of two years or longer. In the German context, an optimal screening strategy may be biennial HPV screening starting at age 30 years preceded by biennial cytology for women aged 25-29 years. Longer screening intervals may be considered in low-risk women with good screening adherence and in populations with low HPV-incidence. (C) 2011 Elsevier Ltd. All rights reserved.

5575Background: There is limited information regarding the impact of radical surgery including pelvic and para-aortic lymphadenectomy (LNE) and subsequent chemotherapy on sexuality in patients (pts...

Aim: Clinical trials have demonstrated the efficacy of the tetravalent human papillomavirus (HPV) vaccination in the prevention of cervical cancer and genital warts associated with HPV types 6, 11, 16 and 18. We used an empirically calibrated Markov cohort model of the natural history of HPV to assess the cost-effectiveness of the vaccine administered to 12-year-old girls alongside existing cervical screening programmes in Germany. Subjects and methods: The model estimated cervical cancer (CC), cervical intraepithelial neoplasia (CIN) and genital wart lifetime risks and total lifetime health care costs, life years gained and quality-adjusted life years (QALY) gained. The analysis was conducted from the perspective of the German health care payer. Results: In the base case (considering a lifetime duration of protection and 100% efficacy) it was estimated that 2,835 cervical cancer cases and 679 deaths could be prevented among a cohort of 400,000, at an incremental cost per QALY gained of 10,530 €. A total of 120 girls needed to be vaccinated to prevent 1 case of CC. Cost-effectiveness is sensitive to a duration of protection of less than 20 years and to the discount rate for costs and benefits. Conclusion: A policy of vaccinating adolescent girls has been recommended by the German Standing Committee on Vaccinations. This study has demonstrated that such a policy is cost-effective based on thresholds of cost-effectiveness that apply in Germany.

OBJECTIVE: In February 2006 a pilot project was started in the city of Wolfsburg offering regular routine screening for cervical cancer to members of the Deutsche BKK, a large German health insurance company. The aims of the project are to investigate the feasibility and acceptance of primary HPV screening with defined patient pathways and extended screening intervals. METHODS: The project consists of screening using conventional cytology plus HPV testing with HC2 (for high-risk persons only) for all participants. Women need to be 30 years or older, must be a member of the DBKK and give their written consent. Women with negative results on cytology and HC2 will be retested after 5 years instead of annual intervals as is usually the case in Germany. When both tests are positive, women are called immediately for colposcopy; in women with a negative cytology but positive HC2 test, cytology will be repeated after 6 and HC2 testing after 12 months. In the event of positive findings women will be referred for colposcopy. Women with inconspicuous cytological findings (Pap I/II) and a negative HPV HR test will only be retested again after 5 years but will continue to report for their annual gynaecological preventive medical examinations. RESULTS: From February 2006 to September 2007 12 885 women agreed to participate in the project. 657 (5.1 %) had positive HC2 results and 258 (2 %) had atypical Pap smears at recruitment. 127 (1 %) women were referred for colposcopy, 42 of whom were diagnosed with CIN3 or worse, including 3 invasive cancers and 4 adenocarcinoma in situ. 19/42 women in the CIN3+ group were detected by HPV testing alone; all patients with CIN3+ were HC2 positive. Acceptance of the screening concept is high, less than 1 % of the screening population did not want to participate. No case of severe anxiety related to HPV testing was reported.

Objectives: Paget's disease of the vulva as an extramammary form is a rare and hard to treat epidermal neoplasia. In 12% underlying invasive Paget's carcinoma and in 4% associated adenocarcinoma wil be found. After surgical intervention a relapse is seen in 30%. The aim of this study was to find less invasive or mutilating therapy strategies than re-excision, x-ray or chemotherapy. Successful treatment of Paget's disease of the vulva with Imiquimod was described in a few case reports. Methods: Data of fourteen patients from the Medical School Hanover and the Department of Gynecology and Obstetrics of the urban clinic Wolfsburg with Paget's disease or carcinoma of the vulva were reviewed between September 1992 and March 2006. The primary therapy was surgery of the clinical lesions. Recurrent Paget's disease was treated by excision again and/or by a local therapy with Imiquimod 5% ointment. Results: In ten cases primary Paget's disease was diagnosed. One patient with an earlier carcinoma of the bladder showed secondary Paget's disease with a minimally invasive Paget's carcinoma. Three women showed an invasive Paget's carcinoma of the vulva, one of them with an associated adenocarcinoma. Treatment of recurrent Paget's disease (n= 5) was surgery or therapy with the immune stimulator Imiquimod (n = 3). Both total and partial remissions were noted. Conclusion: Surgery remains the primary therapy for Paget's disease of the vulva. For the treatment of recurrent Paget's disease new options are available based on the use of Imiquimod or Trastuzumab.

UNLABELLED Carcinoma of the vagina is a rare entity of cancer, also a primary carcinoma of the neovagina in patients with vaginal agenesia is of rare occurrence. CASE REPORT We report on a 48-year-old female patient with a squamous cell carcinoma in neovagina after Mayer-Rokitansky-Kuester-Hauser-syndrome. Neovagina was constructed by method of Vecchietti 28 years before. Operative treatment consisted of anterior exenteration with construction of a modified Mainz-1-pouch. There were no complications intra- or postoperative. Microscopic findings showed a G2-differentiated invasive squamous cell carcinoma of the neovagina at stage FIGO III with an infiltration of urethra and the bladder neck. The tumor could be resected completely, no infestation of lymph nodes was observed. In the further process the aftercare is planned. In a systematic literature review 19 female patients with a primary carcinoma of neovagina after agenesia of vagina could be identified. CONCLUSIONS Female patients with a neovagina require a regular gynaecologic examination in order not to survey a malignant transformation although a malignoma in neovagina is rare. A possible therapy option is the radical operation, there are no data of long-term prognosis at present.

Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages

Cervical cancer is the most common malignant tumor among women in Tanzania and other countries in tropical Africa. Genital schistosomiasis has been proposed as a possible cofactor in the genesis of this malignant disease that might contribute to its high incidence in regions where bilharzias is endemic. One hundred nine Tanzanian patients from an area with endemic bilharzias who were transferred to a gynecologic out-patient clinic were age-matched with 109 German controls. In patients and controls, separate samples were taken for cytologic assessment and human papillomavirus (HPV) DNA detection using the Hybrid Capture 2 assay (HC2) and PCR (GP5+/6 +). Samples that tested positive for HPV DNA with general primers were re-tested with HPV type-specific primers. After application of 3% acetic acid, punch biopsies were taken from any cervical lesion. Patients were interviewed for recent symptoms or clinical history suggestive of bilharzias. Urine samples from all patients were examined for the presence of schistosoma hematobium ova. Additionally six Tanzanian patients with invasive cervical cancer were included for separate analysis. Patients and controls had an identical prevalence of HPV-DNA (21.5%) using HC2. Based on PCR results with general primers, the corresponding prevalence was 34.5% for Tanzanian cases and 26.9% for German controls. A history suggestive of bilharzias and/or active schistosomiasis were associated with a significantly increased risk for infection with high-risk HPV types. We conclude that infection with Schistosoma hematobium seems to favor persistent genital HPV infection either by traumatizing the genital epithelium and/or by local immunosuppression.

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.

The objective of the study was to investigate the efficacy and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT), a novel therapy for women with cervical intraepithelial neoplasia (CIN)1/2, to define the appropriate population and endpoints for a phase 3 program.This was a double-blind, randomized, placebo-controlled, dose-finding study that included a total of 262 women with biopsy-confirmed CIN 1/2 based on local pathology. Patients received 1 or 2 topical treatments of HAL hydrochloride 0.2%, 1%, 5%, and placebo ointment and were evaluated for response after 3-6 months based on biopsy, Papanicolaou test, and oncogenic human papillomavirus (HPV) test. All efficacy analyses were performed on blinded central histology review to avoid interreader variability. Adverse events, blood biochemistry, and vital signs were assessed after 3 months.There were no statistically significant differences between placebo and either the CIN 1 or combined CIN 1/2 populations. A clear dose effect with a statistically significant response in the HAL 5% group of 95% (18/19 patients) compared to 57% (12/21 patients) in the placebo group (P.001) was observed at 3 months in women with CIN 2, including an encouraging 83% (5/6 patients) clearance of HPV 16/18 compared to 33% (2/6 patients) in the placebo group at 6 months. The treatment was easy to use and well accepted by patients and gynecologists. Only local self-limiting adverse reactions including discharge, discomfort, and spotting were reported.HAL PDT is a novel therapy that shows promise in the treatment of CIN 2 including clearance of oncogenic HPV, but not of CIN 1. The positive risk/benefit balance makes HAL PDT a tissue-preserving alternative in women of childbearing age who wish to preserve the cervix. Confirmatory studies are planned.

Aim This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. Methods We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16INK4a expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. Results HPV DNA was detected in 74% (95% confidence interval (CI): 70–78%) of invasive cancers and in 96% (95% CI: 92–98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16INK4a overexpression was found in 87% of HPV DNA positive vaginal cancer cases. Conclusions HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.

Objective. Women infected with the human immunodeficiency virus (HIV) have an increased risk of cervical neoplasia while the value of cytologic screening is limited due to a high prevalence of inflammatory disease. The study was conducted to determine whether testing for human papillomavirus (HPV) DNA could improve primary screening for cervical cancer of these patients. Methods. One hundred thirty-eight HIV-infected women were examined between 1990 and 1998. Ninety-four patients with a total of 279 women-years were eligible for incidence evaluation. Colposcopy, cytology, and HPV DNA testing with the hybrid capture I assay were performed at each visit. Results. Seventeen cases of high-grade cervical neoplasia were diagnosed at study entry and 13 developed CIN II or CIN III during follow-up. The hybrid capture I assay detected 94.1% of prevalent and 100% of incident high-grade neoplasia, while the corresponding sensitivity of Pap smears using CIN I or worse as the referral criteria was 82.3% for prevalent and 69.2% for incident high-grade neoplasia. Eleven of 13 patients who progressed to histologically confirmed CIN II/III tested positive for HPV DNA at study entry compared with 5/13 women presenting with any degree of cytologic atypia at recruitment. The Pap smears of 36/94 women remained normal throughout the study while 54/94 patients remained negative for high-risk HPV types. Conclusion. Hybrid capture I identified high-grade cervical neoplasia more accurately than the Pap smear and appeared to be beneficial for primary cervical cancer screening in HIV-infected women.

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.

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.

OBJECTIVE The incidence of vulvar squamous cell carcinomas located between the clitoris and urethra in young women is rising in distinct geographic regions, but characteristics of the tumors indicating certain carcinogenic mechanisms are unknown. The present study aimed at characterizing these vulvar cancers for their human papillomavirus (HPV), p16(INK4a), and p53 status, revealing potential pathways of carcinogenesis. MATERIALS AND METHODS Squamous cell vulvar cancers of the anterior fourchette were retrospectively collected from 8 German hospitals, with additional squamous cell cancers located at other sites of the vulva from 2 of the hospitals. All tumors were analyzed for HPV DNA by polymerase chain reaction and for p16(INK4a) and p53 expression by immunohistochemistry. RESULTS Potentially HPV-associated tumors (HPV and p16(INK4a) positive, 21.4% [27/126] of the anterior fourchette and 27.7% [13/47] from other locations), p53-overexpressing tumors (35.7% [45/126] and 29.8% [14/47]), and a third group (HPV/p16(INK4a) negative/p53 not overexpressed, 42.9% [54/126] and 42.6% [20/47]) were observed among tumors from the anterior fourchette as well as among vulvar cancers from other locations. Women with vulvar cancers of the anterior fourchette were of young age irrespective of the HPV/p16(INK4a)/p53 status. CONCLUSIONS Different types of vulvar cancers can be found in squamous cell tumors of the anterior fourchette, similar to the finding in vulvar cancers from other locations and to what has previously been reported for vulvar squamous cell carcinomas in general.

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

Lesions Classified as PAP III: A repeat Pap smear as well as a smear for human papillomavirus (HPV)-DNA detection with the Hybrid Capture assay (Digene diagnostics/Murex, Burgwedel) were collected from 30 women with Pap smears recurrently classified as Pap III. All patients underwent colposcopy and histological assessment. The repeat Pap smear distinguished correctly in 15, colposcopy in 19 and the Hybrid Capture assay in 27 cases between neoplastic and inflammatory lesions. All invasive neoplasms were positive for HPV-DNA. HPV typing seems to be a suitable non-invasive method for early selection of cervical lesions that need histological assessment in women with smears classified as,,Pap III.

100 patients with CIN on referral Pap and with a distinct cervical lesion on colposcopy were treated with the loop electrosurgical excisional procedure (LEEP). Compared with 60 women who underwent cold-knife conization, the number of lesions classified as CIN-3 or more did not differ between the two groups (53% vs 53.3%). Severe haemorrhage and cervical stenosis were only observed after conization. Involvement of resection margins was found in 18% of all LEEP and in 16.7% of all cone biopsies. 3-12 months after LEEP the rate of cytologically and biopsy proven neoplasia was 2.2%. LEEP is a safe and effective procedure and should be used as the treatment of choice for distinct cervical lesions.

A total of 158 women who were either HIV-infected or under iatrogenic immunosuppression were examined regularly during a 4-year period to evaluate if certain vulvar neoplasms and cervical neoplasia have similar associated risk factors. Patients with CIN were matched prospectively with immunocompetent controls with CIN. Forty-eight cervical lesions were detected among patients, including 2 invasive carcinoma and 15 CIN-3 lesions, compared to 11 vulvar lesions, including 2 invasive carcinoma and 7 VIN-3 lesions. Women who had more than five life-time partners were more likely to have HPV-DNA positive cervical swabs and vulvar scrapes as well as cervical and/or vulvar neoplasia. Compared to 2.7% of controls 15.2% of patients with CIN had coexisting high-grade lesions of the vulva. With 1 exception all patients with vulvar neoplasia either suffered from symptomatic immunodeficiency or received immunosuppressive drugs for more than 10 years. Except for 1 VIN-3 lesion, all vulvar neoplasms were associated with HPV-DNA types 16,31, and/or 33. Six of nine patients as well as the 2 controls with coexisting vulvar and cervical neoplasia had the same HPV-type associated with both lesions. All vulvar lesions were classified as either “warty” or “basaloid.” In conclusion cervical and bowenoid/basaloid vulvar neoplasia seem to have a similar HPV-related genesis. Malfunction of the cellular immune response appears to be a cofactor in the genesis of HPV-associated neoplasia at both sites.

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.