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Objectives Colposcopy training and assessment is not uniform across Europe with individual countries determining their own required standards and regulations. In light of the significant changes in colposcopic practice that have occurred over the past decade and the expansion of the European Federation for Colposcopy (EFC) membership, a study was conducted firstly, to assess the current requirements for training in each of the member countries and secondly, to review an EFC-approved core training curriculum for colposcopy. Study design A questionnaire survey of the EFC representatives from all member countries investigating their country's current practices/requirements with regard to training, assessment and accreditation for colposcopy. A two-round Delphi consultation with representation from the full, associate and three potential member countries was conducted using a 5-point Likert scale for scoring opinions. The results were analysed with respect to each country's population size and World Bank economic classification. Results For the questionnaire survey, responses were received from 31/34 countries invited to participate. Training programmes were reported to be in place in 21 of the 31 countries but only 17 of the 21 countries had a committee overseeing the training programme. An assessment was part of the training programme in 20 countries with multiple choice questions and portfolios the most common assessment tools. Countries with a population size less than 2 million have a statistically significant lower probability of having a structured training/assessment programme, 1/5 compared to 20/26 for a populations greater than 2 million, p = 0.013. For the Delphi study, responses were received from 34/39 countries invited to participate. Of the 51 competencies previously identified only 2 did not receive full support: ‘perform bacterial swabs’ and ‘provide data to national body’. There was no significant difference in the responses given by member, associate member or potential member countries. Conclusions There is considerable variation in colposcopy training and assessment across Europe. This study has enabled consensus opinion with the EFC on the contents of an EFC core curriculum. The revised curriculum has a mandate from the EFC member countries to be implemented across Europe as the standard for colposcopic training.

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.

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.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.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).HAL PDT shows a favorable efficacy and safety profile and represents a promising alternative to observation and surgical procedures in patients with CIN 1.

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.

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 aged30 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, p0.001). 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.

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.

Human papillomavirus type 16 (HPV16) transcription in HPV16-positive vulvar intraepithelial neoplasia (VIN), cervical intraepithelial neoplasia (CIN) and cervical carcinomas was analyzed using RNA-RNA in situ hybridization. Subgenomic probes were constructed which specifically detected individual spliced E6/E7 transcripts as well as transcripts initiated within the E7 open reading frame (ORF). In most biopsies, viral RNA was predominantly initiated in the E6 ORF at promoter P97 and contained the E6*1 splice. Three of 7 VIN, 13 of 37 CIN and 1 of 13 cervical carcinomas expressed significant amounts of mRNA that were initiated within the E7 ORF. Promoter activity in the E7 ORF correlated with epithelial differentiation and viral late gene (L1) expression. Our data therefore do not support the finding of Bohm et al. (1993) which suggested that the predominant transcript(s) in HPV16-associated high-grade neoplasms and genital carcinomas is initiated within the E7 ORF. Rather, our data suggest that the major HPV16 transcript in high-grade cervical neoplasms and carcinomas is initiated in the E6 ORF and encodes the E7 oncoprotein. © 1996 Wiley-Liss, Inc.

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.

ObjectivesHuman 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).MethodsRealTime 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.ResultsBoth 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%.ConclusionsThese results support the use of RealTime for routine detection of HPV infections in a referral population.

Approximately 70% of all cancers of the vagina and 40% of vulval cancers are associated with high grade human papillomavirus (HPV). The corresponding prevalence in vulval intraepithelial neoplasia (VIN) 2/3 and vaginal intraepithelial neoplasia (VAIN) 2/3 lesions is in the range of 85–95%. While there is no efficient screening for these neoplasms in the general population, risk groups such as immunocompromised women and patients with a history of cervical intraepithelial neoplasia may benefit from colposcopy follow-up. Frank invasive cancers are a clinical diagnosis but most preinvasive lesions are diagnosed by colposcopy with biopsies. There are two distinct entities of VIN and squamous cell cancer of the vulva. HPV is linked to the common undifferentiated VIN and basaloid cancers while the rare differentiated VIN and the keratinizing cancers are HPV-negative. Lichen sclerosus seems to play a role in the genesis of these tumors. Surgery is the treatment of choice for preinvasive and early tumors, although application of imiquimod is another option for VIN2/3.

Most cases of low-grade cervical intraepithelial neoplasia (CIN) associated with oncogenic human papillomavirus (HPV) types regress spontaneously within years. Unknown co-factors seem to be necessary for a progression to malignancy. To determine the possible role of cellular immunodeficiency as such a co-factor in the genesis of genital neoplasia, 48 HIV-infected women and 52 allograft recipients were examined periodically during a 3-year period. Colposcopy, cytology and HPV-DNA typing (ViraType) were performed at each visit. Each cervical lesion was matched prospectively with 2 lesions from immunocompetent controls. In all, 29/100 patients suffered from cervical neoplasms, including 2 advanced cervical cancers and 9 CIN3 lesions. Correlation between grade of lesion and HPV DNA 16/18 was significant. Low-grade lesions among patients progressed more often than among controls and recurrent lesions after destructive treatment were seen more frequently among patients than among controls. All patients with CD4-lymphocyte counts of < 400/microliters or immunosuppression for more than 3 years suffered from progressive lesions. We conclude that malfunction of the cellular immune response following either HIV-induced depletion or iatrogenic inhibition of CD4-lymphocyte activation, enhances the progression of HPV-induced cervical lesions to malignancy.

HPV play an essential role in the genesis of almost all cervical cancer, all CIN3, the majority of VaIN, vaginal cancers and VIN, while approximately 60% of squamous cell cancers of the vulva are not linked to HPV.

OBJECTIVE: To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). DESIGN: Multinational cohort study with joint database analysis. SETTING: Seven primary HPV screening studies in six European countries. PARTICIPANTS: 24,295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. MAIN OUTCOME MEASURE: Long term cumulative incidence of CIN3+. RESULTS: The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%. CONCLUSIONS: A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

Persistent infection with human papillomaviruses (HPV) is a prerequisite for the development of cervical cancer. Vaccination with virus-like particles (VLP) has demonstrated efficacy in prophylaxis but lacks therapeutic potential. HPV16 L1E7 chimeric virus-like particles (CVLP) consist of a carboxy-terminally truncated HPV16L1 protein fused to the amino-terminal part of the HPV16 E7 protein and self-assemble by recombinant expression of the fusion protein. The CVLP are able to induce L1- and E7-specific cytotoxic T lymphocytes. We have performed a first clinical trial to gain information about the safety and to generate preliminary data on the therapeutic potential of the CVLP in humans. A randomized, double blind, placebo-controlled clinical trial has been conducted in 39 HPV16 mono-infected high grade cervical intraepithelial neoplasia (CIN) patients (CIN 2/3). Two doses (75 mug or 250 mug) of CVLP were applied. The duration of the study was 24 weeks with 2 optional visits after another 12 and 24 weeks. The vaccine showed a very good safety profile with only minor adverse events attributable to the immunization. Antibodies with high titers against HPV16 L1 and low titers against HPV16 E7 as well as cellular immune responses against both proteins were induced. Responses were equivalent for both vaccine concentrations. A trend for histological improvement to CIN 1 or normal was seen in 39% of the patients receiving the vaccine and only 25% of the placebo recipients. Fifty-six percent of the responders were also HPV16 DNA-negative by the end of the study. Therefore, we demonstrated evidence for safety and a nonsignificant trend for the clinical efficacy of the HPV16 L1E7 CVLP vaccine.

Incidence and mortality rates of cervical cancer are higher in Germany than in other Western European countries. Type-specific human papillomavirus (HPV) distribution was investigated for the first time in Germany in an epidemiological study including 8,101 women. Women above the age of 30 years, self-referring for cervical cancer screening, were enrolled in two study centers in Hannover (Northern Germany) and Tubingen (Southern Germany). Participants were screened by the Pap smear and the hybrid capture 2 (HC2) test using the high-risk probe. All samples that were positive by the HC2 test were genotyped using the prototype PGMY09/11 PCR line blot assay. Most women in the study population had a negative Pap smear (96.7%). Prevalence of high-risk type HPV detected by HC2 was 6.4% and prevalence of carcinogenic types detected by PGMY09/11 was 4.3%. Of the PGMY09/11 PCR-positive women, 70.2% had a single infection, 28.1% had multiple infections and 1.7% remained uncharacterized. 32 different HPV types were detected using PGMY09/11 PCR. HPV 16, 31, 52, 51, 18, and 45 were the most common carcinogenic types in the study population. Among women with histologically confirmed high-grade lesions HPV 16, 45, 58, 18, 31, 33, and 52 were the predominant types. These results provide valuable information for the management of HPV infections in Germany, both in terms of future strategies of screening and vaccination.

Overexpression of p16INK4a has been proposed as a biomarker helpful for the identification of dysplastic cervical epithelial cells on histologic slides as well as in cervical smears. Since a few nontransformed cells in the genital tract in some instances may also express p16INK4a, we evaluated whether applying established morphologic criteria for cervical dysplasia allows a distinction of dysplastic from nondysplastic p16INK4a-stained cells in cytologic samples.Liquid-based cytology samples were obtained from a screening population (n=50), and from patients attending a dysplasia clinic (n=40). Slides prepared from these samples were stained with the conventional Papanicolaou stain procedure. From each specimen, a second slide was prepared in parallel and immunostained for p16INK4a. Cytologic diagnoses for most patients attending the dysplasia clinic could be compared to the reported histologic diagnoses on punch biopsy samples taken from the patients at the time of colposcopy. This allowed a comparison of the cytology and p16INK4a immunostaining results with subsequent hematoxylin and eosin-based histologic diagnoses.Overall, in 10% of slides obtained from patients with nonsuspicious smears, few p16INK4a-positive cells were found. Using established morphologic criteria and applying these criteria on cells showing any p16INK4a immunoreactivity, p16INK4a-positive normal or metaplastic cells could be discriminated from p16INK4a-expressing dysplastic cells. In 21 of 22 cases (95%) of high grade lesions (cervical intraepithelial neoplasia 2 or higher in follow-up histology), easily recognizable p16INK4a-positive dysplastic cells could be detected, with the remaining case lacking dysplastic cells in the thin-layer slide used for p16INK4a immunostaining.Established morphologic criteria for cervical dysplasia can be readily applied to p16INK4a-immunostained cytologic specimens. Thus, p16INK4a immunostaining may help to avoid ambiguities in the interpretation of cervical cytology samples and facilitate more rapid diagnosis and possibly even automated screening of cytologic slides.

The objective of this study was to assess the safety and efficacy of a novel therapeutic, ZYC101a, for the treatment of women with histologically confirmed cervical intraepithelial neoplasia (CIN) 2/3. ZYC101a contains plasmid-DNA-encoding fragments derived from the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18, and is formulated within small biodegradable microparticles.A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 microg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy.The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P =.12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P =.007). ZYC101a activity was not restricted to HPV-16-or HPV-18-positive lesions.ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years.I

Paget disease of the vulva is a rare lesion that accounts for1% of vulva neoplasms. A 12% prevalence of invasive Paget carcinoma and a 4% prevalence of associated adenocarcinomas are described. Furthermore, a high recurrence rate of 30% after surgical therapy is observed. This study aims to search for therapeutic strategies for recurrent Paget disease, which are less mutilating and less aggressive than reexcision, x-ray therapy, or chemotherapy. Trastuzumab (Herceptin) is a recombinant monoclonal antibody against HER-2/neu, approved by the U.S. FDA for the treatment of patients with HER-2/neu-positive metastatic breast carcinomas. The results of recent studies indicate that HER-2/neu oncoprotein may play a role in the pathogenesis of extramammary Paget disease.Using HercepTest, we analyzed HER-2/neu overexpression in seven noninvasive Paget lesions, two invasive lesions, and one Paget disease of the vulva with underlying adenocarcinoma. In addition, we investigated five mammary Paget diseases.Overexpression of HER-2/neu oncoprotein labeling exclusively the membranes of Paget cells was demonstrated in 8 out of 10 cases. One noninvasive and one with underlying adenocarcinoma stained negatively. Overexpression of HER-2/neu was demonstrated in all five cases of mammary Paget disease.Using HercepTest as a standardized detection system, overexpression of HER-2/neu can be demonstrated in a majority of both noninvasive and invasive Paget disease of the vulva. The use of Trastuzumab should be considered for the treatment of patients with recurrent Paget disease of the vulva with overexpression of HER-2/neu.

Cavernous haemangiomas of the uterine cervix are very rare and usually harmless. Nevertheless, the case reported of a 31-year old multiparous woman in the 34+1 gestational week, who presented herself with a fast growing cervical haemangioma, indicates, that this benign tumour may cause obstetrical complications.

www.thelancet.com Vol 379 May 26, 2012 1949 2 Zanotti-Fregonara P, Jan S, Taieb D, et al. Absorbed 18F-FDG dose to the fetus during early pregnancy. J Nucl Med 2010; 51: 803–05. 3 Bartlett RM, Nickles RJ, Barnhart TE, Christian BT, Holden JE, DeJesus OT. Fetal dose estimates for (18)F-fl uoro-L-thymidine using a pregnant monkey model. J Nucl Med 2010; 51: 288–92. 4 McCollough CH, Schueler BA, Atwell TD, et al. Radiation exposure and pregnancy: when should we be concerned? Radiographics 2007; 27: 909–17. outside of well designed clinical trials seems reasonable.

Few human cancers are as well understood as cancer of the uterine cervix. When Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine in honour of his research on the causal role of human papillomavirus (HPV) in the genesis of this tumour, the natural history of cervical cancer seemed to be deciphered, apart from small pieces of the puzzle. As a result, cervical cancer research shifted towards next-generation vaccines, therapies, and best screening strategies, and basic researchers had a new focus on the role of HPV in other malignancies. In The Lancet Oncology, Xavier Castellsague and coworkers 1 report on one of the missing pieces of the puzzle of cervical cancer epidemiology, the role of intrauterine devices (IUDs). Their surprising results should spark new research and might lead to revision of our current understanding of the genesis of cervical cancer. The analysis of ten case–control studies of cervical cancer and 16 HPV prevalence surveys from four continents was carefully done, and fi ndings were corrected for confounding eff ects such as number of Papanicolaou (Pap) smears. The study found that IUD use did not aff ect risk of HPV infection, but was associated with a signifi cantly lower risk for cervical cancer. At fi rst glance, the main implication of this fi nding is that it provides a high level of evidence to contradict a widespread assumption that IUD use increases the risk of cervical cancer. However, restored confi dence in the safety of IUDs is really just a secondary result. The protective eff ect of IUD use challenges some key elements in the current model of the natural history of cervical cancer. The type of IUD used was not documented in this analysis, but if the protective eff ect was related to gestagens, copper, or infl ammation, there should be a positive correlation between protective eff ect and duration of use. Instead, the risk reduction was similar for IUD use of a few months up to 9 years. The best explanation for this observation is that the process of loop insertion, rather than the type of loop or duration of IUD use, is associated with a reduced risk of cervical cancer. Castellsague and co-workers 1 propose that complete destruction of precancerous lesions by loop insertion is a theoretical explanation for the eff ect. But in clinical practice, even low-grade cervical intraepithelial neoplasia (CIN) show a complex and often multifocal distribution within individually shaped transformation zones. To remove CIN lesions with clear margins, usually the complete transformation zone needs to be excised with tissue loss measured in cubic centimetres. The superfi cial trauma associated with loop insertion might occasionally result in complete destruction of tiny CIN lesions located in the external ostium of the cervical canal, but as a colposcopist, I doubt that this mechanical eff ect can explain the observed signifi cant reduction in cancer risk. Instead, I postulate that the tissue trauma associated with loop insertion induces a cellular immune response that might fi nally clear persistent HPV infections and preinvasive lesions. Small cohort studies have already shown that taking cervical biopsies increases the spontaneous regression rates of CIN, and that the residual dysplastic tissue remaining after surgical treatment is cleared in many cases. Also, the importance of the cellular immune response in determining the clinical course of CIN has been well known for decades. 2