Punch biopsies shorten time to clearance of high-risk human papillomavirus infections of the uterine cervix.

BACKGROUND: The primary objective was to determine human papilloma virus (HPV) clearance rate after cervical biopsy among women with persistent high-risk HPV infection compared with spontaneous HPV clearance rate in the absence of biopsy. METHODS: We collected data from a dedicated screening program of women aged 30-70 years old. Inclusion criteria for the baseline non-interventional cohort were a positive HPV test (hybrid capture 2, HC2) and normal cytology. In the baseline cohort women were followed with approximately yearly HPV-tests and cytology until HPV regressed (one negative HPV test) or interventions in the form of diagnostic biopsies or therapy. Women who had a diagnostic biopsy were included in the biopsy cohort and followed until HPV regression or therapy. Observed HPV regression rates and time to HPV regression were compared between baseline and biopsy cohorts. For the comparison, we used Fisher's exact test for the HPV regression rates and interval-censored, accelerated failure time model for time to HPV regression. RESULTS: Among the 1079 women included in the baseline cohort, 499 (46.3%) had HPV clearance and 475 were referred for colposcopy with biopsy. The biopsy cohort comprised all women who were not treated and had at least one HC2 test after biopsy (201/475; 42.3%). Of those, 138 (68.7%) experienced HPV regression. In the biopsy cohort, time to clearance of HPV infection was approximately halved (0.46, 95% CI 0.38-0.56) compared with the baseline cohort. This result was robust in a wide range of sensitivity analyses. CONCLUSIONS: A higher proportion of women cleared their HPV infection, and time to HPV clearance was shorter in the biopsy cohort than in the baseline cohort. It is reassuring for clinicians to know that conservative management of patients with HPV persistency is successful when colposcopy with biopsies excludes high-grade disease.

Relevance of HPV Screening for Triaging Equivocal Cytology Findings in the Pap II-p, Pap III and Pap IIID Groups - Results of Two Long-Term Studies.

Introduction: The use of HPV screening for the triage of ASC-US (atypical squamous cells of undetermined significance) cytology results has been established as a sound standard by international trials whereas the data for other cytology findings are in part contradictory. There is a lack of long-term studies on the use of HPV triage in Germany. Materials and Methods: For the present study data from a primary HPV screening project involving women aged over 30 years, ongoing since 2006, and an epidemiological study on women aged between 20 and 27 years, ongoing since 2009, were used. Upon recruitment, all women underwent a smear test for cytology and screening for "high-risk" HPV using Hybrid Capture 2 (HC2). If both tests were positive or if there were persisting remarkable cytology findings or a positive HPV test, then clarification by colposcopy was performed. Results: Altogether, among 282 women with Pap II-p (ASC-US), Pap III (ASC-H) or Pap IIID (LSIL + CIN2) and negative HPV test there was no case of CIN3+. Among the women under 30 years of age, however, 69 % (ASC-US) to 85 % (LSIL + CIN2) of the remarkable findings were HPV positive, also among the older women with Pap IIID, the 71 % prevalence of HPV was too high for a triage and even without triage there was a 23 % risk for CIN3+. On the other hand, of the women over 30 years old with ASC-US (Pap II-p) findings, only 21 % were positive for HPV and the risk for CIN3+ in this group was high at 29 %. Also for ASC-H (Pap III) findings in the age group of over 30 years with an HPV prevalence of 56 % there was an efficient triage for CIN3+. Discussion: In summary, the HPV triage of ASC-US (Pap II-p) findings in women aged over 30 years was found to be efficient; in contrast, LSIL + CIN2 (Pap IIID) findings in this age group justified an immediate referral to colposcopy whereas cytology control appeared to be sufficient for younger women.

Colposcopy training and assessment across the member countries of the European Federation for Colposcopy.

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.

Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.

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 p16(INK4a) 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%). p16(INK4a) 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.

Cost-effectiveness of primary HPV screening for cervical cancer in Germany--a decision analysis.

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.

Short version of the German evidence-based Guidelines for prophylactic vaccination against HPV-associated neoplasia.

Persistent infection with HPV 16 and 18 has been causally associated with the development of cervical cancer and its precursor lesions as well as with other carcinomas and their precursors, e.g. some vulvar and vaginal cancers. Furthermore HPV 6 and 11 are responsible for anogenital condylomata acuminata in more than 90% of cases. With the recently developed prophylactic bivalent (HPV 16 and 18) and quadrivalent (HPV 6, 11, 16 and 18) vaccines, it is possible to prevent infection of the cervical epithelium and other squamous epithelia, the development of premalignant lesions and, in the case of the quadrivalent vaccine, the development of condylomata acuminata. The following paper represents a summary of the full-text version of the German evidence-based Guidelines, including all evidence-based recommendations regarding the safety as well as the efficacy of the vaccines in preventing CIN, VIN/VaIN, genital warts and other HPV-associated lesions.

Primary cervical cancer truly negative for high-risk human papillomavirus is a rare but distinct entity that can affect virgins and young adolescents.

Cancer of the uterine cervix is almost exclusively associated with human papillomavirus (HPV). Carcinogenesis is slow, the minimal time from initial HPV infection to invasive carcinoma seems to be less than ten years. In order to identify rapid onset cervical cancer, we carried out a retrospective re-analysis of an extended cohort of patients with invasive cervical cancer, and reviewed cases identified within the cancer registry of Lower Saxony or using Medline or ISI data. No instances of a rapid-onset cancer or true HPV-DNA negative cancer were found among our hospital cohort of 178 women with primary cancer of the uterine cervix. Registry data identified four out of 5,878 patients who were diagnosed with primary cervical cancer at 14 to 20 years of age. They were classified as clear-cell and endometriod adenocarcinoma and tested persistently negative for high-risk HPV-DNA. Fourteen more cases of cervical cancer in virgins and very young women were identified by a Medline search, mostly with unknown histologic type or rare subtypes of adenocarcinoma. In conclusion, rare adenocarcinoma of the uterine cervix may represent an entity unrelated to HPV, thus explaining instances of rapid onset cervical cancer.

Cost of screening and treatment of cervical dyskaryosis in Germany.

Human papillomavirus (HPV) infection is the principal cause of cervical cancer. Clinical trials with HPV vaccines have shown high efficacy against HPV-induced precancerous cervical lesions. Before implementing a vaccination programme, up-to-date data on cervical dyskaryosis, incidence and annual treatment costs are needed. We assessed resource use and costs for 12 months following diagnosis for women with abnormal Pap smears in Germany based on a sample of 138 women who had received abnormal results on Pap smears taken during March and April of 2004. Most women had a Pap IIID (57%) vs Pap III (20%) or Pap IV (23%). Women with a Pap IV consulted their gynaecologist more frequently than those with a Pap III or Pap IIID (5.6 visits vs 4.2 and 4.6 visits, respectively). Only 9% of patients underwent colposcopy plus biopsy; this may be due to the lack of histological assessment by coloposcopy and biopsy done currently in Germany. More women in the Pap IV group had a cold knife conisation, compared with those in the Pap IIID group, (84% vs 27%) hysterectomy (22% vs 4%) and laser coagulation (12.5% vs 4%). Median treatment duration was shorter for women with a Pap III than for those with Pap IIID and IV (3 vs 5 months, respectively). Overall, 28.3% of the women were hospitalised (median 5; range 1-33 days). The estimated average annual cost per patient was Euro 1,055, Euro 943 and Euro 3,174 for Pap III, IIID and IV, respectively. The cost of managing precancerous cervical lesions in Germany was shown to be high.

[What does HPV vaccination mean for gynecologic cancer screening?]. / Was bedeutet die HPV-Impfung für die gynäkologische Krebsvorsorge?

Human papilloma viruses (HPV) of the high-risk type cause almost all cervical carcinomas and some other anogenital tumors. Development of a carcinoma is uncommon; most infections heal spontaneously. When carcinomas develop, the latent phase is at least 8, more often 15-30 years. A negative HPV test thus excludes the risk of developing cervical carcinoma for many years. The approved vaccine against HPV 6/11/16/18 and the soon-to-be-approved one against HPV 16/18 are extremely safe and effective. Vaccinated individuals are almost 100% protected by the vaccines containing virus-like particles. Current studies suggest that 70-80% of high-grade cervical neoplasias can be avoided, as well as other vaginal, vulvar, and anal neoplasias. The yearly costs for treating precursors of these cancers exceed the cost of vaccinating all girls born in a given year. Thus HPV vaccination is cost effective, even when a modified cancer screening program is retained.

[Squamous cell carcinoma in neovagina at Mayer-Rokitansky-Küster-Hauser-syndrome]. / Plattenepithelkarzinom der Neovagina nach Mayer-Rokitansky-Küster-Hauser-Syndrom.

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.

[HIV and pregnancy]. / HIV-infizierte Schwangere. Richtiges Vorgehen schützt das Kind zu 99%.

Through an optimal interdisciplinary management, it is possible to reduce the mother-to-child transmission of HIV-1 from more than 40% to less than 2%. The following are essential for this success: A risk-adapted antiviral therapy during the pregnancy and birth, a transmission prophylaxis for the new born child, delivery by Caesarean section, the early treatment of concomitant gynecological infections and abstention from breastfeeding. Unidentified HIV-positive pregnant women and inadequate support for HIV-positive pregnant women account for the majority of new HIV-1 infections in children in Germany. Hence, the HIV test should be an obligatory component of prenatal care and HIV-positive pregnant women should receive assistance at an appropriate center.

HER-2/neu expression in Paget disease of the vulva and the female breast.

OBJECTIVES: Paget disease of the vulva is a rare lesion that accounts for <1% 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Human papillomavirus, coinfection with Schistosoma hematobium, and cervical neoplasia in rural Tanzania.

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.