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

BACKGROUND: Randomised controlled trials showed human papillomavirus (HPV)-based screening leads to a significant reduction in cervical cancer incidence compared with cytology-based screening only. METHODS: Non-hysterectomised participants ≥30 years underwent co-testing with Papanicolaou (Pap) smear and HR-HPV testing (Hybrid Capture 2; HC2). Women with normal findings had their next screening round after 5 years, and HC2+ and Pap abnormal cases were immediately referred for colposcopy, while cases with discordant findings had repeat testing after 12 months with referral to colposcopy in cases with persistent positive findings. RESULTS: Twenty-six thousand six hundred and twenty-four women were recruited between February 2006 and December 2016. Two hundred and seventy-four CIN3+ cases were diagnosed (270 HPV+, 4 HPV-), including 31 invasive cervical cancers (29 HPV+, 2 HPV-). No CIN3+ was detected in HPV- women with abnormal cytology. We observed a significant decline in the 5-year incidence of CIN3+ (from 0.96% [95% CI 0.85-1.09%] to 0.16% [95% CI 0.10-0.25%]; p < 0.0001) and cervical cancer (from 0.10% [95% CI 0.07%-0.15%] to 0.025% [95% CI 0.01-0.08%]; p = 0.01) between the first and subsequent rounds. Approximately 90% (246/274) of CIN3+ cases were diagnosed at first colposcopy. CONCLUSIONS: The decline in disease rates with 5-yearly co-testing seems mainly attributable to HPV testing since no CIN3+ occurred in HPV-/Pap+ women.

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

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

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

BACKGROUND: High-risk human papilloma virus (HR-HPV) infection is associated with the development of cervical cancer. HPV vaccination reduces the risk of developing malignant lesions and is expected to change the dynamics of HPV transmission. Data from non-vaccinated women may provide an important benchmark to allow the impact of HPV vaccination programs to be assessed.This study was designed to prospectively determine the changing dynamics of HR-HPV infection and associated genital diseases in young women, most of whom were non-vaccinated. METHODS: Data from a population-based cohort study, comprising women of two predefined birth cohorts (women born in 1983/84 or 1988/89), were analyzed between 19 October 2009 and 31 December 2010 to determine risk factors for high-risk HPV infection and the association between specific HR-HPV types and atypical Pap smear test results. HPV status was determined by Hybrid Capture 2 (HC2) assay and genotyping. RESULTS: The prevalence of HR-HPV was 22.8% in the 1983/84 cohort (150/659) and 23.7% in the 1988/99 cohort (142/599). Only the number of sexual partners was a significant risk factor for HPV infection (odds ratios 22.687 and 6.124 for more than five versus one partner 84 cohort,/84 and 1988/89 cohorts, respectively) in multivariate analysis. HPV16 positive-women were significantly more likely to have abnormal Pap smears of any degree than HPV16-negative women (22.0% versus 3.61%, p < 0.0001 for the 1983/84 cohort and 9.09% versus 2.52%, p = 0.0482 for the 1988/89 cohort). CIN3 was diagnosed in six women 84 cohort,/84 cohort and two in the 1988/89 cohort. All women with CIN3 tested positive for HC2-HR and all six CIN3 cases 84 cohort,/84 cohort tested positive for HPV16. In the 1988/89 cohort, the rate of HPV16 infection was significantly lower in vaccinated than non-vaccinated women (1.59% versus 8.88%; p = 0.003). CONCLUSIONS: HR-HPV infection was highly prevalent in both cohorts and associated with an increased risk of abnormal Pap smears and biopsy proven CIN2+. HPV16 infection was associated with a high risk of clinically relevant lesions. HPV vaccination significantly decreased the risk of HPV16 infection.

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

OBJECTIVE: Testing for human papillomavirus (HPV) has been shown to increase the sensitivity and negative predictive value for detection of high-grade cervical intraepithelial neoplasia (CIN2+), either when used in conjunction with Pap cytology testing or alone. However, there is no satisfying clinical management algorithm for women testing Pap negative/HPV positive. We therefore evaluated the clinical utility of a novel dual biomarker-based approach (p16/Ki-67 Dual-stained cytology) for the identification of CIN2+ in women with Pap negative/HPV positive screening results, without the need to refer all women to immediate colposcopy. METHODS: All women aged ≥30 enrolled during 2007/2008 into a regional prospective Pap/HPV co-testing screening pilot project and tested Pap negative, but positive for HPV (n=425) were included in the analysis. p16/Ki-67 Dual-stained cytology was performed from residual cellular material available from the liquid-based cytology vial collected during the initial Pap/HPV co-testing screening visit. Results were correlated to the presence of CIN2+ confirmed during preliminary follow-up. RESULTS: p16/Ki-67 Dual-stained cytology tested positive at baseline in 108 out of 425 (25.4%) Pap negative/HPV positive cases. Sensitivity of Dual-stain testing for the detection of biopsy-confirmed CIN2+ during preliminary follow-up within the group of Pap negative/HPV positive women was 91.9% for CIN2+ (34/37 cases), and 96.4% for CIN3+ (27/28 cases). Specificity was 82.1% for CIN2+ on biopsy, and 76.9% for CIN3+, respectively. CONCLUSIONS: Triaging Pap negative/HPV positive screening test results with p16/Ki-67 Dual-stained cytology may identify women with a high probability of underlying CIN2+ and may efficiently complement HPV-based screening programs to prevent cervical cancer.

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

BACKGROUND: Currently, the German cervical cancer screening program encompasses an annual cytological Papanicolaou (Pap) smear. However, primary screening for cervical cancer using human papillomavirus (HPV) DNA testing detects cervical pre-cancerous lesions with a significantly higher sensitivity than the Pap smear-based cytology. OBJECTIVES: In order to develop viable modalities for primary cervical screening incorporating DNA testing for high-risk (HR) types of HPV, we started a pilot project in the city of Wolfsburg, Germany, in February 2006. This program provided a risk-adapted HPV testing-based strategy with defined patient pathways and extended screening intervals for women of 30 years or older. We report here the data of a 3-year follow-up. STUDY DESIGN: In the context of the usual routine screening at their office-based gynecologists, women were offered conventional cytology plus the Hybrid Capture 2 (HC2) HPV DNA test. Women with inconspicuous cytological findings (Pap I/II) and negative HC2 test were re-tested after 5 years but continued their annual gynecological examinations. When cytology and HC2 were positive, women were immediately referred to colposcopy. In women with a negative cytology but positive HC2 test, Pap smear was repeated after 6 mo and HC2 testing after 12 mo, and women were called for colposcopy if the HC2 test was persistently positive. RESULTS: From February 2006 to December 2008, 16,724 women agreed to participate in the project. Overall, 906 (5.41%) had positive HC2 results and 338 (2.02%) showed atypical Pap smears at recruitment. There were 417 (2.48%) women referred for colposcopy, 104 of whom were diagnosed with cervical intraepithelial neoplasia (CIN) 3 or worse, including 8 invasive cancers and 8 adenocarcinoma in situ (ACIS). No case of CIN 3 or worse occurred in HC2 negative women. CONCLUSIONS: The presented risk-adapted Wolfsburg Cervical Cancer Prevention Project ("Wolfsburg Model") has been shown to be effective and feasible in identifying women at risk and for avoiding unnecessary procedures for those who are double negative, thus allowing longer screening intervals and cost savings. Acceptance rates for the program were high for both participating women and gynecologists.

Association of the BRCA1 missense variant R1699W with a malignant phyllodes tumor of the breast.

Familial breast carcinomas that are attributable to BRCA1 or BRCA2 mutations have characteristic morphologic and immunhistochemical features. BRCA1-associated carcinomas are poorly differentiated infiltrating ductal carcinomas frequently exhibiting morphologic features of typical or atypical medullary carcinomas such as prominent lymphocytic infiltrate and pushing margins. We report on a patient carrying the deleterious BRCA1 germline mutation R1699W, who presented with a malignant phyllodes tumor of the breast. The re-investigation of archival material by a reference pathologist of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) revealed BRCA-associated pronounced pushing margins. In a total of 618 unrelated index patients who are registered in the GCHBOC database, no other phyllodes tumor has been described, while 10 carriers of the R1699W mutant have been identified. We conclude that the histopathologic appearance of the phyllodes tumor indicates an association with the BRCA1 mutation R1699W although it is a rare event in BRCA-positive families.

On the pathogenesis and clinical course of mesenteric lymph node cavitation and hyposplenism in coeliac disease.

BACKGROUND: Coeliac disease is a disorder characterised by malabsorption related to abnormal small bowel structure and intolerance to gluten. There are several reports of an increased risk for malignancy in coeliac disease and its relation to gluten-free, reduced gluten, or normal diet. While a normal diet is associated with an excess of cancer of the mouth, pharynx, oesophagus, and also of lymphoma, treatment with a gluten-free diet restores the cancer risk back to normal. PATIENT: In the present study, we report on a 63-year-old female patient with a history of coeliac disease for twenty years who presented with persistent diarrhoea, weight loss, and an abdominal mass. RESULTS: The gastroenterological work-up revealed small bowel mucosal atrophy, absence of functional splenic tissue, and evidence for an involution of a mesenteric lymph node, termed cavitation. DISCUSSION: This triad has been previously described to represent a rare disease entity related to coeliac disease. We report a two-year follow-up and a review of the literature on the pathogenesis, prognosis, and therapeutical implications of this disease entity.

Focal and Diffuse Beta Cell Changes in Persistent Hyperinsulinemic Hypoglycemia of Infancy.

In recent years our understanding of the changes in the endocrine pancreas in persistent hyperinsulinemic hypoglycemia in infancy, a form of congenital hypoglycemia, has increased considerably, in terms of both morphological classification and molecular pathogenesis. This review summarizes the current state of knowledge about the pathological lesions in the pancreas and their relationship to recently reported molecular findings.