Further research should not only focus on HPV mediated pathogenic pathways but also on the non-HPV related molecular and genetic factors that play a role in penile cancer development. Options for prevention of penile cancer include (neonatal) circumcision, limitation of penile HPV infections (either by prophylactic vaccination or condom use), prevention of phimosis, treatment of chronic inflammatory conditions, limiting PUVA treatment, smoking cessation and hygienic measures.

Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P<0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival (P=0.022) and disease-specific survival (P=0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages (P=0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors (P=0.001 for squamous cell carcinoma and P=0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.

Background: The association between lichen sclerosus and vulvar squamous cell carcinoma (VSCC) has long been recognized, but large epidemiologic studies are lacking.Methods: Data of women diagnosed with vulvar pathology in the Netherlands were retrieved from the Dutch Pathology Registry. All vulvar pathology reports of this historical cohort were reviewed to construct a research database, including 3,038 women with lichen sclerosus diagnosed between 1991 and 2011. The incidence rate of lichen sclerosus and the cumulative incidence of VSCC among women with lichen sclerosus were estimated.Results: Between 1991 and 2011, the incidence rate of lichen sclerosus increased from 7.4 to 14.6 per 100,000 woman-years. The median age at time of lichen sclerosus diagnosis was 59.8 years and the cumulative VSCC incidence was 6.7%. The 10-year VSCC incidence in women with lichen sclerosus was associated

In sexually active couples, HPV type concordance was more prevalent than expected by chance and was associated with increased viral loads. These data provide biological support for HPV transmission between sex partners.

Key words: cervical intraepithelial neoplasia; human papillomavirus; condom use; clinical coursePersistent infection of the cervical epithelium with high-risk types of HPV plays a major role in the development, maintenance and progression of CIN. 1,2 HPV has been found in 99.7% of cervical cancers worldwide. 3 Sexual intercourse is the primary mode for transmission or acquisition of HPV, and prevalence is related to many determinants involving sexual behavior characteristics. 4 -6 Case-control studies of male sexual partners of women with cervical cancer have shown a relation between male sexual behavior and cervical cancer. 7,8 The presence of HPV DNA in penile swabs conveyed a 5-fold risk of cervical cancer to their wives. 5 Studies on the risk factors of CIN supported a protective effect of condom use in women, emphasizing the venereal nature. 9 -11 Coker et al. 12 found that among high-risk HPV-positive women longer-duration barrier method use was associated with a reduced risk of CIN. Manhart and Koutsky 13 reported in a meta-analysis that data on effects of condom use preventing HPV infection and HPV-related conditions were inconsistent. However, none of these studies was conducted explicitly to assess the effectiveness of condoms at preventing HPV infection and HPV-related conditions.Previously, we showed that flat penile lesions are associated with the presence of HPV and that regression is dependent on the presence of HPV 14 (see also Bleeker and Hogewoning, 2003, accompanying paper). Continuous transmission of HPV in sexual partners having HPV-associated genital lesions might reduce the chance of viral clearance. In a randomized clinical trial, we investigated the influence of condom use on the clinical course of HPV-associated genital lesions and HPV infection in sexual partners. In the present report, we evaluate the effects of condom use on CIN regression and HPV clearance. MATERIAL AND METHODS Study population and designWomen referred to the colposcopy clinic of the Albert Schweitzer Hospital, Dordrecht, the Netherlands, from January 1995 to June 2002 were asked to bring in their male sexual partner. Eligible were women with an abnormal cervical smear (mild dysplasia or worse) and/or cCIN and/or hCIN. Women were evaluated for CIN by colposcopy and by histologic evaluation of cervical biopsy specimens at baseline. Cervical smears were taken for cytology and HPV testing by PCR. The outline of the study was verbally explained and written information given to couples who had no other sexual partners. Willing couples returned within 2 weeks to discuss the study protocol in detail, and additional questions were answered. Both the period of condom use, i.e., only during the study and for at least 3 months, and the instructions on condom use, i.e., during genital-genital contact, were discussed with participants. Latex condoms (Durex fetherlite; Netherlands LRC, Leerdam, the Netherlands) with basic lubricant (without spermicidal and/or virus-inactivating substances) were given free, to increase study com...

We assessed clearance rates of 14 high-risk human papillomavirus (hrHPV) types in hrHPV-positive women with normal cytology and borderline/mild dyskaryosis (BMD) in a population-based cervical screening cohort of 44 102 women. The 6-month hrHPV type-specific clearance rates, that is, clearance of the same type as detected at baseline, in women with normal and BMD smears were 43% (95% confidence interval (CI) 39 -47) and 29% (95% CI 24 -34), respectively. Corresponding 18-month clearance rates were markedly higher, namely 65% (95% CI 60 -69) and 41% (95% CI 36 -47), respectively. The lowest clearance rates in women with normal cytology were observed for HPV16, HPV18, HPV31, and HPV33. Significantly reduced 18-month clearance rates at a significance level of 1% were observed for HPV16 (49%, 95% CI 41 -59) and HPV31 (50%, 95% CI 39 -63) in women with normal cytology, and for HPV16 (19%, 95% CI 12 -29) in women with BMD. Among women who did not clear hrHPV, women with HPV16 persistence displayed an increased detection rate of XCIN3 (normal Po0.0001; BMD, P ¼ 0.005). The type-specific differences in clearance rates indicate the potential value of hrHPV genotyping in screening programs. Our data support close surveillance (i.e. referral directly, or within 6 months) of women with HPV16 and are inconclusive for surveillance of women with HPV18, HPV31, and HPV33. For the other hrHPV-positive women, it seems advisable to adopt a conservative management with a long waiting period, as hrHPV clearance is markedly higher after 18 months than after 6 months and the risk for XCIN3 is low.

The risk of vulvar squamous cell carcinoma (VSCC) in patients with high-grade vulvar intraepithelial neoplasia (VIN) is considered lower in high-grade squamous intraepithelial lesion (HSIL) compared to differentiated VIN (dVIN), but studies are limited. Our study investigated both the incidence of high-grade VIN and the cumulative incidence of VSCC in patients with HSIL and dVIN separately. A database of women diagnosed with highgrade VIN between 1991 and 2011 was constructed with data from the Dutch Pathology Registry (PALGA). The European standardized incidence rate (ESR) and VSCC risk were calculated, stratified for HSIL and dVIN. The effects of type of VIN (HSIL vs dVIN), age and lichen sclerosis (LS) were estimated by Cox regression. In total, 1148 patients were diagnosed with high-grade VIN between 1991 and 2011. Between 1991-1995 and 2006-2011, the ESR of HSIL increased from 2.39 (per 100 000 woman-years) to 3.26 and the ESR of dVIN increased from 0.02 to 0.08. The 10-year cumulative VSCC risk was 10.3%; 9.7% for HSIL and 50.0% for dVIN (log rank P < .001). Type of VIN, age and presence of LS were independent risk factors for progression to VSCC, with hazard ratios of 3.0 (95% confidence interval [CI] 1.3-7.1), 2.3 (95% CI 1.5-3.4) and 3.1 (95% CI 1.8-5.3), respectively. The incidence of high-grade VIN is rising. Because of the high cancer risk in patients with dVIN, better identification and timely recognition are urgently needed.

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