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 with concurrent vulvar intraepithelial neoplasia (VIN; 18.8% in women with VIN and 2.8% in women without VIN) and age at time of lichen sclerosus diagnosis (5.9% in women of ≥70 years, 3% in women between 50 and 70 years, and 1.8% in women <50 years). The effects of presence of VIN and age remained significant in adjusted Cox regression analysis. Conclusion: This historical cohort showed a nearly 100% increase in incidence of lichen sclerosus between 1991 and 2011. Concurrent VIN and age ≥70 years at time of lichen sclerosus diagnosis are important risk factors for vulvar cancer development. Impact: The incidence of lichen sclerosus is rising and special attention is needed in particular in women with concurrent VIN because of their high risk of cancer. Cancer Epidemiol Biomarkers Prev; 25(8); 1224–30. ©2016 AACR.

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 CIN3 (normal P<0.0001; BMD, P=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 CIN3 is low.

Women with persistent HPV infections have increased risk of progressive CIN lesions. Transmission of HPV between sexual partners might maintain viral infection and, consequently, may influence the clinical course of CIN. We investigated the effect of condom use on regression of CIN lesions and on clearance of HPV. Women with CIN and their male sexual partners were randomized for condom use (condom group n = 72 and noncondom group n = 76). They were conservatively managed and followed every 3–6 months by colposcopy, cytology and HPV testing by GP5⁺/6⁺ PCR. Baseline cervical biopsy specimens were taken. Median follow‐up time for women was 15.2 months (range 3.0–85.4). Outcomes of interest were clinical regression of CIN at colposcopy and clearance of HPV. Outcomes were assessed in 64 women of the condom group and 61 women of the noncondom group. Women in the condom group showed a 2‐year cumulative regression rate of 53% vs. 35% in the noncondom group (p = 0.03). The 2‐year cumulative rates of HPV clearance were 23% vs. 4%, respectively (p = 0.02). Although lower regression rates were found if women were HPV‐positive and had ≥CIN2 lesions at baseline, effects of condom use were found both in women with CIN1 and in women with ≥CIN2 lesions. Condom use promotes regression of CIN lesions and clearance of HPV.

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 high‐grade 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.