Abstract
New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In this study, we aimed to investigate the expression of EP4 in vulvar cancer tissue and its association with clinicopathological data and its prognostic relevance on survival. Immunohistochemistry was performed on tumor specimens of 157 patients with vulvar cancer treated in the Department of Obstetrics and Gynecology, Ludwig-Maximilian-University of Munich, Germany, between 1990 and 2008. The expression of EP4 was analyzed using the well-established semiquantitative immunoreactivity score (IRS) and EP4 expression levels were correlated with clinicopathological data and patients' survival. To specify the tumor-associated immune cells, immunofluorescence double staining was performed on tissue samples. In vitro experiments including 5-Bromo-2'-Deoxyuridine (BrdU) proliferation assay and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) viability assay were conducted in order to examine the effect of EP4 antagonist L-161,982 on vulvar carcinoma cells. EP4 expression was a common finding in in the analyzed vulvar cancer tissue. EP4 expression correlated significantly with tumor size and FIGO classification and differed significantly between keratinizing vulvar carcinoma and nonkeratinizing carcinoma. Survival analysis showed a significant correlation of high EP4 expression with poorer overall survival (p = 0.001) and a trending correlation between high EP4 expression and shorter disease-free survival (p = 0.069). Cox regression revealed EP4 as an independent prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. In order to evaluate EP4 as a prognostic marker and possible target for endocrinological therapy, more research is needed on the influence of EP4 in the tumor environment and its impact in vulvar carcinoma.
Highlights
Vulva carcinoma is a relatively uncommon tumor, representing about 2–5% of all gynecological malignancies [1]
We investigated the expression of EP4 in vulvar cancer, its correlation with clinicopathological parameters, its association with overall survival, and the effect oft EP4 antagonism on vulvar cancer cells, aiming to find a prognostic and potentially targetable marker in vulvar cancer
In line with studies showing the impact of cyclooxygenase enzyme 2 (COX-2) on carcinogenesis, previous studies the alsoeffects described the effects the impact ing of COX-2 on carcinogenesis, previous studies described of EP4
Summary
Vulva carcinoma is a relatively uncommon tumor, representing about 2–5% of all gynecological malignancies [1] It is mainly a disease in postmenopausal women; incidence rates have been increasing in recent years, especially in younger women due to the rise in human papilloma virus (HPV) infections [2]. Treatment options for advanced vulva cancer are limited due to the lack of large prospective randomized clinical trials regarding systemic treatment [9]. In this context, predictive biomarkers and target-based therapies would play an important role in the improvement of clinical outcomes, especially in advanced stages of disease.
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