Prognostic Significance of Estrogen Receptor Alpha in Oral Squamous Cell Carcinoma

Simple Summary: Although the survival rate has improved over the past decades, the prognosis of oral squamous cell carcinoma (OSCC) is still poor, and new treatment strategies are required. The aim of this study was to evaluate estrogen receptor alpha (ERa) expression in OSCC in a large patient cohort as a potential prognostic marker and therapeutic target. The findings indicated a rare expression of ERa that, however, was associated with a dramatic decrease of overall survival in male patients. In ERa-positive OSCC patients, an ER-based therapeutic (adjuvant) approach in the future might be conceivable based on the findings of this study. Introduction: Several studies suggest an estrogen receptor alpha (ERa)-mediated influence on the pathogenesis of oral squamous cell carcinoma (OSCC), as described for other malignancies that are not considered to be primarily hormone-dependent. Recently, an association between ERa expression and improved survival in oropharyngeal squamous cell carcinoma (OPSCC) has been found. However, the prognostic relevance of ERa in OSCC has not been proven to date. Therefore, the aim of this study was to evaluate ERa expression in OSCC in a large patient cohort and analyze its influence on survival and recurrence. Material and Methods: A total of 316 patients with primary OSCC who received initial surgical therapy were included in this analysis. The expression of ERa was evaluated on tissue microarrays by immunohistochemistry in the primary tumor and/or primary lymph node metastases. The expression level was quantified by light microscopy using the immunoreactive score (IRS) for estrogen receptor detection. An IRS equal to or greater than 2 was considered positive. The 5-year overall survival (OS) and relapse-free survival (RFS) were examined by the Kaplan-Meier method and log-rank test. Results: A total of 316 patients (111 females; 205 males) with a mean age of 61.3 years (range 27-96 years) were included in this study. In 16 patients (5.1%; 6 females and 10 males), positive ERa expression was found in the primary tumor (n = 11; 11/302) or lymph node metastases (n = 5; 5/52). Patients with positive ERa expression in primary tumors/primary lymph node metastases had a significantly lower OS and RFS (p = 0.012; p = 0.0053) compared to ERa-negative patients. Sub-group analysis in relation to gender revealed a highly significant influence of ERa expression on OS and RFS in males but not in females, both for the ERa-positive primary tumor cohort (males: p = 0.0013; p < 0.0001; females: p = 0.56; p = 0.89) and the ERa-positive primary tumor/primary lymph node metastasis cohort (males: p < 0.0001; p < 0.0001; females: p = 0.95; p = 0.96). In multivariate cox regression analysis, the ERa IRS of primary tumors (dichotomized; ERa+ vs. ERa-) was an independent risk factor for OS (HR = 4.230; 95%CI 1.616-11.076; p = 0.003) and RFS (HR = 12.390; 95%CI 4.073-37.693; p < 0.001) in the male cohort. There was a significant difference (p = 0.006) of ERa positivity with regard to the localization of the primary tumor. ERa positivity in the primary tumor was significantly associated (p = 0.026) with UICC stage, with most of the cases being diagnosed in stage IV. Furthermore, there was a significantly (p = 0.049) higher rate of bone infiltration in ERa-positive patients. Conclusion: Expression of ERa is rare in OSCC; however, it is associated with a dramatic decrease in OS in male patients. Further studies are necessary to confirm our results and to evaluate the exact mechanism underlying this observation. Hence, ERa-positive OSCC patients might benefit from an ER-based therapeutic (adjuvant) approach in the future.