Prognostic Significance of Estrogen Receptor Alpha in Oral Squamous Cell Carcinoma

Abstract

Introduction: Several studies suggest an estrogen receptor alpha (ERα)-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 ERα expression and improved survival in oropharyngeal squamous cell carcinoma (OPSCC) has been found. However, the prognostic relevance of ERα in OSCC has not been proven to date. Therefore, the aim of this study was to evaluate ERα 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 ERα 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 ERα expression was found in the primary tumor (n = 11; 11/302) or lymph node metastases (n = 5; 5/52). Patients with positive ERα expression in primary tumors/primary lymph node metastases had a significantly lower OS and RFS (p = 0.012; p = 0.0053) compared to ERα-negative patients. Sub-group analysis in relation to gender revealed a highly significant influence of ERα expression on OS and RFS in males but not in females, both for the ERα-positive primary tumor cohort (males: p = 0.0013; p < 0.0001; females: p = 0.56; p = 0.89) and the ERα-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 ERα IRS of primary tumors (dichotomized; ERα+ vs. ERα−) 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 ERα positivity with regard to the localization of the primary tumor. ERα 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 ERα-positive patients. Conclusion: Expression of ERα 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, ERα-positive OSCC patients might benefit from an ER-based therapeutic (adjuvant) approach in the future.

Exogenous Estrogen in the Development of Head and Neck Cancer

“…A review published in 2022 by Qin et al described the interaction of estrogen receptors and androgen receptors in HNC. Whereas estrogen receptors beta (ERβ; but not estrogen receptor α [ERα]) are expressed in healthy oral mucosa, the expression of estrogen receptors is altered in OSCC, oropharyngeal squamous cell carcinoma, and precancerous oral lesions . A prognostic role of the expression of ERα in oropharyngeal squamous cell carcinoma and OSCC has been suggested.…”

“…Whereas estrogen receptors beta (ERβ; but not estrogen receptor α [ERα]) are expressed in healthy oral mucosa, 20 the expression of estrogen receptors is altered in OSCC, oropharyngeal squamous cell carcinoma, and precancerous oral lesions. [21][22][23][24] A prognostic role of the expression of ERα in oropharyngeal squamous cell carcinoma 21,22 and OSCC 23 has been suggested. Differences in hormone receptor expression and hormone responsiveness may account for differences in the development of HNC at different sublocalizations, as suggested for other malignant neoplasms that are not primarily known as hormone-sensitive cancers.…”

Worse prognosis in females with new onset of depression after oral cancer diagnosis: a retrospective case-control study

“…The relevance of sex hormones in the development of cancerous lesions in the oral cavity has previously been discussed. In a cohort of 316 patients, the positive expression of estrogen receptor alpha (ERα) was associated with lower OS and RFS, compared to patients with a negative ERα expression status ( 31 ). Gender-specific analyses demonstrated a highly significant prognostic effect of the ERα status in male patients, in which positive ERα was associated with worse survival outcomes.…”

Expression of Sex Hormones in Oral Squamous Cell Carcinoma: A Systematic Review on Immunohistochemical Studies

“…Doll et al concluded that patients with positive ER-α expression had significantly lower overall and relapse-free survival (RFS) than those with negative ER-α expression. For the primary tumor and primary tumor/primary lymph node metastasis cohorts with ER-positive primary tumors, ER expression was significantly associated with overall survival (OS) and relapse-free survival in males but not in females [ 10 ]. There was a significant correlation between positivity and tumor localization.…”