The Potential Prognostic and Therapeutic Implications of Prolactin Receptor and Growth Hormone-releasing Hormone Receptor Expression in Uterine Leiomyosarcomas

Abstract

The management of uterine leiomyosarcomas (uLMS) remains challenging. The rate of recurrence and metastasis is high, with 5-yr survival reaching only 40% to 50% in patients with tumor confined to the uterus (FIGO stage I or II). Prolactin receptor (PRLR) and growth hormone-releasing hormone receptor (GHRHR) have been implicated in the carcinogenesis of malignant tumors of the breast, endometrium, ovary, liver, and prostate. GHRHR antagonists inhibit in vitro growth of many human tumors and the expression of PRLR is associated with resistance to chemotherapy. The immunohistochemical expression of PRLR and GHRH in 24 primary and 2 recurrent uLMS was evaluated. Representative sections were stained with PRLR and GHRHR antibodies and immunoreactivity was calculated using H -score. The results were correlated with clinicopathologic data using Kaplan-Meier survival and multivariable Cox proportion hazard regression analyses. All tumors were positive for both markers with predominantly moderate to strong expression of PRLR (89%) and GHRHR (82%). Patients with tumors showing moderate to strong expression of PRLR were significantly less likely to achieve disease-free survival ( P =0.004) and significantly more likely to have a poor overall survival ( P =0.049). No significant difference in mean PRLR expression was found between tumors with higher mitotic counts (>20/10 hpf) and lower mitotic counts (20 or less/10 hpf). Furthermore, in 2 patients where the primary and recurrent tumors were tested, there was stronger expression of PRLR in the recurrence compared with the primary. This correlation was not found with GHRHR. Both PRLR and GHRHR may play a role in carcinogenesis in uLMS, as they do in other malignant neoplasms. To our knowledge, this study is the first evaluating the expression of these receptors in uLMS. Moderate or high expression of PRLR may serve as a prognostic marker associated with recurrences and increased mortality in uLMS patients.