Prognostic significance of erythropoietin expression in human endometrial carcinoma

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Abstract
BACKGROUND Erythropoietin (Epo), which is induced by hypoxia, controls erythropoiesis and protects neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, and resistance to therapy. The authors recently demonstrated hypoxia‐stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervical carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas. METHODS The authors characterized the expression of Epo, EpoR, hypoxia‐inducible factor (HIF)‐1α, estrogen receptor (ER), and progesterone receptor (PR) by immunohistochemical methods using endometrial carcinoma samples from 107 women and benign endometrial samples from 59 women in various phases of the menstrual cycle. They then analyzed potential correlations of Epo and EpoR immunostaining and clinicopathologic tumor features with outcome. RESULTS In benign endometrial tissue samples, Epo and EpoR expression increased over the course of the cycle, with the highest levels observed in the late secretory phase. Epo expression in benign endometrial samples showed a negative correlation with ER and PR expression. The authors found Epo and EpoR expression in 95.3 % and 100% of endometrial carcinoma samples, respectively. Increased EpoR, but not Epo, expression in tumors was associated with advanced‐stage disease, lymphovascular invasion, lymph node metastasis, and loss of ER expression. Increased Epo expression was observed in perinecrotic tumor regions in a pattern similar to the HIF‐1α expression pattern. Increased Epo expression was significantly associated with adverse clinical outcome on both univariate and multivariate analysis. CONCLUSIONS Hypoxia‐inducible autocrine Epo signaling in endometrial carcinoma may contribute to tumor progression and increased aggressiveness. Increased Epo expression in endometrial carcinomas may be an independent prognostic and/or predictive factor. Cancer 2004. Published 2004 American Cancer Society.