Sexual Dimorphism in Small-intestinal Neuroendocrine Tumors: Lower Prevalence of Mesenteric Disease in Premenopausal Women

Context: Small-intestinal neuroendocrine tumors (SI-NETs) have a modest but significantly higher prevalence and worse prognosis in male patients. Objective: This work aims to increase understanding of this sexual dimorphism in SI-NETs. Patients and Methods: Retrospectively, SI-NET patients treated in a single tertiary center were included and analyzed for disease characteristics. Estrogen receptor 1 (ESR1) and 2 (ESR2), progesterone receptor (PGR), and androgen receptor (AR) messenger RNA (mRNA) expression was assessed in primary tumors and healthy intestine. Estrogen receptor alpha (ERα) and AR protein expression were analyzed by immunohistochemistry in primary tumors and mesenteric metastases. Results: Of the 559 patients, 47% were female. Mesenteric metastasis/fibrosis was more prevalent in men (71% / 46%) than women (58% / 37%; P = 0.001 and P = 0.027, respectively). In women, prevalence of mesenteric metastases increased gradually with age from 41.1% in women <50 years to 71.7% in women >70 years. Increased expression of ESR1 and AR mRNA was observed in primary tumors compared to healthy intestine (both P < 0.001). ERα staining was observed in tumor cells and stroma with a strong correlation between tumor cells of primary tumors and mesenteric metastases (rho = 0.831, P = 0.02), but not in stroma (rho = -0.037, P = 0.91). AR expression was only found in stroma. Conclusion: Sexual dimorphism in SI-NETs was most pronounced in mesenteric disease, and the risk of mesenteric metastasis in women increased around menopause. The combination of increased ERα and AR expression in the SI-NET microenvironment suggests a modulating role of sex steroids in the development of the characteristic SI-NET mesenteric metastasis and associated fibrosis.