Angiogenesis and vascular maturation in neuroendocrine tumors

Neuroendocrine tumors (NETs) are highly vascularized, but the process of proliferation and maturation of vascular structures during tumor development and progression has remained unknown. We examined the structural alterations of intratumoral blood vessels in human gastroenteropancreatic NET. Microvessel density was evaluated using the endothelial cell markers vasohibin-1 (VASH-1), CD31, and endoglin in 135 cases. Double immunohistochemistry staining was performed to localize endothelium and pericytes on the same vessels using the pericyte marker nestin. The ratio of Ki-67/CD31 was significantly correlated with that of VASH-1/CD31 positivity (P <.001), indicating that the ratio of VASH-1/CD31 also reflects the status of neovascularization in NET. This ratio was higher in NET than in its nonneoplastic counterpart (P =.10) and tended to increase according to World Health Organization (WHO) grade, although the differences were not statistically significant (P =.32). The ratio of VASH-1/nestin-positive vessels, representing the maturation of neovessels, was also significantly higher in NET than in its nonneoplastic counterparts (P =.003). Among WHO grades, the ratio increased from grade 1 to grade 2 (P =.36) and decreased in neuroendocrine carcinoma (P =.34). Our results demonstrated that VASH-1/CD31 can be an ideal immunohistochemical marker for characterizing neovascularization in NET. The VASH-1/CD31 content increased with WHO grade, and the vessels covered by pericytes decreased in higher grades. These structural changes in the vessels are considered to play an important role in inducing tumor-cell proliferation.