Pancreatic endocrine neoplasms (PENs) are uncommon, generally well-differentiated neoplasms that demonstrate prominent endocrine differentiation. Although the majority of PENs remain localized, malignant spread may occur via lymphatic or hematogenous routes. Angiogenic growth factors, including the vascular endothelial growth factor (VEGF) family, have been implicated in new vessel growth and hematogenous metastases, although this has not been studied in PENs. We therefore examined 19 primary well-differentiated PENs and 7 liver metastases to determine the expression of VEGF-A and its family member VEGF-C by immunolabeling analysis. VEGF-A immunoreactivity was evident only in scattered cells throughout all lesions. VEGF-C, however, demonstrated low-to-moderate expression in primary PENs by semiquantitative histoscore analysis (factor of labeling intensity by percentage of positive cells), with significantly increased expression in liver metastases (mean histoscore indices: primary PEN, 4.7 versus liver metastases, 9.5; Student's t test; P =.002773). Microvascular density of primary PENs and liver metastases did not appear to linearly correlate with VEGF-C expression. Examination of the VEGF-C-specific receptors VEGFR-2/KDR/Flk-1 and VEGFR-3/Flt-4 demonstrated intense endothelial immunoreactivity for VEGFR-2, as well as VEGFR-2 and -3 expression on the majority of neoplastic cells, suggesting a possible role in autocrine/paracrine neoplastic growth regulation. We postulate that the upregulation of VEGF-C may be involved in PEN progression and metastases, although not via a direct proangiogenic mechanism.