The Neuropilins and Their Ligands in Hematogenous Metastasis of Salivary Adenoid Cystic Carcinoma-An Immunohistochemical Study.

PURPOSE: We investigated the expression of neuropilin-1 (NRP1), neuropilin-2 (NRP2), vascular endothelial growth factor-A (VEGF-A), semaphorin-3A (Sema-3A), and semaphorin-3F (Sema-3F) in normal salivary gland (NSG) tissue, nonmetastatic salivary adenoid cystic carcinoma (SACC), and metastatic SACC to better understand their role in intratumoral angiogenesis and hematogenous metastasis of SACC.

PATIENTS AND METHODS: The study included 60 SACC patients, equally divided between nonmetastatic SACC and metastatic SACC. We used 30 NSG samples as the control. The expression of cytokines was studied by immunohistochemistry and compared using the integrated optical density. The relationship between NRP1, NRP2, VEGF-A, and Sema-3A expression and microvessel density (MVD) was analyzed in the 3 groups.

RESULTS: In metastatic SACC, the expression levels of NRP1 and VEGF-A were significantly greater than those in nonmetastatic SACC and NSG. The expression of Sema-3A and Sema-3F was significantly lower in metastatic SACC than that in nonmetastatic SACC and NSG (P < .0001). No significant differences were found in NRP2 expression among the 3 groups (P = .43). The MVD of metastatic SACC was significantly greater than that of nonmetastatic SACC and NSG (P < .0001). However, the lymphatic vessel density of the 3 groups was not significantly different statistically. The relationship between MVD and NRP1 or VEGF-A showed a significant positive correlation (P < .0001, for both). However, a significant negative correlation was found between the MVD and Sema-3A or Sema-3F expression (P < .0001, for both).

CONCLUSIONS: Hematogenous metastasis of SACC is correlated with high expression of NRP1 and VEGF-A and low expression of Sema-3A and Sema-3F. The increased numbers of microvessels induced by VEGF-A signaling, combined with NRP1, could be one of the key reasons leading to the enhanced hematogenous metastasis in SACC.