The role of VEGF-C/D and Flt-4 in the lymphatic metastasis of early-stage invasive cervical carcinoma

Background: To investigate the role of vascular endothelial growth factors (VEGF)-C/D and their receptor Flt-4 in the lymphatic metastasis of early-stage invasive cervical carcinoma. Methods: Immunohistochemical (IHC) staining with the antibodies against VEGF-C, VEGF-D, and Flt-4 was used to examine the expression of them in 97 cases of early-stage cervical carcinoma (Ia-IIa). Meanwhile, the lymphatic vessel density (LVD) was measured using the antibody against lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). We then analyzed the correlation between Flt-4-positive vessel density (FVD), LVD and clinicopathological features of the tumors. Results: (1) The positive rates of VEGF-C, VEGF-D, and Flt-4 were 57.7%, 60.8%, and 52.6% in the cervical tumor samples, respectively. (2) The expression levels of VEGF-C, VEGF-D, and Flt-4 were significantly correlated with lymphatic metastasis and lymphatic vessel invasion. LVD was significantly associated with lymph node metastasis and lymphatic vessel invasion. On the other hand, FVD was strongly associated with clinical staging. (3) The expression levels of VEGF-C and VEGF-D were significantly correlated with LVD and FVD, while Flt-4 levels showed no correlation with LVD or FVD. Conclusion: VEGF-C/D and Flt-4 may play an important role in the process of lymphatic metastasis of early-stage invasive cervical carcinoma through paracrine and autocrine mechanisms.