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Lymph node metastasis, including lymph node micrometastasis (LMM), is one of the most important prognostic factors in esophageal squamous cell carcinoma (ESCC). Vascular endothelial growth factor C (VEGF-C) plays a key role in the process of lymphangiogenesis. We examined VEGF-C expression and tumor microvessel density of the primary tumors in ESCC and analyzed relationships between VEGF-C expression and clinicopathologic findings including LMM in submucosal ESCC. The subjects were 87 patients with submucosal ESCC. Immunohistochemical staining of VEGF-C and CD34 was performed with primary tumors, and staining of cytokeratin was performed with dissected lymph nodes. Microvessel density was calculated from CD34 expression, and LMM was detected by cytokeratin staining. VEGF-C overexpression significantly correlated with depth of tumor invasion, lymphatic invasion, and lymph node metastasis (P < 0.05, P < 0.0001, and P < 0.0001, respectively). High microvessel density also correlated with lymphatic invasion and lymph node metastasis (P < 0.005 and P < 0.05, respectively). LMM was detected in 8 cases and 14 lymph nodes by cytokeratin staining. VEGF-C overexpression and high microvessel density were found in tumors with lymph node metastasis and/or LMM, compared with tumors without nodal metastasis or LMM (P < 0.0001 and P < 0.01, respectively). The present findings indicate that in ESCC with submucosal invasion, VEGF-C overexpression of the primary tumor is a strong high risk factor for lymph node metastasis, including LMM. [Copyright &y& Elsevier]