Clinical Significance of Vascular Endothelial Growth Factor C Expression and Angiogenesis at the Deepest Invasive Site of Advanced Colorectal Carcinoma

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Abstract
Aim: Vascular endothelial growth factor C (VEGF-C) is known to be associated with the development of the lymphatic vascular system. The aim of this study was to elucidate the clinical significance of VEGF-C expression and microvessel density (MVD) at the deepest invasive site in advanced colorectal carcinoma (CRC). Methods: 152 patients who had undergone surgical resection for advanced CRC entered this study. VEGF-C expression was examined immunohistochemically with anti-VEGF-C polyclonal antibody C-20. Tumor MVD was determined immunohistochemically with anti-CD34 antibody. VEGF-C expression was defined as positive if distinct staining of the cytoplasm was observed in at least 10% of tumor cells at the deepest invasive site, central portion and superficial part of the tumor. MVD was estimated by averaging the count of three ×400 fields in the most vascular area at the deepest invasive site. Results: VEGF-C expression was detected in 71 of 152 lesions (46.7%) at the deepest invasive site. VEGF-C expression correlated significantly with poorer histologic grade, depth of invasion, lymphatic invasion, lymph node metastasis, venous invasion, liver metastasis and Duke’s stage. At the central portion and superficial part, there were no significant differences between VEGF-C expression and clinicopathological findings. VEGF-C expression at the deepest invasive site also correlated significantly with MVD. In cases with curative surgery, patients with VEGF-C expression at the deepest invasive site had a significantly poorer prognosis than those without VEGF-C expression. Furthermore, prognosis for patients with both VEGF-C expression and high MVD at the deepest invasive site was significantly poorer than that of patients without VEGF-C expression and with low MVD. Multivariate analysis with logistic regression for 5-year survival in patients with curative surgery showed that lymph node metastasis and VEGF-C expression were significant risk factors. Conclusions: VEGF-C expression at the deepest site of tumor invasion can be a useful predictor of poor prognosis in advanced CRC and show a close relation to angiogenesis.