Expression of Vascular Endothelial Growth Factor C and D (VEGF-C and -D) is an Important Risk Factor for Lymphatic Metastasis in Undifferentiated Early Gastric Carcinoma

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Abstract
Background: Vascular endothelial growth factor C (VEGF-C) and D (VEGF-D) are considered to be potentially lymphangiogenic and can selectively induce hyperplasia of the lymphatic vasculature. In this study, we aimed to clarify the relation between expression of VEGF-C and -D and lymphatic metastasis in early gastric cancers. Methods: Using the specific antibodies, we classified 105 cases which were treated as gastrectomy with standard lymphadenectomy at the First Department of Surgery, Tokyo University Hospital, between 1994 and 2001, into three groups (diffuse type, focal type and negative type) for VEGF-C and two groups (positive and negative) for VEGF-D. Results: There was a significant correlation between the expression of VEGF-C and -D and lymphatic invasion but not with venous invasion. All of the 22 cases that were negative for VEGF-C and -D were histologically classified as adenocarcinoma of undifferentiated type and showed negative lymph node metastasis and also negative lymphatic invasion. VEGF-C was positive in all tumors of differentiated type, while its expression varied in tumors of undifferentiated type. The VEGF-D positive rate is much lower than that of VEGF-C. In undifferentiated tumors in particular, VEGF-D was positive only in 4/64 (6%) and three of these four had nodal metastasis. Therefore, in tumors of differentiated type, expression of VEGF-C and -D had no clinical relevance. In tumors of undifferentiated type, the negative expression of VEGF-C suggests lack of nodal metastasis, while the positive expression of VEGF-D suggests nodal metastasis. The lymph node metastasis was significantly related to the expression of VEGF-C and -D in adenocarcinomas of undifferentiated type but not in those of differentiated tumors. Conclusions: In early gastric cancers of histologically undifferentiated type with negative expression of VEGF-C and -D, limited surgery might be safely applied because the possibility of nodal metastasis is very low. These observations are based only on retrospective analysis of a small case series and further evaluation with a larger number of cases is necessary.