Clinicopathological and prognostic significance of vascular endothelial growth factors (VEGF)-C and -D and VEGF receptor 3 in invasive breast carcinoma

Abstract Aims Vascular endothelial growth factors C and D (VEGF-C and VEGF-D) play a major role in lymphangiogenesis and activate VEGF receptor 3 (VEGFR-3). Our purpose was to study the clinicopathologic and clinical value of VEGF-C, VEGF-D and VEGFR-3 in invasive breast carcinoma. Material and methods Immunohistochemistry was performed in paraffin-embedded tissue specimens from 177 invasive breast carcinomas to detect the proteins VEGF-C, VEGF-D, VEGFR-3, p53, Ki67, c-erbB-2, topoIIα and ER/PR. The results were statistically processed. Results VEGF-C, VEGF-D and VEGFR-3 were found to be predominantly expressed in the cytoplasm of the malignant cells. VEGF-C occasionally showed a submembranous intensification. VEGF-D and VEGFR-3 were also immunodetected in the nuclei of the malignant cells. Nuclear VEGF-D was positively correlated to p53, Ki67 and topoIIα proteins’ expression ( p  = 0.003, p  = 0.009 and p  = 0.017 respectively) and nuclear VEGFR-3 to topoIIα ( p  = 0.034). Cytoplasmic expression of VEGF-C and its submembranous intensification were found to be independent indicators of patients’ overall and disease-free survival, respectively ( p  = 0.003 and p  = 0.044 respectively). The group with high expression of both cytoplasmic VEGF-C and stromal VEGFR-3 showed poor overall survival ( p  = 0.024) and the group with both submembranous VEGF-C and stromal VEGFR-3 immunostaining showed poor both disease-free and overall survival ( p  = 0.012 and p  = 0.038 respectively). Conclusion VEGF-D and VEGFR-3 seem to exert proliferative activity in invasive breast carcinomas. VEGF-C was found to be an independent indicator of patient's poor prognosis and the simultaneous expression of tumor VEGF-C and stromal VEGFR-3 yielded additional prognostic information.