Prognostic Value of Lymphangiogenesis and Lymphovascular Invasion in Invasive Breast Cancer

The major cause of death from breast cancer is dissemination of the primary tumor leading to formation of metastases. Spread to axillary lymph nodes is often the first step of generalization.1 Thus, the presence of lymph node metastasis represents a major criterion for evaluating the potential prognosis of breast cancer patients and predicts the choice of additional chemotherapy and/or radiation therapy after surgery of primary tumor.2 Tumor-associated lymphatic vessels are considered as the main rout of tumor cells to axillary lymph nodes.3 Lymphovascular invasion (LVI) of tumor cells is a prerequisite for the dissemination via the lymphatic system. Tumor cells exposed to more microvessels are more likely to spread to distant sites and to lymph nodes.4,5 Therefore, antilymphangiogenic therapies have been suggested as novel therapeutic concepts, and first preliminary experimental studies show promising results.6 Studies of lymphatic vessels and lymphogenic metastasis have been hampered by the lack of specific lymphatic markers.7 Until recently, immunohistochemical identification of lymphatic vessels was, somehow unreliably, achieved by comparing staining of pan-endothelial markers like PECAM-1/CD318,9 with markers of the basal lamina, eg, collagen type IV.10 Vessels that reacted with CD31 but lacked a basement membrane staining with red blood cells in their lumens were deemed lymphatic.9 More recently, lymphatic vessel identification has been made possible by the identification of the vascular endothelial growth factor receptor-3 (VEGFR-3), which is predominantly expressed on lymphatic endothelium in normal adult tissue but is also up-regulated on blood vessel endothelium in tumors limiting its use in visualizing tumor-associated lymphangiogenesis.11,12 Until now, two studies about the clinical relevance of lymphangiogenesis in human breast cancer exist: Jacquemier et al using VEGFR-3 as lymphatic marker saw no association between their microvessel count and the patient's lymph node status or overall survival.13 The second study by Nathanson et al applying an immunohistochemical staining combination with factor VIII, collagen 4, and VEGFR-3 to identify lymphatic vessels, in contrast, described a significant correlation between high VEGFR-3-microvessel density and the patient's lymph node status.3 The predictive value of LVI, determined by the presence of neoplastic cell emboli within spaces showing a clear endothelial lining, is also being discussed controversially.14–16 The identification of podoplanin as a specific marker of the lymphatic endothelium and the development of a polyclonal antibody have enabled us to selectively stain lymphatic vessels.17 Therefore, to our knowledge, this study presents the first data correlating lymphangiogenesis and lymphovascular invasion on the prognosis in a representative cohort of breast cancer patients. Although respective, preliminary evidence does exist,3,13,15,18 the prognostic relevance of lymphangiogenesis and lymphovascular invasion in breast cancer has not yet been investigated in a large cohort using a specific lymphatic marker. The aim of this study was the investigation of lymphangiogenesis and lymphovascular invasion, its predictive role of lymph node involvement, and its prognostic relevance in a large series of breast cancer with long-term follow-up.