The anatomical relation between a malignant
tumor and its vascular and lymphatic bed is an important factor influencing
metastasis. Lack of specific markers for the lymphatic endothelium has long hampered a reliable detection of lymphatics. Here, we demonstrate that lymphatic endothelium can reliably be identified in a panel of different normal tissues and of benign and malignant
tumors. Application of the previously described PAL-E/CD31 double staining protocol differentiates between blood capillaries and veins on one hand and lymphatic vessels on the other. Blood vessel marker CD34, absent from lymphatics, was used additionally to classify arteries. We found that the lymphatic
vascular endothelial growth factor receptor-3 (VEGFR-3, also known as
Flt-4) was present on both lymphatic and blood vessels in 76 of 113 malignant
tumors [
adenocarcinoma of kidney (n = 3), colon (n = 3) and liver (n = 3), breast (n = 9) and
squamous cell carcinoma (n = 5), primary (n = 81), and metastatic (n = 9)
melanoma]. No evident signs of
tumor-induced lymphangiogenesis were observed. Evaluation of a series of 110 melanocytic skin lesions indicated that
VEGFR-3 expression is confined to the lymphatic vasculature in benign lesions. However, its expression emerges on the blood neovasculature in malignant lesions as soon as metastatic potential develops. We conclude that induction of
VEGFR-3 expression on
tumor blood vessels may be a general phenomenon that would make
VEGFR-3 a marker for
tumor endothelium. In addition, we propose
VEGFR-3 expression as a new microvascular progression marker in cutaneous
melanoma.