Expression of the Vascular Endothelial Growth Factor C Receptor VEGFR-3 in Lymphatic Endothelium of the Skin and in Vascular Tumors

Abstract

It is difficult to identify lymph vessels in tissue sections by histochemical staining, and thus a specific marker for lymphatic endothelial cells would be more practical in histopathological diagnostics. Here we have applied a specific antigenic marker for lymphatic endothelial cells in the human skin, the vascular endothelial growth factor receptor-3 (VEGFR-3), and show that it identifies a distinct vessel population both in fetal and adult skin, which has properties of lymphatic vessels. The expression of VEGFR-3 was studied in normal human skin by in situ hybridization, iodinated ligand binding, and immunohistochemistry. A subset of developing vessels expressed the VEGFR-3 mRNA in fetal skin as shown by in situ hybridization and radioiodinated vascular endothelial growth factor (VEGF)-C bound selectively to a subset of vessels in adult skin that had morphological characteristics of lymphatic vessels. Monoclonal antibodies against the extracellular domain of VEGFR-3 stained specifically endothelial cells of dermal lymph vessels, in contrast to PAL-E antibodies, which stained only blood vessel endothelia. In addition, staining for VEGFR-3 was strongly positive in the endothelium of cutaneous lymphangiomatosis, but staining of endothelial cells in cutaneous hemangiomas was weaker. These results establish the utility of anti-VEGFR-3 antibodies in the identification of lymphovascular channels in the skin and in the differential diagnosis of skin lesions involving lymphatic or blood vascular endothelium.

Splenic Angiosarcoma: A Clinicopathologic and Immunophenotypic Study of 28 Cases

“…VEGFR-3 has been found in most endothelia during embryogenesis. Later in development, it becomes restricted to lymphatic endothelium in most tissue (24,25). It has also been found to be upregulated in the endothelial cells of tumor neovascularization (26) and is consistently expressed in lymphangiomas (25), Kaposi's sarcoma (24), and in hemangiomas and angiosarcomas (27).…”

Immunodetection and quantification of vascular endothelial growth factor receptor‐3 in human malignant tumor tissues

“…The major site of expression in the adult organism is in the lymphatics, and it has been employed as a marker for lymphatic vessels in normal and pathological tissue samples 32 and has been used to demonstrate an apparent lymphatic origin of Kaposi's sarcoma cells. 15 VEGFR-3 is one of several markers for lymphatic endothelial cells.…”

A multivariate analysis of blood vessel and lymph vessel invasion as predictors of ovarian and lymph node metastases in patients with cervical carcinoma

“…Recently, it has been suggested that the VEGFR-3 may be useful in the differentiation of lymphatic vessels from blood vessels. 15 The usefulness of a combined assessment using both factor VIII-related antigen and VEGFR-3 should be investigated further. BVI, which predominantly includes capillary vessel invasion, appears to be a significant predictor of ovarian metastasis and patient survival when determined separately from LVI on HE stained sections.…”