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Intratumoral Lymphangiogenesis and Lymph Node Metastasis in Head and Neck Cancer¹

Oxford Centre for Head and Neck Oncology, Radcliffe Infirmary, Oxford OX2 6HE [N. J. P. B., G. C.]; Medical Research Council Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS [R. P., S. B., D. G. J.]; Imperial Cancer Research Fund Molecular Oncology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU [R. L., J. M., A. L. H.]; Gynaecology Cancer Research Unit, St. Bartholomew’s Hospital, London EC1A 7BE [P. v. T.], United Kingdom

How tumors access and spread via the lymphatics is not understood. Although it is clear that dissemination via the blood system involves hemangiogenesis, it is uncertain whether tumors also induce lymphangiogenesis or simply invade existing peritumoral vessels. To address the issue we quantitated tumor lymph vessels in archival specimens of head and neck cancer by immunostaining for the recently described lymphatic endothelial marker LYVE-1, the vascular endothelial marker CD34, and the pKi67 proliferation marker, correlating lymph vessel density and proliferation index with clinical and pathological variables. Discrete "hotspots" of intratumoral small proliferating lymphatics were observed in all carcinomas, and a high intratumoral lymph vessel density was associated with neck node metastases (n = 23; P = 0.027) and an infiltrating margin of tumor invasion (P = 0.046) in the oropharyngeal subgroup. Quantitation of the lymphangiogenic growth factor vascular endothelial growth factor C by real-time PCR and immunohistochemistry revealed higher levels of mRNA in tumor tissue than in normal samples (n = 8; P = 0.017), but no obvious correlation with intratumoral lymphatics. Our results provide new evidence that proliferating lymphatics can occur in human cancers and may in some cases contribute to lymph node metastasis.

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