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Molecular Oncology, Markers, Clinical Correlates |
Department of Pathology, The Gade Institute, University of Bergen, N-5021 Bergen, Norway [O. S., L. A. A.], and Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom [D. G. J.]
The aim of this study was to determine lymphatic vessel density (LVD) in a series of nodular melanoma and correlate the findings with the expression of several angiogenic factors, including vascular endothelial growth factor-C, basic fibroblast growth factor (bFGF), patient survival, and clinico-pathologic data. Patients with nodular melanoma and complete follow-up information were included. Lymphatic vessels were immunostained with the LYVE-1 and Podoplanin antibodies, and LVD was evaluated in both intra- and peri-tumoral (LVDpt) areas. Median LVD was 6.3 and 12.5 vessels/mm2 in intra- and peri-tumoral areas, and coexpression of LYVE-1 and Ki-67/MIB-1 in lymphatic endothelial cells within the tumor was demonstrated, indicating active but low-grade lymphangiogenesis. Increased LVDpt was significantly associated with localization on the extremities (P = 0.005), decreased tumor thickness (P = 0.036), absence of vascular invasion (P = 0.004), brisk lymphocytic infiltration (P = 0.018), low proliferative rate by Ki-67 (P = 0.011), increased bFGF expression in tumor cells (P = 0.01) as well as in endothelial cells (P = 0.008), and decreased tumor cell expression of Ephrin-A1 (P = 0.009). Decreased LVD in intra-tumoral areas and LVDpt both predicted improved survival rates in multivariate analyses (for LVDpt, Hazard ratio: 2.1, P = 0.009). We found that decreased LVD was present in thicker and more proliferative tumors (Ki-67) and that increased LVD was significantly associated with improved patient survival in multivariate analysis. In addition, our data suggest the presence of low-grade intra-tumoral lymphangiogenesis in melanoma and a stimulating role of bFGF in lymphangiogenesis.
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