title: Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma.
abstract: 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/mm(2) 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.
authors.affiliation: Department of Pathology, The Gade Institute, University of Bergen, N-5021 Bergen, Norway.
authors.forename: Oddbjørn
authors.initials: O
authors.lastname: Straume
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
mesh_terms: D002455:Cell Division; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic; D011379:Prognosis; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D033921:Vesicular Transport Proteins
chemical_list: D006023:Glycoproteins; D019394:Ki-67 Antigen; C119248:LYVE1 protein, human; D033921:Vesicular Transport Proteins; D016222:Fibroblast Growth Factor 2