title: Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival.
abstract: Malignant melanomas of the skin are distinguished by their propensity for early metastatic spread via lymphatic vessels to regional lymph nodes, and lymph node metastasis is a major determinant for the staging and clinical management of melanoma. However, the importance of tumor-induced lymphangiogenesis for lymphatic melanoma spread has remained unclear. We investigated whether tumor lymphangiogenesis occurs in human malignant melanomas of the skin and whether the extent of tumor lymphangiogenesis may be related to the risk for lymph node metastasis and to patient survival, using double immunostains for the novel lymphatic endothelial marker LYVE-1 and for the panvascular marker CD31. Tumor samples were obtained from clinically and histologically closely matched cases of primary melanomas with early lymph node metastasis (n = 18) and from nonmetastatic melanomas (n = 19). Hot spots of proliferating intratumoral and peritumoral lymphatic vessels were detected in a large number of melanomas. The incidence of intratumoral lymphatics was significantly higher in metastatic melanomas and correlated with poor disease-free survival. Metastatic melanomas had significantly more and larger tumor-associated lymphatic vessels, and a relative lymphatic vessel area of >1.5% was significantly associated with poor disease-free and overall survival. In contrast, no differences in the density of tumor-associated blood vessels were found. Vascular endothelial growth factor and vascular endothelial growth factor-C expression was equally detected in a minority of cases in both groups. Our results reveal tumor lymphangiogenesis as a novel prognostic indicator for the risk of lymph node metastasis in cutaneous melanoma.
authors.affiliation: Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Soheil S
authors.initials: SS
authors.lastname: Dadras
authors.forename: Thomas
authors.initials: T
authors.lastname: Paul
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bertoncini
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Brown
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
authors.forename: Ulf
authors.initials: U
authors.lastname: Ellwanger
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
mesh_terms: D000328:Adult; D000368:Aged; D001808:Blood Vessels / Q000473:pathology; D016228:Endothelial Growth Factors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D007249:Inflammation / Q000473:pathology; D008198:Lymph Nodes / Q000098:blood supply / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D042582:Vascular Endothelial Growth Factor C
chemical_list: D016228:Endothelial Growth Factors; D012333:RNA, Messenger; D042582:Vascular Endothelial Growth Factor C