Dadras Soheil S, Paul Thomas, Bertoncini Jennifer, Brown Lawrence F, Muzikansky Alona, Jackson David G, Ellwanger Ulf, Garbe Claus, Mihm Martin C, Detmar Michael
Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Am J Pathol. 2003 Jun;162(6):1951-60. doi: 10.1016/S0002-9440(10)64328-3.
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.
皮肤恶性黑色素瘤的特点是易于通过淋巴管早期转移至区域淋巴结，而淋巴结转移是黑色素瘤分期和临床管理的主要决定因素。然而，肿瘤诱导的淋巴管生成在黑色素瘤淋巴转移中的重要性仍不明确。我们使用针对新型淋巴管内皮标志物LYVE-1和全血管标志物CD31的双重免疫染色，研究了肿瘤淋巴管生成是否发生在人类皮肤恶性黑色素瘤中，以及肿瘤淋巴管生成的程度是否可能与淋巴结转移风险和患者生存率相关。肿瘤样本取自临床和组织学上紧密匹配的早期淋巴结转移原发性黑色素瘤病例（n = 18）和非转移性黑色素瘤病例（n = 19）。在大量黑色素瘤中检测到肿瘤内和肿瘤周围增殖的淋巴管热点。转移性黑色素瘤中肿瘤内淋巴管的发生率显著更高，且与无病生存期差相关。转移性黑色素瘤具有显著更多且更大的肿瘤相关淋巴管，相对淋巴管面积>1.5%与无病生存期和总生存期差显著相关。相比之下，肿瘤相关血管密度未发现差异。两组中均有少数病例检测到血管内皮生长因子和血管内皮生长因子-C表达。我们的结果表明，肿瘤淋巴管生成是皮肤黑色素瘤淋巴结转移风险的一种新的预后指标。
