Prognostic value of uPAR expression and angiogenesis in primary and metastatic melanoma

Angiogenesis is important for the progression of cutaneous melanoma. Here, we analyzed the prognostic impact of the angiogenic factor urokinase plasminogen activator resecptor (uPAR), vascular proliferation index (VPI) and tumor necrosis as a measure of hypoxia in a patient series of nodular melanomas (n = 255) and matched loco-regional metastases (n = 78). Expression of uPAR was determined by immunohistochemistry and VPI was assessed by dual immunohistochemistry using Factor-VIII/Ki67 staining. Necrosis was recorded based on HE-slides. As novel findings, high uPAR expression and high VPI were associated with each other, and with increased tumor thickness, presence of tumor necrosis, tumor ulceration, increased mitotic count and reduced cancer specific survival in primary melanoma. In matched cases, VPI was decreased in metastases, whereas the frequency of necrosis was increased. Our findings demonstrate for the first time the impact on melanoma specific survival of uPAR expression and VPI in primary tumors, and of increased necrosis as an indicator of tumor hypoxia in loco-regional metastases. These findings support the importance of tumor angiogenesis in melanoma aggressiveness, and suggest uPAR as an indicator of vascular proliferation and a potential biomarker in melanoma.

血管生成（Angiogenesis）对于皮肤黑色素瘤（cutaneous melanoma）的进展具有重要意义。本研究针对255例结节性黑色素瘤患者队列及78例匹配的局部区域转移灶（loco-regional metastases），分析了血管生成因子尿激酶型纤溶酶原激活物受体（urokinase plasminogen activator receptor, uPAR）、血管增殖指数（vascular proliferation index, VPI）以及反映缺氧状态的肿瘤坏死的预后价值。研究采用免疫组织化学法检测uPAR的表达水平，通过因子VIII/Ki67双重免疫组织化学染色评估VPI，并基于苏木精-伊红（HE）切片记录肿瘤坏死情况。本研究的全新发现包括：高uPAR表达与高VPI水平呈正相关，且二者均与原发性黑色素瘤的肿瘤厚度增加、肿瘤坏死存在、肿瘤溃疡形成、核分裂象计数升高以及癌症特异性生存期缩短显著相关。在匹配病例中，转移灶内的VPI水平降低，而坏死发生率升高。本研究首次证实，原发性肿瘤中uPAR表达与VPI水平、以及局部区域转移灶中反映肿瘤缺氧的坏死程度升高，均对黑色素瘤特异性生存期存在影响。上述结果证实了肿瘤血管生成在黑色素瘤侵袭性中的重要作用，并提示uPAR可作为血管增殖的检测指标及黑色素瘤潜在的生物标志物。