Abstract
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.
Highlights
In melanoma, angiogenesis is involved in tumor progression and metastasis [4, 5], and microvessel density (MVD) has been shown to be an adverse prognostic factor [6,7,8]
We analyzed for the first time a relationship between the vascular proliferation index (VPI), a novel tissue-based angiogenesis marker, and melanoma-specific patient survival, using a large cohort of primary tumors and matched loco-regional metastases
We found a significant impact of VPI on melanoma survival, suggesting that neo-angiogenesis is an aggressive feature of the melanoma microenvironment
Summary
There was no known history of familial occurrence During this time period, the sentinel node procedure was not performed in Norway, and our series lacks complete staging. Sufficient tumor tissue for immunohistochemistry was available in 248 of the primary melanoma cases and 68 of the loco-regional metastatic melanomas. Sufficient tumor tissue for immunohistochemistry was available in 242 of the primary melanomas and 69 of the paired loco-regional metastases. Staining was first performed in primary melanoma by IMB, and the staining protocol was adjusted (antibody dilution and incubation time) to obtain an optimal result when metastases were subsequently stained by EH. The staining procedure was performed using the secondary goat anti-mouse antibody (1031–04, Southern Biotech, Birmingham, AL, USA) diluted in anti-rabbit EnVision labelled polymer method (DAKO K4003) at 1:100 for 30 minutes.
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