Can angiotropism and lymphovascular invasion refine the current cutaneous melanoma staging system?

Background: Several prognostic factors for primary cutaneous melanoma (PCM) have been identified, and these predict metastasis and survival, to a certain extent. We sought to determine the frequency of angiotropism (AT) and lymphovascular invasion (LVI) in PCM and the relationship between AT, LVI, and other clinicopathological parameters and patient's prognosis. Methods: This study included 538 cases of PCM diagnosed between 2003 and 2016. It comprised 246 females and 292 males whose clinicopathological variables were evaluated with respect to LVI and AT using univariate and multivariate analyses. Overall survival (OS) was assessed by Kaplan–Meier (KM) analysis and Cox regression multivariate analysis. Results: AT occurred more frequently than LVI. Ulceration, mitotic rate, and Breslow thickness were found to be highly associated with both LVI and AT (p < 0.01). All LVI+ cases had AT, with a significant positive correlation (p < 0.01). Both AT and LVI predicted lymph node (LN) metastasis (odds ratio [OR] = 1.47, 1.12, respectively). Multivariate analysis showed LN metastasis, Breslow thickness, LVI, and AT as predictors of OS. LVI and AT independently predicted adverse OS by Cox regression analysis (hazard ratio [HR] = 1.66, 1.49, respectively) and with KM survival analysis. Conclusion: AT is a marker for angiotropic extravascular migratory tumor spread (angiotropic EVMM), and LVI is a marker for intra‐lymphovascular tumor spread. Both predict poor prognosis. Given its ease of detection, AT could be adopted as a histologpathological feature in the routine assessment of primary cutaneous malignant melanoma cases

Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion

Aims Ran GTPase is involved in nucleocytoplasmic shuttling of proteins and is overexpressed in several cancers. The expression of Ran in malignant melanoma (MM) and its functional activity have not been described and were investigated in this study.Methods The prognostic value of Ran expression was tested in a series of 185 primary cutaneous MM cases using immunohistochemistry. The functional activity of Ran was investigated in the two melanoma cell lines. Ran expression was knocked down using two siRNAs and the effect on the expression of the c-Met oncogene, a potential downstream target of Ran, was tested. Functional effects of Ran knockdown on cell motility and cell proliferation were also assessed.Results Positive Ran expression was seen in 12.4% of MM and was associated with advanced clinical stage and greater Breslow thickness. Positive expression was an independent marker of shorter overall survival (p=0.023). Knockdown of Ran results in decreased expression of c-Met and the downstream c-met signalling targets ERK1/2. There was a significant reduction in cell migration (p [less than] 0.001) and cell invasion (p [less than] 0.001). c-Met knockdown decreased the expression of Ran through MAPK and PI3K-AKT in A375 cell line, inhibited the cell viability and migration of both A375 and G361 melanoma cell lines while invasion was enhanced.Conclusion Ran is a poor prognostic marker in cutaneous MM. It upregulates expression of the oncogene c-Met and, possibly through this, it promotes cell motility which may in turn promote metastasis