Malignant melanoma continues to remain one of the most aggressive malignancies worldwide and, despite significant advances in immunotherapy and targeted strategies, the mortality rate is increasing. The aim of our study was to understand the mechanisms involved in the development of malignant melanoma in patients with primary tumors locally advanced with pathological status pIIIb and pIVb, using expression profiling of miRNAs through microarray analysis, mutational status and frequency among patients. NGS cancer panels and the usual IHC staining performed in the clinic were used. MiR-205, miR-122, miR-192, miR125b, miR-21-5p, miR-210, miR-29c, miR-221, miR-143-3p, let-7c and let-7b are a few relevant miRNAs identified in our study to be involved in targeting major genes in malignant melanoma. Moreover, our data demonstrated that S-100 remains the most suitable marker for melanocytic lesions among IHC markers, and that HMB-45, Melan-A and MITF exhibited a sensitive specificity, together with S100. Our results revealed a specific profile between males and females in both molecular analyses. Furthermore, we demonstrated that the actual biomarkers used for immunohistochemistry staining are not specific enough to offer a complete overview of the tumor status. Therefore, we propose the evaluation of several miRNAs’ candidates in larger patient cohorts and in correlation with the mutational status of melanomas in males and females, separately. [ABSTRACT FROM AUTHOR]