Melanoma is a human neurocristopathy associated with developmental defects in the neural crest-derived epidermal melanocytes. At the present time, at least three hypotheses were identified that may explain melanoma aetiology, as follows: (1) a model of linear progression from differentiated melanocytes to metastatic cancer cells (2) a model involving the appearance of melanoma stem-like cells, and (3) an epigenetic progenitor model of cancer. Treating metastatic melanoma is one of the most serious challenges in the 21st century. This is justified because of a subpopulation of cells presenting a remarkable molecular heterogeneity, which is able to explain the drug resistance and the growing mortality rates worldwide. Fortunately, there are now evidences sustaining the importance of genetic, epigenetic, and metabolomic alterations as biomarkers for classification, staging, and better management of melanoma patients. To illustrate some fascinating insights in this field, the genes BRAFV600E and CTLA4 have been recognized as bona fide targets to benefit melanoma patients. Our research attempts to carefully evaluate data from the literature in order to highlight the link between a molecular disease model and the key contribution of biomarkers in treating malignant melanoma metastases. 1. Introduction Historically, the first report of malignant tumor formations in the skin from anatomic sites where nevi had previously existed was proposed by Virchow [1]. Melanotic nevi and cutaneous melanoma are defined as human neurocristopathies associated with developmental defects in the neural crest-derived epidermal melanocytes. One consequence of changes in skin melanocyte development is its malignant transformation to cutaneous melanoma [2, 3]. In the sixties, Clark and coauthors described three different clinical types of primary human skin melanomas based on histological growth patterns: superficial spreading melanoma (SSM), nodular melanoma (NM), and lentigo maligna melanoma (LMM). Any melanoma, except NM, was showed to present a biphasic growth pattern: an initial and long period of time characterized by superficial growth followed by rapid deeper invasion. Curiously, NM subtype does not appear to have a superficial growth component, and it was characterized by uniform invasiveness. Moreover, they observed five anatomic levels of invasion (Clark's levels I–V), based on extracellular matrix architecture, as follows: level I (tumor cells were above the basement membrane—in situ melanoma), level II (tumor cells invading the papillary dermis), level III (tumor cells
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