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Metastatic melanoma is defined by the dissemination of primary melanoma cells to distant organs including but not limited to the lymph nodes, lungs, liver, brain, and bone ( Tumor Intrinsic and Extrinsic Functions Necessary for Successful Tumor Cell Dissemination Stepwise Molecular Evolution for the Transition of Primary Melanoma to Metastatic Melanoma Melanoma has the highest mutational burden of any cancer as a result of UV induced DNA damage and/or DNA replication errors ( Figure 1 ) ( BRAF mutations ( BRAF and NRAS are frequently mutually exclusive, with NRAS mutations sometimes found in nevi, especially congenital nevi ( in situ , that is accompanied with the acquisition of the TERT promoter mutations, and a high mutational burden ( TERT gene encodes for telomerase reverse transcriptase, the catalytic component of telomerase, an enzyme required for the maintenance of telomeres ( CDKN2A , TP53 , PTEN , and genes encoding SWI/SWF chromatin remodeling complex subunits, primary melanoma enters the invasive phase and becomes malignant melanoma ( de novo , however de novo melanomas may arise from clinically undetectable precursor lesions, and these lesions may follow similar trajectory as detectable lesions ( Figure 1 ) ( Figure 1 In addition to the genetic defects associated with metastatic melanoma development there are several dysregulated key signaling pathways that occur during melanoma progression such as the WNT, MAPK, and PI3K/AKT pathways (34, 35)

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