Ulceration is a common negative prognostic marker of solid tumors including melanoma. The signaling basis of ulceration is being elucidated. PHIP has been found to be amplified in wild-type melanomas, resulting in Akt activation and aerobic glycolysis (Warburg effect), associated with ulceration. The ulceration phenotype likely represents the genotype of the reactive oxygen driven tumor, in which reactive oxygen drives angiopoietin-2 production, tumor growth, and invasion. This phenotype is amenable to pharmacologic intervention.