Melanoma Hyperpigmentation Is Strongly Associated With KIT Alterations

Abstract

KIT alterations have been identified in melanoma and treatment with imatinib has met with some success. However, the relationship between KIT and melanoma histology remains uncharacterized, and its role in melanoma pathogenesis unknown. We evaluated 70 melanomas from 70 patients seen at a single institution from 1997 to 2008. Cases were analyzed for KIT protein expression relative to histologic variables: subtype, sun damage, tumor infiltrating lymphocytes, melanoma in situ, vertical growth phase (VGP), location, and hyperpigmentation. Twenty-eight cases demonstrated 3+ membranous staining. Univariate analysis revealed 5 significant variables: sun damage (inverse, P = 0.015), tumor location (trunk>extremities>head and neck, P = 0.005), subtype (epithelioid>spindle, mixed>desmoplastic, P < 0.001), VGP (inverse, P = 0.024), and hyperpigmentation [22/26 (85% hyperpigmented cases) and 6/44 (14% nonhyperpigmented cases), P < 0.001]. Upon multivariate analysis, only hyperpigmentation and VGP remained statistically significant (P = 0.002, P = 0.019). Mutational analyses for KIT exons 9 and 11, and BRAF were performed on cases with 3+ labeling. Two of 27 of cases contained mutations in KIT exon 11, whereas only 1 case contained a V600E BRAF mutation, suggesting that KIT and BRAF mutations may be redundant events. Although KIT mutations were uncommon overall, pigmentation in conjunction with immunohistochemistry and nodular growth phase raised their frequency to 2 (40%) of 5 cases. We expand the context of KIT aberrations to involve areas other than acral and mucosal sites and demonstrate an inverse relationship between KIT abnormalities and sun damage. There is a strong correlation to hyperpigmentation that overrides factors including sun damage, tumor location, and histologic subtype, which may be used to identify cases with KIT aberrations.