Genetic Analysis of Spitzoid Melanomas in Children

Melanoma is currently the sixth most common cancer in the United States with incidence rates increasing faster than for any other cancer. ii The lifetime risk of developing invasive melanoma in the United States is currently 1 in 71 compared with an estimate of 1 in 600 in 1960. However, despite these rising figures, melanoma of all types in childhood remains uncommon. Children represent 2% of melanoma patients in population-based studies iii, iv and melanoma accounts for only 3% of malignancies occurring in patients under the age of 20 years and 0.4% in pre-pubescent patients. The diagnosis of melanoma in this age group is also complicated by the presence of a benign melanocytic neoplasm called a Spitz nevus, which typically occurs in children and adolescents. Spitz nevi resemble a subset of melanoma referred to as “Spitzoid melanoma” or “melanoma with Spitz nevus-like features;” however, Spitzoid melanoma, like all other subsets of melanoma, is rare in children and occurs more commonly, though infrequently, in adults. Both Spitz nevi and Spitzoid melanoma present as solitary papules or nodules with or without pigmentation. Interestingly, the classic “ABCD (Asymmetry, Border irregularity, Color variation, Diameter > 6 mm) rule” for diagnosing melanoma does not apply to Spitzoid melanoma lesions and therein lays the difficulty in making a critical clinical diagnosis. Furthermore, although the gold standard for diagnosing melanoma is by histopathologic examination, studies detailing the histopathologic features of Spitzoid melanomas over the past few decades have failed to establish objective criteria for differentiating between these lesions and benign Spitz nevi, even when reviewed by expert pathologists. Subsequently, there are several reports in the literature of metastatic melanomas being initially misdiagnosed as Spitz nevi and resulting in fatal outcomes. Given the rarity of Spitzoid melanoma, the difficulty of diagnosis, and the potentially fatal outcomes of misdiagnosis, evaluation of these lesions presents a challenge to dermatologists, pathologists, and pediatric oncologists. The biologic behavior of Spitzoid melanoma is poorly understood and the genetic basis of these tumors is largely unknown. Unlike other melanomas and melanocytic nevi which demonstrate mutations in key signal transducers including RAS and BRAF in the RAS/RAF/MAPK signaling pathway responsible for regulating cell growth, differentiation, and apoptosis, we and others reported the absence of common RAS and BRAF mutations in both Spitzoid melanoma and Spitz nevi. x Therefore, it is unclear whether the Spitz nevus and Spitzoid melanoma are two distinct entities or they represent opposing ends of a biologic spectrum. Regardless, it appears that Spitzoid melanomas may have biologic behavior different from conventional melanomas and further elucidation of the molecular basis and biological nature of these tumors is required. In order to provide insights into the pathogenesis of Spitzoid melanomas, in this study we will first search for chromosomal abnormalities in patients with Spitzoid melanoma and compare their chromosomal profiles with those of appropriately matched healthy controls. Second, we will evaluate the expression of downstream molecules (phosphorylated MEK1, 2 and ERK) of the RAS/RAF/MAPK signaling pathway in Spitzoid melanoma and compare these levels with appropriately matched conventional melanoma controls. These studies will serve as the initial steps toward a molecular-based understanding of these tumors.