Silva JH et al. of AMS and familial melanoma in the United States in 1985, while about 4 million had sporadic AMS.3,21 Genetics AMS can be sporadic or hereditary, in which case autosomal dominant inheritance is suggested with variable expressivity and incomplete penetrance.22 To date, no susceptibility gene has been identified for this syndrome.22 However, there are reports of associations between devel- opment of AMS and changes in chromosomes 9p21 and 1p36.23 It was demonstrated that the presence of dysplastic nevi increases the risk of melanoma in patients with germline mutations in CDKN2A, the main genomic locus of melanoma susceptibility.24,25 This genomic locus harbors two important genes involved in cell cycle control, senescence and apoptosis: p16 and p14ARF. The presence of a susceptibility gene for the development of dysplastic nevi was also observed on chromosome 7q21.3 in patients with the p16 gene mutation in four families with familial melanoma.20 A high incidence of somatic mutations of the BRAF gene has also been detected in patients with dysplastic nevi and primary melanomas.8 Moreover, melanocytic lesions of rapid growth or development are more likely to have mutations in this gene when compared to lesions without a history of changes in their clinical aspects.8 Other genetic changes described in dysplastic nevi include microsatellite instability, loss of heterozygosity (LOH) and increased activity of the telomerase enzyme.12 Currently, it is known that only 20% to 30% of melanomas arise in association with a melanocytic nevus, which indicates that the Clark’s theory of progression can explain only one of the paths from carcinogenesis to melanoma.26 Patients with dysplastic nevi may have a reduced ability to repair UV-induced DNA damage.8 Although genetic and environmental interactions are clearly involved in the melanocytic transformation patho- genesis, the understanding of its molecular mechanisms still remains incomplete.8 Clinical Diagnosis Clinically, a dysplastic nevus is most often a spotted lesion of 5 mm or more in diameter, with irregular and poorly defined borders and variable shades of brown, and it may present a reddish hue, with bleaching accomplished using vitropressure.18 It often presents a central papule, surrounded by a pigmented macular ring, giving the appearance of a ‘‘fried egg’’.18 Thus, there is considerable overlap with the ABCDE rule used for clinical diagnosis of melanoma, namely, A: asymmetry, B: irregular borders C: varied colors, D: diameter . 6 mm and E: elevation (simultaneous presentation of macular and papular compo- nents) (Figure 1).3,12,18 Dysplastic nevi may be present in any topography, including double-covered areas (such as buttocks and breasts), iris, instep and scalp.1,3,18,27 However, despite their occurrence in these unusual areas, the torso is the most common site for dysplastic nevi to develop.18,27 These lesions usually occur in puberty but can present in prepubescent children and in adults, and they may remain relatively dynamic in adulthood or disappear.3,18,27 It is also observed that the number of dysplastic nevi correlates directly with the total count of melanocytic nevi of the individual.27 Furthermore, from a clinical standpoint, it is CLINICS 2011;66(3):493-499 494 Figure 1 - Macroscopic image of two melanocytic lesions whose characteristics are superimposed by the ABCD rule (asymmetry, irregular borders, varied coloration, diameter greater than 6 mm): Left - dysplastic nevus; Right – cutaneous melanoma. known that the atypical nevus can evolve from a seemingly common melanocytic nevus or show atypical features from its first emergence.27 As dynamic lesions, they may become progressively more or less atypical in their clinical aspect.27 Although the majority of dysplastic nevi remain stable, regress over time or evolve benignly, monitoring of these lesions is essential. Their prophylactic excision is not justified.8,27 AMS has already been described by several authors and institutions based on clinical characteristics of patients and their personal and/or family history of melanoma, with or without histopathological confirmation of an atypical nevus.3 According to Newton et al.1, AMS can be defined through a scoring system, assigning one point for each feature, as seen in Table 1. Patients with scores greater than or equal to Table 1 - AMS classifications and their specific characteristics. CLASSIFICATION CHARACTERISTICS COMMENTS Newton et al. 1) two or more clinically atypical Scores greater (1993) nevi, 2) more than 100 nevi in than or equal patients between 20 and 50 years to 3 of age, 3) more than 50 nevi in characterize patients under 20 years of age or the AMS more than 50 years of age, 4) phenotype. more than one nevus in buttocks or instep, 5) nevi on the anterior scalp, 6) one or more pigmented lesions in the iris. Classical (1990) 1) 100 or more melanocytic nevi, Requires all 2) one or more melanocytic features for nevi greater than or equal to diagnosis. High 8mm in its largest diameter, demand for and 3) one or more clinically total count of atypical melanocytic nevi nevi for classification; low sensitivity National 1) occurrence of melanoma in one Requires Institutes of or more first or second degree histological Health (NIH) – relatives, 2) a large number of specific Consensus melanocytic nevi, often greater features, still 1992 than 50, some being atypical and controversial often variable in size, and 3) and considers melanocytic nevi that present only patients certain histological features * with family (*defined by Consensus) histories of melanoma Adapted from Newton et al.1993 1, Slade et al.1995 3