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Atypical Mole Syndrome and Dysplastic Nevi: Identification of Populations at Risk for Developing Melanoma - Review Article

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Atypical Mole Syndrome and Dysplastic Nevi: Identification of Populations at Risk for Developing Melanoma - Review Article CLINICS 2011;66(3):493-499 DOI:10.1590/S1807-59322011000300023 REVIEW Atypical mole syndrome and dysplastic nevi: identification of populations at risk for developing melanoma - review article Juliana Hypo´ lito Silva,I Bianca Costa Soares de Sa´,II Alexandre Leon Ribeiro de A´ vila,II Gilles Landman,III Joa˜ o Pedreira Duprat NetoII I Oncology School Celestino Bourroul - Hospital AC Camargo, Sa˜ o Paulo, SP, Brazil. II Skin Oncology Department - Hospital AC Camargo - Sa˜ o Paulo, SP, Brazil. III Pathology Department - Hospital AC Camargo - Sa˜ o Paulo, SP, Brazil. Atypical Mole Syndrome is the most important phenotypic risk factor for developing cutaneous melanoma, a malignancy that accounts for about 80% of deaths from skin cancer. Because the diagnosis of melanoma at an early stage is of great prognostic relevance, the identification of Atypical Mole Syndrome carriers is essential, as well as the creation of recommended preventative measures that must be taken by these patients. KEYWORDS: Dysplastic Nevus Syndrome; dysplastic nevi; melanoma; early diagnosis; Risk Factors. Silva JH, de Sa´ BC, Avila ALR, Landman G, Duprat Neto JP. Atypical mole syndrome and dysplastic nevi: identification of populations at risk for developing melanoma - review article. Clinics. 2011;66(3):493-499. Received for publication on November 23, 2010; First review completed on November 24, 2010; Accepted for publication on November 24, 2010 E-mail: [email protected] Tel.: 55 11 2189-5135 INTRODUCTION Several studies have shown that the presence of dysplas- tic nevi considerably increases the risk of developing The incidence of cutaneous melanoma has increased melanoma, which demonstrates that these lesions, aside rapidly worldwide.1-5 Although it corresponds to only 4% of 4 from being precursors to disease are also important risk all skin cancers, it accounts for 80% of skin cancer deaths. 4,7,14-19 markers. Nevertheless, the risk magnitude varies Because early detection of the disease is implicit in its cure 3,4,15,16,20 among patients with this type of pigmented lesion. and only 14% of patients with metastatic disease survive 4-6 There are still controversies in the literature regarding the beyond 5 years, knowledge of factors that increase an nomenclature, clinical definition, dermoscopic characteris- individual’s risk for developing melanoma and diagnosis at tics and histopathological, genetic and molecular patterns of an early stage of the disease have great prognostic dysplastic nevi.4,8 relevance. In this literature review of dysplastic nevi and AMS, we The risk factors for developing melanoma are both genetic demonstrate the importance of a complete dermatological and environmental, especially the presence of multiple examination for the evaluation and monitoring of patients melanocytic nevi, dysplastic nevi and atypical mole syn- with dysplastic nevi and AMS and suggest criteria for drome (AMS), as the main clinical phenotypic susceptibil- 4-9 follow-up. ity. In 1820, Norris10 described what is currently considered in a family predisposed to melanoma. In 1978, Clark11 Epidemiology reported an increased incidence of cutaneous melanoma in Dysplastic nevi are relatively common in the general 8 families with multiple melanocytic lesions, introducing the population. Reports have described the prevalence ranging melanoma tumor progression model from melanocytic from 2% to 53% in different studies, depending on the 8 nevi.11,12 At the time, Clark used the term B-K mole syndrome diagnostic criteria (clinical or histological). A more accurate using the initials of the patients surnames.11 Currently, the estimate is considered to be about 2%-8% of Caucasians, terms AMS, Dysplastic Nevus Syndrome and Familial with a predilection for young individuals (less than 30 to 40 18 Atypical Multiple-Mole Melanoma Syndrome (FAMMM) years of age). The frequency of dysplastic nevi in patients 18 have been employed.12 In 1985, Elder13 extended the theory with a history of melanoma is much higher: 34% to 59%. of ‘‘nevus-melanoma’’ for sporadic dysplastic nevi as a Evidence suggests that sun exposure, in addition to genetic possible precursor to sporadic melanoma. susceptibility, may increase the appearance of such nevi.1,8,18 Data concerning the prevalence of AMS are difficult to Copyright ß 2011 CLINICS – This is an Open Access article distributed under document in part due to the large variability in the the terms of the Creative Commons Attribution Non-Commercial License (http:// diagnostic criteria employed by different studies. Based on creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non- commercial use, distribution, and reproduction in any medium, provided the estimates by the National Institutes of Health (NIH), it has original work is properly cited. been estimated that about 32,000 individuals were carriers 493 CLINICS 2011;66(3):493-499 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 Figure 1 - Macroscopic image of two melanocytic lesions whose germline mutations in CDKN2A, the main genomic locus characteristics are superimposed by the ABCD rule (asymmetry, of melanoma susceptibility.24,25 This genomic locus harbors irregular borders, varied coloration, diameter greater than two important genes involved in cell cycle control, 6 mm): Left - dysplastic nevus; Right – cutaneous melanoma. senescence and apoptosis: p16 and p14ARF. The presence of a susceptibility gene for the development of dysplastic known that the atypical nevus can evolve from a seemingly nevi was also observed on chromosome 7q21.3 in patients common melanocytic nevus or show atypical features from with the p16 gene mutation in four families with familial its first emergence.27 As dynamic lesions, they may become melanoma.20 progressively more or less atypical in their clinical aspect.27 A high incidence of somatic mutations of the BRAF gene Although the majority of dysplastic nevi remain stable, has also been detected in patients with dysplastic nevi and regress over time or evolve benignly, monitoring of these primary melanomas.8 Moreover, melanocytic lesions of lesions is essential. Their prophylactic excision is not rapid growth or development are more likely to have justified.8,27 mutations in this gene when compared to lesions without a AMS has already been described by several authors and history of changes in their clinical aspects.8 institutions based on clinical characteristics of patients and Other genetic changes described in dysplastic nevi their personal and/or family history of melanoma, with or include microsatellite instability, loss of heterozygosity without histopathological confirmation of an atypical 12 (LOH) and increased activity of the telomerase enzyme. nevus.3 Currently, it is known that only 20% to 30% of melanomas According to Newton et al.1, AMS can be defined through arise in association with a melanocytic nevus, which a scoring system, assigning one point for each feature, as indicates that the Clark’s theory of progression can explain seen in Table 1. Patients with scores greater than or equal to only one of the paths from carcinogenesis to melanoma.26 Patients with dysplastic nevi may have a reduced ability 8 to repair UV-induced DNA damage. Table 1 - AMS classifications and their specific Although genetic and environmental interactions are characteristics. clearly involved in the melanocytic transformation patho- genesis, the understanding of its molecular mechanisms still CLASSIFICATION CHARACTERISTICS COMMENTS remains incomplete.8 Newton et al. 1) two or more clinically atypical Scores greater (1993) nevi, 2) more than 100 nevi in than or equal Clinical Diagnosis patients between 20 and 50 years to 3 Clinically, a dysplastic nevus is most often a spotted of age, 3) more than 50 nevi in characterize lesion of 5 mm or more in diameter, with irregular and patients under 20 years of age or the AMS poorly defined borders and variable shades of brown, and it more than 50 years of age, 4) phenotype. more than one nevus in buttocks may present a reddish hue, with bleaching accomplished 18 or instep, 5) nevi on the anterior using vitropressure. It often presents a central papule, scalp, 6) one or more pigmented surrounded by a pigmented macular ring, giving the lesions in the iris. appearance of a ‘‘fried egg’’.18 Thus, there is considerable Classical (1990) 1) 100 or more melanocytic nevi, Requires all overlap with the ABCDE rule used for clinical diagnosis of 2) one or more melanocytic features for melanoma, namely, A: asymmetry, B: irregular borders C: nevi greater than or equal to diagnosis. High 8mm in its largest diameter, demand for varied colors, D: diameter . 6 mm and E: elevation and 3) one or more clinically total count of (simultaneous presentation of macular and papular compo- atypical melanocytic nevi nevi for 3,12,18 nents) (Figure 1). classification; Dysplastic nevi may be present in any topography, low sensitivity including double-covered areas (such as buttocks and National 1) occurrence of melanoma
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