Excerpt from Atypical Mole (Dysplastic Nevus)

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Background

In 1820, Norris proposed an association between nevi and melanoma. He described a family in which 2 members developed melanoma, while other family members had "many moles on various parts of their bodies." However, the exact appearance of these lesions is unknown.

In 1974, Munro¹ described an association of lesions and a family history of melanoma. These nevi had the clinical and microscopic appearance of what are now called atypical moles (AMs). In 1978 and 1981, Clark et al^{2, 3} described these lesions as dysplastic nevi when they were observed as a familial phenomenon.

AMs and dysplastic nevi are acquired melanocytic lesions of the skin whose clinical and histologic definitions are controversial and still evolving. Numerous definitions and criteria have been proposed, including the use of the term AMs for clinically abnormal nevi and dysplastic nevi for histologically abnormal nevi. Unfortunately, when clinically abnormal nevi are evaluated histologically, some studies have shown a lack of concordance, with some clinically abnormal nevi having no dysplastic features and some normal-appearing nevi having some dysplastic features.^{4, 5, 6}

The terms AMs and dysplastic nevi continue to be used interchangeably, regardless of clinical or histologic appearance. Modern molecular methods, including genetic markers, cytokines, proliferation indexes, and cyclins, are all undergoing study to help determine which AMs may progress to melanoma, although no single marker has been determined.^{7, 8}

AMs differ from common acquired melanocytic nevi in several respects, including diameter and lack of pigment uniformity. Unfortunately, some AMs cannot be clinically distinguished from melanoma. The clinical and histologic appearances of AMs occurring in a familial setting appear to overlap with sporadically occurring AMs.

The US National Institutes of Health Consensus Conference on the diagnosis and treatment of early melanoma defined a syndrome of familial AM and melanoma (FAMM). The criteria for FAMM syndrome are as follows⁹:

• The occurrence of malignant melanoma in 1 or more first- or second-degree relatives
• The presence of numerous (often >50) melanocytic nevi, some of which are clinically atypical
• Many of the associated nevi showing certain histologic features (see Histologic Findings)

For additional information on malignant melanoma, see Malignant Melanoma.

Pathophysiology

AMs can be inherited or sporadic. Formal genetic analysis has suggested an autosomal dominant mode of inheritance. Unfortunately, genetic studies have not shown consistent data.

Germline mutations in 3 genes, CDK2NA¹⁰ and CDK4,¹¹ mapped to 9p21 and 12q14, and CMM1, mapped to 1p,¹² have been linked to a subset of hereditary melanomas and FAMM syndrome. In addition, somatic mutations in PTEN, BRAF,¹³ and MCR1 (melanocortin-1 receptor)¹⁴ have been associated with melanoma. Unfortunately, studies have found no alterations in these genes in some patients with FAMM syndrome, and the genes thought to be responsible for most familial and sporadic AMs are still unknown.

Ultraviolet (UV) light (UV-A and UV-B) has been proposed as both an initiator and a promoter in the transformation of melanocytes into atypical melanocytes or melanoma. UV light exposure may be required for full expression of FAMM syndrome.

Genetics and UV radiation may also result in a variable number and anatomical distribution of melanocytic nevi. Some patients with the AM syndrome have many large and highly atypical nevi, whereas other patients with this syndrome have many nevi but only a few are atypical.

Frequency

United States

The prevalence of AMs in white populations has been reported to be as high as 17%.¹⁵ AMs can be inherited or occur sporadically. Familial AMs may be inherited as an autosomal dominant trait. Sporadic lesions are those AMs that occur in patients without a family history of AMs.¹⁶

International

In Australia and New Zealand, the prevalence of AMs has been reported to be 5-10%.¹⁷ In Germany, approximately 2% of 500 white males aged 16-25 years were reported to have AMs on biopsy analysis. Eighteen percent of a population of white adults studied in Sweden were determined to have AMs clinically, although only 8% demonstrated histologic features of AMs. The marked differences in prevalence between different populations may be due to true differences between these populations or they may be related to differing clinical and histologic definitions of this entity.

Mortality/Morbidity

Melanoma can develop from precursor nevi and AMs. While many melanomas arise de novo, superficial spreading melanoma may arise from AMs.¹⁸ The exact risk of an individual nevus transforming into a melanoma is thought to be 1 in 200,000, and cutaneous melanomas are associated with precursor lesions at least 50% of the time in patients younger than 30 years.¹⁹ Patients with numerous AMs are at a higher risk of developing melanoma than those individuals with only a few AMs. This risk is more pronounced with a family history of melanoma.

• A personal or family history of melanoma is more predictive for the future development of a melanoma than is the number of AMs.
• Among whites in the United States, the lifetime risk of developing a cutaneous melanoma is approximately 0.6%, or 1 in 150 individuals. In some studies of patients with FAMM, the overall lifetime risk of melanoma has been estimated to be 100%.²⁰
• The risk of melanoma is greater for those individuals who have 1 relative with melanoma than for those with no affected relative. The lifetime risk of melanoma may approach 100% in individuals with AMs who are from families prone to melanoma (ie, families having 2 or more first-degree relatives with melanoma).
• Individuals who have nevi with clinical or histologic characteristics of AMs but no family history of AMs or melanoma might also be at an increased risk for the development of melanoma. Several prospective studies have demonstrated that patients with AMs without an obvious family history of melanoma have an increased risk for the occurrence of melanoma.^{16, 21} However, the relative risks for melanoma are lower than in those individuals with a clear family history of melanoma. Thus, the presence of AMs (sporadic or familial) may identify patients at increased risk for melanoma, much like fair skin or UV exposure.

Race

Individuals at the highest risk of AMs are persons of northern European background (Celtic) with light-colored hair and freckles. AMs are rare in black, Asian, or Middle Eastern populations.

Sex

No sexual predilection is reported for AMs.

Age

In familial AMs, lesions begin to develop in childhood, most frequently during the first decade of life. Lesions may not be clinically specific early on, but typical features usually develop by the end of puberty.

AMs can develop throughout a person's lifetime. AMs may also change or regress throughout adulthood. New or changing pigmented nevi are common in adults, and new or changing nevi in patients older than 50 years are more likely to be melanoma than in patients younger than 50 years.²²

In one study, AMs in 51% of adult patients showed evidence of clinical change over time. These facts lead to the clinically challenging situation in adults as how to adequately evaluate (1) a change in a long-standing pigmented lesion or (2) the development of a new and clinically atypical lesion. An excisional biopsy should always be considered if the development of a melanoma is a concern.²³

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