Atypical Mole Syndrome (AMS)

Genetic disorder characterized by the presence of abnormal nevi that predispose to melanoma development.

BK Mole Syndrome; Familial Atypical Mole Melanoma (FAMM) Syndrome; Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome; Hereditary Dysplastic Nevus Syndrome; Nevoid Melanoma Syndrome.

First reported in 1820 by W. Norris.

Prevalence in white population of America and Europe is approximately 2 to 5%. In Sweden, 18% of white adults have atypical moles clinically but only 8% have the typical histologic features. No sex predilection. Atypical moles are rare in black, Asian, and Middle Eastern populations.

Clinical history and family examinations suggest an autosomal dominant mode of inheritance. A first proposed assignment of a melanoma gene (CMM1) chromosome 1p36 was not confirmed. A second proposed gene (cell cycle regulator CDKN2A [P16], a cyclin-dependent kinase) has been mapped to chromosome 9p21, and this gene assignment has been confirmed. Germline mutations in this gene occur in approximately 20% of kindreds with familial atypical mole syndrome. Penetrance is variable. Exposure to ultraviolet light plays a role in the phenotypic expression of the syndrome.

Dysplastic nevi appear to be histogenetic precursors of melanomas.

Clinically based on the presence and specific appearance of nevi. The National Institutes of Health Consensus Conference requires the following criteria to establish the diagnosis:

1. 1. First-degree (e.g., parent, sibling or child) or second-degree relative (e.g., grandparent, grandchild, aunt, uncle) with malignant melanoma

2. 2. Large number of nevi, often more than 50, some of which are atypical nevi

3. 3. Nevi that demonstrate certain microscopic features

Histologic examination of dysplastic nevi shows compound nevi with evidence of abnormal growth. Nevus cell nests within the epidermis may be enlarged and show abnormal coalescence with adjacent nests. As part of this process, single nevus cells begin to replace the normal basal cell layer along the dermoepidermal junction. Cytologically, the atypical features consist of irregular, often angulated, nuclear contours frequently combined with hyperchromasia. Associated alterations occur in the superficial dermis, with sparse lymphocytic infiltrate, loss of melanin pigment from presumably destroyed nevus cells, phagocytosis of melanin pigment by dermal macrophages, and linear fibrosis surrounding the involved epidermal rete ridges. This atypical nevus syndrome phenotype is the most potent risk factor for melanoma in families and in the general population. Although most dysplastic nevi are stable lesions, transition to melanoma is well known and can occur within a few months. Atypical mole syndrome (AMS) represents the highest risk factor known for malignant melanoma. A 7-year followup of 14 families indicated affected individuals having at least two relatives with malignant melanoma have a 100% lifetime risk of developing a melanoma, whereas all other affected persons have a lifetime risk of approximately 18%. An increased risk for development of pancreatic cancer has been reported for some mutations. The synonymous name BK moles is derived from the initials of the surnames of the two families studied initially.

Multiple dysplastic nevi are the hallmark of AMS. In familial AMS, the lesions usually appear during the first decade of life. Typical features are present by the end of puberty. During adolescence, the nevi become dysplastic and more numerous. The nevi usually are larger than ordinary moles (6-15 mm) and have a different distribution over the body (in sun-exposed but also in non-sun-exposed areas) such as the scalp, buttocks, and female breasts. For the diagnosis, at least two atypical nevi must be present, although most often they are numerous. Clinically, atypical nevi are characterized by variable pigmentation and irregular, ill-defined borders. Pathologic changes of the nevi include irregular borders, a mixture of colors, indistinct margins, and a persistent macular component. If a black area develops within a nevus, the lesion should be excised to rule out a melanoma. Small and nondysplastic nevi appear by age 5 to 6 years.

Melanoma can become metastatic mainly in the lymph nodes, brain, liver, lungs, and bone; thus, a complete workup should be obtained if metastatic disease is suspected.

There are no specific considerations per se, except in the case of metastatic disease, where affected organs should be taken into account and the anesthesia plan tailored consequently.

None reported (patients with AMS usually require a sunscreen with a sun protection factor of at least 15).