A Natural History of Melanomas and Dysplastic Nevi
A Natural History of Melanomas and Dysplastic Nevi
Background: Few long-term clinical and histologic data for melanocytic lesions have been available based on the mutation status of families at an increased risk of melanoma. In the current study, the authors describe the clinical and histologic features of dysplastic nevi and melanoma over time in families at an increased risk of melanoma with differing germline mutations in CDKN2A, CDK4, or not yet identified genes.
Methods: Thirty-three families with > 2 living members with invasive melanoma were evaluated clinically and followed prospectively for up to 25 years. All the participants were evaluated by the same study team at the Clinical Center of the National Institutes of Health or in local clinics. After informed consent was obtained, family members (N=844) were examined and photographed. Blood was obtained for genetic studies; genotyping for CDKN2A and CDK4 was performed. Sequential photographs of melanocytic lesions were taken as part of the clinical evaluations. When melanocytic lesions were removed, the histology was reviewed. Representative photographs and photomicrographs were selected for six classes of lesions and three mutation groups.
Results: All the families were found to have members with dysplastic nevi and melanoma; 17 had mutations in CDKN2A, 2 had mutations in CDK4, and 14 had no mutations in either genes identified. The majority of dysplastic nevi either remain stable or regress; few change in a manner that should cause concern for melanoma. With careful surveillance, melanomas can be found early.
Conclusions: The melanomas and dysplastic nevi that were found to occur in the study families did not appear to vary by the type of mutation identified in the families.
Dysplastic nevi first were described over 20 years ago among members of melanoma-prone families (Clark, Reimer, Greene, Ainsworth, & Mastrangelo, 1978; Goldstein, Struewing, Chidambaram, Fraser, & Tucker, 2000; Greene et al., 1985; Lynch, Frichot, & Lynch, 1978). In many melanoma-prone families, dysplastic nevi are important risk factors (Greene et al., 1985; Kroon, Bergman, Coebergh, & Ruiter, 1999; MacKie, McHenry, & Hole, 1993; Platz et al., 1997) and nonobligate precursor lesions for melanoma (Clark et al., 1984; Clark et al., 1989; Clark & Tucker, 1998; Clemente et al., 1991; DeWit et al., 1993; Elder, Clark, Elenitsas, Guerry, & Halpern, 1993). Since these relations were established, the presence of dysplastic nevi has been used clinically to identify the individuals in these melanoma-prone families who are at the highest risk of developing melanoma (Greene et al., 1999; Kroon et al., 1999; MacKie et al., 1993). Based on the presence of dysplastic nevi, clinical guidelines for members of high-risk families were developed. The guidelines include surveillance of pigmented lesions, routine clinical examinations, and the use of sun-protective measures. Adherence to these guidelines appears to decrease the risk of new melanomas and changing nevi and aids in detecting melanoma at an earlier stage (Tucker et al., 1993).
It now is well established that the etiology of familial melanoma is heterogeneous and complex (Goldstein et al., 1994). Two genes have been identified: CDKN2A, a tumor suppressor; and CDK4, a protooncogene. Mutations in CDKN2A have been found in approximately 20% of families evaluated worldwide, whereas mutations in CDK4 have been reported in three families (Goldstein & Tucker, 1997; Soufir et al., 1998; Zuo et al., 1996). Both these genes play an important role in cell cycle control in the retinoblastoma pathway. Despite one gene being a tumor suppressor and the other a protooncogene, there are no apparently significant differences in phenotype between families with CDKN2A mutations and families with CDK4 mutations (Goldstein et al., 2000). The estimated penetrances of these genes remain imprecise. Therefore, to make use of mutation status for melanoma risk assessment is problematic (Kefford, Newton-Bishop, Bergman, & Tucker, 1999). Additional genes that are significant in the development of melanoma currently are being sought.
As genes associated with melanoma susceptibility have been identified, the role of dysplastic nevi in the clinical management of family members has been questioned (Bishop et al., 2000). Although dysplastic nevi and melanoma early on were hypothesized to be pleiotropic effects of a single gene (Bale, Chakravarti, & Greene, 1986), dysplastic nevi recently have been shown to be a risk factor for melanoma independent of mutation status in these families (Goldstein, Martinez, Tucker, & Demenais, 2000). These nevi also are a substantial risk factor for melanoma outside of melanoma-prone families (Garbe et al., 1994; Halpern et al., 1991; Halpern et al., 1993; Holly, Kelly, Shpall, & Chiu, 1987; Kang, Barnhill, Mihm, Fitzpatrick, & Sober, 1994; Marghoob et al., 1994; Newton et al., 1993; Roush, Nordlund, Forget, Gruber, & Kirkwood, 1988; Schneider, Moore, & Sagebiel; 1994; Tucker et al., 1997) and are estimated to occur in 5% to 10% of the general population (Cooke, Spears, Elder, & Greene, 1989; Crutcher & Sagebiel, 1984). The natural history of dysplastic nevi in individuals who are not from melanoma-prone families has been described previously (Halpern et al., 1991; Halpern et al., 1993; Kang et al., 1994; Marghoob et al., 1994; Newton et al., 1993).
Although some reports have found a correlation between the clinical and histologic characteristics of dysplastic nevi, the genetic status of the affected individuals has not been included. The current atlas demonstrates the natural history of dysplastic nevi and primary melanomas within melanoma-prone families with differing germline mutations. We prospectively observed and photographically documented these lesions for > 20 years.
Abstract
Background: Few long-term clinical and histologic data for melanocytic lesions have been available based on the mutation status of families at an increased risk of melanoma. In the current study, the authors describe the clinical and histologic features of dysplastic nevi and melanoma over time in families at an increased risk of melanoma with differing germline mutations in CDKN2A, CDK4, or not yet identified genes.
Methods: Thirty-three families with > 2 living members with invasive melanoma were evaluated clinically and followed prospectively for up to 25 years. All the participants were evaluated by the same study team at the Clinical Center of the National Institutes of Health or in local clinics. After informed consent was obtained, family members (N=844) were examined and photographed. Blood was obtained for genetic studies; genotyping for CDKN2A and CDK4 was performed. Sequential photographs of melanocytic lesions were taken as part of the clinical evaluations. When melanocytic lesions were removed, the histology was reviewed. Representative photographs and photomicrographs were selected for six classes of lesions and three mutation groups.
Results: All the families were found to have members with dysplastic nevi and melanoma; 17 had mutations in CDKN2A, 2 had mutations in CDK4, and 14 had no mutations in either genes identified. The majority of dysplastic nevi either remain stable or regress; few change in a manner that should cause concern for melanoma. With careful surveillance, melanomas can be found early.
Conclusions: The melanomas and dysplastic nevi that were found to occur in the study families did not appear to vary by the type of mutation identified in the families.
Dysplastic nevi first were described over 20 years ago among members of melanoma-prone families (Clark, Reimer, Greene, Ainsworth, & Mastrangelo, 1978; Goldstein, Struewing, Chidambaram, Fraser, & Tucker, 2000; Greene et al., 1985; Lynch, Frichot, & Lynch, 1978). In many melanoma-prone families, dysplastic nevi are important risk factors (Greene et al., 1985; Kroon, Bergman, Coebergh, & Ruiter, 1999; MacKie, McHenry, & Hole, 1993; Platz et al., 1997) and nonobligate precursor lesions for melanoma (Clark et al., 1984; Clark et al., 1989; Clark & Tucker, 1998; Clemente et al., 1991; DeWit et al., 1993; Elder, Clark, Elenitsas, Guerry, & Halpern, 1993). Since these relations were established, the presence of dysplastic nevi has been used clinically to identify the individuals in these melanoma-prone families who are at the highest risk of developing melanoma (Greene et al., 1999; Kroon et al., 1999; MacKie et al., 1993). Based on the presence of dysplastic nevi, clinical guidelines for members of high-risk families were developed. The guidelines include surveillance of pigmented lesions, routine clinical examinations, and the use of sun-protective measures. Adherence to these guidelines appears to decrease the risk of new melanomas and changing nevi and aids in detecting melanoma at an earlier stage (Tucker et al., 1993).
It now is well established that the etiology of familial melanoma is heterogeneous and complex (Goldstein et al., 1994). Two genes have been identified: CDKN2A, a tumor suppressor; and CDK4, a protooncogene. Mutations in CDKN2A have been found in approximately 20% of families evaluated worldwide, whereas mutations in CDK4 have been reported in three families (Goldstein & Tucker, 1997; Soufir et al., 1998; Zuo et al., 1996). Both these genes play an important role in cell cycle control in the retinoblastoma pathway. Despite one gene being a tumor suppressor and the other a protooncogene, there are no apparently significant differences in phenotype between families with CDKN2A mutations and families with CDK4 mutations (Goldstein et al., 2000). The estimated penetrances of these genes remain imprecise. Therefore, to make use of mutation status for melanoma risk assessment is problematic (Kefford, Newton-Bishop, Bergman, & Tucker, 1999). Additional genes that are significant in the development of melanoma currently are being sought.
As genes associated with melanoma susceptibility have been identified, the role of dysplastic nevi in the clinical management of family members has been questioned (Bishop et al., 2000). Although dysplastic nevi and melanoma early on were hypothesized to be pleiotropic effects of a single gene (Bale, Chakravarti, & Greene, 1986), dysplastic nevi recently have been shown to be a risk factor for melanoma independent of mutation status in these families (Goldstein, Martinez, Tucker, & Demenais, 2000). These nevi also are a substantial risk factor for melanoma outside of melanoma-prone families (Garbe et al., 1994; Halpern et al., 1991; Halpern et al., 1993; Holly, Kelly, Shpall, & Chiu, 1987; Kang, Barnhill, Mihm, Fitzpatrick, & Sober, 1994; Marghoob et al., 1994; Newton et al., 1993; Roush, Nordlund, Forget, Gruber, & Kirkwood, 1988; Schneider, Moore, & Sagebiel; 1994; Tucker et al., 1997) and are estimated to occur in 5% to 10% of the general population (Cooke, Spears, Elder, & Greene, 1989; Crutcher & Sagebiel, 1984). The natural history of dysplastic nevi in individuals who are not from melanoma-prone families has been described previously (Halpern et al., 1991; Halpern et al., 1993; Kang et al., 1994; Marghoob et al., 1994; Newton et al., 1993).
Although some reports have found a correlation between the clinical and histologic characteristics of dysplastic nevi, the genetic status of the affected individuals has not been included. The current atlas demonstrates the natural history of dysplastic nevi and primary melanomas within melanoma-prone families with differing germline mutations. We prospectively observed and photographically documented these lesions for > 20 years.