Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa continued...
Pigmentary characteristics are important determinants of melanoma susceptibility. There is an inverse correlation between melanoma risk and skin color that goes from lightest skin to darkest skin. Darker-skinned ethnic groups (blacks, darker Hispanics, Asians) have a very low risk of melanoma; however, individuals in these groups develop melanoma on less-pigmented acral surfaces (palms, soles, nail beds). Among relatively light-skinned individuals, skin color is modified by genetics and behavior. MC1R is one of the major genes controlling pigmentation (see below); other pigmentation genes are under investigation.
Clinically, several pigmentary characteristics are evaluated to assess the risk of melanoma and other types of skin cancer. These include the following:
- Fitzpatrick skin type. The following six skin phenotypes were defined on the basis of response to sun exposure at the beginning of summer.
- Type I: Extremely fair skin, always burns, never tans.
- Type II: Fair skin, always burns, sometimes tans.
- Type III: Medium skin, sometimes burns, always tans.
- Type IV: Olive skin, rarely burns, always tans.
- Type V: Moderately pigmented brown skin, never burns, always tans.
- Type VI: Markedly pigmented black skin, never burns, always tans.
- Number of nevi or nevus density.
- Abnormal or atypical nevi.
Patients with multiple nevi demonstrate increased risk of melanoma. While there is evidence that both the presence of multiple nevi and the presence of multiple clinically atypical nevi are associated with an increased risk of melanoma, most studies demonstrate a stronger risk of melanoma with the presence of atypical nevi.[52,53,54,55] In addition, patients with multiple atypical nevi, regardless of personal and/or family history of melanoma, are at significantly increased risk of developing melanoma than are patients without atypical nevi. A population-based study in the United Kingdom that identified genetic risk factors for the development of nevi showed that some of the same variants are modestly associated with melanoma risk.
Melanoma is 1.6 to 2.5 times more common among recipients of organ transplants than in the general population, an excess that has generally been attributed to the effects of immunosuppressive therapy administered to avoid allograft rejection.
Generally, a family history of melanoma appears to increase risk of melanoma by about twofold. A family cancer registry study assessed over 20,000 individuals with melanoma and found a SIR of 2.62 for offspring of individuals with melanoma and 2.94 for siblings. A study looking at the contribution of family history to melanoma risk showed a population-attributable fraction ranging from less than 1% in northern Europe to 6.4% in Australia, suggesting that only a small percentage of melanoma cases are caused by familial factors. Rarely, however, in some families many generations and multiple individuals develop melanoma and are at much higher risk. For individuals from these families, the incidence of melanoma is higher for sun-protected rather than sun-exposed skin. The major hereditary melanoma susceptibility gene, CDKN2A, is found to be mutated in approximately 35% to 40% of families with three or more melanoma cases. To date, more than half of the families with multiple cases of melanoma have no identified mutation.[62,63] The definition of a familial cluster of melanoma varies by geographical region, worldwide, because of the role played by UV radiation in melanoma pathogenesis. In heavily insolated regions (regions with high ambient sun exposure), three or more affected family members are required; in regions with lower levels of ambient sunlight, two or more affected family members are considered sufficient to define a familial cluster.