Risk Factors for Malignant Melanoma In Situ
Risk Factors for Malignant Melanoma In Situ
To date, there have been few large studies on in situ melanoma, and there are scant data on risk factors for MMIS. Past studies examining phenotypic risk have either excluded MMIS entirely or have pooled the lesions with invasive malignant melanoma, although the proportion of invasive to in situ lesions varies widely. Park et al. conducted the only previous phenotypic prospective study of MMIS lesions in participants residing in 2 US states, and they did not assess the number of nevi, which is a significant risk factor in invasive malignant melanoma as well as in multiple primary melanoma.
In this study, we examined data on cases of malignant melanoma in situ as confirmed by primary pathology report in a large population of US women and men, allowing for comparison of 3 separate cohorts that are well matched in regard to race, education, occupation, and risk factor exposure. Individual multivariate and meta-analyses demonstrated that the number of extremity nevi is associated with increased risk of MMIS, with risk increasing with higher nevus counts. Importantly, this risk was significant even for subjects with only 1 or 2 nevi on an extremity. Fitzpatrick skin type demonstrated increasing risk from type IV (least risk) to type I (a 2-fold risk). Family history, hair color, skin reaction to the sun, and the number of severe sunburns also made statistically significant contributions to the risk of melanoma in situ. Conversely, ultraviolet index of state of residence at birth, at age 15 years, and at age 30 years was not associated with significant differences in risk.
These findings are consistent with the limited data that exist for MMIS and nevi. In a prospective study of 40,000 Swedish women, Nielsen et al. demonstrated that self-reported nevi counts of the left arm were significantly associated with increased risk of pooled invasive/in situ melanoma, although given the relatively small number of in situ lesions (n = 60) grouped with the invasive malignant melanoma lesions (n = 155), it is difficult to ascertain the exact relative contribution of MMIS. Interestingly, the younger women in the NHS2 cohort had a strikingly higher prevalence of 6 of more nevi. This could be attributed to a variety of reasons, including propensity for nevi on the legs due to clothing and sun exposure behavior, increased surface area of the legs as compared with the arms, or the fact that nevi counts tend to peak in the second decade of life and then regress or alter their pigment with aging. However, the data may also indicate that nevus-prone persons are susceptible to younger-onset MMIS and may therefore require closer screening. Moreover, the data may suggest that nevi contribute to the risk of superficial spreading melanoma in situ more than to lentigo maligna melanoma in situ. Lentigo maligna melanoma in situ, a subtype of melanoma in situ, is more commonly diagnosed in elderly patients and is thought to result from chronic sun exposure. The younger population of women had a much lower incidence of lentigo maligna melanoma in situ, and when phenotypic risk was analyzed excluding lentigo maligna melanoma in situ, the relative risk in subjects with high nevus burdens increased further in the NHS and HPFS cohorts (Web Table 3), whereas susceptibility to burn and number of sunburns were associated with significantly decreased risk in all 3 cohorts. Divergence of risk for superficial spreading melanoma and lentigo maligna melanoma has been supported by past studies of small numbers of pooled in situ/invasive lesions, which found no association between nevi and lentigo maligna melanoma risk, whereas no previous data exist for a population of purely in situ lesions.
Family history of malignant melanoma was associated with increased relative risk in all 3 cohorts. These results are consistent with what has been demonstrated in combined in situ/invasive analyses as well as the findings from Park et al., who found a comparable increased relative risk in MMIS, although without statistical significance. Natural red hair, but not blond, was associated with a significantly elevated risk of MMIS among women, whereas dark brown or black hair was protective. Nonsignificance of hair color among men is most likely attributable to the small sample size, although it is not clear why few incident cases of MMIS occurred in red-haired male participants.
In regard to sun exposure, these data show that the number of sunburns as well as the host's skin reaction to bright sunlight plays a more significant role in MMIS risk than does the ultraviolet index of the state of residence at birth, at age 15 years, and at age 30 years. The ultraviolet index, developed by the National Weather Service (Silver Spring, Maryland) and the US Environmental Protection Agency (Washington, DC), is a measure of ultraviolet radiation levels weighted according to the McKinlay-Diffey erythema action spectrum and adjusts for altitude, cloud cover, stratospheric ozone concentrations, and latitude. Past analyses have shown an association between ultraviolet index and the development of single or multiple basal or squamous cell carcinomas, whereas the association between ultraviolet index and melanoma has rarely been studied, and no consensus exists for the role of ultraviolet index in melanoma risk. No previous data exist for melanoma in situ, and this study did not demonstrate a significant association. It is important to note that the risk of MMIS increases with an increasing number of sunburns, and although more men reported high sunburn counts than did women, risk for each stratum was similar across the cohorts with no significant heterogeneity in the meta-analysis. Burn susceptibility was also associated with increased risk, and when incorporated into a Fitzpatrick skin score, it showed a strong trend of increasing risk for more sun-sensitive participants. It is known that intense, intermittent sun exposure and its interaction with differentially pigmented skin play a role in the development of both invasive melanoma and benign nevi, and although this has only begun to be investigated in MMIS, the contribution appears to be similar. Importantly, these findings indicate that a history of the number of sunburns, as well as an estimate of sun sensitivity via Fitzpatrick skin type or other measure, should be included in all patient evaluations when screening for malignant melanoma.
The relative strengths of this study were the ability to analyze both phenotypic risk and ultraviolet index in a large number of pathologically confirmed MMIS lesions and to assess similarities across 3 large cohorts of women and men living in every US state. The cohorts were similar with regard to occupational and cultural exposure, education, socioeconomic status, medical knowledge, and access to health care, thus minimizing many confounders of studies of this magnitude; the consistency of findings across all 3 cohorts increases the validity of the data. For these same reasons, however, conclusions should be limited to a population of US women and men with similar characteristics. This underscores the need for further examination of MMIS in persons of different national, racial, and economic backgrounds. The ultraviolet index analysis is limited in that it accounts for only 3 time points (birth, age 15 years, and age 30 years) and cannot account for residence between or after those time points. More complete lifetime residential data would provide a more accurate assessment of the role of ultraviolet index in the risk for MMIS. Because lifetime duration and intensity of sun exposure are difficult to quantify, the ultraviolet index of residence, number of sunburns sustained, and self-reported burning responses are imperfect measures of this exposure. In an attempt to minimize misclassification of the outcome, all primary pathology reports were reviewed by an experienced dermatologist (A.A.Q.). Further, to accommodate any potential recent trends in the diagnostic behavior of clinicians, all analyses were repeated on MMIS diagnosed only within the last 10 years; there were no appreciable changes in patterns of risk factors across the 3 cohorts that could not be attributed to decreased sample size (data not shown). Similarly, to investigate whether the association with phenotypic factors may have been a result of increased screening within a high-risk population, sensitivity analyses were conducted in multivariate models adjusting for marital status in the NHS cohort and physical examination and prostate-specific antigen testing in the HPFS cohort. Controlling for these variables did not alter the relative risks or the significance of the data (data not shown).
This study is the largest analysis of phenotypic risk of MMIS to date in 3 large cohorts with more than 20 years of follow-up, and it is the first to demonstrate the risk conferred by nevi. The presence of photodistributed nevi was the strongest predictor of MMIS, and family history, hair color, burning reaction, the number of lifetime sunburns, and Fitzpatrick skin type all contributed to additional increased risk. The lack of association with ultraviolet index suggests that host phenotypic characteristics and sun protection behaviors, particularly in regard to severe sunburns, play a more significant role in risk for MMIS than does ambient ultraviolet exposure and should serve as a basis for patient education and risk modification. These findings are largely congruent with what is known regarding invasive melanoma, but as our understanding of malignant melanoma becomes more sophisticated, investigation of in situ lesions and how they compare with deeper, aggressive forms is important to our overall understanding of malignant melanoma. Further study should aim to elucidate the role of in situ melanoma within the greater spectrum of cutaneous malignant melanoma and to allow practitioners a better understanding of persons at risk, providing the basis to further develop effective screening practices.
Discussion
To date, there have been few large studies on in situ melanoma, and there are scant data on risk factors for MMIS. Past studies examining phenotypic risk have either excluded MMIS entirely or have pooled the lesions with invasive malignant melanoma, although the proportion of invasive to in situ lesions varies widely. Park et al. conducted the only previous phenotypic prospective study of MMIS lesions in participants residing in 2 US states, and they did not assess the number of nevi, which is a significant risk factor in invasive malignant melanoma as well as in multiple primary melanoma.
In this study, we examined data on cases of malignant melanoma in situ as confirmed by primary pathology report in a large population of US women and men, allowing for comparison of 3 separate cohorts that are well matched in regard to race, education, occupation, and risk factor exposure. Individual multivariate and meta-analyses demonstrated that the number of extremity nevi is associated with increased risk of MMIS, with risk increasing with higher nevus counts. Importantly, this risk was significant even for subjects with only 1 or 2 nevi on an extremity. Fitzpatrick skin type demonstrated increasing risk from type IV (least risk) to type I (a 2-fold risk). Family history, hair color, skin reaction to the sun, and the number of severe sunburns also made statistically significant contributions to the risk of melanoma in situ. Conversely, ultraviolet index of state of residence at birth, at age 15 years, and at age 30 years was not associated with significant differences in risk.
These findings are consistent with the limited data that exist for MMIS and nevi. In a prospective study of 40,000 Swedish women, Nielsen et al. demonstrated that self-reported nevi counts of the left arm were significantly associated with increased risk of pooled invasive/in situ melanoma, although given the relatively small number of in situ lesions (n = 60) grouped with the invasive malignant melanoma lesions (n = 155), it is difficult to ascertain the exact relative contribution of MMIS. Interestingly, the younger women in the NHS2 cohort had a strikingly higher prevalence of 6 of more nevi. This could be attributed to a variety of reasons, including propensity for nevi on the legs due to clothing and sun exposure behavior, increased surface area of the legs as compared with the arms, or the fact that nevi counts tend to peak in the second decade of life and then regress or alter their pigment with aging. However, the data may also indicate that nevus-prone persons are susceptible to younger-onset MMIS and may therefore require closer screening. Moreover, the data may suggest that nevi contribute to the risk of superficial spreading melanoma in situ more than to lentigo maligna melanoma in situ. Lentigo maligna melanoma in situ, a subtype of melanoma in situ, is more commonly diagnosed in elderly patients and is thought to result from chronic sun exposure. The younger population of women had a much lower incidence of lentigo maligna melanoma in situ, and when phenotypic risk was analyzed excluding lentigo maligna melanoma in situ, the relative risk in subjects with high nevus burdens increased further in the NHS and HPFS cohorts (Web Table 3), whereas susceptibility to burn and number of sunburns were associated with significantly decreased risk in all 3 cohorts. Divergence of risk for superficial spreading melanoma and lentigo maligna melanoma has been supported by past studies of small numbers of pooled in situ/invasive lesions, which found no association between nevi and lentigo maligna melanoma risk, whereas no previous data exist for a population of purely in situ lesions.
Family history of malignant melanoma was associated with increased relative risk in all 3 cohorts. These results are consistent with what has been demonstrated in combined in situ/invasive analyses as well as the findings from Park et al., who found a comparable increased relative risk in MMIS, although without statistical significance. Natural red hair, but not blond, was associated with a significantly elevated risk of MMIS among women, whereas dark brown or black hair was protective. Nonsignificance of hair color among men is most likely attributable to the small sample size, although it is not clear why few incident cases of MMIS occurred in red-haired male participants.
In regard to sun exposure, these data show that the number of sunburns as well as the host's skin reaction to bright sunlight plays a more significant role in MMIS risk than does the ultraviolet index of the state of residence at birth, at age 15 years, and at age 30 years. The ultraviolet index, developed by the National Weather Service (Silver Spring, Maryland) and the US Environmental Protection Agency (Washington, DC), is a measure of ultraviolet radiation levels weighted according to the McKinlay-Diffey erythema action spectrum and adjusts for altitude, cloud cover, stratospheric ozone concentrations, and latitude. Past analyses have shown an association between ultraviolet index and the development of single or multiple basal or squamous cell carcinomas, whereas the association between ultraviolet index and melanoma has rarely been studied, and no consensus exists for the role of ultraviolet index in melanoma risk. No previous data exist for melanoma in situ, and this study did not demonstrate a significant association. It is important to note that the risk of MMIS increases with an increasing number of sunburns, and although more men reported high sunburn counts than did women, risk for each stratum was similar across the cohorts with no significant heterogeneity in the meta-analysis. Burn susceptibility was also associated with increased risk, and when incorporated into a Fitzpatrick skin score, it showed a strong trend of increasing risk for more sun-sensitive participants. It is known that intense, intermittent sun exposure and its interaction with differentially pigmented skin play a role in the development of both invasive melanoma and benign nevi, and although this has only begun to be investigated in MMIS, the contribution appears to be similar. Importantly, these findings indicate that a history of the number of sunburns, as well as an estimate of sun sensitivity via Fitzpatrick skin type or other measure, should be included in all patient evaluations when screening for malignant melanoma.
The relative strengths of this study were the ability to analyze both phenotypic risk and ultraviolet index in a large number of pathologically confirmed MMIS lesions and to assess similarities across 3 large cohorts of women and men living in every US state. The cohorts were similar with regard to occupational and cultural exposure, education, socioeconomic status, medical knowledge, and access to health care, thus minimizing many confounders of studies of this magnitude; the consistency of findings across all 3 cohorts increases the validity of the data. For these same reasons, however, conclusions should be limited to a population of US women and men with similar characteristics. This underscores the need for further examination of MMIS in persons of different national, racial, and economic backgrounds. The ultraviolet index analysis is limited in that it accounts for only 3 time points (birth, age 15 years, and age 30 years) and cannot account for residence between or after those time points. More complete lifetime residential data would provide a more accurate assessment of the role of ultraviolet index in the risk for MMIS. Because lifetime duration and intensity of sun exposure are difficult to quantify, the ultraviolet index of residence, number of sunburns sustained, and self-reported burning responses are imperfect measures of this exposure. In an attempt to minimize misclassification of the outcome, all primary pathology reports were reviewed by an experienced dermatologist (A.A.Q.). Further, to accommodate any potential recent trends in the diagnostic behavior of clinicians, all analyses were repeated on MMIS diagnosed only within the last 10 years; there were no appreciable changes in patterns of risk factors across the 3 cohorts that could not be attributed to decreased sample size (data not shown). Similarly, to investigate whether the association with phenotypic factors may have been a result of increased screening within a high-risk population, sensitivity analyses were conducted in multivariate models adjusting for marital status in the NHS cohort and physical examination and prostate-specific antigen testing in the HPFS cohort. Controlling for these variables did not alter the relative risks or the significance of the data (data not shown).
This study is the largest analysis of phenotypic risk of MMIS to date in 3 large cohorts with more than 20 years of follow-up, and it is the first to demonstrate the risk conferred by nevi. The presence of photodistributed nevi was the strongest predictor of MMIS, and family history, hair color, burning reaction, the number of lifetime sunburns, and Fitzpatrick skin type all contributed to additional increased risk. The lack of association with ultraviolet index suggests that host phenotypic characteristics and sun protection behaviors, particularly in regard to severe sunburns, play a more significant role in risk for MMIS than does ambient ultraviolet exposure and should serve as a basis for patient education and risk modification. These findings are largely congruent with what is known regarding invasive melanoma, but as our understanding of malignant melanoma becomes more sophisticated, investigation of in situ lesions and how they compare with deeper, aggressive forms is important to our overall understanding of malignant melanoma. Further study should aim to elucidate the role of in situ melanoma within the greater spectrum of cutaneous malignant melanoma and to allow practitioners a better understanding of persons at risk, providing the basis to further develop effective screening practices.
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